Public Release: 

JCI table of contents: October 1, 2002

JCI Journals

Please find below two highlighted articles and the full table of contents for the October 1 issue.

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NOT ALL MAMMALS VOMIT -- OR HOW TO STUDY EMESIS IN MICE

If biologists have learned anything over the past decade, it is how similar all mammals are at the genetic level. Greater than 90% of the genes found in mice are also found in humans, and we even share a significant amount of genes and genetic circuitries with creatures as different as fruit flies or puffer fish. This might not come as much of a surprise to physiologists who have long used animals to learn about basic mechanisms in organ function that are shared across vertebrates or mammals, but the extent of overlap is still impressive to most.

In many areas of biomedical research, rats or mice are the animal model of choice. And while most researchers are aware that mice are not just furry little humans that walk on all fours, some fundamental differences surprise even the experts. Among 10 scientists who identify themselves as mouse geneticists, only one was aware that mice (and in fact all rodents) lack a very fundamental behavior: they do not vomit.

While that in itself raises all sorts of interesting questions (for example about the evolution of vomiting, and its advantages and disadvantages for the survival of a species), it poses a very specific problem when one tries to use rodents to study a drug with side effects that include nausea and emesis (the medical term for vomiting).

Annette Robichaud and colleagues at the Merck Frosst Centre for Therapeutic Research in Montreal, Quebec, have faced this problem while developing drugs that inhibit a class of enzymes called class 4 phosphodiesterases, or PDE4s. PDE4 inhibitors have promise for the treatment of airway inflammatory diseases such as asthma, but their therapeutic potential has been limited by side effects of nausea and emesis. These side effects are thought to be caused by inhibition of PDE4s outside the airways. The PDE4 subfamily is composed of 4 subtypes that are present in overlapping but distinct tissues of the body, and the hope is that it might be possible to develop subtype-specific inhibitors that are effective in the airways but do not interfere with PDE4 activity in other tissues.

As a step towards that goal, the researchers at Merck Frosst set out to determine which PDE4 subtype is mediating the emetic response. The most direct way to do so is to take advantage of genetically engineered mice that lack particular subtypes. However, since mice do not exhibit an emetic response, Robichaud and colleagues had to measure a different response that is thought to correlate with emesis in creatures like us that do vomit. Fortunately, such a surrogate response exists: PDE inhibitors reverse the anesthetic effects of a different class of drugs called alpha2-adrenoceptor agonists, and this is thought to act via the same mechanism as the unwanted side effects.

As Robichaud and colleagues report in the October 1 issue of the Journal of Clinical Investigation, by studying the inhibitors ability to reverse anesthesia in mice that lacked two of the PDE4 subtypes, PDE4B and PDE4D, they could infer that inhibition of PDE4D is what mediates much of the emetic response.

The next step will be the development of selective PDE4 inhibitors that do not interfere with PDE4D function. Such drugs would be predicted not to affect alpha2-adrenoceptor agonist-mediated anesthesia in mice. More importantly, and to vindicate this complicated approach to pre-clinical drug development, they will hopefully maintain the beneficial anti-inflammatory effects in human airways without causing human patients to feel sick and vomit.

CONTACT:
Debra Polomeno
Public Relations
Merck Frosst Centre for Therapeutic Research
P.O. Box 1005
Pointe-Claire-Dorval
PQ H9R 4P8
CANADA
Phone 1: 514-428-3540
Fax 1: 514-428-4922
E-mail: debra_polomeno@merck.com

See PDF of the article at: https://www.the-jci.org/press/15506.pdf

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RELAXED MICE MAY PROVIDE NEW CLUES FOR TREATING ANXIETY

Your heart is racing, you're sweating, trembling, feel exhausted and cannot breathe - for over 20 million Americans who face chronic and excessive anxiety each day, these physical reactions to real or imagined danger are well known. Prescription anxiolytics (anxiety-reducing medications), such as clonazepam (Klonopin), alprazolan (Xanax) and lorazepam (Ativan) have been widely employed in the treatment of anxiety disorders to relieve these physical symptoms while other forms of behavioral therapy proceed, however their long-term use is discouraged due to their somewhat addictive potential and sedating side effects. A study reported in the October 1 issue of the Journal of Clinical Investigation (JCI) by Dr. Robert Messing and colleagues from the Ernest Gallo Clinic and Research Center at the University of California, San Francisco, reveals that mice lacking a form of the enzyme protein kinase C (PKCe) are supersensitive to their brain's own calming neurosteroids and exhibit reduced anxiety. The authors suggest that inhibitors of PKCe may be useful in treating anxiety.

