Human but not mouse islets transplanted into immunodeficient NSG mice effectively accumulate lipid droplets (LDs). Because chronic lipid exposure is associated with islet β-cell dysfunction, we investigated LD accumulation in the intact human and mouse pancreas over a range of ages and states of diabetes. Very few LDs were found in normal human juvenile pancreatic acinar and islet cells, with numbers subsequently increasing throughout adulthood. While accumulation appeared evenly distributed in postjuvenile acinar and islet cells in donors without diabetes, LDs were enriched in islet α- and β-cells from donors with type 2 diabetes (T2D). LDs were also found in the islet β-like cells produced from human embryonic cell–derived β-cell clusters. In contrast, LD accumulation was nearly undetectable in the adult rodent pancreas, even in hyperglycemic and hyperlipidemic models or 1.5-year-old mice. Taken together, there appear to be significant differences in pancreas islet cell lipid handling between species, and the human juvenile and adult cell populations. Moreover, our results suggest that LD enrichment could be impactful to T2D islet cell function.

As Braves manager Brian Snitker evaluates who might serve as his closer, A.J. Minter has made it clear he wants to be the guy who is consistently called upon to handle high-leverage threats that develop in late innings.

The whitening and loss of brown adipose tissue (BAT) during obesity and aging promote metabolic disorders and related diseases. The imbalance of Ca²⁺ homeostasis accounts for the dysfunction and clearance of mitochondria during BAT whitening. Capsaicin, a dietary factor activating TRPV1, can inhibit obesity induced by high-fat diet (HFD), but whether capsaicin inhibits BAT loss and the underlying mechanism remain unclear. In this study, we determined that the inhibitory effects of capsaicin on HFD-induced obesity and BAT whitening were dependent on the participation of SIRT3, a critical mitochondrial deacetylase. SIRT3 also mediated all of the beneficial effects of capsaicin on alleviating reactive oxygen species generation, elevating mitochondrial activity, and restricting mitochondrial calcium overload induced by HFD. Mechanistically, SIRT3 inhibits mitochondrial calcium uniporter (MCU)-mediated mitochondrial calcium overload by reducing the H3K27ac level on the MCU promoter in an AMPK-dependent manner. In addition, HFD also inhibits AMPK activity to reduce SIRT3 expression, which could be reversed by capsaicin. Capsaicin intervention also inhibited aging-induced BAT whitening through this mechanism. In conclusion, this study emphasizes a critical role of the AMPK/SIRT3 pathway in the maintenance of BAT morphology and function and suggests that intervention in this pathway may be an effective target for preventing obesity- or age-related metabolic diseases.

Jamaica Football Federation (JFF) general secretary Dalton Wint says that any potential changes to the Concacaf hexagonal round for the FIFA World Cup qualifiers could present challenges to the nation’s aim of qualifying for Qatar 2022. Wint’s...

Bone pain is the most common type of pain from cancer and is present in around one third of patients with bone metastases, currently, improvements in cancer treatments mean that many patients are living with metastatic cancer for several years. Christopher Kane, NIHR academic clinical fellow in palliative medicine at Leeds University School of...

Pleural effusions are common, with an estimated 1-1.5 million new cases in the United States and 200 000-250 000 in the United Kingdom each year. Rahul Bhatnagar, academic clinical lecturer at the University of Bristol, describes how pleural effusions may be investigated and treated in the community and secondary care, with a particular focus on...

Nick Oliver, consultant diabetologist at Imperial Healthcare NHS Trust and Philippa Cooper, who has type I diabetes, join us to explain how structured education works for patients, and give tips on self management. Read the full review: http://www.bmj.com/content/352/bmj.i998

In February World Health Organization (WHO) declared the microcephaly epidemic in South America an international public health emergency. Today, the US Centers for Disease Control and Prevention, the CDC, has confirmed that it’s is Zika virus which is causing that microcephaly.  The outbreak was originally spotted in Recife, in Brazil, and it’s...

There's a crisis in old age care - not just in the UK, around the world, as population demographics shift, and the proportion of older people increase - there's a worry about who's going to look after them, and how much is it going to cost? However, a new analysis on bmj.com says this picture need not be so gloomy - they say that encouraging...

You’ll have read in a clinical trial “Most patients had an acceptable adverse-event profile.” Or that a drug “has a manageable and mostly reversible safety profile.” And that “the tolerability was good overall.” In this podcast, Bishal Gyawali (@oncology_bg) joins us to describe what events those terms were actually describing in cancer drug...

