JCI table of contents, 16 February 2004

02/10/04

During mammalian reproduction, including that of humans, large amounts of calcium are transferred from mother to offspring through breast milk. Subsequently, adaptive mechanisms are required to maintain a healthy balance of calcium in the mother's body. These involve the breakdown of calcium stores in bone and increased dietary calcium intake in order to maintain a steady supply of calcium to the breast for purposes of milk production. The factors involved in the regulation of calcium stores are largely unknown.

The calcium-sensing receptor (CaR) is known to regulate how our cells respond to fluctuations in extracellular calcium levels. A report from John Wysolmerski and colleagues from Yale University in the February 16 issue of the Journal of Clinical Investigation reveals that in mice, at the transition from pregnancy to lactation, expression of CaR on mammary epithelial cells is upregulated. Dietary restriction of calcium upregulated parathyroid hormone-related protein production during lactation, decreased the calcium content of milk, increased milk osmolality and protein concentration, and decreased overall milk production. Most of these effects were prevented by the infusion of calcimimetic compounds, implicating CaR as the key mediator of these processes. This indicates that the lactating mammary gland can sense calcium increases and losses and adjusts its secretion of calcium accordingly. This helps match milk production with the availability of calcium in the mother's body.

TITLE: The calcium-sensing receptor regulates mammary gland parathyroid hormone–related protein production and calcium transport

AUTHOR CONTACT:
John J. Wysolmerski
Yale University School of Medicine, New Haven, Connecticut, USA.
Phone: 203-785-7447
Fax: 203-785-6015
E-mail: john.wysolmerski@yale.edu

View the PDF of this article at: https://www.the-jci.org/press/18776.pdf

**********************************************

How much is too much VEGF?

Vascular endothelial growth factor (VEGF) is responsible for the growth of blood vessels and VEGF delivery is being tested in clinical trials for its ability to promote vessel growth in heart and muscle when adequate blood supply is lacking. However, the expression of VEGF needs to be tightly controlled in order to avoid excessive vessel growth and the development of abnormally dense collections of vessels known as hemangiomas. To address this need, Helen Blau and colleagues from Stanford University investigated the relationship between VEGF dosage and blood vessel formation. In their report in the February 16 issue of the Journal of Clinical Investigation the authors implanted myoblast cells, which expressed VEGF, into the muscles of mice and documented the resulting new vessel growth. Blau and colleagues were able to distinguish a threshold level of VEGF that distinguished normal from abnormal blood vessel growth. The data indicate that long-term continuous delivery of VEGF, when maintained below a threshold microenvironmental level, can lead to normal blood vessel growth. These findings may guide strategies for therapeutic VEGF delivery.

TITLE: Microenvironmental VEGF concentration, not total dose, determines a threshold between normal and aberrant angiogenesis

AUTHOR CONTACT:
Helen Blau
Stanford University School of Medicine, Stanford, California, USA.
Phone: 650-723-6209
Fax: 650-736-0080
E-mail: hblau@stanford.edu

View the PDF of this article at: https://www.the-jci.org/press/18420.pdf

**********************************************

Neurons so excited that they just can't hide it

Ataxia is a lethal neurological disorder characterized by a lack of muscle coordination. The cerebellar cortex, the surface layer of the hindbrain, is often the target in ataxia and how a disruption in this region results in ataxia is of considerable interest. A report by K. George Chandy and colleagues from the University of California Irvine in the February 16 issue of the Journal of Clinical Investigation links ataxia to enhanced hyperexcitability of neurons in the deep cerebellar nuclei (DCN).

