Mario Luca Morieri
Apr 1, 2020; 69:771-783
Genetics/Genomes/Proteomics/Metabolomics

4 September 2019 , Volume 95, Number 5

6 November 2019 , Volume 95, Number 6

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The idea of home is so complicated to me; home isn’t here people look at me like I am from somewhere else. Where is home? Writing became an expression of my discomfort a language an arrangement of unbroken rage writing poetry to question why? Poetry to reclaim my identity and to be home again. My […]

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The global COVID-19 spread has gone from bad to worse, with over 3.2 million confirmed cases and close to 250,000 deaths, not only has this pandemic claimed innumerable lives, it has also destabilised economies by freezing trade and other economic...

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.

A year ago, Danny Farquhar was not going to be in the middle of a spring storyline. That's going to change this spring as he tries to win a spot in the Yankees' bullpen

HYDERABAD, India (AP) — A gas leak at a chemical factory owned by a South Korean company in southern India early Thursday left at least 11 people dead and about 1,000 struggling to breathe. The chemical styrene, used to make plastic and...

Dozens of United States children have been hospitalised with a serious inflammatory condition possibly linked with the coronavirus and first seen in Europe. New York authorities announced Wednesday that 64 potential cases had been reported to...

BRIDGETOWN, Barbados (CMC): Former Windies fast bowler Kenny Benjamin says that cricket in the Caribbean is suffering from players’ lack of loyalty and commitment and that intervention is required to save the sport. The Antiguan called for coaches...

Jackie Applebee is a GP in Tower Hamlets in London, and is concerned that the way the GP funding formula is working doesn't take account of the earlier health needs of people in deprived areas. For more about the Tower Hamlets Save Our Surgery campaign, visit their facebook page https://www.facebook.com/SaveOurGPsurgeries BMJ Voices is a...

Europe's common agricultural policy (CAP) on sugar is due to change, and Emilie Aguirre, from the UKCRC Centre for Diet and Activity Research at the University of Cambridge, argues that an influx of cheap high fructose corn syrup (HFCS, isoglucose) into the European market will have a negative effect on on the health of the continent. Read the...

When healthy volunteers are scanned as part of a research project, unexpected findings, with uncertain implications, can be thrown up. Joanna Wardlaw, professor of applied neuroimaging and honorary consultant neuroradiologist at the University of Edinburgh, joins us to discuss how her group deals with these incidental findings, and what...

Allocation concealment - blinding which arm of a trial a patient is randomised to - is being questioned in an analysis published on thebmj.com. David Torgerson, director of the York Trials Unit at the university of York and colleagues have been looking at the way in which trials do this randomisation, and how they subsequently report it - and...

If you’re of a scientific persuasion, watching policy debates around Brexit, or climate change, or drug prohibition are likely to cause feelings of intense frustration about the dearth of evidence in those discussions. In this podcast we're joined by Chris Bonell, professor of public health sociology - in this podcast he airs those frustrations,...

Diabetes is synonymous with sugar, but diabetes insipidus, "water diabetes", can't be forgotten. Between 2009 and 2016, 4 people died in hospital in England, when lifesaving treatment for the condition was not given. In this podcast, we hear some practical tips for non-specialists to aid diagnosis, and how patients should be managed during...

We’ve been banging the drum about transparency of payment to doctors for years - we’ve even put a moratorium on financial conflicts of interest in the authors of any of our education articles. Not because we think that all doctors who receive money from industry are being influenced to push their agenda - but because we have no way of telling when...

In 2001, Gottfried Hirnschall joined the WHO to work on the global response to HIV/AIDs, 18 years later he just retired as the director of WHO’s department for HIV and Hepatitis. The intervening period, almost half the time we’ve been aware of the disease the fight against the infection has been characterised by scientific breakthroughs, and...

In the UK, for just over a year, we've been paying the "Soft Drinks Industry Levy" - a tax on sugary beverages intended to reduce our consumption of free sugars. That was based on taxes that had happened in other countries, however, in the UK high sugar snacks, such as confectionery, cakes, and biscuits make a greater contribution to intakes of...

