Invitation Only Research Event

When you run SAS Deployment Wizard to install or update SAS 9.4 software, the file system is examined. If any files that the wizard needs to delete are found to be locked, they are reported as unwritable f

Contact between inflammatory cells and endothelial cells (ECs) is a crucial step in vascular inflammation. Recently, we demonstrated that the cell-surface level of endomucin (EMCN), a heavily O-glycosylated single-transmembrane sialomucin, interferes with the interactions between inflammatory cells and ECs. We have also shown that, in response to an inflammatory stimulus, EMCN is cleared from the cell surface by an unknown mechanism. In this study, using adenovirus-mediated overexpression of a tagged EMCN in human umbilical vein ECs, we found that treatment with tumor necrosis factor α (TNF-α) or the strong oxidant pervanadate leads to loss of cell-surface EMCN and increases the levels of the C-terminal fragment of EMCN 3- to 4-fold. Furthermore, treatment with the broad-spectrum matrix metalloproteinase inhibitor batimastat (BB94) or inhibition of ADAM metallopeptidase domain 10 (ADAM10) and ADAM17 with two small-molecule inhibitors, GW280264X and GI254023X, or with siRNA significantly reduced basal and TNFα-induced cell-surface EMCN cleavage. Release of the C-terminal fragment of EMCN by TNF-α treatment was blocked by chemical inhibition of ADAM10 alone or in combination with ADAM17. These results indicate that cell-surface EMCN undergoes constitutive cleavage and that TNF-α treatment dramatically increases this cleavage, which is mediated predominantly by ADAM10 and ADAM17. As endothelial cell-surface EMCN attenuates leukocyte–EC interactions during inflammation, we propose that EMCN is a potential therapeutic target to manage vascular inflammation.

Endocrine cells of the pancreatic islet interact with their microenvironment to maintain tissue homeostasis. Communication with local macrophages is particularly important in this context, but the homeostatic functions of human islet macrophages are not known. Here we show that the human islet contains macrophages in perivascular regions that are the main local source of the anti-inflammatory cytokine Il-10 and the metalloproteinase MMP9. Macrophage production and secretion of these homeostatic factors is controlled by endogenous purinergic signals. In obese and diabetic states, macrophage expression of purinergic receptors, MMP9, and Il-10 is reduced. We propose that in those states exacerbated beta cell activity due to increased insulin demand and increased cell death produces high levels of ATP that downregulate purinergic receptor expression. Loss of ATP sensing in macrophages may reduce their secretory capacity.

Heme-regulatory motifs (HRMs) are present in many proteins that are involved in diverse biological functions. The C-terminal tail region of human heme oxygenase-2 (HO2) contains two HRMs whose cysteine residues form a disulfide bond; when reduced, these cysteines are available to bind Fe3+-heme. Heme binding to the HRMs occurs independently of the HO2 catalytic active site in the core of the protein, where heme binds with high affinity and is degraded to biliverdin. Here, we describe the reversible, protein-mediated transfer of heme between the HRMs and the HO2 core. Using hydrogen-deuterium exchange (HDX)-MS to monitor the dynamics of HO2 with and without Fe3+-heme bound to the HRMs and to the core, we detected conformational changes in the catalytic core only in one state of the catalytic cycle—when Fe3+-heme is bound to the HRMs and the core is in the apo state. These conformational changes were consistent with transfer of heme between binding sites. Indeed, we observed that HRM-bound Fe3+-heme is transferred to the apo-core either upon independent expression of the core and of a construct spanning the HRM-containing tail or after a single turnover of heme at the core. Moreover, we observed transfer of heme from the core to the HRMs and equilibration of heme between the core and HRMs. We therefore propose an Fe3+-heme transfer model in which HRM-bound heme is readily transferred to the catalytic site for degradation to facilitate turnover but can also equilibrate between the sites to maintain heme homeostasis.

Jay S. Skyler
Feb 1, 2017; 66:241-255
Perspectives in Diabetes

Bruce Bochy announced on Monday that his 25th season as a manager -- his 13th in an absurdly successful run with the Giants -- would be his last. In making the announcement, Bochy is going to give all of us the opportunity to say thanks during a 2019 season that will be something of a victory lap whether he likes it or not.

11 February 2020

Members Event

Event participants

Jenny Norton, Producer, Parts of a Circle: History of the Karabakh Conflict
Famil Ismayilov, Journalist
Leon Aslanov, Middle East Analyst, Integrity UK
Chair: Laurence Broers, Associate Fellow, Russia and Eurasia Programme, Chatham House; Director, Caucasus Programme, Conciliation Resources

Invitation Only Research Event

“As the large wooden doors of the chapel opened and I saw my bride for the first time, our minds and hearts communicated in a way only love could evoke.” This sincere sentiment, echoed by the proud groom, only expresses a drop in the ocean of...