Within the cerebellum a class of output neurons known as Purkinje cells convey signals away from the cerebellum to the DCN. These cells also provide an inhibitory signal to DCN neurons, which ensures a normal firing rate and regular muscle coordination. Chandy and colleagues developed mice in which the small-conductance calcium-activated potassium (SK) channels – regulators of firing frequency – in the DCN were silenced. The authors found that these neurons had an increased firing rate and the mice were ataxic. Importantly, the Purkinje cells input into the DCN remained intact and no other signs of degeneration in the cerebellar cortex or elsewhere in the brain were observed, indicating a direct relationship between DCN firing rate, regulation by SK channels, and proper muscle coordination. The report suggests that reestablishing a normal DCN firing rate might have therapeutic potential in the treatment of this debilitating disease.

TITLE: Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia

AUTHOR CONTACT:
K. George Chandy
University of California, Irvine, Irvine, California, USA.
Phone: 949-824-6370
Fax: 949-824-3143
E-mail: gchandy@uci.edu

View the PDF of this article at: https://www.the-jci.org/press/20216.pdf

ACCOMPANYING COMMENTARY: Into the depths of ataxia

AUTHOR CONTACT:
Harry T. Orr
Institute of Human Genetics, University of Minnesota, Minneapolis, Minnesota, USA.
Phone: 612-625-3647
Fax: 612-626-7031
E-mail: harry@lenti.med.umn.edu

View the PDF of this commentary at: https://www.the-jci.org/press/21092.pdf

**********************************************

The eosinophil enigma in asthma

Eosinophils are cells that accumulate in high numbers in the lungs of asthmatic patients and cause tissue damage. Interleukin-5 (IL-5) is a key signaling factor in the differentiation and proliferation of eosinophils in the bone marrow and their release into the blood, and as such is a prime therapeutic target in the treatment of asthma. Some studies have even demonstrated that deleting the gene encoding IL-5, or blocking IL-5 activity with antibodies is able to suppress eosinophil recruitment to the lung and allergic asthma. However, in clinical trials anti–IL-5 antibody did not improve lung function in asthmatics, despite marked reduction in eosinophil numbers, causing some researchers to conclude that eosinophils are not the cause of lung dysfunction. The role of eosinophils in lung dysfunction has therefore remained a contentious issue.

In the February 16 issue of the Journal of Clinical Investigation David Broide and colleagues from the University of California show that in a chronic repetitive allergen challenge mouse model, IL-5 gene deletion suppresses lung eosinophilia and tissue damage in parallel. These results echo observations made in humans. The data suggest that the eosinophil, despite its checkered history, does indeed make an important contribution to the pathology of asthma.

In an accompanying commentary, Timothy Williams from Imperial College London discusses how these findings add spice to the ongoing debate regarding the role of eosinophils in asthma. Despite early setbacks understanding the mechanisms by which eosinophils mediate lung injury may yet lead to a suitable therapy for allergic diseases such as asthma.

TITLE: Inhibition of airway remodeling in IL-5-deficient mice

AUTHOR CONTACT:
David H. Broide University of California, San Diego, La Jolla, California, USA.
Phone: 858-534-2374
Fax: 858-534-2110
E-mail: dbroide@ucsd.edu

View the PDF of this article at: https://www.the-jci.org/press/19133.pdf

ACCOMPANYING COMMENTARY: The eosinophil enigma

AUTHOR CONTACT:
Timothy J. Williams
Imperial College London, London, United Kingdom.
Phone: 44-020-7594-3159
Fax: 44-020-7594-3119
E-mail: tim.williams@imperial.ac.uk

View the PDF of this commentary at: https://www.the-jci.org/press/21073.pdf

**********************************************

Mast cells and surviving sepsis

Sepsis – the presence of organisms in the blood – is a common and life-threatening disease for which there is little treatment. Mast cells play a role in protecting the host during infection by secreting the cysteine protease dipeptidyl peptidase I (DPPI). To examine the role of DDPI in sepsis, Paul Wolters and colleagues from the University of California, examined mice with and without DDPI in a model of septic peritonitis. In the February 16 issue of the Journal of Clinical Investigation they report that DDPI-/- mice were far more likely to survive sepsis, and it was the absence of DDPI from mast cells, rather than in other cell types, that was responsible for this survival advantage. The report indicates that mast cell DDPI harms the septic host and that DDPI is subsequently a novel potential therapeutic target for the treatment of sepsis.

