Jeffersonsummers6319
Improving our understanding of mammalian pancreas development is crucial for the development of more effective cellular therapies for diabetes. Most of what we know about mammalian pancreas development stems from mouse genetics. We have learnt that a unique set of transcription factors controls endocrine and exocrine cell differentiation. Transgenic mouse models have been instrumental in studying the function of these transcription factors. Mouse and human pancreas development are very similar in many respects, but the devil is in the detail. To unravel human pancreas development in greater detail, in vitro cellular models (including directed differentiation of stem cells, human beta cell lines and human pancreatic organoids) are used; however, in vivo validation of these results is still needed. The current best 'model' for studying human pancreas development are individuals with monogenic forms of diabetes. Fedratinib In this review, we discuss mammalian pancreas development, highlight some discrepancies between mouse and human, and discuss selected transcription factors that, when mutated, cause permanent neonatal diabetes. Graphical abstract.For much of the last century, our knowledge regarding the pancreas in type 1 and type 2 diabetes was largely derived from autopsy studies of individuals with these disorders or investigations utilising rodent models of either disease. While many important insights emanated from these efforts, the mode for investigation has increasingly seen change due to the availability of transplant-quality organ-donor tissues, improvements in pancreatic imaging, advances in metabolic assessments of living patients, genetic analyses, technological advances for laboratory investigation and more. As a result, many long-standing notions regarding the role for and the changes that occur in the pancreas in individuals with these disorders have come under question, while, at the same time, new issues (e.g., beta cell persistence, disease heterogeneity, exocrine contributions) have arisen. In this article, we will consider the vital role of the pancreas in human health and physiology, including discussion of its anatomical features and dual (exocrine and endocrine) functions. Specifically, we convey changes that occur in the pancreas of those with either type 1 or type 2 diabetes, with careful attention to the facets that may contribute to the pathogenesis of either disorder. Finally, we discuss the emerging unknowns with the belief that understanding the role of the pancreas in type 1 and type 2 diabetes will lead to improvements in disease diagnosis, understanding of disease heterogeneity and optimisation of treatments at a personalised level. Graphical abstract.Mitoxantrone (MTX) is used to treat several types of cancers and to improve neurological disability in multiple sclerosis. Unfortunately, cardiotoxicity is a severe and common adverse effect in MTX-treated patients. Herein, we aimed to study early and late mechanisms of MTX-induced cardiotoxicity using murine HL-1 cardiomyocytes. Cells were exposed to MTX (0.1, 1 or 10 µM) during short (2, 4, 6, or 12 h) or longer incubation periods (24 or 48 h). At earlier time points, (6 and 12 h) cytotoxicity was already observed for 1 and 10 µM MTX. Proteomic analysis of total protein extracts found 14 proteins with higher expression and 26 with lower expression in the cells exposed for 12 h to MTX (pH gradients 4-7 and 6-11). Of note, the expression of the regulatory protein 14-3-3 protein epsilon was increased by a factor of two and three, after exposure to 1 and 10 µM MTX, respectively. At earlier time-points, 10 µM MTX increased intracellular ATP levels, while decreasing media lactate levels. At later stages (24 and 48 h), MTX-induced cytotoxicity was concentration and time-dependent, according to the MTT reduction and lactate dehydrogenase leakage assays, while caspase-9, -8 and -3 activities increased at 24 h. Regarding cellular redox status, total glutathione increased in 1 µM MTX (24 h), and that increase was dependent on gamma-glutamylcysteine synthetase activity. Meanwhile, for both 1 and 10 µM MTX, oxidized glutathione was significantly higher than control at 48 h. Moreover, MTX was able to significantly decrease proteasomal chymotrypsin-like activity in a concentration and time-independent manner. In summary, MTX significantly altered proteomic, energetic and oxidative stress homeostasis in cardiomyocytes at clinically relevant concentrations and our data clearly demonstrate that MTX causes early cardiotoxicity that needs further study.
The guidelines of the German Society for Neurology regarding the diagnostics and treatment of acute ischemic stroke contain the general recommendation of treatment on astroke unit (SU) and the use of recanalizing treatment (intravenous thrombolysis, IVT; mechanical thrombectomy, MT) in appropriate patients. The nationwide availability of all three components represents a large organizational and healthcare political challenge.
Updated nationwide analysis of treatment rates in Germany based on aregionalized evaluation.
Based on the patient's place of residence, nationwide data of all hospitalized patients were evaluated using the German diagnosis-related groups (DRG) statistics from 2018 and compared with previous years. The rates for SU treatment, IVT and MT in the 412 German regional districts were analyzed. The 412 regions were grouped according to the degree of urbanization.
Nationwide, atotal of 224,647 patient cases with amain diagnosis of acute ischemic stroke were treated in 1382 hospitals in Germany in 2018. Overall, relatively high treatment rates were determined (SU = 73.3%; IVT = 16.4%; MT = 6.5%). Only 10.2% of treatments in the SU were performed on aSU located at a hospital with no neurology department. The regionalized analysis showed large treatment ranges for all three therapeutic components, with significantly lower treatment rates in regions with alower degree of urbanization (SU, IVT, MT rates urban = 75.4%, 17.4%, 7.5% and rural = 67.1%; 15.4%, 5.3%, respectively).
Hospitalized healthcare in Germany shows high treatment rates for both SU admission and acute recanalization treatment in patients with acute ischemic stroke; however, there is further optimization potential in rural regions.
Hospitalized healthcare in Germany shows high treatment rates for both SU admission and acute recanalization treatment in patients with acute ischemic stroke; however, there is further optimization potential in rural regions.
