Inhibition of the JAK/STAT Pathway with Baricitinib Reduces the Multiple Organ Dysfunction Caused by Hemorrhagic Shock in Rats.

OBJECTIVE: The aim of this study was to investigate (a) the effects of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway inhibitor (baricitinib) on the MODS in a rat model of hemorrhagic shock (HS) and (b) whether treatment with baricitinib attenuates the activation of JAK/STAT, NF-κB and NLRP3 caused by HS. BACKGROUND: Post-traumatic MODS, which is in part due to excessive systemic inflammation, is associated with high morbidity and mortality. The JAK/STAT pathway is a regulator of numerous growth factor and cytokine receptors and, hence, is considered a potential master regulator of many inflammatory signaling processes. However, its role in trauma-hemorrhage is unknown. METHODS: An acute HS rat model was performed to determine the effect of baricitinib on MODS. The activation of JAK/STAT, NF-κB and NLRP3 pathways were analyzed by western blotting in the kidney and liver. RESULTS: We demonstrate here for the first time that treatment with baricitinib (during resuscitation following severe hemorrhage) attenuates the organ injury and dysfunction and the activation of JAK/STAT, NF-κB and NLRP3 pathways caused by HS in the rat. CONCLUSIONS: Our results point to a role of the JAK/STAT pathway in the pathophysiology of the organ injury and dysfunction caused by trauma/hemorrhage and indicate that JAK inhibitors, such as baricitinib, may be repurposed for the treatment of the MODS after trauma and/or hemorrhage

Keratocystic odontogenic tumor overexpresses invadopodia-related proteins, suggesting invadopodia formation

OBJECTIVE: Keratocystic odontogenic tumor (KOT) is an odontogenic neoplasm that shows aggressive clinical behavior and local invasiveness. Invadopodia are actin-rich cellular protrusions exhibiting proteolytic pericellular activity, thereby inducing focal invasion in neoplastic cells and increasing neoplasms aggressiveness. Thus, this study aimed to evaluate immunoexpression of invadopodia-related proteins, cortactin, MT1-MMP, Tks4, and Tks5, in KOT. STUDY DESIGN: Immunohistochemistry of 16 cases of KOT, eight cases of calcifying cystic odontogenic tumor (CCOT), and eight samples of the oral mucosa (OM) was carried out to assess the expression of the above described invadopodia-related proteins in the basal and suprabasal layer. RESULTS: KOT samples showed higher and significant immunoexpression of cortactin, MT1-MMP, TKs4, and TKs5 compared with the CCOT and OM samples. Significant expression of all these proteins was observed in the basal layer compared with the suprabasal layer in KOT. CONCLUSIONS: Overexpression of cortactin, MT1-MMP, TKs4, and TKs5 was observed in KOT compared with samples of CCOT and OM. These proteins were also overexpressed in the basal over the suprabasal layer of KOT samples. Taken together, these results suggest the participation of invadopodia-related proteins on the pathogenesis of this lesion

Ecosystem heterogeneity and diversity mitigate Amazon forest resilience to frequent extreme droughts

© 2018 The Authors. New Phytologist © 2018 New Phytologist Trust The impact of increases in drought frequency on the Amazon forest's composition, structure and functioning remain uncertain. We used a process- and individual-based ecosystem model (ED2) to quantify the forest's vulnerability to increased drought recurrence. We generated meteorologically realistic, drier-than-observed rainfall scenarios for two Amazon forest sites, Paracou (wetter) and Tapajós (drier), to evaluate the impacts of more frequent droughts on forest biomass, structure and composition. The wet site was insensitive to the tested scenarios, whereas at the dry site biomass declined when average rainfall reduction exceeded 15%, due to high mortality of large-sized evergreen trees. Biomass losses persisted when year-long drought recurrence was shorter than 2–7 yr, depending upon soil texture and leaf phenology. From the site-level scenario results, we developed regionally applicable metrics to quantify the Amazon forest's climatological proximity to rainfall regimes likely to cause biomass loss > 20% in 50 yr according to ED2 predictions. Nearly 25% (1.8 million km2) of the Amazon forests could experience frequent droughts and biomass loss if mean annual rainfall or interannual variability changed by 2σ. At least 10% of the high-emission climate projections (CMIP5/RCP8.5 models) predict critically dry regimes over 25% of the Amazon forest area by 2100

Inhibition of Macrophage Migration Inhibitory Factor Activity Attenuates Haemorrhagic Shock-Induced Multiple Organ Dysfunction in Rats

