Glucocorticoids: novel agents to stimulate beta-cell neogenesis?

This is the author accepted manuscript. The final version is available from AME Publishing Company via the DOI in this record

Studies of insulin and proinsulin in pancreas and serum support the existence of aetiopathological endotypes of type 1 diabetes associated with age at diagnosis

Aims/hypothesis: It is unclear whether type 1 diabetes is a single disease or if endotypes exist. Our aim was to use a unique collection of pancreas samples recovered soon after disease onset to resolve this issue. Methods: Immunohistological analysis was used to determine the distribution of proinsulin and insulin in the islets of pancreas samples recovered soon after type 1 diabetes onset (<2 years) from young people diagnosed at age <7 years, 7-12 years and ≥13 years. The patterns were correlated with the insulitis profiles in the inflamed islets of the same groups of individuals. C-peptide levels and the proinsulin:C-peptide ratio were measured in the circulation of a cohort of living patients with longer duration of disease but who were diagnosed in these same age ranges. Results: Distinct patterns of proinsulin localisation were seen in the islets of people with recent-onset type 1 diabetes, which differed markedly between children diagnosed at <7 years and those diagnosed at ≥13 years. Proinsulin processing was aberrant in most residual insulin-containing islets of the younger group but this was much less evident in the group ≥13 years (p < 0.0001). Among all individuals (including children in the middle [7-12 years] range) aberrant proinsulin processing correlated with the assigned immune cell profiles defined by analysis of the lymphocyte composition of islet infiltrates. C-peptide levels were much lower in individuals diagnosed at <7 years than in those diagnosed at ≥13 years (median <3 pmol/l, IQR <3 to <3 vs 34.5 pmol/l, IQR <3-151; p < 0.0001), while the median proinsulin:C-peptide ratio was increased in those with age of onset <7 years compared with people diagnosed aged ≥13 years (0.18, IQR 0.10-0.31) vs 0.01, IQR 0.009-0.10 pmol/l; p < 0.0001). Conclusions/interpretation: Among those with type 1 diabetes diagnosed under the age of 30 years, there are histologically distinct endotypes that correlate with age at diagnosis. Recognition of such differences should inform the design of future immunotherapeutic interventions designed to arrest disease progression.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.We are grateful to Diabetes UK for financial support via project grant 16/0005480 (to NGM and SJR) and to JDRF for a Career Development Award to SJR (5-CDA-2014-221-A-N). The research was performed with the support of the Network for Pancreatic Organ Donors with Diabetes (nPOD), a collaborative type 1 diabetes research project sponsored by JDRF. Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at http://www.jdrfnpod.org//for-partners/npod-partners/. ATH and BMS are supported by the NIHR Exeter Clinical Research Facility. BMS is supported as part of the MRC MASTERMIND consortium. TJM is funded by an NIHR clinical senior lecturer fellowship. ATH is supported by a Wellcome Trust Senior Investigator Award (WT098395/Z/12/Z) and an NIHR Senior Investigator award. RAO is supported by a Diabetes UK Harry Keen Fellowship.published version, accepted version (12 month embargo

Technology Readiness Level Assessment Process as Applied to NASA Earth Science Missions

Technology assessments of fourteen science instruments were conducted within NASA using the NASA Technology Readiness Level (TRL) Metric. The instruments were part of three NASA Earth Science Decadal Survey missions in pre-formulation. The Earth Systematic Missions Program (ESMP) Systems Engineering Working Group (SEWG), composed of members of three NASA Centers, provided a newly modified electronic workbook to be completed, with instructions. Each instrument development team performed an internal assessment of its technology status, prepared an overview of its instrument, and completed the workbook with the results of its assessment. A team from the ESMP SEWG met with each instrument team and provided feedback. The instrument teams then reported through the Program Scientist for their respective missions to NASA's Earth Science Division (ESD) on technology readiness, taking the SEWG input into account. The instruments were found to have a range of TRL from 4 to 7. Lessons Learned are presented; however, due to the competition-sensitive nature of the assessments, the results for specific missions are not presented. The assessments were generally successful, and produced useful results for the agency. The SEWG team identified a number of potential improvements to the process. Particular focus was on ensuring traceability to guiding NASA documents, including the NASA Systems Engineering Handbook. The TRL Workbook has been substantially modified, and the revised workbook is described

