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The host environment is a crucial factor for considering the transplant of stem cell–derived immature pancreatic cells in patients with type 1 diabetes. Here, we investigated the effect of insulin (INS)-deficient diabetes on the fate of immature pancreatic endocrine cell grafts and the underlying mechanisms. Human induced pluripotent stem cell–derived pancreatic endocrine progenitor cells (EPCs), which contained a high proportion of chromogranin A⁺ NK6 homeobox 1⁺ cells and very few INS⁺ cells, were used. When the EPCs were implanted under the kidney capsule in immunodeficient mice, INS-deficient diabetes accelerated increase in plasma human C-peptide, a marker of graft-derived INS secretion. The acceleration was suppressed by INS infusion but not affected by partial attenuation of hyperglycemia by dapagliflozin, an INS-independent glucose-lowering agent. Immunohistochemical analyses indicated that the grafts from diabetic mice contained more endocrine cells including proliferative INS-producing cells compared with that from nondiabetic mice, despite no difference in whole graft mass between the two groups. These data suggest that INS-deficient diabetes upregulates the INS-secreting capacity of EPC grafts by increasing the number of endocrine cells including INS-producing cells without changing the graft mass. These findings provide useful insights into postoperative diabetic care for cell therapy using stem cell–derived pancreatic cells.

FORMER NATIONAL footballer Aldrick ‘Allie’ McNab is concerned about the effect of the COVID-19 pandemic on the Caribbean’s football development. The coronavirus has caused the postponement, suspension, and cancellation of a number of sporting...

Pharma companies say that money spent on promotion is essential to educate doctors about the best drugs - but when a medical student asked Joseph Ross, associate professor of medicine and public health at Yale, if those companies are promoting the right drugs for that message to be true, the answer wasn't available. Ross and Tyler Greenaway, his...

If you read the Christmas BMJ in the last few weeks, you might have noticed a lot around art and health - the way in which engagement in arts can help in prevention and treatment, but can also affect those more nebulous things which really matter to patients - loneliness, self expression, being connected to the wider community. That obviously...

This edition of talk evidence was recorded before the big increase in covid-19 infections in the UK, and then delayed by some self isolation. We'll be back with more evidence on the pandemic very soon. As always Duncan Jarvies is joined by Helen Macdonald (resting GP and editor at The BMJ) and Carl Heneghan (active GP, director of Oxford...

Tears flowed yesterday down the face of Donaree Anderson, cousin of 15-year-old Nyron Taylor, one of two children shot dead in west Kingston hours apart on Wednesday. Eight-year-old Toya Brown was the other child killed just days into the month...

Led by vice president of home clubhouse operations Rick Stowe, who began working for the club in 1981 and became head of the clubhouse in 1997, the Reds have a well-oiled machine with regard to packing up and moving out.

Schwann cell–derived exosomes communicate with dorsal root ganglia (DRG) neurons. The current study investigated the therapeutic effect of exosomes derived from healthy Schwann cells (SC-Exos) on diabetic peripheral neuropathy (DPN). We found that intravenous administration of SC-Exos to type 2 diabetic db/db mice with peripheral neuropathy remarkably ameliorated DPN by improving sciatic nerve conduction velocity and increasing thermal and mechanical sensitivity. These functional improvements were associated with the augmentation of epidermal nerve fibers and remyelination of sciatic nerves. Quantitative RT-PCR and Western blot analysis of sciatic nerve tissues showed that SC-Exo treatment reversed diabetes-reduced mature form of miRNA (miR)-21, -27a, and -146a and diabetes-increased semaphorin 6A (SEMA6A); Ras homolog gene family, member A (RhoA); phosphatase and tensin homolog (PTEN); and nuclear factor-B (NF-B). In vitro data showed that SC-Exos promoted neurite outgrowth of diabetic DRG neurons and migration of Schwann cells challenged by high glucose. Collectively, these novel data provide evidence that SC-Exos have a therapeutic effect on DPN in mice and suggest that SC-Exo modulation of miRs contributes to this therapy.

