Milk production may involve a transient development of insulin resistance in non-mammary tissues to support redistribution of maternal macronutrients to match the requirements of the lactating mammary gland. In the present study, adipose and liver metabolic responses were measured in the fasting state and during a 2-step (10 and 20 mU/m²/min) hyperinsulinemic-euglycemic clamp with stable isotopes, in 6-week postpartum women who were lactating (n=12) or formula-feeding (n=6) their infants and who were closely matched for baseline characteristics (e.g., parity, body composition, intrahepatic lipid). When controlling for the low insulin concentrations of both groups, the lactating women exhibited a fasting rate of endogenous glucose production (EGP) that was 2.6-fold greater, and a lipolysis rate that was 2.3-fold greater than the formula-feeding group. During the clamp, the groups exhibited similar suppression rates of EGP and lipolysis. In the lactating women only, higher prolactin concentrations were associated with greater suppression rates of lipolysis, lower intrahepatic lipid and plasma triacylglycerol concentrations. These data suggest that whole-body alterations in glucose transport may be organ specific and facilitate nutrient partitioning during lactation. Recapitulating a shift toward noninsulin-mediated glucose uptake could be an early postpartum strategy to enhance lactation success in women at risk for delayed onset of milk production.

In type 2 diabetes, β-cells endure various forms of cellular stress, including oxidative stress and endoplasmic reticulum stress, secondary to increased demand for insulin production and extracellular perturbations, including hyperglycemia. Chronic exposure to stress causes impaired insulin secretion, apoptosis, and loss of cell identity, and a combination of these processes leads to β-cell failure and severe hyperglycemia. Therefore, a better understanding of the molecular mechanisms underlying stress responses in β-cells promises to reveal new therapeutic opportunities for type 2 diabetes. In this perspective, we discuss posttranscriptional control of gene expression as a critical, but underappreciated, layer of regulation with broad importance during stress responses. Specifically, regulation of mRNA translation occurs pervasively during stress to activate gene expression programs; however, the convenience of RNA sequencing has caused translational regulation to be overlooked compared with transcriptional controls. We highlight the role of RNA binding proteins in shaping selective translational regulation during stress and the mechanisms underlying this level of regulation. A growing body of evidence indicates that RNA binding proteins control an array of processes in β-cells, including the synthesis and secretion of insulin. Therefore, systematic evaluations of translational regulation and the upstream factors shaping this level of regulation are critical areas of investigation to expand our understanding of β-cell failure in type 2 diabetes.

Barttin is the accessory subunit of the human ClC-K chloride channels, which are expressed in both the kidney and inner ear. Barttin promotes trafficking of the complex it forms with ClC-K to the plasma membrane and is involved in activating this channel. Barttin undergoes post-translational palmitoylation that is essential for its functions, but the enzyme(s) catalyzing this post-translational modification is unknown. Here, we identified zinc finger DHHC-type containing 7 (DHHC7) protein as an important barttin palmitoyl acyltransferase, whose depletion affected barttin palmitoylation and ClC-K-barttin channel activation. We investigated the functional role of barttin palmitoylation in vivo in Zdhhc7−/− mice. Although palmitoylation of barttin in kidneys of Zdhhc7−/− animals was significantly decreased, it did not pathologically alter kidney structure and functions under physiological conditions. However, when Zdhhc7−/− mice were fed a low-salt diet, they developed hyponatremia and mild metabolic alkalosis, symptoms characteristic of human Bartter syndrome (BS) type IV. Of note, we also observed decreased palmitoylation of the disease-causing R8L barttin variant associated with human BS type IV. Our results indicate that dysregulated DHHC7-mediated barttin palmitoylation appears to play an important role in chloride channel dysfunction in certain BS variants, suggesting that targeting DHHC7 activity may offer a potential therapeutic strategy for reducing hypertension.