Severe and excessive anxiety is associated with irregular levels of neurotransmitters in the brain. These chemicals ferry signals between nerve endings and regulate the activity of nerve cells. An inhibitory agent within the central nervous system, gamma aminobutyric acid (or GABA), is the most important blocker of this communication between neurons and helps control nerve cells from firing too fast. The GABAA receptor forms a closed channel that is triggered to open upon the binding of GABA. A rush of chloride ions through the open channel into the cell inhibits the release of neurotransmitters. In this way, drugs such as barbiturates and the benzodiazepines mentioned above decrease anxiety, induce sleep and even anesthesia.

Earlier studies by this group reveal that mice lacking the gene for PKCe have an increased sensitivity to alcohol, benzodiazepines and barbiturates. These observations have now been extended to include a supersensitivity to the brain's own endogenous neurosteroids that routinely regulate neuron activity. In mice lacking PKCe, the interaction of endogenous neurostreroids with the GABAA receptor (in the presence of GABA) caused the channel to open, and the significant increase in chloride ions rushing into the cell had a greater effect on the inhibition of neurotransmission and significantly reduced anxious behavior in these mice. "Given that enhancers of GABAA receptor activity have proven clinically problematic, the finding that PKCe deficiency yields anxiolytic-like results is promising and it is attractive to imagine that PKCe blockade would result in anxiolysis by making our brains more sensitive to our own endogenous anxiolytics" noted Dr. Joshua Gordon of the Center for Neurobiology and Behavior at New York's Columbia University in his accompanying Commentary in the JCI. Further research is required to define the mechanisms by which PKCe and neurosteroids modulate GABA receptors but these results suggest that PKCe is a possible target for the development of novel therapeutics for the treatment of anxiety.

CONTACT:
Robert Messing
Univ. of Calif. San Francisco
Gallo Center
5858 Horton St., Suite 200
Emeryville, CA 94608
Phone 1: 510-985-3950
Fax 1: 510-985-3101
E-mail: romes@itsa.ucsf.edu

Accompanying Commentary: Anxiolytic drug targets: beyond the usual suspects

Joshua Gordon
Columbia University
Center for Neurobiology and Behavior
New York State Psychiatric Institute
10051 Riverside Drive, Unit 87
New York, NY 10032
USA
Phone 1: 212-543-5309
Fax 1: 212-543-5074
E-mail: jg343@columbia.edu

See PDF of the article at: https://www.the-jci.org/press/15903.pdf

and the commentary at: https://www.the-jci.org/press/16846.pdf

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Table of Contents:

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Anti-peptide autoantibodies and fatal anaphylaxis in NOD mice in response to insulin self-peptides B:9-23 and B:13-23

More than 90% of insulin-reactive T cells from islets of NOD mice react with a particular part of the insulin protein, known as peptide B:9-23. Its sequence is identical in mouse and man, and human T cells also recognize the peptide. Vaccination with an altered peptide ligand of B:9-23 can suppress diabetes in the NOD mouse model and is currently in phase 1 clinical trials. Having been involved in mouse studies that used the peptide in the presence of Freud's adjuvant, George S. Eisenbarth and colleagues have continued to investigate different vaccination regimes in NOD mice. As they report beginning on page xxx, administration of the peptide in the absence of adjuvant provoked a fatal anaphylactic response in NOD mice that depended on the age at vaccination onset, the mode of administration, and the dose. This is an initial report that leaves many questions open, and its relevance for the human situation is unclear. Nevertheless, clinicians involved in studies of peptide vaccines should be aware of the results.