This week the Trump administration has banned the sale of flavoured vapes in the USA. The reason for that is the sudden rash of cases of pulmonary disease, including deaths, linked to vaping. The mechanism by which vaping may be causing damage to the lungs is as yet unclear, and our understanding is hampered by the heterogeneous nature of the...

This week we saw the release of the much awaited Yellowhammer documents from the government, documents which outline some of the risks involved with Britain’s sudden departure from the EU. The documents themselves outline that there are risks to the supply of medicines - but do not set out the detail of how those risks have been mitigated, and...

The BMJ in partnership with The Harvard Global Health Institute has launched a collection of articles exploring how to achieve effective universal health coverage (UHC). The collection highlights the importance of quality in UHC, potential finance models, how best to incentivise stakeholders, and some of the barriers to true UHC. One of those...

Shane Rea
Nov 1, 1997; 46:1667-1677
Perspectives in Diabetes

Charles M. Alexander
May 1, 2003; 52:1210-1214
Complications

This study aims to model genetic, immunologic, metabolomics, and proteomic biomarkers for development of islet autoimmunity (IA) and progression to type 1 diabetes in a prospective high-risk cohort. We studied 67 children: 42 who developed IA (20 of 42 progressed to diabetes) and 25 control subjects matched for sex and age. Biomarkers were assessed at four time points: earliest available sample, just prior to IA, just after IA, and just prior to diabetes onset. Predictors of IA and progression to diabetes were identified across disparate sources using an integrative machine learning algorithm and optimization-based feature selection. Our integrative approach was predictive of IA (area under the receiver operating characteristic curve [AUC] 0.91) and progression to diabetes (AUC 0.92) based on standard cross-validation (CV). Among the strongest predictors of IA were change in serum ascorbate, 3-methyl-oxobutyrate, and the PTPN22 (rs2476601) polymorphism. Serum glucose, ADP fibrinogen, and mannose were among the strongest predictors of progression to diabetes. This proof-of-principle analysis is the first study to integrate large, diverse biomarker data sets into a limited number of features, highlighting differences in pathways leading to IA from those predicting progression to diabetes. Integrated models, if validated in independent populations, could provide novel clues concerning the pathways leading to IA and type 1 diabetes.

The wet weather last Saturday (May 2) could not dampen the spirits of award-winning gospel artiste and ordained evangelist Kevin Downswell as he ventured into the St Catherine community of Central Village, where he spent some of his formative years...

Reduced storage of dietary fatty acids (DFAs) in abdominal adipose tissues with enhanced cardiac partitioning has been shown in subjects with type 2 diabetes (T2D) and prediabetes. We measured DFA metabolism and organ partitioning using positron emission tomography with oral and intravenous long-chain fatty acid and glucose tracers during a standard liquid meal in 12 obese subjects with T2D before and 8–12 days after bariatric surgery (sleeve gastrectomy or sleeve gastrectomy and biliopancreatic diversion with duodenal switch). Bariatric surgery reduced cardiac DFA uptake from a median (standard uptake value [SUV]) 1.75 (interquartile range 1.39–2.57) before to 1.09 (1.04–1.53) after surgery (P = 0.01) and systemic DFA spillover from 56.7 mmol before to 24.7 mmol over 6 h after meal intake after surgery (P = 0.01), with a significant increase in intra-abdominal adipose tissue DFA uptake from 0.15 (0.04–0.31] before to 0.49 (0.20–0.59) SUV after surgery (P = 0.008). Hepatic insulin resistance was significantly reduced in close association with increased DFA storage in intra-abdominal adipose tissues (r = –0.79, P = 0.05) and reduced DFA spillover (r = 0.76, P = 0.01). We conclude that bariatric surgery in subjects with T2D rapidly reduces cardiac DFA partitioning and hepatic insulin resistance at least in part through increased intra-abdominal DFA storage and reduced spillover.

