Marc Prentki
Mar 1, 1996; 45:273-283
Original Article

J. Denis McGarry
Jan 1, 2002; 51:7-18
Banting Lecture 2001

Lipodystrophies are a group of disorders characterized by absence or loss of adipose tissue and abnormal fat distribution, commonly accompanied by metabolic dysregulation. Although considered rare disorders, their prevalence in the general population is not well understood. We aimed to evaluate the clinical and genetic prevalence of lipodystrophy disorders in a large clinical care cohort. We interrogated the electronic health record (EHR) information of >1.3 million adults from the Geisinger Health System for lipodystrophy diagnostic codes. We estimate a clinical prevalence of disease of 1 in 20,000 individuals. We performed genetic analyses in individuals with available genomic data to identify variants associated with inherited lipodystrophies and examined their EHR for comorbidities associated with lipodystrophy. We identified 16 individuals carrying the p.R482Q pathogenic variant in LMNA associated with Dunnigan familial partial lipodystrophy. Four had a clinical diagnosis of lipodystrophy, whereas the remaining had no documented clinical diagnosis despite having accompanying metabolic abnormalities. We observed a lipodystrophy-associated variant carrier frequency of 1 in 3,082 individuals in our cohort with substantial burden of metabolic dysregulation. We estimate a genetic prevalence of disease of ~1 in 7,000 in the general population. Partial lipodystrophy is an underdiagnosed condition. and its prevalence, as defined molecularly, is higher than previously reported. Genetically guided stratification of patients with common metabolic disorders, like diabetes and dyslipidemia, is an important step toward precision medicine.

Treatment of patients with advanced medullary thyroid carcinoma (MTC) is still a challenge. For more than 2 decades, it has been known that the cholecystokinin 2 receptor is a promising target for the treatment of MTC with radiolabeled minigastrin analogs. Unfortunately, kidney toxicity has precluded their therapeutic application so far. In 6 consecutive patients, we evaluated with advanced 3-dimensional dosimetry whether improved minigastrin analog ¹⁷⁷Lu-DOTA-(d-Glu)₆-Ala-Tyr-Gly-Trp-Nle-Asp-PheNH₂ (¹⁷⁷Lu-PP-F11N) is a suitable agent for the treatment of MTC. Methods: Patients received 2 injections of about 1 GBq (~80 μg) of ¹⁷⁷Lu-PP-F11N with and without a solution of succinylated gelatin (SG, a plasma expander used for nephroprotection) in a random crossover sequence to evaluate biodistribution, pharmacokinetics, and tumor and organ dosimetry. An electrocardiogram was obtained and blood count and blood chemistry were measured up to 12 wk after the administration of ¹⁷⁷Lu-PP-F11N to assess safety. Results: In all patients, ¹⁷⁷Lu-PP-F11N accumulation was visible in tumor tissue, stomach, and kidneys. Altogether, 13 tumors were eligible for dosimetry. The median absorbed doses for tumors, stomach, kidneys, and bone marrow were 0.88 (interquartile range [IQR]: 0.85–1.04), 0.42 (IQR: 0.25–1.01), 0.11 (IQR: 0.07–0.13), and 0.028 (IQR: 0.026–0.034) Gy/GBq, respectively. These doses resulted in median tumor-to-kidney dose ratios of 11.6 (IQR: 8.11–14.4) without SG and 13.0 (IQR: 10.2–18.6) with SG; these values were not significantly different (P = 1.0). The median tumor-to-stomach dose ratio was 3.34 (IQR: 1.14–4.70). Adverse reactions (mainly hypotension, flushing, and hypokalemia) were self-limiting and not higher than grade 1. Conclusion: ¹⁷⁷Lu-PP-F11N accumulates specifically in MTC at a dose that is sufficient for a therapeutic approach. With a low kidney and bone marrow radiation dose, ¹⁷⁷Lu-PP-F11N shows a promising biodistribution. The dose-limiting organ is most likely the stomach. Further clinical studies are necessary to evaluate the maximum tolerated dose and the efficacy of ¹⁷⁷Lu-PP-F11N.

