Age-related mitochondrial DNA depletion and the impact on pancreatic beta cell function

Type 2 diabetes is characterised by an age-related decline in insulin secretion. We previously identified a 50% age-related decline in mitochondrial DNA (mtDNA) copy number in isolated human islets. The purpose of this study was to mimic this degree of mtDNA depletion in MIN6 cells to determine whether there is a direct impact on insulin secretion. Transcriptional silencing of mitochondrial transcription factor A, TFAM, decreased mtDNA levels by 40% in MIN6 cells. This level of mtDNA depletion significantly decreased mtDNA gene transcription and translation, resulting in reduced mitochondrial respiratory capacity and ATP production. Glucose-stimulated insulin secretion was impaired following partial mtDNA depletion, but was normalised following treatment with glibenclamide. This confirms that the deficit in the insulin secretory pathway precedes K+ channel closure, indicating that the impact of mtDNA depletion is at the level of mitochondrial respiration. In conclusion, partial mtDNA depletion to a degree comparable to that seen in aged human islets impaired mitochondrial function and directly decreased insulin secretion. Using our model of partial mtDNA depletion following targeted gene silencing of TFAM, we have managed to mimic the degree of mtDNA depletion observed in aged human islets, and have shown how this correlates with impaired insulin secretion. We therefore predict that the age-related mtDNA depletion in human islets is not simply a biomarker of the aging process, but will contribute to the age-related risk of type 2 diabetes

Candida albicans Hypha Formation and Mannan Masking of β-Glucan Inhibit Macrophage Phagosome Maturation

Received 28 August 2014 Accepted 28 October 2014 Published 2 December 2014 This is an open-access article distributed under the terms of the Creative Commons Attribution 3.0 Unported license. ACKNOWLEDGMENTS We thank Janet Willment, Aberdeen Fungal Group, University of Aberdeen, for kindly providing the soluble Dectin-1-Fc reporter. All microscopy was performed with the assistance of the University of Aberdeen Core Microscopy & Histology Facility, and we thank the IFCC for their assistance with flow cytometry. We thank the Wellcome Trust for funding (080088, 086827, 075470, 099215, 097377, and 101873). E.R.B. and A.J.P.B. are funded by the European Research Council (ERC-2009-AdG-249793), and J.L. is funded by a Medical Research Council Clinical Training Fellowship.Peer reviewedPublisher PD

Autistic traits are associated with enhanced working memory capacity for abstract visual stimuli

We tested whether the association between autistic traits and enhanced performance in visual-perceptual tasks extends to visual working memory capacity. We predicted that any positive effect of autistic traits on visual working memory performance would be greatest during domain-specific tasks, in which visual resources must be relied upon. We used a visual ‘matrix’ task, involving recall of black-and-white chequered patterns which increased in size, to establish participants’ capacity (span). We assessed 144 young adults’ (M = 22.0 yrs, SD = 2.5) performance on abstract, ‘low semantic’ versus ‘high semantic’ task versions. The latter offered multimodal coding due to the availability of long-term memory resources that could supplement visual working memory. Participants also completed measures of autistic traits and trait anxiety. Autistic traits, especially Attention to Detail, Attention Switching, and Communication, positively predicted visual working memory capacity, specifically in the low semantic task, which relies on visual working memory resources. Autistic traits are therefore associated with enhanced processing and recall of visual information. The benefit is removed, however, when multimodal coding may be incorporated, emphasising the visual nature of the benefit. Strengths in focused attention to detail therefore appear to benefit domain-specific visual working memory task performance

Disease Control and Prevention

— i — Some thoughts about traumatic brain injury (TBI) data… …People are uneducated about traumatic brain injury. They don’t recognize it when it happens to them or their loved ones; they don’t know the extent of the public health problem…. This is my dream for people who will sustain a traumatic brain injury: ….At the time the TBI is diagnosed,…the injured person receives information about the consequences of traumatic brain injury and sources of education and support. ….All traumatic brain injuries will be counted, including mild TBIs. The Centers for Disease Control and Prevention will develop

Proceedings From the Symposium on Kidney Disease in Older People: Royal Society of Medicine, London, January 19, 2017

