Inhibition of SLPI ameliorates disease activity in experimental autoimmune encephalomyelitis

<p>Abstract</p> <p>Background</p> <p>The secretory leukocyte protease inhibitor (SLPI) exerts wide ranging effects on inflammatory pathways and is upregulated in EAE but the biological role of SLPI in EAE, an animal model of multiple sclerosis is unknown</p> <p>Methods</p> <p>To investigate the pathophysiological effects of SLPI within EAE, we induced SLPI-neutralizing antibodies in mice and rats to determine the clinical severity of the disease. In addition we studied the effects of SLPI on the anti-inflammatory cytokine TGF-β.</p> <p>Results</p> <p>The induction of SLPI neutralizing antibodies resulted in a milder disease course in mouse and rat EAE. SLPI neutralization was associated with increased serum levels of TGF-β and increased numbers of FoxP3+ CD4+ T cells in lymph nodes. <it>In vitro</it>, the addition of SLPI significantly decreased the number of functional FoxP3+ CD25^hiCD4+ regulatory T cells in cultures of naive human CD4+ T cells. Adding recombinant TGF-β to SLPI-treated human T cell cultures neutralized SLPI's inhibitory effect on regulatory T cell differentiation.</p> <p>Conclusion</p> <p>In EAE, SLPI exerts potent pro-inflammatory actions by modulation of T-cell activity and its neutralization may be beneficial for the disease.</p

Clinical significance of stromal apoptosis in colorectal cancer

BackgroundEpithelial and stromal cells play an important role in the development of colorectal cancer (CRC). We aimed to determine the prognostic significance of both epithelial and stromal cell apoptosis in CRC.MethodsTotal apoptosis was determined by caspase-3 activity measurements in protein homogenates of CRC specimens and adjacent normal mucosa of 211 CRC patients. Epithelial apoptosis was determined by an ELISA specific for a caspase-3-degraded cytokeratin 18 product, the M30 antigen. Stromal apoptosis was determined from the ratio between total and epithelial apoptosis.ResultsEpithelial and stromal apoptosis, as well as total apoptosis, were significantly higher in CRC compared with corresponding adjacent normal mucosa. Low total tumour apoptosis (&lt; or = median caspase-3 activity) was associated with a significantly worse disease recurrence (hazard ratio (HR), 95% confidence interval (95% CI): 1.77 (1.05-3.01)), independent of clinocopathological parameters. Epithelial apoptosis was not associated with clinical outcome. In contrast, low stromal apoptosis (&lt; or = median caspase-3/M30) was found to be an independent prognostic factor for overall survival, disease-free survival and disease recurrence, with HRs (95% CI) of 1.66 (1.17-2.35), 1.62 (1.15-2.29) and 1.69 (1.01-2.85), respectively.InterpretationStromal apoptosis, in contrast to epithelial apoptosis, is an important factor with respect to survival and disease-recurrence in CRC

Latitudinal diversity gradients in New World bats: are they a consequence of niche conservatism?

The increase in species diversity from the Poles to the Equator is a major biogeographic pattern, but the mechanisms underlying it remain obscure. Our aim is to contribute to their clarification by describing the latitudinal gradients in species richness and in evolutionary age of species of New World bats, and testing if those patterns may be explained by the niche conservatism hypothesis. Maps of species ranges were used to estimate species richness in a 100 x 100 km grid. Root distances in a molecular phylogeny were used as a proxy for the age of species, and the mean root distance of the species in each cell of the grid was estimated. Generalised additive models were used to relate latitude with both species richness and mean root distance. This was done for each of the three most specious bat families and for all Chiroptera combined. Species richness increases towards the Equator in the whole of the Chiroptera and in the Phyllostomidae and Molossidae, families that radiated in the tropics, but the opposite trend is observed in the Vespertilionidae, which has a presumed temperate origin. In the whole of the Chiroptera, and in the three main families, there were more basal species in the higher latitudes, and more derived species in tropical areas. In general, our results were not consistent with the predictions of niche conservatism. Tropical niche conservatism seems to keep bat clades of tropical origin from colonizing temperate zones, as they lack adaptations to survive cold winters, such as the capacity to hibernate. However, the lower diversity of Vespertilionidae in the Neotropics is better explained by competition with a diverse pre-existing community of bats than by niche conservatism.MJRP was supported by Foundation for Science and Technology, Portugal (www.fct.pt), fellowship SFRH/BD/19620/2004 and SFRH/BPD/ 72845/2010. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank J. P. Granadeiro and R. Lemos for advice on statistical methods, J. A. Diniz-Filho for support with SAM software, and M. A. Dias and P. E. Cardoso for help with the distributional maps. O. R. P. Bininda-Emonds kindly gave us access to the Chiroptera species-level phylogeny. Bat data was provided by NatureServe in collaboration with Bruce Patterson, Wes Sechrest, Marcelo Tognelli, Gerardo Ceballos, the Nature Conservancy-Migratory Bird Program, Conservation International-CABS, World Wildlife Fund-US, and Environment Canada-WILDSPACE - http://www.natureserve.org/infonatura.publishe