Type 1 diabetes is an autoimmune-mediated disease that culminates in the targeted destruction of insulin-producing β-cells. CD4 responses in NOD mice are dominated by insulin epitope B:9-23 (InsB_9-23) specificity, and mutation of the key T-cell receptor (TCR) contact residue within the epitope prevents diabetes development. However, it is not clear how insulin self-antigen controls the selection of autoimmune and regulatory T cells (Tregs). Here we demonstrate that mutation of insulin epitope results in escape of highly pathogenic T cells. We observe an increase in antigen reactivity, clonality, and pathogenicity of insulin-specific T cells that develop in the absence of cognate antigen. Using a single TCR system, we demonstrate that Treg development is greatly diminished in mice with the Y16A mutant epitope. Collectively, these results suggest that the tyrosine residue at position 16 is necessary to constrain TCR reactivity for InsB_9-23 by both limiting the development of pathogenic T cells and supporting the selection of Tregs.

Members Event Webinar

Event participants

Professor Matthew Goodwin, Visiting Senior Fellow, Europe Programme, Chatham House
Professor David Cutts, Associate Fellow, Europe Programme, Chatham House

Invitation Only Research Event

Event participants

Alistair Burt, Conservative Member of Parliament (1983-97 and 2001-19); Minister of State for the Middle East, UK Foreign & Commonwealth Office and Minister of State at the Department for UK International Development (2017-19)

Members Event

Event participants

Stephen Gethins, Candidate for Fife North East and Shadow Spokesperson for Foreign and Commonwealth Office (2018-19), Scottish National Party (remote)
Dominic Raab, Candidate for Esher & Walton, Foreign Secretary and First Secretary of State (2019), Conservative Party
Emily Thornberry, Candidate for Islington South & Finsbury and Shadow Foreign Secretary (2016-19), Labour Party
Chuka Umunna, Candidate for Cities of London & Westminster and Spokesperson for Foreign and Commonwealth Affairs (2019), Liberal Democrat Party
Chair: Ritula Shah, The World Tonight, BBC Radio 4
 

Members Event

Event participants

John Casson, Associate Fellow, Europe Programme, Chatham House
Tom Raines, Head, Europe Programme, Chatham House
Dr Yu Jie, Senior Research Fellow, Asia-Pacific Programme, Chatham House
Antony Froggatt, Senior Research Fellow, Energy, Environment and Resource Governance, Chatham House

Members Event

Event participants

Helen Thompson, Professor of Political Economy, University of Cambridge; Host, Talking Politics
Chairs: Hans Kundnani, Senior Research Fellow, Europe Programme, Chatham House
Laura Cram, Professor of European Politics, University of Edinburgh. Co-Editor, Government and Opposition: An International Journal of Comparative Politics
 

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.

A discussion marking the 25th anniversary of the 1990 Immigration Act, where experts examinine the history of the legislation, how it was accomplished politically, and the stakeholders and issues that were critical to its passage.

On the campaign trail, Donald Trump made immigration the centerpiece of his campaign, offering a more detailed policy agenda than on any other issue. In the year since the election that propelled the Republican into the White House, how has the Trump administration’s record matched up with the rhetoric? This policy brief examines the executive orders and other changes to existing policy and practice made during 2017.

These fact sheets provide a sketch of key characteristics of the foreign-born and English Learner (EL) populations in select states. The fact sheets look at the demographics of these states, discuss EL student outcomes as measured by standardized tests, and conclude with an overview of state accountability mechanisms that affect ELs under relevant provisions of the Every Student Succeeds Act and predecessor No Child Left Behind Act.

States are in the midst of designing new policies to hold schools accountable for the education of English Learner (EL) students, as mandated by the federal Every Student Succeeds Act (ESSA). This series of fact sheets sketches the characteristics of immigrant and EL students in 25 states, the gaps between their educational outcomes and those of their peers, and the accountability policies each state is developing.