OBJECTIVE: The aim of this study was to investigate (a) macrophage migration inhibitory factor (MIF) levels in polytrauma patients and rats after haemorrhagic shock (HS), (b) the potential of the MIF inhibitor ISO-1 to reduce multiple organ dysfunction syndrome (MODS) in acute (short-term and long-term follow-up) HS rat models and (c) whether treatment with ISO-1 attenuates NF-κB and NLRP3 activation in HS. BACKGROUND: The MODS caused by an excessive systemic inflammatory response following trauma is associated with a high morbidity and mortality. MIF is a pleiotropic cytokine which can modulate the inflammatory response, however, its role in trauma is unknown. METHODS: The MIF levels in plasma of polytrauma patients and serum of rats with HS were measured by ELISA. Acute HS rat models were performed to determine the influence of ISO-1 on MODS. The activation of NF-κB and NLRP3 pathways were analysed by western blot in the kidney and liver. RESULTS: We demonstrated that (a) MIF levels are increased in polytrauma patients on arrival to the emergency room and in rats after HS, (b) HS caused organ injury and/or dysfunction and hypotension (post-resuscitation) in rats, while (c) treatment of HS-rats with ISO-1 attenuated the organ injury and dysfunction in acute HS models and (d) reduced the activation of NF-κB and NLRP3 pathways in the kidney and liver. CONCLUSION: Our results point to a role of MIF in the pathophysiology of trauma-induced organ injury and dysfunction and indicate that MIF inhibitors may be used as a potential therapeutic approach for MODS after trauma and/or haemorrhage

Reserve size, dispersal and population viability of wide ranging carnivores: the case of jaguars in Emas National Park, Brazil

Protected areas may be important refuges for large carnivores, but many are not large enough to sustain viable populations. Without sufficient dispersal between protected areas, large carnivore populations inside them are at risk of becoming genetically isolated and demographically vulnerable. In this study, we use the jaguar population in and around Emas National Park in the Brazilian Cerrado as a case study to evaluate the demographic sustainability of a large carnivore population within a small and potentially isolated protected area. We used camera trapping data and spatially explicit capture-recapture models to estimate density and corresponding population size of jaguars in Emas National Park. We then used a matrix-based age and sex structured stochastic population model to evaluate the demographic viability of jaguar populations across a range of population sizes, including those estimated for Emas. We detected 10 individual jaguars during our survey with a total of 74 detections. Our density estimation became unbiased using a buffer width of 30 km and produced a density of 0.17 jaguars per 100 km2. The estimated population sizes of 10 to 60 animals suffered extinction risks of 70-90% without net immigration. However, only a low number of immigrants were required to suppress extinction risk towards zero. Our density estimate for jaguars was lower than in previous studies, and our simulations suggested that this population may have a substantial extinction risk. Ensuring dispersal and connectivity outside of protected areas, through the implementation of habitat corridors, can greatly reduce this extinction risk, and we suggest that this scenario is potentially applicable to many other large carnivore populations

Oatmeal particle size alters glycemic index but not as a function of gastric emptying rate

The aim of this study was to determine the extent to which oat particle size in a porridge could alter glucose absorption, gastric emptying, gastrointestinal hormone response, and subjective feelings of appetite and satiety. Porridge was prepared from either oat flakes or oat flour with the same protein, fat, carbohydrate, and mass. These were fed to eight volunteers on separate days in a crossover study, and subjective appetite ratings, gastric contents, and plasma glucose, insulin, and gastrointestinal hormones were determined over a period of 3 h. The flake porridge gave a lower glucose response than the flour porridge, and there were apparent differences in gastric emptying in both the early and late postprandial phases. The appetite ratings showed similar differences between early- and late-phase behavior. The structure of the oat flakes remained sufficiently intact to delay their gastric emptying, leading to a lower glycemic response, even though initial gastric emptying rates were similar for the flake and flour porridge. This highlights the need to take food structure into account when considering relatively simple physiological measures and offering nutritional guidance

Impact of cerebral blood flow and amyloid load on SUVR bias

BACKGROUND: Despite its widespread use, the semi-quantitative standardized uptake value ratio (SUVR) may be biased compared with the distribution volume ratio (DVR). This bias may be partially explained by changes in cerebral blood flow (CBF) and is likely to be also dependent on the extent of the underlying amyloid-β (Aβ) burden. This study aimed to compare SUVR with DVR and to evaluate the effects of underlying Aβ burden and CBF on bias in SUVR in mainly cognitively unimpaired participants. Participants were scanned according to a dual-time window protocol, with either [18F]flutemetamol (N = 90) or [18F]florbetaben (N = 31). The validated basisfunction-based implementation of the two-step simplified reference tissue model was used to derive DVR and R1 parametric images, and SUVR was calculated from 90 to 110 min post-injection, all with the cerebellar grey matter as reference tissue. First, linear regression and Bland-Altman analyses were used to compare (regional) SUVR with DVR. Then, generalized linear models were applied to evaluate whether (bias in) SUVR relative to DVR could be explained by R1 for the global cortical average (GCA), precuneus, posterior cingulate, and orbitofrontal region. RESULTS: Despite high correlations (GCA: R2 ≥ 0.85), large overestimation and proportional bias of SUVR relative to DVR was observed. Negative associations were observed between both SUVR or SUVRbias and R1, albeit non-significant. CONCLUSION: The present findings demonstrate that bias in SUVR relative to DVR is strongly related to underlying Aβ burden. Furthermore, in a cohort consisting mainly of cognitively unimpaired individuals, the effect of relative CBF on bias in SUVR appears limited. EudraCT Number: 2018-002277-22, registered on: 25-06-2018

