Canakinumab reverses overexpression of inflammatory response genes in tumour necrosis factor receptor-associated periodic syndrome

OBJECTIVE: To explore whether gene expression profiling can identify a molecular mechanism for the clinical benefit of canakinumab treatment in patents with tumour necrosis factor receptor-associated periodic syndrome (TRAPS). METHODS: Blood samples were collected from 20 patients with active TRAPS who received canakinumab 150 mg every 4 weeks for 4 months in an open-label proof-of-concept phase II study, and from 20 aged-matched healthy volunteers. Gene expression levels were evaluated in whole blood samples by microarray analysis for arrays passing quality control checks. RESULTS: Patients with TRAPS exhibited a gene expression signature in blood that differed from that in healthy volunteers. Upon treatment with canakinumab, many genes relevant to disease pathogenesis moved towards levels seen in the healthy volunteers. Canakinumab downregulated the TRAPS-causing gene (TNF super family receptor 1A (TNFRSF1A)), the drug-target gene (interleukin (IL)-1B) and other inflammation-related genes (eg, MAPK14). In addition, several inflammation-related pathways were evident among the differentially expressed genes. Canakinumab treatment reduced neutrophil counts, but the observed expression differences remained after correction for this. CONCLUSIONS: These gene expression data support a model in which canakinumab produces clinical benefit in TRAPS by increasing neutrophil apoptosis and reducing pro-inflammatory signals resulting from the inhibition of IL-1β. Notably, treatment normalised the overexpression of TNFRSF1A, suggesting that canakinumab has a direct impact on the main pathogenic mechanism in TRAPS. TRIAL REGISTRATION NUMBER: NCT01242813

Non‑ambulatory pigs in two Brazilian growing‑finishing farms : a clinic, etiological and pathological perspective on 76 cases

Background: Non-ambulatory pigs, colloquially known as downers or downed pigs, are animals presented with limited to no mobility, usually as a result of pre-existing neurologic or musculoskeletal conditions. Impaired ambulation is a major cause of euthanasia in pigs, leading to economic losses and animal welfare concerns. Additionally, reaching the underlying diagnosis of impaired ambulation in pigs is commonly a challenging task for swine practitioners. The aim of this necropsy-based study was to report the clinical, etiological, and pathological findings of 76 non-ambulatory grower-finisher pigs, and to correlate tail-biting lesions with the causes of death/reason for euthanasia in non-ambulatory pigs. Necropsies of downed pigs were performed during on-site visits to two pig farms in southern Brazil. Results: The diagnosis of the conditions was based on the clinical, macroscopic, histopathological, bacteriological, immunohistochemical, and molecular findings. The diseases diagnosed in non-ambulatory pigs in this study were suppurative arthritis (29/76), suppurative spondylitis (10/76), PVC-2 associated diseases (8/76), bone fracture (7/76), non-suppurative meningoencephalomyelitis (4/76), suppurative meningoencephalitis (6/76), fibrocartilaginous thromboembolism (3/76), epiphysiolysis (3/76), ascending bacterial myelitis (3/76), and other conditions (3/76). The frequency of suppurative arthritis, suppurative spondylitis, and ascending bacterial myelitis/meningitis was higher in pigs with tail biting lesions than controls (P < 0.001). Conclusions: Non-ambulatory pigs were observed during the entire rearing period, however, the occurrence of non-ambulatory pigs increased in animals aged ≥ 150 days. Infectious diseases were the most common cause of downed pigs, mainly associated with chronic bacterial infections. Tail biting lesions were an important predisposing factor to suppurative arthritis, suppurative spondylitis, and ascending bacterial myelitis/meningitis

Causas de morte em suínos de crescimento e terminação em duas granjas tecnificadas no Sul do Brasil