OBJECTIVE

Neonatal diabetes has been shown to be associated with high neuropsychiatric morbidity in a genotype-phenotype–dependent manner. However, the specific impact of different mutations on intellectual functioning is still insufficiently characterized. Specifically, only a small number of subjects with developmental delay have been comprehensively assessed, creating a knowledge gap about patients carrying the heaviest burden.

Itamar Raz
Jun 1, 2013; 36:1779-1788
Diabetes Care Expert Forum

William T. Cefalu
Jan 1, 2018; 41:14-31
Diabetes Care Expert Forum

William T. Cefalu
Jan 1, 2018; 41:14-31
Diabetes Care Expert Forum

Dentists who have had a dental plan payment check lost in the mail could consider a way to receive safe and secure payment through electronic funds transfer payments.

The ADA is recommending that dentists nationwide postpone elective procedures in response to the spread of the coronavirus, COVID-19, across the country.

Despite the ADA Council on Dental Benefits’ efforts, the practice of using automated electronic means for verifying eligibility and benefits, checking claim status or receiving and reconciling payment remains underutilized by many dental providers according to an index, said Dr. Randall Markarian, council chair.

OBJECTIVE

Incorporation of comorbidity burden to inform diabetes management in older adults remains challenging. High-sensitivity cardiac troponins are objective, quantifiable biomarkers that may improve risk monitoring in older adults. We assessed the associations of elevations in high-sensitivity cardiac troponin I (hs-cTnI) and T (hs-cTnT) with comorbidities and improvements in mortality risk stratification.

OBJECTIVE

We analyzed data from inpatients with diabetes admitted to a large university hospital to predict the risk of hypoglycemia through the use of machine learning algorithms.

With the U.S. administration calling for the United States to adopt a more “merit-based” immigrant selection system, this conversation focused on what policymakers should consider in designing—and managing—immigrant selection systems in a time of intense labor-market and demographic change.

A 29 years old female presented to us in the metabolic clinic of the University of Port Harcourt Teaching Hospital (UPTH) on account of a week history of easy fatigability, weakness, and lower extremity muscle cramps associated with numbness and tingling sensation in the peri-oral area, fingers and toes. Two weeks prior to the onset of her presenting symptoms, she had visited a local pharmaceutical shop on account of a distressing epigastric discomfort and was subsequently placed on daily oral omeprazole 20mg daily for a month by a pharmacist. She had been on the omeprazole medication for two weeks before her present symptoms manifested. Her past medical history was not suggestive of hypoparathyroidism nor pancreatitis. She was married with three children and has an uneventful family, social and obstetric histories. On examination, she was a healthy well-oriented young female with positive Trousseau’s, Chvostek’s and epigastric tenderness signs. Further Laboratory evaluation revealed she had low plasma magnesium, low plasma albumin-corrected calcium, and low serum parathyroid hormone levels, while other laboratory parameters were essentially normal. A diagnosis of omeprazole-induced electrolyte disorders (hypomagnesaemia and hypocalcaemia) associated with hypoparathyroidism was made following the review of her clinical examination and laboratory findings. She was subsequently managed with oral magnesium supplements following the withdrawal of the omeprazole medication (replaced with oral ranitidine), monitored weekly, and full recovery was achieved after three weeks.

Poland announced a delay of its Sunday presidential election, Europe's first planned vote during the coronavirus pandemic.

Since its launch in 2015, the Express Entry system has changed how economic immigration to Canada happens and how it fits into public and political debates. And while it has proven successful in cutting through application backlogs, some challenges remain. This report looks at how and why this points-based system was introduced, what its impact has been, and how it could be further finetuned.

MPI and OECD experts discuss what policymakers should consider in designing and managing immigrant selection systems in a time of intense labor-market and demographic change.

The Trump administration’s plan to create a "merit-based" U.S. immigration system, lessening the longstanding focus on family reunification in favor of more economic migrants, has met with a lackluster response from Democrats and Republicans alike. This Policy Beat article explores how the Trump proposal would reshape immigration to the United States, and how it compares to selection systems in other countries and past debates about changing the U.S. system.

