Bariatric surgery procedures have similar therapeutic benefits in obese adults
Obesity is associated with insulin resistance and type 2 diabetes, both of which can be significantly improved by weight loss. Gastric bypass and adjustable gastric banding are two bariatric surgery techniques that are frequently used to effect weight loss in obese patients, but it is unclear if the two procedures produce different outcomes. In this issue of the Journal of Clinical Investigation, researchers led by Samuel Klein at the University of Washington School of Medicine in St. Louis compared the effects of 20% weight loss induced by either gastric bypass or adjustable gastric banding on metabolic response. They found that patients had different metabolic responses after eating, but both procedures equally improved insulin sensitivity and glucose tolerance. The researchers concluded that weight loss itself is primarily responsible for the therapeutic effects of gastric bypass and adjustable gastric banding in non-diabetic obese adults.
TITLE:
Gastric bypass and banding equally improve insulin sensitivity and β-cell function
AUTHOR CONTACT:
Samuel Klein
Washington University School of Medicine, St Louis, MO, USA
Phone: 314-362-8708; E-mail: sklein@dom.wustl.edu
View this article at: http://www.jci.org/articles/view/64895?key=31c84cf8f52f834d9914
Identifying the cause of anesthesia-induced seizures
Antifibrinolytic drugs are frequently used to prevent blood loss during surgery, but sometimes cause convulsive seizures. In this issue of the Journal of Clinical Investigation, researchers led by Beverly Orser at the University of Toronto investigated the molecular mechanisms that underlie this side effect. By studying antifibrinolytics in mice, Orser and colleagues found that the drugs inhibited the activity of glycine receptors in the brain, leading to seizures. Seizures could be prevented by co-treatment with the general anesthetic isoflurane. This study explains the causes of and proposes treatment for antifibrinolytic-induced seizures. In a companion commentary, Debra Schwinn of the University of Washington reviews the connection between seizures and antifibrinolytic drugs.
TITLE:
Tranexamic acid concentrations associated with human seizures inhibit glycine receptors
AUTHOR CONTACT:
Irene Lecker
Faculty of Medicine, University of Toronto, Toronto, ON, CAN
Phone: 416-978-1518; E-mail: irene.lecker@utoronto.ca
View this article at: http://www.jci.org/articles/view/63375?key=806b0eca4232a067ca57
ACCOMPANYING COMMENTARY
TITLE:
Understanding the TXA seizure connection
AUTHOR CONTACT:
Debra Schwinn
University of Washington, Seattle, WA, USA
Phone: 206-543-2673; Fax: 206-543-2958; E-mail: debra-schwinn@uiowa.edu
View this article at: http://www.jci.org/articles/view/66724?key=bd9895d06f784ef4366f
Parallel structure: Surprising similarities between kidney cells and neurons
The primary function of the kidneys is to filter the blood to remove waste and retain blood cells and proteins. Podocytes are specialized kidney cells that form a filtering structure known as a slit diaphragm. Disruption of the podocytes results in the enlargement of the slit diaphragm, causing nephrotic syndrome, and, eventually, renal failure. In this issue of the Journal of Clinical Investigation, researchers led by Shuta Ishibe and Pietro De Camilli at Yale University identified a protein network in podocytes that is responsible for maintaining the structural integrity of the slit diaphragms. By engineering mice that lack components of this protein network, Ishibe, Camilli, and colleagues found that they could block the formation of the slit diaphragms in the kidney. Interestingly, they found that this protein network is highly similar to the networks that mediate the development of neuronal synapses. In a companion commentary, Rosemary Sampogna and Qais Al-Awqati of Columbia University discuss how these findings alter our understanding of how slit diaphragms function in the ever-changing environment of the kidney.
TITLE:
Role of dynamin, synaptojanin and endophilin in podocyte foot processes
AUTHOR CONTACT:
Shuta Ishibe
Yale University School of Medicine, New Haven, CT, USA
Phone: 203-737-4170; E-mail: shuta.ishibe@yale.edu
View this article at: http://www.jci.org/articles/view/65289?key=b558c1e93de5879b6116
ACCOMPANYING COMMENTARY
TITLE:
Taking a bite: endocytosis in the maintenance of the slit diaphragm
AUTHOR CONTACT:
Qais Al-Awqati
Dept. Of Medicine & Physiology, New York, NY, USA
Phone: 212-305-3512; Fax: 212-305-3475; E-mail: qa1@columbia.edu
View this article at: http://www.jci.org/articles/view/65785?key=28148c95a955cf51dfc9
Mutations in αKlotho underlie a genetic form of rickets
FGF23, a growth factor that regulates the metabolism of calcium and phosphate, binds and activates a circulating receptor known as αKlotho (cKL). In a study published in the Journal of Clinical Investigation, researchers led by Kenneth White at Indiana University describe a patient with a chromosomal translocation that results in increased levels of αKlotho. The patient presented with rickets, low blood phosphate and calcium levels, and increased FGF23. To determine how αKlotho effects these changes, White and colleagues over-expressed cKL in mice and found that increased cKL resulted in enhanced FGF23 levels, decreased serum calcium and phosphate levels, low bone mineral content, and bone fractures. These data establish cKL as an important regulator of FGF23 production and phosphate metabolism and may have implications for the treatment of rickets. In a companion commentary, Harald Jüppner of Massachusetts General Hospital and Myles Wolf of the University of Miami discuss the role of FGF23 and αKlotho in mineral metabolism.