Tumor cells can spread to distant sites through their ability to switch between mesenchymal and amoeboid (bleb-based) migration. Because of this difference, inhibitors of metastasis must account for each migration mode. However, the role of vimentin in amoeboid migration has not been determined. Because amoeboid leader bleb–based migration (LBBM) occurs in confined spaces and vimentin is known to strongly influence cell-mechanical properties, we hypothesized that a flexible vimentin network is required for fast amoeboid migration. To this end, here we determined the precise role of the vimentin intermediate filament system in regulating the migration of amoeboid human cancer cells. Vimentin is a classic marker of epithelial-to-mesenchymal transition and is therefore an ideal target for a metastasis inhibitor. Using a previously developed polydimethylsiloxane slab–based approach to confine cells, RNAi-based vimentin silencing, vimentin overexpression, pharmacological treatments, and measurements of cell stiffness, we found that RNAi-mediated depletion of vimentin increases LBBM by ∼50% compared with control cells and that vimentin overexpression and simvastatin-induced vimentin bundling inhibit fast amoeboid migration and proliferation. Importantly, these effects were independent of changes in actomyosin contractility. Our results indicate that a flexible vimentin intermediate filament network promotes LBBM of amoeboid cancer cells in confined environments and that vimentin bundling perturbs cell-mechanical properties and inhibits the invasive properties of cancer cells.

Motor protein-based active transport is essential for mRNA localization and local translation in animal cells, yet how mRNA granules interact with motor proteins remains poorly understood. Using an unbiased yeast two–hybrid screen for interactions between murine RNA-binding proteins (RBPs) and motor proteins, here we identified protein interaction with APP tail-1 (PAT1) as a potential direct adapter between zipcode-binding protein 1 (ZBP1, a β-actin RBP) and the kinesin-I motor complex. The amino acid sequence of mouse PAT1 is similar to that of the kinesin light chain (KLC), and we found that PAT1 binds to KLC directly. Studying PAT1 in mouse primary hippocampal neuronal cultures from both sexes and using structured illumination microscopic imaging of these neurons, we observed that brain-derived neurotrophic factor (BDNF) enhances co-localization of dendritic ZBP1 and PAT1 within granules that also contain kinesin-I. PAT1 is essential for BDNF-stimulated neuronal growth cone development and dendritic protrusion formation, and we noted that ZBP1 and PAT1 co-locate along with β-actin mRNA in actively transported granules in living neurons. Acute disruption of the PAT1–ZBP1 interaction in neurons with PAT1 siRNA or a dominant-negative ZBP1 construct diminished localization of β-actin mRNA but not of Ca2+/calmodulin-dependent protein kinase IIα (CaMKIIα) mRNA in dendrites. The aberrant β-actin mRNA localization resulted in abnormal dendritic protrusions and growth cone dynamics. These results suggest a critical role for PAT1 in BDNF-induced β-actin mRNA transport during postnatal development and reveal a new molecular mechanism for mRNA localization in vertebrates.

Lens proteins become increasingly cross-linked through nondisulfide linkages during aging and cataract formation. One mechanism that has been implicated in this cross-linking is glycation through formation of advanced glycation end products (AGEs). Here, we found an age-associated increase in stiffness in human lenses that was directly correlated with levels of protein–cross-linking AGEs. α-Crystallin in the lens binds to other proteins and prevents their denaturation and aggregation through its chaperone-like activity. Using a FRET-based assay, we examined the stability of the αA-crystallin–γD-crystallin complex for up to 12 days and observed that this complex is stable in PBS and upon incubation with human lens–epithelial cell lysate or lens homogenate. Addition of 2 mm ATP to the lysate or homogenate did not decrease the stability of the complex. We also generated complexes of human αA-crystallin or αB-crystallin with alcohol dehydrogenase or citrate synthase by applying thermal stress. Upon glycation under physiological conditions, the chaperone–client complexes underwent greater extents of cross-linking than did uncomplexed protein mixtures. LC-MS/MS analyses revealed that the levels of cross-linking AGEs were significantly higher in the glycated chaperone–client complexes than in glycated but uncomplexed protein mixtures. Mouse lenses subjected to thermal stress followed by glycation lost resilience more extensively than lenses subjected to thermal stress or glycation alone, and this loss was accompanied by higher protein cross-linking and higher cross-linking AGE levels. These results uncover a protein cross-linking mechanism in the lens and suggest that AGE-mediated cross-linking of α-crystallin–client complexes could contribute to lens aging and presbyopia.