CONTACT:
George Eisenbarth
University of Colorado Health Sciences Center
Barbara Davis Center for Childhood Diabetes
Box B140
4200 East 9th Avenue
Denver, CO 80262
Phone 1: 303-315-4891
Phone 2: 303-315-4124 other fax
Fax 1: 303-315-4892
E-mail: george.eisenbarth@uchsc.edu

See PDF of the article at: https://www.the-jci.org/press/15488.pdf

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The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation

Iron homeostasis is critical for human health. As mammals cannot regulate iron excretion, homeostasis depends on the regulation of dietary iron absorption in the duodenum in response to metabolic needs. Previous studies by Sophie Vaulont and colleagues had implicated hepcidin, a small peptide synthesized in the liver, in the regulation of iron uptake. Usf2 knockout mice lack hepcidin and develop iron overload, whereas overexpression of a hepcidin transgene in the liver leads to iron deficiency and anemia. A study in this issue (pages xxx-yyy) that examines hepcidin levels in other conditions further supports a central role for the peptide in iron homeostasis. Hepcidin mRNA levels dramatically decreased in anemia and hypoxia (both conditions of increased iron absorption), and increased several-fold in response to inflammation. In wild-type mice, this increase was associated with a two-fold decrease in serum iron, whereas iron levels stayed constant, despite inflammation, in mice that lacked hepcidin.

CONTACT:
Sophie Vaulont
Institut Cochin- faculté de Médecine cochin-Port royal
24 rue du faubourg St Jacques
Paris, NULL 75014
USA
Phone 1: 33-144-412-408
Fax 1: 33-144-412-421
E-mail: vaulont@cochin.inserm.fr

See PDF of the article at: https://www.the-jci.org/press/15686.pdf

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Defective insulin secretion in pancreatic b cells lacking type 1 IGF receptor

Early in the development of type 2 diabetes, pancreatic b cells proliferate to compensate for their deteriorating ability to synthesize, store, and secrete insulin in response to metabolic changes. Several lines of evidence have implicated the type 1 IGF receptor (IGF1R) in b cell proliferation, but the perinatal lethality associated with lack of IGF1R function in knockout mice has precluded the in vivo analysis of IGF signaling through this receptor in b cells. Argiris Efstratiadis and colleagues have engineered mice that specifically lack IGF1R in b cells. Unexpectedly, these mice had normal b cell mass but revealed a hitherto unrecognized role for IGF1R-mediated signaling in insulin secretion (see pages xxx-yyy.).

CONTACT:
Domenico Accili
Columbia University
Berrie Research Pavilion
1150 St. Nicholas Av. Room 238A
New York, NY 10032
Phone 1: 212-304-5332
Fax 1: 212-304-7390
E-mail: da230@columbia.edu

See PDF of the article at: https://www.the-jci.org/press/15276.pdf

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Lack of prolactin receptor signaling in mice results in lactotroph proliferation and prolactinomas by dopamine-dependent and -independent mechanisms

Growth of lactotrophs -- prolactin-producing cells in the pituitary -- is controlled through a negative feedback loop that involves the action of prolactin on dopaminergic neurons in the hypothalamus. Subsequent neuronal dopamine release and binding to lactotroph D2 receptors inhibits lactotroph proliferation. To investigate whether prolactin also affects lactotrophs directly, Malcolm J. Low and colleagues compared mice lacking D2 receptors with prolactin receptor knockout mice (pages xxx-yyy). Females from both mutant strains developed large prolactinomas -- pituitary adenomas that produce prolactin. Males had smaller tumors overall, but a significant difference between the two strains emerged: Males lacking the prolactin receptor had larger tumors and higher prolactin levels, along with an additive effect of the compound mutations. Together with data from pharmacologic studies, these results suggest that prolactin inhibits lactotrophs through two distinct mechanisms, indirectly through dopaminergic neurons in the hypothalamus, and directly through an autocrine or paracrine loop in the pituitary.