β-Cell antigen recognition by autoreactive T cells is essential in type 1 diabetes (T1D) pathogenesis. Recently, insulin hybrid peptides (HIPs) were identified as strong agonists for CD4 diabetogenic T cells. Here, using BDC2.5 transgenic and NOD mice, we investigated T-cell recognition of the HIP2.5 epitope, which is a fusion of insulin C-peptide and chromogranin A (ChgA) fragments, and compared it with the WE14 and ChgA_29–42 epitopes. We measured in situ two-dimensional affinity on individual live T cells from thymus, spleen, pancreatic lymph nodes, and islets before and after diabetes. Although preselection BDC2.5 thymocytes possess higher affinity than splenic BDC2.5 T cells for all three epitopes, peripheral splenic T cells maintained high affinity only to the HIP2.5 epitope. In polyclonal NOD mice, a high frequency (~40%) of HIP2.5-specific islet T cells were identified at both prediabetic and diabetic stages comprising two distinct high- and low-affinity populations that differed in affinity by 100-fold. This high frequency of high- and low-affinity HIP2.5 T cells in the islets potentially represents a major risk factor in diabetes pathogenesis.

The signal peptide of preproinsulin is a major source for HLA class I autoantigen epitopes implicated in CD8 T cell (CTL)–mediated β-cell destruction in type 1 diabetes (T1D). Among them, the 10-mer epitope located at the C-terminal end of the signal peptide was found to be the most prevalent in patients with recent-onset T1D. While the combined action of signal peptide peptidase and endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) is required for processing of the signal peptide, the mechanisms controlling signal peptide trimming and the contribution of the T1D inflammatory milieu on these mechanisms are unknown. Here, we show in human β-cells that ER stress regulates ERAP1 gene expression at posttranscriptional level via the IRE1α/miR-17-5p axis and demonstrate that inhibition of the IRE1α activity impairs processing of preproinsulin signal peptide antigen and its recognition by specific autoreactive CTLs during inflammation. These results underscore the impact of ER stress in the increased visibility of β-cells to the immune system and position the IRE1α/miR-17 pathway as a central component in β-cell destruction processes and as a potential target for the treatment of autoimmune T1D.

Authoritarian states have long attempted to restrict citizens’ movement. But what happens when their reach extends beyond their borders? The October 2018 assassination of Saudi journalist Jamal Khashoggi brought into sharp relief the long arm of these regimes in reaching citizens abroad. This phenomenon, “transnational authoritarianism,” further shows that the relationship between migration and authoritarianism is becoming more complex.

Andrew J.M. Boulton
Jan 1, 2005; 23:9-15
Feature Articles

The United Nations more than tripled its humanitarian aid appeal on Thursday from $2 billion to $6.7 billion to accommodate its updated global plan to help the poorest nations fight the coronavirus pandemic.

A manuscript authored by the American Dental Association Science & Research Institute and Council on Scientific Affairs won the 2020 William J. Gies Award in clinical research from the American and International Associations for Dental Research.

OBJECTIVE

The vast number of antihyperglycemic medications and growing amount of evidence make clinical decision making difficult. The aim of this study was to investigate the safety of antihyperglycemic dual and triple therapies for type 2 diabetes management with respect to major adverse cardiovascular events, severe hypoglycemia, and all-cause mortality in a real-life clinical setting.

2 cups of fresh ricotta 4 eggs 2 tbsp. sugar Zest of 1 orange, 1lime and 1 lemon 1 cup of plain flour 60 g soft butter

Triple Citrus Syrup

Did you know you can subscribe to YouTube channels and playlist in Inoreader? Simply paste the URL of the channel…

Andrew J.M. Boulton
Jan 1, 2005; 23:9-15
Feature Articles

Two pieces forthcoming in a special issue of HOPOS, the official journal of the International Society for the History of Philosophy of Science, will be of interest to AHP readers. The special issue, “Descriptive Psychology and Völkerpsychologie—in the Contexts of Historicism, Relativism, and Naturalism,” is guest-edited by Christian Damböck, Uljana Feest, and Martin Kusch. Full details … Continue reading Forthcoming HOPOS Special Issue on Descriptive Psychology and Völkerpsychologie →

Neuropsychology.

Tʻoros Ṛoslin, active 13th century.

Indiana's efforts to give students more control over their academic transcripts may prove a boon for researchers and school reformers, too.

Kansas' auditor found that more than $400 million of state aid intended for poor, black, Latino and ELL students was being spent ineffectively, including on items such as food service supplies and an after-prom party.

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