Barbara H. Braffett
May 1, 2020; 69:1000-1010
Complications

Andrew S. Kimball
Sep 1, 2017; 66:2459-2471
Immunology and Transplantation

Kristian Löbner
Mar 1, 2006; 55:792-797
Pathophysiology

Cheng Hu
Jan 1, 2018; 67:3-11
Perspectives in Diabetes

With Spring Training set to kick off Tuesday, it feels like an opportune time to put together a way-too-early look at who might be with the Giants when they begin their regular season against the Padres on March 28.

This special issue focuses on Diabetes, Covid-19 and Inpatient Management.

Recorded April 14, 2020.

This podcast will cover:

1. Inpatient Medication Management for Persons Admitted with Diabetes
2. Outpatient Medication Management for Persons with Diabetes
   1. Hypoglycemic Medication Management
   2. ACE and ARBs
   3. NSAIDs

Intended for practicing physicians and health care professionals, Diabetes Core Update discusses how the latest research and information published in journals of the American Diabetes Association are relevant to clinical practice and can be applied in a treatment setting.

Presented by:

Neil Skolnik, M.D., Professor of Family and Community Medicine, Sidney Kimmel Medical College, Thomas Jefferson University, Associate Director, Family Medicine Residency Program, Abington Jefferson Health

Dr. Joshua Neumiller, Vice Chair & Allen I. White Distinguished Associate Professor of Pharmacotherapy at Washington State University

Med Treatments India offers one stop solution for medical healthcare services and most affordable treatments facility with best hospitals & alternative treatments in India.

Local real estate players say it could take years for the sector to recover from the economic fallout brought on by the COVID-19 pandemic. While local estimates were unavailable, the international real estate market is projecting a decline from US$...

(CMC): The European Union (EU) will be making a second donation of medical supplies and equipment to Jamaica in support of the country’s efforts to tackle COVID-19, the Head of the EU Delegation to Jamaica, Ambassador Malgorzata Wasilewska,...

Tie the thread to the farmer! Marry the Bride to the Groom! Arrange a wedding for five billion people, We are approaching the end! Road rage is the immediate, And sudden reconfiguration of, A prior expectation and we are doing well, The old lady, the Guru and I, We are making effort. It is, In […]

  We’ve all seen them, Womens circle knitting on, Saturday, Mens having breakfast to learn, How to lead, Ever been inside a church, I mean inside? You know the ones; Don’t Talk on the phone when you’re, Writing notes, Don’t come in late when Next door, Looking over the shoulder of The fat woman in […]

Four companies involved in one of America’s “largest price-fixing cases” are now behind the anti-malaria drug touted by Donald ‘The Great Impeached’ Trump as a snake-oil, cure-all treatment for COVID-19, caused by the novel coronavirus. Several...

At some point over the next six weeks, injuries, improvement or regression will inevitably alter the plan nearly every Major League club brings into Spring Training. The Braves must decide exactly how to round out their rotation and bullpen, but for now it looks like they won't have any position-player battles. Here's the first prediction of how Atlanta's Opening Day roster might look.

Braves manager Brian Snitker joked that he could almost detect a smile as he shared a phone conversation with Nick Markakis after the stoic outfielder re-signed with the club in January. Snitker and others actually saw that smile on Tuesday morning, when Markakis reported to Spring Training to begin his fifth season with the Braves and attempt to push the club past the rebuild he positively enriched through his leadership.