TITLE:
Circulating αKlotho influences phosphate handling by controlling FGF23 production
AUTHOR CONTACT:
Kenneth E White
Indiana University School of Medicine, Indianapolis, IN, USA
Phone: 317-278-6140; Fax: 317-274-2293; E-mail: kenewhit@iupui.edu
View this article at: http://www.jci.org/articles/view/64986?key=7d8ae8802deff9a3caa3
ACCOMPANYING COMMENTARY
TITLE:
αKlotho: FGF23 coreceptor and FGF23-regulating hormone
AUTHOR CONTACT:
Harald Jüppner
Massachusetts Gen Hosp, Boston, MA, USA
Phone: 617-726-3966; Fax: 617-726-7543; E-mail: jueppner@helix.mgh.harvard.edu
View this article at: http://www.jci.org/articles/view/67055?key=97377cc82306b227bcad
USP44 helps cells double check chromosome segregation to prevent cancer
Tumor cells frequently have an irregular number of chromosomes, a condition known as aneuploidy. During cell division, checkpoint proteins stop the process of division to ensure that each daughter cell receives the appropriate number of chromosomes; defects in these checkpoints can cause aneuploidy. In this issue of the Journal of Clinical Investigation, researchers led by Paul Galardy at the Mayo Clinic in Rochester, MN, investigated the role of the checkpoint protein USP44. Using a mouse that lacks Usp44, they found that loss of USP44 prevents chromosomes from splitting evenly between daughter cells. Usp44-deficient mice were prone to spontaneous tumors, particularly in the lungs. Interestingly, low USP44 expression was correlated with poor prognosis in human lung cancer. In a companion commentary, Andrew Holland and Don Cleveland of the University of California, San Diego, discuss how theses findings impact our understanding of aneuploidy in cancer.
TITLE:
USP44 regulates centrosome positioning to prevent aneuploidy and suppress tumorigenesis
AUTHOR CONTACT:
Paul Galardy
Mayo Clinic, Rochester, MN, USA
Phone: 507-284-2695; E-mail: galardy.paul@mayo.edu
View this article at: http://www.jci.org/articles/view/63084?key=3be5fa433c36a4a45295
ACCOMPANYING COMMENTARY
TITLE:
The deubiquitinase USP44 is a tumor suppressor that protects against chromosome missegregation
AUTHOR CONTACT:
Andrew Holland
Ludwig Inst. Cancer Research & UCSD, La Jolla, CA, USA
Phone: 858-534-7899; E-mail: a1holland@ucsd.edu
View this article at: http://www.jci.org/articles/view/66420?key=50440b6db78075ffec3c
A sticky situation: researchers identify mucus-producing pathway in human airway cells
Inflammatory airway diseases such as asthma, COPD, and cystic fibrosis are associated with increased mucus production, but the molecular mechanisms that are responsible for mucus production in these diseases have not been determined. In this issue of the Journal of Clinical Investigation, researchers led by Michael Holtzman at Washington University of St. Louis defined a cell signaling pathway that enhances mucus production in the cells that line the human airway. The pathway, which involves the protein MAPK13, was also activated in human COPD patients. By inhibiting the activity of MAPK13, Holtzman and colleagues were able to reduce mucus production in human airway epithelial cells, suggesting that therapeutics targeting this pathway might be useful for the treatment of mucus production in humans.
TITLE:
IL-13-induced airway mucus production is blocked by MAPK13 inhibition
AUTHOR CONTACT:
Michael Holtzman
Washington University School of Medicine, St. Louis, MO, USA
Phone: 314-362-8970; Fax: 314-362-9002; E-mail: holtzmanm@wustl.edu
View this article at: http://www.jci.org/articles/view/64896?key=33af0229095ae19f52d5
Too much of a good thing: extra VEGF signaling slows tumor growth
Angiogenesis is the formation of new blood vessels. Establishment of a blood supply promotes tumor growth by providing access to oxygen and nutrients. Blood vessel development is largely mediated by a growth factor known as VEGF, which is targeted by anti-angiogenic therapies. In this issue of the Journal of Clinical Investigation, researchers led by Hong Chen at the University of Oklahoma identified two new proteins, epsin1 and epsin2, as important regulators of VEGF-stimulated angiogenesis. VEGF mediates angiogenesis by binding to a cell surface protein that instigates cellular changes that are required for blood vessel formation. Epsins are known to remove proteins from the cell surface, preventing their activation. Normally, the number of VEGF binding proteins (VEGFR) on the cell surface is tightly controlled, but Chen and colleagues found that mice lacking epsin1/2 had a greater number of VEGFR on the cell surface that led to extra VEGF signaling, abnormal tumor vasculature, and slower tumor growth. In a companion commentary, Nancy Klauber-DeMore of the University of North Carolina at Chapel Hill discusses how these findings could contribute to the development of epsin-based therapeutic targeting of tumor angiogenesis.