Clinical studies have suggested that changes in peripheral nerve microcirculation may contribute to nerve damage in diabetic polyneuropathy (DN). High-sensitivity troponin T (hsTNT) assays have been recently shown to provide predictive values for both cardiac and peripheral microangiopathy in type 2 diabetes (T2D). This study investigated the association of sciatic nerve structural damage in 3 Tesla (3T) magnetic resonance neurography (MRN) with hsTNT and N-terminal pro-brain natriuretic peptide serum levels in patients with T2D. MRN at 3T was performed in 51 patients with T2D (23 without DN, 28 with DN) and 10 control subjects without diabetes. The sciatic nerve’s fractional anisotropy (FA), a marker of structural nerve integrity, was correlated with clinical, electrophysiological, and serological data. In patients with T2D, hsTNT showed a negative correlation with the sciatic nerve’s FA (r = –0.52, P < 0.001), with a closer correlation in DN patients (r = –0.66, P < 0.001). hsTNT further correlated positively with the neuropathy disability score (r = 0.39, P = 0.005). Negative correlations were found with sural nerve conduction velocities (NCVs) (r = –0.65, P < 0.001) and tibial NCVs (r = –0.44, P = 0.002) and amplitudes (r = –0.53, P < 0.001). This study is the first to show that hsTNT is a potential indicator for structural nerve damage in T2D. Our results indirectly support the hypothesis that microangiopathy contributes to structural nerve damage in T2D.

Invitation Only Research Event

15 November 2016

The Arizona Diamondbacks agreed to terms on a contract extension with manager Torey Lovullo on Tuesday.

Agencies have criticised the lack of action to protect the health needs of sex workers during the pandemic, with the English Collective of Prostitutes (ECP) warning of a “ticking time bomb of health...

¹⁸F-DCFPyL (2-(3-{1-carboxy-5-[(6-¹⁸F-fluoropyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid) is a promising PET radiopharmaceutical targeting prostate-specific membrane antigen (PSMA). We present our experience with this single-academic-center prospective study evaluating the positivity rate of ¹⁸F-DCFPyL PET/CT in patients with biochemical recurrence (BCR) of prostate cancer (PC). Methods: We prospectively enrolled 72 men (52–91 y old; mean ± SD, 71.5 ± 7.2) with BCR after primary definitive treatment with prostatectomy (n = 42) or radiotherapy (n = 30). The presence of lesions compatible with PC was evaluated by 2 independent readers. Fifty-nine patients had scans concurrent with at least one other conventional scan: bone scanning (24), CT (21), MR (20), ¹⁸F-fluciclovine PET/CT (18), or ¹⁸F-NaF PET (14). Findings from ¹⁸F-DCFPyL PET/CT were compared with those from other modalities. Impact on patient management based on ¹⁸F-DCFPyL PET/CT was recorded from clinical chart review. Results: ¹⁸F-DCFPyL PET/CT had an overall positivity rate of 85%, which increased with higher prostate-specific antigen (PSA) levels (ng/mL): 50% (PSA < 0.5), 69% (0.5 ≤ PSA < 1), 100% (1 ≤ PSA < 2), 91% (2 ≤ PSA < 5), and 96% (PSA ≥ 5). ¹⁸F-DCFPyL PET detected more lesions than conventional imaging. For anatomic imaging, 20 of 41 (49%) CT or MRI scans had findings congruent with ¹⁸F-DCFPyL, whereas ¹⁸F-DCFPyL PET was positive in 17 of 41 (41%) cases with negative CT or MRI findings. For bone imaging, 26 of 38 (68%) bone or ¹⁸F-NaF PET scans were congruent with ¹⁸F-DCFPyL PET, whereas ¹⁸F-DCFPyL PET localized bone lesions in 8 of 38 (21%) patients with negative results on bone or ¹⁸F-NaF PET scans. In 8 of 18 (44%) patients, ¹⁸F-fluciclovine PET had located the same lesions as did ¹⁸F-DCFPyL PET, whereas 5 of 18 (28%) patients with negative ¹⁸F-fluciclovine findings had positive ¹⁸F-DCFPyL PET findings and 1 of 18 (6%) patients with negative ¹⁸F-DCFPyL findings had uptake in the prostate bed on ¹⁸F-fluciclovine PET. In the remaining 4 of 18 (22%) patients, ¹⁸F-DCFPyL and ¹⁸F-fluciclovine scans showed different lesions. Lastly, 43 of 72 (60%) patients had treatment changes after ¹⁸F-DCFPyL PET and, most noticeably, 17 of these patients (24% total) had lesion localization only on ¹⁸F-DCFPyL PET, despite negative results on conventional imaging. Conclusion: ¹⁸F-DCFPyL PET/CT is a promising diagnostic tool in the work-up of biochemically recurrent PC, given the high positivity rate as compared with Food and Drug Administration–approved currently available imaging modalities and its impact on clinical management in 60% of patients.

WITH THE productive sector experiencing a shortage of foreign exchange for the past two months, the Jamaican Manufacturers and Exporters Association, JMEA, says it has appealed to the Bank of Jamaica, BOJ, for direct access to US currency for three...