A UK general election has been called - polling day is on the 12th of December, and from now until then we’re going to be bringing you a weekly election-themed podcast. We want to help you make sense of the promises and pledges, claims and counter-claims, that are being made around healthcare and the NHS out on the campaign trail. This week...

Welcome to the festive talk evidence, giving you a little EBM to take you into the new year. As always Duncan Jarvies is joined by Helen Macdonald (resting GP and editor at The BMJ) and Carl Heneghan (active GP, director of Oxford University’s CEBM and editor of BMJ Evidence)* This month: (1.20) Carl tells us about new research on treating...

R A DeFronzo
Dec 1, 1981; 30:1000-1007
Original Contribution

Eve Van Cauter
Mar 1, 1992; 41:368-377
Original Article

G Xu
Dec 1, 1999; 48:2270-2276
Articles

David E. Cummings
Aug 1, 2001; 50:1714-1719
Rapid Publications

The cardiovascular benefits of fibrates have been shown to be heterogeneous and to depend on the presence of atherogenic dyslipidemia. We investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates (PPAR-α), could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus (rs6008845, C/T) displaying a study-wide significant influence on the effect of fenofibrate on major cardiovascular events (MACE) among 3,065 self-reported white subjects treated with simvastatin and randomized to fenofibrate or placebo in the ACCORD-Lipid trial. T/T homozygotes (36% of participants) experienced a 51% MACE reduction in response to fenofibrate (hazard ratio 0.49; 95% CI 0.34–0.72), whereas no benefit was observed for other genotypes (P_interaction = 3.7 x 10^–4). The rs6008845-by-fenofibrate interaction on MACE was replicated in African Americans from ACCORD (N = 585, P = 0.02) and in external cohorts (ACCORD-BP, ORIGIN, and TRIUMPH, total N = 3059, P = 0.005). Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. Among these individuals, but not among carriers of other genotypes, fenofibrate treatment was associated with lower circulating levels of CCL11—a proinflammatory and atherogenic chemokine also known as eotaxin (P for rs6008845-by-fenofibrate interaction = 0.003). The GTEx data set revealed regulatory functions of rs6008845 on PPARA expression in many tissues. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify patients with type 2 diabetes who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia.

An application earlier this year by Mahoe Gaming Enterprises Limited (MGEL) has not benefited from any preferential treatment by the Betting, Gaming and Lotteries Commission (BGLC). That was the finding of ex-commissioner of the Integrity...

It was not the landing the Jamaicans who arrived at Kingston’s Norman Manley International Airport on Wednesday evening would want again. The 43 Jamaican ship workers of the Marella Discovery 2 were among the 115 people aboard the TUI charter flight that touched down amid the Kingston breeze and evening sunset.

KINGSTOWN, St Vincent, CMC – The St Vincent and the Grenadines Government has denied a United States-based airline permission to land, dashing hopes that an estimated 300 nationals employed with a US-based cruise line would have arrived home...

The COVID-19 pandemic around the world has taken the world by storm, touching the lives of every human being on Earth. The global nature of the crisis has united us as human beings and tragedy and deaths in any country by COVID-19 worry us all....

Studies on magnetic resonance neurography (MRN) in diabetic polyneuropathy (DPN) have found proximal sciatic nerve lesions. The aim of this study was to evaluate the functional relevance of sciatic nerve lesions in DPN, with the expectation of correlations with the impairment of large-fiber function. Sixty-one patients with type 2 diabetes (48 with and 13 without DPN) and 12 control subjects were enrolled and underwent MRN, quantitative sensory testing, and electrophysiological examinations. There were differences in mechanical detection (Aβ fibers) and mechanical pain (A fibers) but not in thermal pain and thermal detection clusters (C fibers) among the groups. Lesion load correlated with lower Aα-, Aβ-, and A-fiber but not with C-fiber function in all participants. Patients with lower function showed a higher load of nerve lesions than patients with elevated function or no measurable deficit despite apparent DPN. Longer diabetes duration was associated with higher lesion load in patients with DPN, suggesting that nerve lesions in DPN may accumulate over time and become clinically relevant once a critical amount of nerve fascicles is affected. Moreover, MRN is an objective method for determining lower function mainly in medium and large fibers in DPN.