People are living longer. On the whole, they have healthier lives and many of the problems previously seen at a younger age now appear in their later years. Kidneys, like other organs, age, and kidney disease in the aged is a prime example. In the United Kingdom, as in other developed countries, the prevalence of end stage kidney disease is highest in the 70- to 79-year-old age group. There are many older people who require renal replacement and are now considered for dialysis. While older patients with end-stage renal disease invariably aspire for a better quality of life, this needs a specialized approach and management. In January 2017, the Royal Society of Medicine held a seminar in London on “Kidney Disease in Older People” with presentations from a multidisciplinary body of experts speaking on various aspects of kidney problems in this age group and its management. The objectives were to increase awareness and improve the understanding of nephrology in the context of geriatric medicine but also geriatrics in its interface with nephrology, especially in the area of chronic kidney disease

Role of the T cell in the genesis of angiotensin II–induced hypertension and vascular dysfunction

Hypertension promotes atherosclerosis and is a major source of morbidity and mortality. We show that mice lacking T and B cells (RAG-1−/− mice) have blunted hypertension and do not develop abnormalities of vascular function during angiotensin II infusion or desoxycorticosterone acetate (DOCA)–salt. Adoptive transfer of T, but not B, cells restored these abnormalities. Angiotensin II is known to stimulate reactive oxygen species production via the nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase in several cells, including some immune cells. Accordingly, adoptive transfer of T cells lacking the angiotensin type I receptor or a functional NADPH oxidase resulted in blunted angiotensin II–dependent hypertension and decreased aortic superoxide production. Angiotensin II increased T cell markers of activation and tissue homing in wild-type, but not NADPH oxidase–deficient, mice. Angiotensin II markedly increased T cells in the perivascular adipose tissue (periadventitial fat) and, to a lesser extent the adventitia. These cells expressed high levels of CC chemokine receptor 5 and were commonly double negative (CD3+CD4−CD8−). This infiltration was associated with an increase in intercellular adhesion molecule-1 and RANTES in the aorta. Hypertension also increased T lymphocyte production of tumor necrosis factor (TNF) α, and treatment with the TNFα antagonist etanercept prevented the hypertension and increase in vascular superoxide caused by angiotensin II. These studies identify a previously undefined role for T cells in the genesis of hypertension and support a role of inflammation in the basis of this prevalent disease. T cells might represent a novel therapeutic target for the treatment of high blood pressure

Emerging health threat and cost of Fusarium mycotoxins in European wheat

Mycotoxins harm human and livestock health, while damaging economies. Here we reveal the changing threat of Fusarium head blight (FHB) mycotoxins in European wheat, using data from the European Food Safety Agency and agribusiness (BIOMIN, World Mycotoxin Survey) for ten years (2010–2019). We show persistent, high, single- and multi-mycotoxin contamination alongside changing temporal-geographical distributions, indicative of altering FHB disease pressure and pathogen populations, highlighting the potential synergistic negative health consequences and economic cost

Abdominal obesity and other risk factors largely explain the high CRP in Indigenous Australians relative to the general population, but not gender differences: a cross-sectional study

Background: Previous studies reported high C-reactive protein (CRP) levels in Indigenous Australians, which may contribute to their high risk of cardiovascular disease. We compared CRP levels in Indigenous Australians and the general population, accounting for obesity and other risk factors.Methods: Cross-sectional study of CRP and risk factors (weight, height, waist and hip circumferences, blood pressure, lipids, blood glucose, and smoking status) in population-based samples from the Diabetes and Related conditions in Urban Indigenous people in the Darwin region (DRUID) study, and the Australian Diabetes, Obesity and Lifestyle study (AusDiab) follow-up.Results: CRP concentrations were higher in women than men and in DRUID than AusDiab. After multivariate adjustment, including waist circumference, the odds of high CRP (>3.0 mg/L) in DRUID relative to AusDiab were no longer statistically significant, but elevated CRP was still more likely in women than men. After adjusting for BMI (instead of waist circumference) the odds for elevated CRP in DRUID participants were still higher relative to AusDiab participants among women, but not men. Lower HDL cholesterol, impaired glucose tolerance (IGT), and higher diastolic blood pressure were associated with having a high CRP in both men and women, while current smoking was associated with high CRP in men but not women.Conclusions: High concentrations of CRP in Indigenous participants were largely explained by other risk factors, in particular abdominal obesity. Irrespective of its independence as a risk factor, or its aetiological association with coronary heart disease (CHD), the high CRP levels in urban Indigenous women are likely to reflect increased vascular and metabolic risk. The significance of elevated CRP in Indigenous Australians should be investigated in future longitudinal studies