3 December 2019

Invitation Only Research Event

Invitation Only Research Event

Event participants

Duncan Robinson, Charlemagne Columnist; Brussels Bureau Chief, the Economist
Chair: Pepijn Bergsen, Research Fellow, Europe Programme, Chatham House

Invitation Only Research Event

Event participants

Richard King, Senior Research Fellow, Energy, Environment and Resources Department, Chatham House
Chair: Duncan Brack, Associate Fellow, Energy, Environment and Resources Department, Chatham House

Invitation Only Research Event

29 January 2020

Policymakers are in danger of sleepwalking into ineffective carbon dioxide removal solutions in the quest to tackle climate change. This paper warns against overreliance on bioenergy with carbon capture and storage (BECCS). 

Incorporation of ribonucleotides into DNA can severely diminish genome integrity. However, how ribonucleotides instigate DNA damage is poorly understood. In DNA, they can promote replication stress and genomic instability and have been implicated in several diseases. We report here the impact of the ribonucleotide rATP and of its naturally occurring damaged analog 1,N6-ethenoadenosine (1,N6-ϵrA) on translesion synthesis (TLS), mediated by human DNA polymerase η (hpol η), and on RNase H2–mediated incision. Mass spectral analysis revealed that 1,N6-ϵrA in DNA generates extensive frameshifts during TLS, which can lead to genomic instability. Moreover, steady-state kinetic analysis of the TLS process indicated that deoxypurines (i.e. dATP and dGTP) are inserted predominantly opposite 1,N6-ϵrA. We also show that hpol η acts as a reverse transcriptase in the presence of damaged ribonucleotide 1,N6-ϵrA but has poor RNA primer extension activities. Steady-state kinetic analysis of reverse transcription and RNA primer extension showed that hpol η favors the addition of dATP and dGTP opposite 1,N6-ϵrA. We also found that RNase H2 recognizes 1,N6-ϵrA but has limited incision activity across from this lesion, which can lead to the persistence of this detrimental DNA adduct. We conclude that the damaged and unrepaired ribonucleotide 1,N6-ϵrA in DNA exhibits mutagenic potential and can also alter the reading frame in an mRNA transcript because 1,N6-ϵrA is incompletely incised by RNase H2.

As the share of U.S. children under age 8 who are Dual Language Learners (DLLs) increases, state policies have an important role to play in ensuring all young learners are able to get their education off to a good start. These fact sheets compare key characteristics of DLLs and their peers nationwide and in 30 states, and identify state policies that support equitable access to high-quality early childhood education and care programs.

For generations, migrants have emigrated from Senegal, particularly from in and around the Senegal River Valley. With France a key destination, French policy changes have had significant impact on Senegalese migrants and the hometown associations through which they support development in Senegal. This article explores how these policy shifts influence development and quality of life in the Senegal River Valley.

One of the most rapidly aging societies in the world, Japan is looking to immigration to address increased labor shortages—albeit slowly and largely without public debate. This country profile offers a brief overview of Japan’s migration history and examines the current immigration system, in particular policies and programs to bring in foreign workers, particularly on a temporary basis.

MPI experts discuss the outcomes from the UN Summit on Large Movements of Refugees and Migrants and President Obama's Leaders Summit on the Global Refugee Crisis and what it means for international cooperation on refugee protection and management of migration flows.

This Transatlantic Council on Migration report describes how the migration of nationals between Germany and Turkey has developed over recent decades; examines the economic, social, and political factors behind this development; and discusses the policy implications and lessons that can be drawn.

OBJECTIVE

Dysglycemia, in this survey defined as impaired glucose tolerance (IGT) or type 2 diabetes, is common in patients with coronary artery disease (CAD) and associated with an unfavorable prognosis. This European survey investigated dysglycemia screening and risk factor management of patients with CAD in relation to standards of European guidelines for cardiovascular subjects.

The Las Vegas Raiders have agreed to a deal with free agent running back Devontae Booker.

Joseph Tran
Oct 1, 2012; 30:173-178
Practical Pointers

Martha M. Funnell
Jul 1, 2004; 22:123-127
Feature Articles

Sara F. Morris
Dec 1, 2010; 28:12-18
Feature Articles

Vanessa J. Briscoe
Jul 1, 2006; 24:115-121
Feature Articles

Kerri L. Cavanaugh
Jul 1, 2007; 25:90-97
Feature Articles