2 July 2014 , Volume 90, Number 4

Invitation Only Research Event

Event participants

Dr Ashwini Swain, Fellow, CUTS Institute for Regulation and Competition
Glada Lahn, Senior Research Fellow, Energy, Environment and Resources, Chatham House
Dr Gareth Price, Senior Research Fellow, Asia Programme, Chatham House

Invitation Only Research Event

We aimed to assess the value of ¹¹C-choline PET in patients with primary hyperparathyroidism and negative or discordant results on ^99mTc-sestamibi imaging and neck ultrasound. Methods: Eighty-seven such patients were assessed and subsequently underwent parathyroidectomy. PET/CT image data were analyzed semiquantitatively using SUV_max and SUV ratios (target to contralateral thyroid gland and carotid artery). A positive PET/CT result was defined as focal uptake significantly higher than regular thyroid tissue. Ectopic foci were also considered positive. Inconclusive PET/CT cases were defined as a lesion with uptake equal to normal thyroid tissue. If no prominent or ectopic uptake was detectable, the PET/CT result was considered negative. Results: When dichotomizing the ¹¹C-choline PET/CT imaging results by defining lesions with both positive and inconclusive uptake as positive, we found 84 of 92 lesions (91.3%) to have true-positive uptake whereas 8 lesions (8.7%) had false-positive uptake. One lesion showed false-negative uptake; the sensitivity was 98.8%. The corresponding positive predictive value for lesions was 91.3%. The mean SUV_max was 6.15 ± 4.92 in 72 lesions with positive uptake (70 patients) and 2.96 ± 2.32 in 20 lesions with inconclusive uptake (18 patients). Conclusion: These results in a large group of patients indicate that ¹¹C-choline PET/CT is a promising tool for parathyroid adenoma localization when ultrasound and ^99mTc-sestamibi imaging yield negative or discordant results.

Knowledge of the molecular events in mitochondrial DNA (mtDNA) replication is crucial to understanding the origins of human disorders arising from mitochondrial dysfunction. Twinkle helicase is an essential component of mtDNA replication. Here, we employed atomic force microscopy imaging in air and liquids to visualize ring assembly, DNA binding, and unwinding activity of individual Twinkle hexamers at the single-molecule level. We observed that the Twinkle subunits self-assemble into hexamers and higher-order complexes that can switch between open and closed-ring configurations in the absence of DNA. Our analyses helped visualize Twinkle loading onto and unloading from DNA in an open-ringed configuration. They also revealed that closed-ring conformers bind and unwind several hundred base pairs of duplex DNA at an average rate of ∼240 bp/min. We found that the addition of mitochondrial single-stranded (ss) DNA–binding protein both influences the ways Twinkle loads onto defined DNA substrates and stabilizes the unwound ssDNA product, resulting in a ∼5-fold stimulation of the apparent DNA-unwinding rate. Mitochondrial ssDNA-binding protein also increased the estimated translocation processivity from 1750 to >9000 bp before helicase disassociation, suggesting that more than half of the mitochondrial genome could be unwound by Twinkle during a single DNA-binding event. The strategies used in this work provide a new platform to examine Twinkle disease variants and the core mtDNA replication machinery. They also offer an enhanced framework to investigate molecular mechanisms underlying deletion and depletion of the mitochondrial genome as observed in mitochondrial diseases.

Though a faceoff between the U.S. executive and legislative branches is now in the courts, with President Trump's decision to declare a national emergency so he can allocate more money for construction of a border wall, a less-noted dispute has been taking place over the Department of Homeland Security's decision to add thousands more immigration detention beds than Congress provides annually, as this article explains.

Immigrants from India are the second-largest foreign-born group in the United States, after Mexicans. Indian immigrants tend to be far more highly educated and have greater English proficiency than the foreign-born population overall. This Spotlight article offers the latest data on Indian immigrants, focusing on population size, state- and city-level distribution, occupation, educational attainment, and more.

In advance of the December 2018 adoption of the Global Compact for Safe, Orderly, and Regular Migration and its commitment to facilitate the return, readmission, and reintegration of migrants, this webinar examines the policies, practices, and contextual factors that make compulsory returns such a difficult issue for international cooperation, and the programs that are being implemented to make reintegration of returnees sustainable.