TITLE: Mast cell dipeptidyl peptidase I mediates survival from sepsis

AUTHOR CONTACT:
Paul Wolters
University of California, San Francisco, San Francisco, California, USA.
Phone: 415-514-2601
Fax: 415-476-9749
E-mail: pjwolt@itsa.ucsf.edu

View the PDF of this article at: https://www.the-jci.org/press/19062.pdf

**********************************************

Understanding reduced sensitivity to steroids

Glucocorticoids are a class of steroids with a broad range of immunomodulatory and anti-inflammatory properties. Synthetic steroids have been used extensively in the treatment of many inflammatory diseases, including autoimmune and allergic disorders, however reduced sensitivity of T cells to glucocorticoids is a common development that complicates the management of chronic inflammatory diseases. In the February 16 issue of the Journal of Clinical Investigation Paul Rothman and Daphne Tsitoura from Columbia University report that it is enhanced MEK/ERK signaling that promotes glucocorticoid resistance in CD4+ T cells. The results suggest that the immune system, by regulating costimulation through MEK/ERK, can modify the effect of glucocorticoids on T cells. Moreover, these findings suggest that MAPK inhibitors may offer a therapeutic solution for glucocorticoid resistance.

TITLE: Enhancement of MEK/ERK signaling promotes glucocorticoid resistance in CD4+ T cells

AUTHOR CONTACT:
Paul B. Rothman
Columbia University College of Physicians and Surgeons, New York, New York, USA.
Phone: 212-305-6982
Fax: 212-305-1870
E-mail: pbr3@columbia.edu

View the PDF of this commentary at: https://www.the-jci.org/press/18975.pdf

**********************************************

Cardioprotective effects of APOE and HDL

High-density lipoprotein (HDL), commonly called "good cholesterol", and its associated apolipoprotein APOE play an important role in preventing atherosclerotic disease. This protective role is associated with the ability to modulate plasma lipid levels, but recent evidence also suggests that APOE and HDL are able to stop the proliferation of aortic smooth muscle cells, which have been implicated in atherosclerosis and heart disease. In the February 16 issue of the Journal of Clinical Investigation Richard Assoian and colleagues from the University of Pennsylvania delve further into this notion by elucidating the mechanism by which HDL and APOE inhibit this proliferation.

The authors used both mouse and human smooth muscle cells to show that APOE and HDL exert their antimitogenic effects through induction of COX-2 gene expression and activation of prostacyclin receptor-signaling pathways. Activation of these pathways led to inhibition of cyclin A expression and blocked entry into what is known as the S-phase of the cellular replication cycle. These studies identify a new target for intervention in the prevention of cardiovascular disease.

TITLE: Antimitogenic effects of HDL and APOE mediated by Cox-2–dependent IP activation

AUTHOR CONTACT:
Richard Assoian
University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Phone: 215-898-7157
Fax: 215-573-5656
E-mail: rka@pharm.med.upenn.edu

View the PDF of this article at: https://www.the-jci.org/press/19097.pdf

**********************************************

Fighting cancer by disrupting protein methylation

The proteins Rho and Ras are often mutated in human tumors. One characteristic that they share is that they end at their carboxyl-terminal with the CAAX motif. The amino acids constituting the –AAX segment are cleaved and the remaining isoprenylcysteine is methylated by the enzyme Icmt. These modifications allow the protein to bind to plasma membranes. A report in the February 16 issue of the Journal of Clinical Investigation by Martin Bergo and colleagues from the Gladstone Institute of Cardiovascular Disease in San Francisco, describes that in mice, in the absence of this methylation, some target proteins have increased stability, while others have decreased stability. The decreased stability of the RhoA protein correlated with an increased resistance to Ras-dependent transformation to an oncogenic (cancer-causing) form, suggesting that this mechanism may be an ideal target for the development of new antitumor therapies.