Here's an early look at how the Orioles' 25-man roster could shape up on Opening Day.

The ability to switch fuels for oxidation in response to changes in macronutrient composition of diet (metabolic flexibility) may be informative of individuals’ susceptibility to weight gain. Seventy-nine healthy, weight-stable participants underwent 24-h assessments of energy expenditure and respiratory quotient (RQ) in a whole-room calorimeter during energy balance (EBL) (50% carbohydrate, 30% fat) and then during 24-h fasting and three 200% overfeeding diets in a crossover design. Metabolic flexibility was defined as the change in 24-h RQ from EBL during fasting and standard overfeeding (STOF) (50% carbohydrate, 30% fat), high-fat overfeeding (HFOF) (60% fat, 20% carbohydrate), and high-carbohydrate overfeeding (HCOF) (75% carbohydrate, 5% fat) diets. Free-living weight change was assessed after 6 and 12 months. Compared with EBL, RQ decreased on average by 9% during fasting and by 4% during HFOF but increased by 4% during STOF and by 8% during HCOF. A smaller decrease in RQ, reflecting a smaller increase in lipid oxidation rate, during HFOF but not during the other diets predicted greater weight gain at both 6 and 12 months. An impaired metabolic flexibility to acute HFOF can identify individuals prone to weight gain, indicating that an individual’s capacity to oxidize dietary fat is a metabolic determinant of weight change.

There won't be many roster battles when the Astros open camp later this week, and they won't be decided until the final days of the team's stay in West Palm Beach, Fla. Houston has an open competition for its fifth starter spot heading into Spring Training, and the club also has to sort out a crowded outfield and the final spots in the bullpen.

With this many stars and this much talent, you can't help but have visions of playing baseball deep into October. And considering it was only a year ago the Astros were talking about defending their World Series title, their window to win another one remains wide open.

The National Confidential Enquiry into Patient Outcome and Death (NCEPOD) has been examining the treatment of acute GI bleeds in England's NHS. Two of the authors, Martin Sinclair, consultant surgeon, and Simon McPherson, consultant vascular radiologist, join us to talk about their findings. Read the full...

Medicine has long been a rewarding career, but doctors say the profession needs to overcome the frustrations of working in the NHS to ensure it remains so. During the Big Debate at BMJ Live in London last week six speakers argued for and against the motion, “This house believes that medicine is the best career in the world.” After presentations...

How should health professionals engage with this increasingly popular but unproved practice? Aubrey Cunnington, a consultant paediatrician from Imperial College London joins us to discuss. Read the full editorial: http://www.bmj.com/content/352/bmj.i227

Medical error is not included on death certificates or in rankings of cause of death. Martin Makary, professor of surgery at Johns Hopkins University School of Medicine, joins us to explain why we don't measure medical error, and why it is so important that we start. Read the full analysis: http://www.bmj.com/content/353/bmj.i2139

"I say to all Australian doctors - young, old, the political and the apolitical - that on this depends not just our ethical credibility as a profession, but our shared humanity. " Following the leaked emails published in The Guardian newspaper, alleging abuse of asylum seekers detained by the Australian government on the Pacific island of Nauru,...

Surrogate endpoints are commonly used in clinical trials to get quicker results, however Michael Baum, emeritus professor at University College London, worries that by not focusing on real outcomes - length of life, and quality of life - that these are being used to justify expensive treatments which may not benefit patients. Read the full...

Evidence shows using electronic health records can increase efficiency, and reduce preventable medical errors - but only if they are used properly. However, in the US, the president of the American Medical Association calls them almost unusable. In this debate, Richard Hurley is joined by George Gellert, Regional Medical Informatics Officer at...

Persistent physical symptoms are common and include those symptoms that last at least three months and are insufficiently explained by a medical condition after adequate examination and investigation. Observational studies in primary care report that women, especially those aged 35-45 years, more commonly present with these symptoms. In this...