A comprehensive overview of radioguided surgery using gamma detection probe technology

The concept of radioguided surgery, which was first developed some 60 years ago, involves the use of a radiation detection probe system for the intraoperative detection of radionuclides. The use of gamma detection probe technology in radioguided surgery has tremendously expanded and has evolved into what is now considered an established discipline within the practice of surgery, revolutionizing the surgical management of many malignancies, including breast cancer, melanoma, and colorectal cancer, as well as the surgical management of parathyroid disease. The impact of radioguided surgery on the surgical management of cancer patients includes providing vital and real-time information to the surgeon regarding the location and extent of disease, as well as regarding the assessment of surgical resection margins. Additionally, it has allowed the surgeon to minimize the surgical invasiveness of many diagnostic and therapeutic procedures, while still maintaining maximum benefit to the cancer patient. In the current review, we have attempted to comprehensively evaluate the history, technical aspects, and clinical applications of radioguided surgery using gamma detection probe technology

Diabetic ketoacidosis

Diabetic ketoacidosis (DKA) is the most common acute hyperglycaemic emergency in people with diabetes mellitus. A diagnosis of DKA is confirmed when all of the three criteria are present — ‘D’, either elevated blood glucose levels or a family history of diabetes mellitus; ‘K’, the presence of high urinary or blood ketoacids; and ‘A’, a high anion gap metabolic acidosis. Early diagnosis and management are paramount to improve patient outcomes. The mainstays of treatment include restoration of circulating volume, insulin therapy, electrolyte replacement and treatment of any underlying precipitating event. Without optimal treatment, DKA remains a condition with appreciable, although largely preventable, morbidity and mortality. In this Primer, we discuss the epidemiology, pathogenesis, risk factors and diagnosis of DKA and provide practical recommendations for the management of DKA in adults and children

Predicting attitudinal and behavioral responses to COVID-19 pandemic using machine learning

At the beginning of 2020, COVID-19 became a global problem. Despite all the efforts to emphasize the relevance of preventive measures, not everyone adhered to them. Thus, learning more about the characteristics determining attitudinal and behavioral responses to the pandemic is crucial to improving future interventions. In this study, we applied machine learning on the multinational data collected by the International Collaboration on the Social and Moral Psychology of COVID-19 (N = 51,404) to test the predictive efficacy of constructs from social, moral, cognitive, and personality psychology, as well as socio-demographic factors, in the attitudinal and behavioral responses to the pandemic. The results point to several valuable insights. Internalized moral identity provided the most consistent predictive contribution-individuals perceiving moral traits as central to their self-concept reported higher adherence to preventive measures. Similar results were found for morality as cooperation, symbolized moral identity, self-control, open-mindedness, and collective narcissism, while the inverse relationship was evident for the endorsement of conspiracy theories. However, we also found a non-neglible variability in the explained variance and predictive contributions with respect to macro-level factors such as the pandemic stage or cultural region. Overall, the results underscore the importance of morality-related and contextual factors in understanding adherence to public health recommendations during the pandemic.Published versio