Effects of an anti-inflammatory VAP-1/SSAO inhibitor, PXS-4728A, on pulmonary neutrophil migration

© Schilter et al. Background and purpose: The persistent influx of neutrophils into the lung and subsequent tissue damage are characteristics of COPD, cystic fibrosis and acute lung inflammation. VAP-1/SSAO is an endothelial bound adhesion molecule with amine oxidase activity that is reported to be involved in neutrophil egress from the microvasculature during inflammation. This study explored the role of VAP-1/SSAO in neutrophilic lung mediated diseases and examined the therapeutic potential of the selective inhibitor PXS-4728A. Methods: Mice treated with PXS-4728A underwent intra-vital microscopy visualization of the cremaster muscle upon CXCL1/KC stimulation. LPS inflammation, Klebsiella pneumoniae infection, cecal ligation and puncture as well as rhinovirus exacerbated asthma models were also assessed using PXS-4728A. Results: Selective VAP-1/SSAO inhibition by PXS-4728A diminished leukocyte rolling and adherence induced by CXCL1/KC. Inhibition of VAP-1/SSAO also dampened the migration of neutrophils to the lungs in response to LPS, Klebsiella pneumoniae lung infection and CLP induced sepsis; whilst still allowing for normal neutrophil defense function, resulting in increased survival. The functional effects of this inhibition were demonstrated in the RV exacerbated asthma model, with a reduction in cellular infiltrate correlating with a reduction in airways hyperractivity. Conclusions and implications: This study demonstrates that the endothelial cell ligand VAP-1/SSAO contributes to the migration of neutrophils during acute lung inflammation, pulmonary infection and airway hyperractivity. These results highlight the potential of inhibiting of VAP-1/SSAO enzymatic function, by PXS-4728A, as a novel therapeutic approach in lung diseases that are characterized by neutrophilic pattern of inflammation

Genetic parameters for faecal egg count, packed-cell volume and body-weight in Santa Inês lambs

Worm infection is one of the main factors responsible for economic losses in sheep breeding in Brazil. Random regression analysis was used to estimate genetic parameters for the factors faecal egg-count (FEC), packed-cell volume (PCV) and body weight (BW) in Santa Inês lambs. Data from 119 female, offspring of nine rams, were collected between December, 2005 and December, 2006, from the experimental flock of Embrapa Tabuleiros Costeiros, the Brazilian Agricultural Research Corporation located in Frei Paulo, SE, Brazil. After weaning, females were drenched until the faecal egg count had dropped to zero. Two natural challenges were undertaken. FEC heritability was extremely variable, this increasing from 0.04 to 0.27 in the first challenge and from 0.01 to 0.52 during the second. PCV heritability peaks were 0.31 and 0.12 in the first and second challenges, respectively. In the second challenge, BW heritability was close to 0.90. The genetic correlations among these traits did not differ from zero. There is the possibility of increasing parasite resistance in Santa Inês by selecting those animals with lower FEC. Selection to increase resistance will not adversely affect lamb-growth, although lambs with a slow growth-rate may be more susceptible to infection

Fostering scientific literacy and critical thinking in elementary science education

Scientific literacy (SL) and critical thinking (CT) are key components of science education aiming to prepare students to think and to function as responsible citizens in a world increasingly affected by science and technology (S&T). Therefore, students should be given opportunities in their science classes to be engaged in learning experiences that promote SL and CT, which may trigger the need to build and develop knowledge, attitudes/values, thinking abilities, and standards/criteria in an integrated way, resulting in their ability to know how to take responsible action in contexts and situations of personal and social relevance. This paper reports on a study to design, implement, and assess science learning experiences focused on CT toward SL goal. Results support the conclusion that the learning experiences developed and implement- ed in a grade 6 science classroom had a significant influence on the students’ CT and SL. Within this elementary school context, the theoretical framework used appears to be a relevant and practical aid for developing learning experiences that promote CT/SL and in supporting teaching practices that are more in line with the goals of critical scientific literacy

A Comparative Study of the Short Term Cold Resistance Response in Distantly Related Drosophila Species: The Role of regucalcin and Frost