TITLE:
Endothelial epsin deficiency decreases tumor growth by enhancing VEGF signaling
AUTHOR CONTACT:
Hong Chen
Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
Phone: 405-271-2750; E-mail: hong-chen@omrf.org
View this article at: http://www.jci.org/articles/view/64537?key=8b9e9a01382464f1fc75
ACCOMPANYING COMMENTARY
TITLE:
Are epsins a therapeutic target for tumor angiogenesis?
AUTHOR CONTACT:
Nancy Demore
University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
Phone: 919-216-9754; E-mail: nancy_demore@med.unc.edu
View this article at: http://www.jci.org/articles/view/66171?key=7e2e14d5e5eda41ede24
Mouse model explains how calcium channel mutation causes hypokalemic periodic paralysis
Hypokalemic periodic paralysis (HypoPP) is a skeletal muscle disorder that is characterized by episodes of severe muscle weakness and low serum potassium levels. It is caused be a genetic mutation in protein channels that pump calcium or sodium ions across the cell membrane, but it is unclear exactly how the calcium channel mutations cause muscle weakness. In this issue of the Journal of Clinical Investigation, researchers led by Stephen Cannon at the University of Texas Southwestern Medical Center created a mouse with the HypoPP-associated calcium channel mutation that had symptoms that were similar to human HypoPP. They found that the mutant calcium channel caused changes in the cellular membrane potential that altered the ability of the muscle fibers to contract. This study explains how an inherited mutation causes HypoPP in humans. In a companion commentary, Alfred George of Vanderbilt University discusses how inherited mutations in channels contribute to human disease.
TITLE:
A calcium channel mutant mouse model of hypokalemic periodic paralysis
AUTHOR CONTACT:
Stephen C. Cannon
Southwestern Medical School, Dallas, TX, USA
Phone: 214-648-2564; Fax: 214-648-6306; E-mail: steve.cannon@utsouthwestern.edu
View this article at: http://www.jci.org/articles/view/66091?key=0f8ffec321a1fe4d328b
ACCOMPANYING COMMENTARY
TITLE:
Leaky channels make weak muscles
AUTHOR CONTACT:
Alfred L George, Jr.
Vanderbilt University, Nashville, TN, USA
Phone: 615-936-2660; Fax: 615-936-2661; E-mail: al.george@vanderbilt.edu
View this article at: http://www.jci.org/articles/view/66535?key=6b5240ca1c7bbbfe9a54
A tale of two heme transporters
Erythropoiesis, or the production of red blood cells, is a tightly regulated process that is sensitive to the balance of the proteins that form hemoglobin, heme and globin. The protein FLVCR1a is responsible for removing excess heme from cells and is essential for erythropoiesis. In this issue of the Journal of Clinical Investigation, researchers led by Emanuela Tolosano at the University of Torino in Italy identified another form of FLVCR1, FLVCR1b, that is responsible for exporting heme from the mitochondria of the cell, the location of heme production. By manipulating the expression of the FLVCR1 proteins in mice, Tolosano and colleagues found that FLVCR1b was required for erythropoiesis. FLVCR1a was not required for erythropoiesis, but was necessary to prevent excess bleeding, swelling, and skeletal abnormalities in the developing mouse embryo. These results indicate that mutations in the Flvcr1 gene may underlie diseases characterized by abnormal heme levels, such as Sideroblastic anemia. In a companion commentary, Mark Fleming of Children's Hospital Boston discusses the role of heme transport in human physiology and disease.
TITLE:
The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation
AUTHOR CONTACT:
Emanuela Tolosano
University of Torino, Torino, UNK, ITA
Phone: 39-011-670-6423; Fax: 39-011-670-6432; E-mail: emanuela.tolosano@unito.it
View this article at: http://www.jci.org/articles/view/62422?key=da4e860633582101d3cb
ACCOMPANYING COMMENTARY
TITLE:
Mitochondrial heme: an exit strategy at last
AUTHOR CONTACT:
Mark Fleming
Children's Hospital Boston, Boston, MA, USA
Phone: 617-919-2664; E-mail: mark.fleming@childrens.harvard.edu
View this article at: http://www.jci.org/articles/view/66607?key=70b59624a5b601a3a137
Journal
Journal of Clinical Investigation