In an accompanying commentary, Steven Clarke and Fuyuhiko Tamanoi from the University of California discuss current approaches underway attempting to inhibit cellular methylation – a promising approach to anticancer therapy.

TITLE: Inactivation of Icmt inhibits transformation by oncogenic K-Ras and B-Raf

AUTHOR CONTACT:
Martin Bergo
Gladstone Institute of Cardiovascular Disease, San Francisco, California, USA.
Phone: 415-695-3774
Fax: 415-285-5632
E-mail: mbergo@gladstone.ucsf.edu

View the PDF of this article at: https://www.the-jci.org/press/18829.pdf

ACCOMPANYING COMMENTARY: Fighting cancer by disrupting C-terminal methylation of signaling proteins

AUTHOR CONTACT:
Steven G. Clarke
University of California, Los Angeles, Los Angeles, California, USA.
Phone: 310-825-8754
Fax: 310-825-1968
E-mail: clarke@mbi.ucla.edu

View the PDF of this commentary at: https://www.the-jci.org/press/21059.pdf

**********************************************

HDL action on cardiovascular health: is the answer NO?

Circulating levels of the "good cholesterol" HDL, are inversely related to the risk of atherosclerosis, and therapeutic increases in HDL have been shown to reduce the incidence of cardiovascular events such as heart attack. In the February 16 issue of the Journal of Clinical Investigation Bodo Levkau and colleagues from Universitätsklinikum Essen, Germany, show that HDL-associated lysphospholipids stimulate the production of the potent anti-atherogenic signaling molecule nitric oxide (NO), by blood vessel walls. The authors demonstrate the mechanism by which HDL stimulates NO release, inducing vessels to relax and blood pressure to be lowered.

In an accompanying commentary, Philip Shaul and Chieko Mineo from the University of Texas state that "with greater understanding in hand regarding both the underlying mechanisms and their implications, it will then be possible to consider therapeutic manipulation of direct HDL action on the endothelium to optimize cardiovascular health."

TITLE: HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3

AUTHOR CONTACT:
Bodo Levkau
Universitätsklinikum Essen, Essen, Germany.
Phone: 49-201-723-4480
Fax: 49-201-723-4481
E-mail: bodo.levkau@medizin.uni-essen.de

View the PDF of this article at: https://www.the-jci.org/press/18004.pdf

ACCOMPANYING COMMENTARY: HDL action on the vascular wall: is the answer NO?

AUTHOR CONTACT:
Philip W. Shaul
University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Phone: 214-648-2015
Fax: 214-648-2481
E-mail: philip.shaul@utsouthwestern.edu

View the PDF of this commentary at: https://www.the-jci.org/press/21072.pdf

**********************************************

Vanin-1 regulates intestinal inflammation

Vanin-1 is highly expressed in the gut and liver, and drives a reaction resulting in cysteamine – thought to be a key factor in several metabolic pathways. To explore the physiological importance of Vanin-1, Philippe Naquet, Bouchra Gharib, and colleagues from INSERM, France, generated Vanin-1–deficient mice that lack cysteamine. They examined the ability of these mice to fight intestinal injury following NSAID administration or infection with the bacterium Schistosoma. In the February 16 issue of the Journal of Clinical Investigation the authors report that that these mice were more tolerant of intestinal injury, their inflammatory response was reduced, and glutathione stores were increased. Oral administration of cysteamine was able to reverse the protective effects of Vanin-1 deficiency. These studies offer the enzymatic activity of Vanin-1 as a potential new target for anti-inflammatory treatments.

