| 1. |
- Ademuyiwa, Adesoji O., et al.
(author)
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Determinants of morbidity and mortality following emergency abdominal surgery in children in low-income and middle-income countries
- 2016
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In: BMJ Global Health. - : BMJ Publishing Group Ltd. - 2059-7908. ; 1:4
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Journal article (peer-reviewed)abstract
- Background: Child health is a key priority on the global health agenda, yet the provision of essential and emergency surgery in children is patchy in resource-poor regions. This study was aimed to determine the mortality risk for emergency abdominal paediatric surgery in low-income countries globally.Methods: Multicentre, international, prospective, cohort study. Self-selected surgical units performing emergency abdominal surgery submitted prespecified data for consecutive children aged <16 years during a 2-week period between July and December 2014. The United Nation's Human Development Index (HDI) was used to stratify countries. The main outcome measure was 30-day postoperative mortality, analysed by multilevel logistic regression.Results: This study included 1409 patients from 253 centres in 43 countries; 282 children were under 2 years of age. Among them, 265 (18.8%) were from low-HDI, 450 (31.9%) from middle-HDI and 694 (49.3%) from high-HDI countries. The most common operations performed were appendectomy, small bowel resection, pyloromyotomy and correction of intussusception. After adjustment for patient and hospital risk factors, child mortality at 30 days was significantly higher in low-HDI (adjusted OR 7.14 (95% CI 2.52 to 20.23), p<0.001) and middle-HDI (4.42 (1.44 to 13.56), p=0.009) countries compared with high-HDI countries, translating to 40 excess deaths per 1000 procedures performed.Conclusions: Adjusted mortality in children following emergency abdominal surgery may be as high as 7 times greater in low-HDI and middle-HDI countries compared with high-HDI countries. Effective provision of emergency essential surgery should be a key priority for global child health agendas.
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| 2. |
- Klionsky, Daniel J., et al.
(author)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Research review (peer-reviewed)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 3. |
- Clark, Reuben
(author)
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Studies on myeloid cell functions in periodontitis
- 2020
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Doctoral thesis (other academic/artistic)abstract
- Periodontitis (PD) is a chronic inflammatory disease characterized by destruction of the tooth supporting tissues; gingiva, periodontal ligament, and alveolar bone. Myeloid cells, including monocytes and macrophages, play a crucial part in the inflammatory host response by clearing pathogens and producing a vast array of inflammatory mediators. However, during chronic inflammation, the actions of these cells can contribute to tissue degradation. By utilizing clinical samples and different cell culture systems, this thesis aimed to investigate the role of monocytes and macrophages, along with factors that regulate them in PD. In study I, we found elevated gene and protein expression of MMP-12 in PD gingival tissue and the expression was mainly attributed to CD68+CD64+CD14+ monocyte-derived cells. These cells displayed low expression of the co- stimulatory molecule CD200R. Induced inflammation in oral tissue cultures reduced the CD200R and increased the MMP-12 expression in monocyte-derived cells. CSF-2 was found to potently induce MMP-12 and a CD200 ligand reduced MMP-12 production in monocyte-derived cells, suggesting that the CD200/CD200R pathway is a potential target to modulate harmful inflammatory processes in PD. In study II, the expression of S100A12 was found to be high in monocytes, decreased during macrophage differentiation, and unaltered upon macrophage polarization. Analysis of S100A12 in different monocyte subsets revealed that classical monocytes had the highest expression followed by the intermediate and non-classical subsets. Peripheral blood monocytes from PD patients were more frequently positive for S100A12 and showed higher secretion in vitro compared with controls. The importance of monocytes for S100A12 production was demonstrated in oral tissue cultures. The protein expression of S100A12 was increased in gingival tissue along with higher frequencies of S100A12+ monocyte-derived cells. S100A12 levels in saliva reflected the severity of PD, suggesting A100A12 as a potential biomarker for disease. The expression of the macrophage growth factors CSF-1 and IL-34 in gingival tissue and gingival fibroblasts (GFs) was investigated in study III. Elevated CSF-1 protein expression was found in gingival tissue from PD patients while the levels of IL-34 were similar in PD and control tissue. CSF-1 and IL-34 were expressed and produced by GFs constitutively and proinflammatory stimuli induced their secretion. CSF-1 and IL-34 secretion did not differ in GFs isolated from PD patients compared with controls in unstimulated condition or in response to TNF-α or IL-1β stimuli. In study IV, we found elevated expression of CSF-1R in gingiva from PD patients. HLADR+CD64+ macrophages displayed similar frequencies in PD and controls with no difference regarding CSF-1R expression. In peripheral blood mononuclear cells, CSF-1R inhibition did not alter the monocyte subsets or the expression of the myeloid markers CD64, CD206 or CD163. However, CSF-1R blockade attenuated MMP production in PD gingival explants. Thus, CSF-1R may contribute to the inflammatory processes leading to tissue degradation in PD. In summary, these studies investigated the involvement of monocytes and macrophages in PD as well as the expression of factors that regulate their functions. Furthermore, strategies to target tissue-destructive myeloid cell related processes were explored.
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| 4. |
- Lira-Junior, Ronaldo, et al.
(author)
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S100A12 Expression Is Modulated During Monocyte Differentiation and Reflects Periodontitis Severity
- 2020
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In: Frontiers in Immunology. - : Frontiers Media S.A.. - 1664-3224. ; 11
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Journal article (peer-reviewed)abstract
- S100A12 is a calcium-binding protein of the S100 subfamily of myeloid-related proteins that acts as an alarmin to induce a pro-inflammatory innate immune response. It has been linked to several chronic inflammatory diseases, however its role in the common oral immunopathology periodontitis is largely unknown. Previous in vitro monoculture experiments indicate that S100A12 production decreases during monocyte differentiation stages, while the regulation within tissue is poorly defined. This study evaluated S100A12 expression in monocyte subsets, during monocyte-to-macrophage differentiation and following polarization, both in monoculture and in a tissue context, utilizing a three-dimensional co-culture oral tissue model. Further, we explored the involvement of S100A12 in periodontitis by analyzing its expression in peripheral circulation and gingival tissue, as well as in saliva. We found that S100A12 expression was higher in classical than in non-classical monocytes. S100A12 expression and protein secretion declined significantly during monocyte-to-macrophage differentiation, while polarization of monocyte-derived macrophages had no effect on either. Peripheral monocytes from periodontitis patients had higher S100A12 expression than monocytes from controls, a difference particularly observed in the intermediate and non-classical monocyte subsets. Further, monocytes from periodontitis patients displayed an increased secretion of S100A12 compared with monocytes from controls. In oral tissue cultures, monocyte differentiation resulted in increased S100A12 secretion over time, which further increased after inflammatory stimuli. Likewise, S100A12 expression was higher in gingival tissue from periodontitis patients where monocyte-derived cells exhibited higher expression of S100A12 in comparison to non-periodontitis tissue. In line with our findings, patients with severe periodontitis had significantly higher levels of S100A12 in saliva compared to non-periodontitis patients, and the levels correlated to clinical periodontal parameters. Taken together, S100A12 is predominantly secreted by monocytes rather than by monocyte-derived cells. Moreover, S100A12 is increased in inflamed tissue cultures, potentially as a result of enhanced production by monocyte-derived cells. This study implicates the involvement of S100A12 in periodontitis pathogenesis, as evidenced by increased S100A12 expression in inflamed gingival tissue, which may be due to altered circulatory monocytes in periodontitis.
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