The molecular basis of short term cold resistance (indexed as chill-coma recovery time) has been mostly addressed in D. melanogaster, where candidate genes (Dca (also known as smp-30) and Frost (Fst)) have been identified. Nevertheless, in Drosophila, the ability to tolerate short term exposure to low temperatures evolved several times independently. Therefore, it is unclear whether variation in the same candidate genes is also responsible for short term cold resistance in distantly related Drosophila species. It should be noted that Dca is a candidate gene for cold resistance in the Sophophora subgenus only, since there is no orthologous gene copy in the Drosophila subgenus. Here we show that, in D. americana (Drosophila subgenus), there is a north-south gradient for a variant at the 5′ non-coding region of regucalcin (a Dca-like gene; in D. melanogaster the proteins encoded by the two genes share 71.9% amino acid identities) but in our D. americana F2 association experiment there is no association between this polymorphism and chill-coma recovery times. Moreover, we found no convincing evidence that this gene is up-regulated after cold shock in both D. americana and D. melanogaster. Size variation in the Fst PEST domain (putatively involved in rapid protein degradation) is observed when comparing distantly related Drosophila species, and is associated with short term cold resistance differences in D. americana. Nevertheless, this effect is likely through body size variation. Moreover, we show that, even at two hours after cold shock, when up-regulation of this gene is maximal in D. melanogaster (about 48 fold expression change), in D. americana this gene is only moderately up-regulated (about 3 fold expression change). Our work thus shows that there are important differences regarding the molecular basis of cold resistance in distantly related Drosophila species

Cellular profile of the peritumoral inflammatory infiltrate in squamous cells carcinoma of oral mucosa: Correlation with the expression of Ki67 and histologic grading

<p>Abstract</p> <p>Background</p> <p>Squamous cells carcinoma is the most important malignant tumor with primary site in the oral cavity and, given the great exposure of mucosa and lips to the etiologic factors of this neoplasm, its incidence is high. Investigation of the prognostic determinants is significant for the expectations of treatment proposal and cure of the patient. The local immune response represented by peritumoral inflammatory infiltrate is a possible prognostic factor.</p> <p>Methods</p> <p>In this study, oral mucosa samples of squamous cells carcinoma were analyzed, separated according to their histological classification as well as the phenotypical profile of the cells comprising the peritumoral inflammatory infiltrate was investigated by immunohistochemical method, in addiction, the cell proliferation index via protein Ki67 expression was determinated.</p> <p>Results</p> <p>The T lymphocytes made up most of this inflammatory infiltrate, and among these cells, there was a predominance of T CD8 lymphocytes relative to the T CD4 lymphocytes. The B lymhocytes were the second most visualized leucocyte cell type followed by macrophages and neutrophils. The immunohistochemical assessment of Ki-67 positive cells revealed a greater expression of this protein in samples of undifferentiated squamous cells carcinoma.</p> <p>Conclusion</p> <p>The results suggest that the cellular immune response is the main defense mechanism in squamous cells carcinoma of oral mucosa, expressed by the large number of T lymphocytes and macrophages, and that the greatest intensity of local response may be associated with the best prognosis.</p

Metabolic Programming during Lactation Stimulates Renal Na+ Transport in the Adult Offspring Due to an Early Impact on Local Angiotensin II Pathways

BACKGROUND: Several studies have correlated perinatal malnutrition with diseases in adulthood, giving support to the programming hypothesis. In this study, the effects of maternal undernutrition during lactation on renal Na(+)-transporters and on the local angiotensin II (Ang II) signaling cascade in rats were investigated. METHODOLOGY/PRINCIPAL FINDINGS: Female rats received a hypoproteic diet (8% protein) throughout lactation. Control and programmed offspring consumed a diet containing 20% protein after weaning. Programming caused a decrease in the number of nephrons (35%), in the area of the Bowman's capsule (30%) and the capillary tuft (30%), and increased collagen deposition in the cortex and medulla (by 175% and 700%, respectively). In programmed rats the expression of (Na(+)+K(+))ATPase in proximal tubules increased by 40%, but its activity was doubled owing to a threefold increase in affinity for K(+). Programming doubled the ouabain-insensitive Na(+)-ATPase activity with loss of its physiological response to Ang II, increased the expression of AT(1) and decreased the expression of AT(2) receptors), and caused a pronounced inhibition (90%) of protein kinase C activity with decrease in the expression of the α (24%) and ε (13%) isoforms. Activity and expression of cyclic AMP-dependent protein kinase decreased in the same proportion as the AT(2) receptors (30%). In vivo studies at 60 days revealed an increased glomerular filtration rate (GFR) (70%), increased Na(+) excretion (80%) and intense proteinuria (increase of 400% in protein excretion). Programmed rats, which had normal arterial pressure at 60 days, became hypertensive by 150 days. CONCLUSIONS/SIGNIFICANCE: Maternal protein restriction during lactation results in alterations in GFR, renal Na(+) handling and in components of the Ang II-linked regulatory pathway of renal Na(+) reabsorption. At the molecular level, they provide a framework for understanding how metabolic programming of renal mechanisms contributes to the onset of hypertension in adulthood