Fitness costs of disrupting circadian rhythms in malaria parasites

Circadian biology assumes that biological rhythms maximize fitness by enabling organisms to coordinate with their environment. Despite circadian clocks being such a widespread phenomenon, demonstrating the fitness benefits of temporal coordination is challenging and such studies are rare. Here, we tested the consequences—for parasites—of being temporally mismatched to host circadian rhythms using the rodent malaria parasite, Plasmodium chabaudi. The cyclical nature of malaria infections is well known, as the cell cycles across parasite species last a multiple of approximately 24 h, but the evolutionary explanations for periodicity are poorly understood. We demonstrate that perturbation of parasite rhythms results in a twofold cost to the production of replicating and transmission stages. Thus, synchronization with host rhythms influences in-host survival and between-host transmission potential, revealing a role for circadian rhythms in the evolution of host–parasite interactions. More generally, our results provide a demonstration of the adaptive value of circadian rhythms and the utility of using an evolutionary framework to understand parasite traits

Transcription factor TFCP2L1 patterns cells in the mouse kidney collecting ducts

Although most nephron segments contain one type of epithelial cell, the collecting ducts consists of at least two: intercalated (IC) and principal (PC) cells, which regulate acid-base and salt-water homeostasis, respectively. In adult kidneys, these cells are organized in rosettes suggesting functional interactions. Genetic studies in mouse revealed that transcription factor Tfcp2l1 coordinates IC and PC development. Tfcp2l1 induces the expression of IC specific genes, including specific H(+)-ATPase subunits and Jag1. Jag1 in turn, initiates Notch signaling in PCs but inhibits Notch signaling in ICs. Tfcp2l1 inactivation deletes ICs, whereas Jag1 inactivation results in the forfeiture of discrete IC and PC identities. Thus, Tfcp2l1 is a critical regulator of IC-PC patterning, acting cell-autonomously in ICs, and non-cell-autonomously in PCs. As a result, Tfcp2l1 regulates the diversification of cell types which is the central characteristic of 'salt and pepper' epithelia and distinguishes the collecting duct from all other nephron segments

Erratum. Blood and Islet Phenotypes Indicate Immunological Heterogeneity in Type 1 Diabetes. Diabetes 2014;63:3835–3845

The article to which this is the erratum is available in ORE at: http://hdl.handle.net/10871/17968In the article, there are two errors in the research design and methods section. In the section with the heading “Studies on Islet-Infiltrating Leukocytes,” the antibody listed as #M0701 should be attributed to Dako and not to Abcam and the Abcam rabbit anti-CD8 catalogue number should read #ab4055 and not #GR404-4. The online version reflects these changes

Is the "Glasgow effect" of cigarette smoking explained by socio-economic status?: A multilevel analysis

Background: The Glasgow area has elevated levels of deprivation and is known for its poor health and associated negative health-related behaviours, which are socially patterned. Of interest is whether high smoking rates are explained by the area's socio-economic profile.&lt;p&gt;&lt;/p&gt; Methods: Data on age, sex, current/previous smoking status, area deprivation, social class, education, economic activity, postcode sector, and health board region were available from Scottish Health Surveys conducted in 1995, 1998 and 2003. Multilevel logistic regression models were applied by sex, unadjusted and adjusted for age, survey year, and socio-economic factors, accounting for geographical hierarchy and missing data.&lt;p&gt;&lt;/p&gt; Results: Compared with the rest of Scotland, men living in Greater Glasgow were 30% and women 43% more likely to smoke [odds ratio (OR) = 1.30, (95% CI = 1.08–1.56) and (OR = 1.43, CI = 1.22–1.68), respectively] before adjustment. In adjusted results, the association between living in Greater Glasgow and current smoking was attenuated [OR = 0.92, CI = 0.78–1.09 for men, and OR = 1.08, CI = 0.94–1.23 for women; results based on multiply imputed data to account for missing values remained borderline significant for women]. Accounting for individuals who had been told to give up smoking by a medical person/excluding ex-smokers did not alter results.&lt;p&gt;&lt;/p&gt; Conclusion: High levels of smoking in Greater Glasgow were attributable to its poorer socio-economic position and the strong social patterning of smoking. Tackling Glasgow's, and indeed Scotland's, poor health must involve policies to alleviate problems associated with poverty.&lt;p&gt;&lt;/p&gt