International Glossina Genome Initiative 2004-2014: a driver for post-genomic era research on the African continent

Human African trypanosomiasis (HAT), also known as sleeping sickness, is a neglected disease that impacts 70 million people distributed over 1.55 million km2 in sub- Saharan Africa and includes at least 50% of the population of theDemocratic Republic of the Congo [1]. Trypanosoma brucei gambiense accounts for more than 98% of the infections in central and West Africa, the remaining infections being from Trypanosoma brucei rhodesiense in East Africa [2]. The parasites are transmitted to the hosts through the bite of an infected tsetse fly. Disease control is challenging as there are no vaccines, and effective, easily delivered drugs are still lacking. Treatment invariably involves lengthy hospitalization, with both medical and socioeconomic consequences.Web of Scienc

Nanostructured 3D Constructs Based on Chitosan and Chondroitin Sulphate Multilayers for Cartilage Tissue Engineering

Nanostructured three-dimensional constructs combining layer-by-layer technology (LbL) and template leaching were processed and evaluated as possible support structures for cartilage tissue engineering. Multilayered constructs were formed by depositing the polyelectrolytes chitosan (CHT) and chondroitin sulphate (CS) on either bidimensional glass surfaces or 3D packet of paraffin spheres. 2D CHT/CS multi-layered constructs proved to support the attachment and proliferation of bovine chondrocytes (BCH). The technology was transposed to 3D level and CHT/CS multi-layered hierarchical scaffolds were retrieved after paraffin leaching. The obtained nanostructured 3D constructs had a high porosity and water uptake capacity of about 300%. Dynamical mechanical analysis (DMA) showed the viscoelastic nature of the scaffolds. Cellular tests were performed with the culture of BCH and multipotent bone marrow derived stromal cells (hMSCs) up to 21 days in chondrogenic differentiation media. Together with scanning electronic microscopy analysis, viability tests and DNA quantification, our results clearly showed that cells attached, proliferated and were metabolically active over the entire scaffold. Cartilaginous extracellular matrix (ECM) formation was further assessed and results showed that GAG secretion occurred indicating the maintenance of the chondrogenic phenotype and the chondrogenic differentiation of hMSCs

Spatial-Temporal Patterns of Amyloid-β Accumulation: A Subtype and Stage Inference Model Analysis

BACKGROUND AND OBJECTIVES: Currently, amyloid-β (Aβ) staging models assume a single spatial-temporal progression of amyloid accumulation. We assessed evidence for Aβ accumulation subtypes by applying the data-driven Subtype and Stage Inference (SuStaIn) model to amyloid-PET data. METHODS: Amyloid-PET data of 3010 subjects were pooled from 6 cohorts (ALFA+, EMIF-AD, ABIDE, OASIS, and ADNI). Standardized uptake value ratios (SUVr) were calculated for 17 regions. We applied the SuStaIn algorithm to identify consistent subtypes in the pooled dataset based on the cross-validation information criterion (CVIC) and the most probable subtype/stage classification per scan. The effect of demographics and risk factors on subtype assignment was assessed using multinomial logistic regression. RESULTS: Participants were mostly cognitively unimpaired (N=1890, 62.8%), had a mean age of 68.72 (SD=9.1), 42.1% was APOE-ε4 carrier, and 51.8% was female. While a one-subtype model recovered the traditional amyloid accumulation trajectory, SuStaIn identified an optimal of three subtypes, referred to as Frontal, Parietal, and Occipital based on the first regions to show abnormality. Of the 788 (26.2%) with strong subtype assignment (>50% probability), the majority was assigned to Frontal (N=415, 52.5%), followed by Parietal (N=199, 25.3%), and Occipital subtypes (N=175, 22.2%). Significant differences across subtypes included distinct proportions of APOE-ε4 carriers (Frontal:61.8%, Parietal:57.1%, Occipital:49.4%), subjects with dementia (Frontal:19.7%, Parietal:19.1%, Occipital:31.0%) and lower age for the Parietal subtype (Frontal/Occipital:72.1y, Parietal:69.3y). Higher amyloid (Centiloid) and CSF p-tau burden was observed for the Frontal subtype, while Parietal and Occipital did not differ. At follow-up, most subjects (81.1%) maintained baseline subtype assignment and 25.6% progressed to a later stage. DISCUSSION: While a one-trajectory model recovers the established pattern of amyloid accumulation, SuStaIn determined that three subtypes were optimal, showing distinct associations to AD risk factors. Nonetheless, further analyses to determine clinical utility is warranted