The aim of this study was to investigate the main causes of death in growing-finishing pigs in southern Brazil. During a one-year period (from 2018 to 2019), two industrial pig herds (18 and 20 thousand pigs each farm) in southern Brazil were monitored along the four seasons of the year (12 days per season on each farm), in order to perform necropsies of all pigs that died in that period. The two farms had an average monthly mortality rate ranging from 0.94 to 3.93% in the evaluated months. At necropsy, tissues were collected, fixed in 10% formalin solution and processed routinely for histopathological examination. When necessary, samples were sent for bacterial culture and PCR to identify etiologic agents. A total of 601 necropsies were performed, with 94.9% of conclusive diagnoses. Infectious diseases corresponded to 64.4% of conclusive diagnosis and non-infectious diseases to 35.6%. The most prevalent causes of death were: pneumonia (33%), gastric ulcers (15.4%), circovirosis (9.9%), systemic bacterial embolism (5.4%), polyserositis (4.4%), dilated cardiomyopathy and torsion of abdominal organs (4.3% each), and bacterial pericarditis (3.4%). Regarding pneumonias (199/601), the main agents identified in these cases were Pasteurella multocida, Influenza A virus and Mycoplasma hyopneumoniae, mainly in associations.O objetivo do presente trabalho foi investigar as principais causas de morte de suínos em fase de crescimento e terminação no Sul do Brasil. Durante o período de um ano (entre 2018 e 2019), duas granjas tecnificadas de suínos no Sul do Brasil foram acompanhadas nas quatro estações (12 dias por estação em cada granja), para realização de necropsias dos suínos que morreram nesse período. As duas propriedades apresentavam mortalidade mensal média entre 0,94 e 3,93% nos meses avaliados. Na necropsia, amostras de órgãos foram colhidas, fixadas em formol 10% e processadas rotineiramente para o exame histopatológico. Quando necessário, amostras foram enviadas para o cultivo bacteriano e PCR para identificação de agentes etiológicos. Foram realizadas um total de 601 necropsias, com 94,9% de diagnósticos conclusivos. As doenças infecciosas corresponderam a 64,4% dos diagnósticos conclusivos e as não infecciosas a 35,6%. As principais causas de morte foram: pneumonias (33%), úlcera gástrica (15,4%), circovirose (9,9%), embolia bacteriana sistêmica (5,4%), polisserosite (4,4%), cardiomiopatia dilatada e torção de órgãos abdominais (4,3% cada) e pericardite bacteriana (3,4%). Com relação às pneumonias (199/601), os principais agentes associadas as lesões foram Pasteurella multocida, vírus da Influenza A e Mycoplasma hyopneumoniae, principalmente associados entre si

Efeito hipolipemiante da suplementação dietética com a farinha do cubiu (solanum sessiliforum dunal) em ratos hipercolesterolêmicos

Studies with fruit and vegetables rich in dietary fber have shown lowering effects on the blood concentrations of total cholesterol (TC), acting preventively against hypercholesterolemia. The aim of this study was to analyze the chemical composition of cocona and evaluate the effect of the consumption of cocona four on lipemia of Wistar rats with hypercholesterolemia. Eight animals were used for each treatment, in 7 groups: control; 3 experimental groups with 5%, 25% and 50% of the recommended fber (AIN-93) from cocona four; 3 groups per feeding with pectin and cellulose as source of dietary fber, in the same proportions of the experimental groups. At the end of the assay, we verifed that there were not signifcant variations in the consumption of the animals and the body weight during the experiment. Treatments with cocna four were responsible for reducing the concentrations of total cholesterol (-21.6%), LDL-c (-56.8%), increasing the excretion of fecal cholesterol (+116%) and lowering the liver cholesterol (-32.1%). None of the treatments signifcantly altered the triglyceride concentrations. Treatments using pectin and cellulose show results similar to cocona. The observed results can be used in further studies aimed at the biotechnological exploitation of this fruit. © 2015, Instituto de Biociencias. All rights reserved

Novel Anti-bacterial Activities of β-defensin 1 in Human Platelets: Suppression of Pathogen Growth and Signaling of Neutrophil Extracellular Trap Formation

Human β-defensins (hBD) are antimicrobial peptides that curb microbial activity. Although hBD's are primarily expressed by epithelial cells, we show that human platelets express hBD-1 that has both predicted and novel antibacterial activities. We observed that activated platelets surround Staphylococcus aureus (S. aureus), forcing the pathogens into clusters that have a reduced growth rate compared to S. aureus alone. Given the microbicidal activity of β-defensins, we determined whether hBD family members were present in platelets and found mRNA and protein for hBD-1. We also established that hBD-1 protein resided in extragranular cytoplasmic compartments of platelets. Consistent with this localization pattern, agonists that elicit granular secretion by platelets did not readily induce hBD-1 release. Nevertheless, platelets released hBD-1 when they were stimulated by α-toxin, a S. aureus product that permeabilizes target cells. Platelet-derived hBD-1 significantly impaired the growth of clinical strains of S. aureus. hBD-1 also induced robust neutrophil extracellular trap (NET) formation by target polymorphonuclear leukocytes (PMNs), which is a novel antimicrobial function of β-defensins that was not previously identified. Taken together, these data demonstrate that hBD-1 is a previously-unrecognized component of platelets that displays classic antimicrobial activity and, in addition, signals PMNs to extrude DNA lattices that capture and kill bacteria