In this interview from Preventing Overdiagnosis 2017 (preventingoverdiagnosis.net) Stacy Carter, associate professor at Sydney Health Ethics - and the author of a recently written BMJ essay the ethical aspects of overdiagnosis, joins us to talk about how the cultural context of medicine seeps into our decision making processes and affects how...

A new Rapid Recommendation from The BMJ suggests that for pregnant women, they may wish to avoid certain antiviral treatments for HIV. This recommendation differs from the WHO's, and to discuss why that is, and what makes that difference important, we're joined by Reed Siemieniuk, a physician and methodologist from McMaster University, and Alice...

As journal editors, we’re aware of the fact that we have a role to play in scientific discourse - that’s why The BMJ has been so keen to talk about the way in which scientific knowledge is constructed, through our Evidence Manifesto. We also know that money has influence in the scientific literature - which is why we have a zero tolerance policy...

More than ½ of patients leave hospital with changes to four or more of their long-term medications - but how appropriate are those changes? New research published on bmj.com looks at antihypertensive medication prescription changes to try and model that - and found that more than half of intensifications occurred in patients with previously well...

2018 will go down in history as a year of reckoning as the year that that some men’s behaviour came back to bite them. The continuing impact of #MeToo across the world has prompted another round of thinking about women’s experiences in medicine, which can be seen this year’s christmas journal In this podcast, Esther Choo and Eleni Lenos, join us...

In this EBM round-up, Carl Heneghan, Helen Macdonald and Duncan Jarvies are back to give you an update Dual vs single therapy for prevention of TIA or minor stroke - how does the advice that dual work better translate in the UK? Carl explains why Japan can teach us to get active and, how GPs can use that information to "drop a decade" in...

Jönköping has been at the centre of the healthcare quality improvement movement for years - but how did a forested region of Sweden, situated between it's main cities, come to embrace the philosophy of improvement so fervently? Goran Henriks, chief executive of learning and innovation at Qulturum in Jönköping joins us to explain. He also tells...

Change requires the application of power - the way in which individuals can accrue power has shifted in our digitally connected world. Traditional ways of influencing change in healthcare (getting the chief executive on side, having a quiet chat with the medical director) are not the only way to build a momentum. Henry Timms - author of “New...

Welcome back to Talk Evidence - where Helen Macdonald and Carl Heneghan take you through what's happening in the world of Evidence. This month we'll be discussing tramadol being prescripted postoperatively, and a new EBM verdict says that should change(1.36). How much preventable harm does healthcare causes (11.20. A canadian project to help...

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...

If you’re lucky enough to not be back at work, you might be feeling like you need to quickly refresh your medical knowledge - and this podcast the BMJ’s education editors take you on a whistlestop tour through the BMJ’s education articles of 2019. Tom Nolan (GP in London) is joined by Navjoyt Ladher (GP in London), Anita Jain (GP in India) and...

Is it possible to have a fair price for medicines? Yes, according to a new collection just published on bmj.com. The authors set out to evaluate how we could improve the functioning of the market for medicines, to honestly compensate industry for innovation, whilst allowing the poorest to afford them. Suerie Moon, co-director of global health at...

There comes a tipping point in all campaigns when the evidence is overwhelming and the only way to proceed is with action. According to David Williams, it’s time to tackle the disproportionate effects of race on patients in the UK. David Williams, from Harvard University, developed the Everyday Discrimination Scale that, in 1997, launched a new...

Last week the BMJ published it’s first special edition into Racism in Medicine. The issues tacked ranged from differential attainment in medical school, to the physiological effects that experiencing everyday discrimination has. The issue was guest edited by Victor Adebowale, the Chief Executive of the social care enterprise Turning Point, and...

There is no doubt that anxiety levels that clinicians are feeling during this pandemic are high. One military medic believes the current situation is comparable to his experience when posted during British campaigns in Afghanistan and Iraq. Cormac Doyle offers advice on how to deal with high-stress conditions, both in a work and at home, as...