The failure of Geert Wilders’ right-wing, anti-Islam Freedom Party (PVV) to become the top vote-getter in the Dutch parliamentary elections is being hailed as proof of the limits of anti-Muslim rhetoric and even the “waning” of the appeal of right-wing populism. But as this commentary explores, a closer reading leads one to a more nuanced interpretation of the results and the recognition that Wilders will remain a major force.

A reflection by MPI's co-founder, Demetrios Papademetriou, as he takes leave from his day-to-day role at MPI on the challenges and opportunities ahead for international migration systems over the next few decades. After opening remarks, Papademetriou engages in a conversation with incoming MPI President Andrew Selee about the trends and realities confronting policymakers and publics.

Since the mid-1990s, Australia has moved away from a focus on family reunification to place greater emphasis on workers coming via temporary and permanent channels. The evolution of the country's points-based model for selecting economic migrants and move to a predominately employer-driven system offer lessons for other countries that seek to develop a tailored and targeted immigration selection system.

As technological developments—from automation to artificial intelligence and machine learning—reshape the world of work, governments face the challenge of updating how they attract, select, and retain economic-stream immigrants. This report, concluding a series on building migration systems for a new age of economic competitiveness, lays out the key considerations for "future-proofing" immigrant selection systems.

This event will feature a screening of the short documentary The Fields of Immokalee, and include a discussion on immigration and politics in Florida and other swing states in the run-up to the 2020 election. 

If Democrats Hillary Clinton and Barack Obama ever took a break from fundraising to bone up on psychology, they might realize the need to talk up . . . John Edwards.

Sen. John McCain's quest for the Republican presidential nomination was once seen as dead, but like those robots in the "Terminator" movies that reassemble themselves after being blown to smithereens, he came back. Five years ago, Sen. Barack Obama (Ill.) was a virtually unknown African American ...

Acknowledgments: Special THANKS to Matthias Beck, Ben Braun, Pamela Harris, Max Hlavacek, Mariel Supina, Julie Vega, and the Discrete Geometry Group/The Villa at FU Berlin. I recently came back from a research visit to the Freie Universität in Berlin where … Continue reading →

Across the United States, nearly 2 million immigrants with college degrees are unemployed or stuck in low-skilled jobs. This skill underutilization, known as “brain waste,” varies significantly by state. These fact sheets offer a profile of these highly skilled immigrants and estimate their forgone earnings and resulting unrealized tax receipts in eight states: California, Florida, Michigan, New York, Ohio, Oregon, Texas, and Washington.

This delicious Argentinian confection (also known as Spanish Caramel/milk jam) is a thick caramel milk-based sauce to die for and is so easy to make at home. Use as a filling for tartlets or cakes, serve over ice cream, as a filling for crepes, as a sauce over baked pears or apples or simply eat from a spoon!

Much has changed in the world of advertising from the picture painted by Mad Men. Shelly Lazarus ’70, Chairman Emeritus, Ogilvy & Mather, was one of the women helping pioneer these changes. Making the journey from ‘the only woman in the room’ to CEO and Chairman of Ogilvy gives Lazarus a lot to reflect on […]

Some biological structures are so small that scientists can't see them with even the most powerful microscopes. That's where molecular animator and TED Fellow Janet Iwasa gets creative. Explore vast, unseen molecular worlds as she shares mesmerizing animations that imagine how they might work.

A short look at the science, pros and cons behind transcranial direct stimulation, or tCDS.

In Florida, Indiana, Kansas, North Carolina, Tennessee and Utah, Republicans are arguing that candidates for local and state school boards should run on party tickets.

A measure now before Virginia's governor would let teachers bargain with local boards over wages and working conditions if a local board authorizes it.

About a dozen teachers running for state legislative seats gathered with their supporters in Tulsa for a watch party on election night. The results were better for some than others.