TITLE: Vanin-1-/- mice show decreased NSAID- and Schistosoma-induced intestinal inflammation associated with higher glutathione stores

AUTHOR CONTACT:
Bouchre Gharib
INSERM, Marseille, France.
Phone: 33-491-32 44-54
Fax: 33-491-79-60-63
E-mail: bouchra.gharib@medecine.univ-mrs.fr

View the PDF of this article at: https://www.the-jci.org/press/19557.pdf

**********************************************

Central role for FGF23 in mineral metabolism

An abnormally low level of phosphates in the blood as well as impaired mineralization of bone mark hypophosphatemic diseases such as rickets and osteomalacia. Previous studies have suggested that a hormone-like molecule probably regulates serum phosphate levels. Fibroblast growth factor 23 (FGF23) has also recently been recognized to play a role in several hypophosphatemic diseases. To investigate this further, Takeyoshi Yamashita and colleagues from KIRIN Brewery Company in Japan created mice lacking FGF23. In the February 16 issue of the Journal of Clinical Investigation the authors describe that Fgf23-/- mice has a shortened life span, a high concentration of phosphates and Vitamin D in their blood, and abnormal bone mineralization. While our current knowledge of the factors regulating mineral metabolism is limited, this study does indicate that FGF23 is essential for normal phosphate and Vitamin D metabolism. Further studies with these mice will aid in better understanding mineral metabolism and hypophosphatemic diseases.

TITLE: Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism

AUTHOR CONTACT:
Takeyoshi Yamashita
KIRIN Brewery Company Ltd., Takasaki, Japan.
Phone: 81-27-346-9789
Fax: 81-27-346-1672
E-mail: tyamashita@kirin.co.jp

View the PDF of this article at: https://www.the-jci.org/press/19081.pdf

**********************************************

Gluco-incretins in control of insulin secretion

Insulin secretion is controlled by the pancreatic beta cell glucose sensor and also by sensors at other sites throughout the body. The gluco-incretin hormones GIP and GLP-1 are secreted after nutrient absorption, and represent a secondary system of insulin secretion control. To further investigate this system, Bernard Thorens and colleagues from the Institute of Pharmacology and Toxicology in Lausanne, Switzerland, analyzed mice in which one or both of these hormone receptor genes were inactivated. Their report in the February 16 issue of the Journal of Clinical Investigation indicates that the absence of the GLP-1 and GIP receptors suppresses insulin secretion by a number of mechanisms, supporting a role for GLP-1 and GIP in insulin secretion regulation. These hormones may therefore play a role in the pathogenesis of type 2 diabetes.

TITLE: Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors

AUTHOR CONTACT:
Bernard Thorens
Institute of Pharmacology and Toxicology, Lausanne, Switzerland.
Phone: 41-21-692-53-90
Fax: 41-21-692-53-55
E-mail: bernard.thorens@ipharm.unil.ch

View the PDF of this article at: https://www.the-jci.org/press/20518.pdf

**********************************************

Oncogenic K-ras contributes only in part to acute myeloid leukemia

Acute myeloid leukemia (AML) is a rapidly progressing cancer of the blood affecting immature cells of the bone marrow. Proteins such as K-ras are critical for the maturation of these cells, and oncogenic mutations in K-ras are present in up to 15% of AML patients. In order to better characterize the biological consequences of expressing oncogenic K-ras in immature bone marrow cells, D. Gary Gilliland and colleagues from Harvard Medical School used a conditional expression strategy in mice and report in the February 16 issue of the Journal of Clinical Investigation that oncogenic K-ras induced a myeloproliferative disorder, but not AML, indicating that additional mutations are required for AML development. This model will be useful for assessing the contribution of cooperating mutations in AML, and also testing the therapeutic utility of ras inhibitors.

TITLE: Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease

AUTHOR CONTACT:
D. Gary Gilliland
Harvard Medical School, Boston, Massachusetts, USA.
Phone: 617-525-5525
Fax: 617-525-5530
E-mail: gillilan@hihg.med.harvard.edu

View the PDF of this article at: https://www.the-jci.org/press/20476.pdf

**********************************************

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
    Published on PsychCentral.com. All rights reserved.

 

 

Happiness is having a large, loving, caring, close-knit family -- in another city.
-- George Burns