The septic milieu triggers expression of spliced tissue factor mRNA in human platelets: Sepsis induces platelet tissue factor mRNA

Activated platelets have previously-unrecognized mechanisms of post-transcriptional gene expression that may influence hemostasis and inflammation. A novel pathway involves splicing of pre-mRNAs in resting platelets to mature, translatable mRNAs in response to cellular activation

Numerical modelling of the transport of trace gases including methane in the subsurface of Mars

We model the transport of gas through the martian subsurface in order to quantify the timescales of release of a trace gas with a source at depth using a Fickian model of diffusion through a putative martian regolith column. The model is then applied to the case of methane previously observed in the martian atmosphere. We investigate which parameters in the model have the greatest effect on transport timescales and find that transport is very sensitive to the pressure profile of the subsurface, but relatively insensitive to the temperature profile. Uncertainties in the composition, structure and physical conditions of the martian subsurface also introduce uncertainties in the timescales calculated. It was found that methane may take several hundred thousand Mars-years to diffuse from a source at depth. Purely diffusive transport cannot explain transient release that varies on timescales of less than one martian year from sources such as serpentinization or methanogenic organisms at depths of more than 2 km. However, diffusion of gas released by the destabilisation of methane clathrate hydrates close to the surface, for example caused by transient mass wasting events or erosion, could produce a rapidly varying flux of methane into the atmosphere of more than 10-3 kg m-2 s-1 over a duration of less than half a martian year, consistent with observations of martian methane variability. Seismic events, magmatic intrusions or impacts could also potentially produce similar patterns of release, but are far more complex to simulate

DOENÇAS DIAGNOSTICADAS PELO LABORATÓRIO DE PATOLOGIA VETERINÁRIA NO QUINQUÊNIO 2013-2017

Este trabalho apresenta a casuística de diagnósticos nos anos de 2013 a 2017 do Laboratório de Patologia Veterinária do IFC Campus Concórdia. Foram 865 diagnósticos em bovinos, 131 em ovinos e 367 em suínos, totalizando 1363. Destes, 1000 (80,4%) foram através de necropsias e 363 (19,6%) através de amostras formolizadas enviadas por veterinários. Em bovinos as doenças mais incidentes foram miosite clostridial com 34 casos (3,8%); babesiose com 31 casos cada (3,6%); leucose enzoótica bovina com 28 casos (3,2%); anaplasmose com 27 casos (3,1%); hemoncose com 26 casos (3,0%); intoxicação por Pteridium arachnoideumcom 26 casos (3,0%); peritonite com 23 casos (2,7%) e endocardite com 23 casos (2,7%). Já em ovinos hemoncose com 28 casos (21,4%) e suínos doença de Glässer com 27 casos (7,3%) e circovirose com 22 casos (6,0%)

High-Throughput Proteomics Detection of Novel Splice Isoforms in Human Platelets

Alternative splicing (AS) is an intrinsic regulatory mechanism of all metazoans. Recent findings suggest that 100% of multiexonic human genes give rise to splice isoforms. AS can be specific to tissue type, environment or developmentally regulated. Splice variants have also been implicated in various diseases including cancer. Detection of these variants will enhance our understanding of the complexity of the human genome and provide disease-specific and prognostic biomarkers. We adopted a proteomics approach to identify exon skip events - the most common form of AS. We constructed a database harboring the peptide sequences derived from all hypothetical exon skip junctions in the human genome. Searching tandem mass spectrometry (MS/MS) data against the database allows the detection of exon skip events, directly at the protein level. Here we describe the application of this approach to human platelets, including the mRNA-based verification of novel splice isoforms of ITGA2, NPEPPS and FH. This methodology is applicable to all new or existing MS/MS datasets