It didn't come as a surprise to anyone when Dana Brown left the Blue Jays as a special assistant to general manager Ross Atkins to join the Braves as vice president of scouting.

By winning his arbitration case against the Astros, pitcher Gerrit Cole stands to make $2,075,000 more this season than if he'd lost. That's a significant victory for Cole, who will double his salary this year and make $13.5 million, and a significant victory for other players to come, the veteran pitcher said.

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...

How can asking patient to tell us their story improve healthcare? Helen Morant, content lead at BMJ, talks us through her project getting healthcare professionals to sit down with patients and record their conversations, and what on earth this has to do with quality improvement. We also hear some of the recordings she has gathered through the...

Global evidence indicates that mandated treatment of drug dependence conflicts with drug users’ human rights and is not effective in treating addiction. Karsten Lunze, associate professor at the Boston University School of Medicine, joins us to describe the evidence, and why he is convinced seemingly counter intuitive hard reduction...

Middle East respiratory syndrome (MERS) is an acute viral respiratory tract infection caused by the novel betacoronavirus. Cases have been limited to the Arabian Peninsula and its surrounding countries, and to travellers from the Middle East or their contacts. The clinical spectrum of infection varies from no symptoms or mild respiratory...

Acute respiratory distress syndrome was first described in 1967 and has become a defining condition in critical care. Around 40% of patients with ARDS will die, and survivors experience long term sequelae. No drug treatments exist for ARDS, however good supportive management reduces harm and improves outcome. In this podcast, John Laffey,...

Around half of trials that supported new cancer drug approvals in Europe between 2014 and 2016 were judged to be at high risk of bias, in a new study. Huseyin Naci,assistant professor of health policy a the London School of Economics joins us to talk about why potential bias may mean potential exaggeration of treatment effects, and could be...

For the next few months Talk Evidence is going to focus on the new corona virus pandemic. There is an enormous amount of uncertainty about the disease, what the symptoms are, fatality rate, treatment options, things we shouldn't be doing. We're going to try to get away from the headlines and talk about what we need to know - to hopefully give you...

Joachim Spranger
Mar 1, 2003; 52:812-817
Pathophysiology

Parish Histories of Jamaica Project, a publication by the JN Foundation in collaboration with the Department of History and Archaeology at The University of the West Indies, Mona, was launched recently. Jenny Jemmott of Department of History and...

Redlining a Holocaust is a rigorously researched oeuvre that establishes Dòwòti Désir as one of the most important figures in contemporary African thought. Redlining is an imaginative and monumental undertaking, a literary, visual, and oratorical...

Fasting hyperinsulinemia precedes the development of type 2 diabetes. However, it is unclear whether fasting insulin hypersecretion is a primary driver of insulin resistance or a consequence of the progressive increase in fasting glycemia induced by insulin resistance in the prediabetic state. Herein, we have discovered a mechanism that specifically regulates non–glucose-stimulated insulin secretion (NGSIS) in pancreatic islets that is activated by nonesterified free fatty acids, the major fuel used by β-cells during fasting. We show that the mitochondrial permeability transition pore regulator cyclophilin D (CypD) promotes NGSIS, but not glucose-stimulated insulin secretion, by increasing mitochondrial proton leak. Islets from prediabetic obese mice show significantly higher CypD-dependent proton leak and NGSIS compared with lean mice. Proton leak–mediated NGSIS is conserved in human islets and is stimulated by exposure to nonesterified free fatty acids at concentrations observed in obese subjects. Mechanistically, proton leak activates islet NGSIS independently of mitochondrial ATP synthesis but ultimately requires closure of the K_ATP channel. In summary, we have described a novel nonesterified free fatty acid–stimulated pathway that selectively drives pancreatic islet NGSIS, which may be therapeutically exploited as an alternative way to halt fasting hyperinsulinemia and the progression of type 2 diabetes.

Insulin-induced hypoglycemia leads to far-ranging negative consequences in patients with diabetes. Components of the counterregulatory response (CRR) system that help minimize and reverse hypoglycemia and coordination between those components are well studied but not yet fully characterized. Here, we tested the hypothesis that acyl-ghrelin, a hormone that defends against hypoglycemia in a preclinical starvation model, is permissive for the normal CRR to insulin-induced hypoglycemia. Ghrelin knockout (KO) mice and wild-type (WT) littermates underwent an insulin bolus-induced hypoglycemia test and a low-dose hyperinsulinemic-hypoglycemic clamp procedure. Clamps also were performed in ghrelin-KO mice and C57BL/6N mice administered the growth hormone secretagogue receptor agonist HM01 or vehicle. Results show that hypoglycemia, as induced by an insulin bolus, was more pronounced and prolonged in ghrelin-KO mice, supporting previous studies suggesting increased insulin sensitivity upon ghrelin deletion. Furthermore, during hyperinsulinemic-hypoglycemic clamps, ghrelin-KO mice required a 10-fold higher glucose infusion rate (GIR) and exhibited less robust corticosterone and growth hormone responses. Conversely, HM01 administration, which reduced the GIR required by ghrelin-KO mice during the clamps, increased plasma corticosterone and growth hormone. Thus, our data suggest that endogenously produced acyl-ghrelin not only influences insulin sensitivity but also is permissive for the normal CRR to insulin-induced hypoglycemia.