CONTACT:
Malcolm Low
OHSU
Vollum Institute, L 474
3181 SW Sam Jackson Park Road
Portland, OR 97201
Phone 1: 503-494-4672 Fax 1: 503-494-4976 E-mail: low@ohsu.edu

See PDF of the article at: https://www.the-jci.org/press/15912.pdf

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PPAR gamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis

CONTACT:
Arja Kaipainen
Harvard Medical School
Enders 1050
300 Longwood Avenue
Boston, MA 02115
Phone 1: 617-355-6167
Fax 1: 617-355-7662
E-mail: arja.kaipainen@tch.harvard.edu

See PDF of the article at: https://www.the-jci.org/press/15634.pdf

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Inhibition of endothelial cell survival and angiogenesis by protein kinase A

CONTACT:
Judith Varner
University of California, San Diego
Cancer Center
9500 Gilman Drive
La Jolla, CA 92093-0912
Phone 1: 858-822-0086
Fax 1: 858-822-1325
E-mail: jvarner@ucsd.edu

Accompanying Commentary: Endothelial integrins and angiogenesis: not so simple anymore

Dean Sheppard
San Francisco General Hospital
Lung Biology Center
Building 1, Room 150
1001 Potrero Avenue
San Francisco, CA 94110
Phone 1: 415-206-5901
Fax 1: 415-206-4123
E-mail: deans@itsa.ucsf.edu

See PDF of the article at: https://www.the-jci.org/press/14268.pdf

and the commentary at: https://www.the-jci.org/press/16713.pdf

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Pivotal role of CEACAM1 protein in the inhibition of activated decidual lymphocyte functions

CONTACT:
Ofer Mandelboim
Hadassah Medical School
The Lautenberg Center for General and Tumor Immunology
Jerusalem 91120,
ISR
Phone 1: 9722-675-7515
Phone 2: 9722-675-7516
Fax 1: 9722-642-4653
E-mail: oferman@md2.huji.ac.il

See PDF of the article at: https://www.the-jci.org/press/15643.pdf

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Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice

CONTACT:
J. Charles Jennette
Dept. Of Pathology
University Of North Carolina
303 Brinkhous-Bullite
Chapel Hill, NC 27599-7525
Phone 1: 919-966-2421
Fax 1: 919-966-4542
E-mail: jcj@med.unc.edu

Accompanying Commentary: Antineutrophil cytoplasmic antibody and vasculitis: much more than a disease marker

Vivette D'Agati
Columbia Univ Col P and S
630 W 168th St
New York, NY 10032
USA
Phone 1: 212-305-7460
E-mail: vdd1@columbia.edu

See PDF of the article at: https://www.the-jci.org/press/15918.pdf

and the commentary at: https://www.the-jci.org/press/16699.pdf

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The role of bile salt export pump mutations in progressive familial intrahepatic cholestasis type II

CONTACT:
Lin Wang
Yale University
New Haven, CT 06510
USA
Phone 1: 203-785-3149
E-mail: wangl@yale.edu

See PDF of the article at: https://www.the-jci.org/press/15968.pdf

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IL-12 enhances the natural killer cell cytokine response to Ab-coated tumor cells

CONTACT:
William E. Carson
The Ohio State University
Arthur G. James Comprehensive Cancer Center
N924 Doan Hall
410 W. 10th Avenue
Columbus, OH 43210
Phone 1: 614-293-6306
Fax 1: 614-688-4755
E-mail: carson-1@medctr.osu.edu

See PDF of the article at: https://www.the-jci.org/press/15950.pdf

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Ecto-5¢-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia

CONTACT:
Sean Colgan
Brigham And Women's Hospital
Center for Experimental Therapeutics & Reperfusion Injury, Thorn 704
75 Francis Street
Boston, MA 02115
Phone 1: 617-732-5500 ext: 1401
Fax 1: 617-278-6957
E-mail: colgan@zeus.bwh.harvard.edu

See PDF of the article at: https://www.the-jci.org/press/15337.pdf

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Clinical and molecular analysis of patients with defects in m heavy chain gene

CONTACT:
Mary Ellen Conley
St. Jude Children's Research Hospital
Dept. Of Immunology Rm 5062E
332 N. Lauderdale
Memphis, TN 38101
Phone 1: 901-495-2576
Fax 1: 901-495-3977
E-mail: maryellen.conley@stjude.org

See PDF of the article at: https://www.the-jci.org/press/15658.pdf

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