Identifying nurses' rewards: a qualitative categorization study in Belgium

BACKGROUND: Rewards are important in attracting, motivating and retaining the most qualified employees, and nurses are no exception to this rule. This makes the establishment of an efficient reward system for nurses a true challenge for every hospital manager. A reward does not necessarily have a financial connotation: non-financial rewards may matter too, or may even be more important. Therefore, the present study examines nurses' reward perceptions, in order to identify potential reward options. METHODS: To answer the research question "What do nurses consider a reward and how can these rewards be categorized?", 20 in-depth semi-structured interviews with nurses were conducted and analysed using discourse and content analyses. In addition, the respondents received a list of 34 rewards (derived from the literature) and were asked to indicate the extent to which they perceived each of them to be rewarding. RESULTS: Discourse analysis revealed three major reward categories: financial, non-financial and psychological, each containing different subcategories. In general, nurses more often mentioned financial rewards spontaneously in the interview, compared to non-financial and psychological rewards. The questionnaire results did not, however, indicate a significant difference in the rewarding potential of these three categories. Both the qualitative and quantitative data revealed that a number of psychological and non-financial rewards were important for nurses in addition to their monthly pay and other remunerations. In particular, appreciation for their work by others, compliments from others, presents from others and contact with patients were highly valued. Moreover, some demographical variables influenced the reward perceptions. Younger and less experienced nurses considered promotion possibilities as more rewarding than the older and more senior ones. The latter valued job security and working for a hospital with a good reputation higher than their younger and more junior colleagues. CONCLUSION: When trying to establish an efficient reward system for nurses, hospital managers should not concentrate on the financial reward possibilities alone. They also ought to consider non-financial and psychological rewards (in combination with financial rewards), since nurses value these as well and they may lead to a more personalized reward system

Circulating C-peptide levels in living children and young people and pancreatic beta cell loss in pancreas donors across type 1 diabetes disease duration.

This is the author accepted manuscript. The final version is available from the American Diabetes Association via the DOI in this record Data Availability: Further information about the data is available from the corresponding author upon request.C-peptide declines in type 1 diabetes although many long-duration patients retain low, but detectable levels. Histological analyses confirm that beta cells can remain following type 1 diabetes onset. We explored the trends observed in C-peptide decline in UK Genetic Resource Investigating Diabetes (UK GRID) cohort (N=4,079), with beta cell loss in pancreas donors from the network for Pancreatic Organ donors with Diabetes (nPOD) biobank and the Exeter Archival Diabetes Biobank (EADB) (combined N=235), stratified by recently reported age at diagnosis endotypes (< 7, 7-12, ≥ 13 years) across increasing diabetes durations. The proportion of individuals with detectable C-peptide declined beyond the first year after diagnosis, but this was most marked in the youngest age group (< 1 year duration: age < 7 years: 18/20 (90%), 7-12 years: 107/110 (97%), ≥ 13 years: 58/61 (95%) versus. 1-5 years post diagnosis: < 7 years: 172/522 (33%), 7-12 years: 604/995 (61%), ≥ 13 years: 225/289 (78%)). A similar profile was observed in beta cell loss, with those diagnosed at younger ages experiencing more rapid loss of islets containing insulin-positive (insulin+) beta cells < 1 year post diagnosis: age < 7 years: 23/26 (88%), 7-12 years: 32/33 (97%), ≥ 13 years: 22/25 (88%) versus. 1-5 years post diagnosis: < 7 years: 1/12 (8.3%) ,7-12 years: 7/13 (54%), ≥ 13 years: 7/8 (88%)). These data should be considered in the planning and interpretation of intervention trials designed to promote beta cell retention and function.Diabetes UKDiabetes UKDiabetes UKThe Leona M. & Harry B. Helmsley Charitable TrustJuvenile Diabetes Research FoundationWellcome Trus