There will be a lot of attention paid to D-backs infielder Jake Lamb when Spring Training gets underway. Lamb, of course, is coming off a season that was almost entirely lost to a left shoulder injury. His healthy return would play a big part in helping the D-backs' offense overcome the departures of Paul Goldschmidt and A.J. Pollock during the offseason.

11 February 2020

One of the least developed countries in sub-Saharan Africa, the Democratic Republic of the Congo has experienced significant migration outflows and inflows tied to political and economic crises in recent decades. While most Congolese migrants head to neighboring countries, destinations have diversified, with an uptick in those leaving for opportunities in Europe and beyond. This country profile explores historical and contemporary patterns of migration to and from DR Congo.

OBJECTIVE

We examined the association of lactation duration with incident type 2 diabetes among women with a history of gestational diabetes mellitus (GDM).

Angelo Avogaro
May 1, 2011; 34:S285-S290
Hypertension

TODAY Study Group
Jun 1, 2013; 36:1758-1764
TODAY Study

OBJECTIVE

Obesity is associated with microvascular insulin resistance, which is characterized by impaired insulin-mediated microvascular recruitment. Glucagon-like peptide 1 (GLP-1) recruits skeletal and cardiac muscle microvasculature, and this action is preserved in insulin-resistant rodents. We aimed to examine whether GLP-1 recruits microvasculature and improves the action of insulin in obese humans.

Beginning March 25, the ADA is offering members two free e-books a week. Until March 31, members can access “Managing the Regulatory Environment: Best Practices” and “A Dentist’s Guide to the Law: 228 Things Every Dentist Should Know” free of charge.

A recorded webinar will stream April 27 outlining the Association’s interim recommendation for personal protective equipment in dental settings as some states consider loosening social distancing mandates.

Anakinra, a drug developed to treat rheumatoid arthritis might help patients who have developed acute respiratory distress syndrome caused by COVID-19, a small study published by The Lancet Rheumatology has found.

OBJECTIVE

The LEADER trial (ClinicalTrials.gov reg. no. NCT01179048) demonstrated a reduced risk of cardiovascular (CV) events for patients with type 2 diabetes who received the glucagon-like peptide 1 receptor agonist liraglutide versus placebo. The mechanisms behind this CV benefit remain unclear. We aimed to identify potential mediators for the CV benefit observed with liraglutide in the LEADER trial.

According to conventional wisdom, front-runners win presidential nominations. Democrats and Republicans who start the race for a presidential nomination with the largest amount of money and the best poll numbers are supposed to be the ones most likely to walk away with victory months later.

Last year, as the financial meltdown was getting underway, a scientist named Yaneer Bar-Yam developed a computer model of the economy. Instead of the individuals, companies and brokers that populate the real economy, the model used virtual actors. The computer world allowed Bar-Yam to do what...

“I’m a confused Mexican Jew.” So says Daniel Lubetzky, Founder and CEO of KIND Snack, in his very personal interview with Columbia faculty member David Rogers at BRITE ’16. Their discussion touched on the many ideas behind KIND Snacks, from the beginnings of the company, to the strategic thinking that forces Lubetzky to stay away […]

The June 2020 issue of History of Psychiatry is now online. Full details follow below: “Wild melancholy. On the historical plausibility of a black bile theory of blood madness, or hæmatomania,” Jan Verplaetse. Abstract: Nineteenth-century art historian John Addington Symonds coined the term hæmatomania (blood madness) for the extremely bloodthirsty behaviour of a number of … Continue reading New History of Psychiatry: Melancholy, Madness, Chinese Psychiatry, Psychedelic Therapy, and More →

AHP readers may be interested in a recent piece on “History of Spanish Psychology, 1800–2000” in the Oxford Research Encyclopedia of Psychology. Full details below. “History of Spanish Psychology, 1800–2000,” by Javier Bandrés. Abstract: In the history of Spanish psychology in the 19th century, three stages can be distinguished. An eclectic first stage was defined … Continue reading History of Spanish Psychology, 1800–2000 →

The clitoris is an organ that has been wildly misunderstood and mischaracterized for most of human history. The last three decades have dramatically changed the way that scientists think and talk about the clitoris; however, many myths and misconceptions remain.

In much of the world, gender is viewed as binary: man or woman, each assigned characteristics and traits designated by biological sex. But that's not the case everywhere, says France Villarta. In a talk that's part cultural love letter, part history lesson, he details the legacy of gender fluidity and inclusivity in his native Philippines -- and emphasizes the universal beauty of all people, regardless of society's labels.