Salmonella And The Intestinal Cell Defense Mechanism Against It

Salmonella is widely prevalent in the animal kingdom. The reason we do not suffer from severe intestinal infections very often is due to our body’s defence system, which manages to digest invading bacteria. This is why, generally speaking, a healthy human being will only fall ill if he consumes more than 100.000 salmonella bacteria via a contaminated food source, such as eggs or meat. An international team of researchers, led by Prof. Ivan Dikic from the Goethe University in Frankfurt has now found out how body cells recognise salmonella and render it harmless. Understanding this process at a molecular level is crucial in identifying new targets for treatment. Tropical and sub-tropical countries in particular, where various sub-species of salmonella are common, are experiencing a rapid increase in resistance to antibiotics, with children at greatest risk.

Salmonella infection begins with bacteria entering the epithelial cells of the intestinal mucosa. To prevent them multiplying there, special cell organelles, called autophagosomes are activated. These encircle the invaders and then become absorbed in other organelles – lysosomes – that contain certain special digestive enzymes, which break down the bacteria into their constituent parts. But how exactly do the autophagosomes recognise salmonella? Prof. Ivan Dikic and his research group at the Biochemistry Institute II have now shed light on this mechanism.

As reported in a current article in the scientific journal Science, the salmonella are marked as ‘waste material’ by the molecule ubiquitin. In order for the autophagosomes to become active, the marked bacteria have to bind to another molecule – LC3 – on the autophagosomal membrane. Here, the protein optineurin plays a key role, linking the marked Salmonella to the autophagosmal LC3, thereby setting off a process of selective autophagy. But optineurin becomes active as a link only after being chemically modified by an enzyme, (in this case it is phosphorylated by the protein kinase TBK1). “We suspect that phosphorylation acts as a regulated switch to trigger selective autophagy of bacteria but might also prove significant in other cargoes like protein aggregates or damaged mitochondria” explains Prof. Ivan Dikic, underlining the importance of these findings. It is thought that impaired autophagy processes may be implicated in, among other things, the development of cancer as well as neurodegenerative diseases.

In the area of infectious diseases, these findings are particularly relevant in view of the fact that gastrointestinal disease caused by Salmonella enterica has rapidly increased since the mid-1980s. In Germany, approx. 30,000 cases were reported to the health authorities in 1985, but by 2005 the figure has risen to 52,000. Worldwide, 94 million people fall ill each year with acute gastroenteritis, and 155,000 of these die. Typhoid, a disease also caused by Salmonella, affects 16 million people annually and mortality rates reach 200,000, with children in particular falling victim to the disease. Bacteria are becoming increasingly resistant to antibiotics so that the potential for treating disease is limited. Chloramphenicol, a formerly popular broad-spectrum antibiotic, is now ineffective, and even Fluoroquinolones, currently a commonly prescribed antibiotic, is proving inadequate in fighting bacteria. As co-author Prof. Dirk Bumann from the Biozentrum at Basel University puts it: “There is a pressing need to find new forms of treatment for infectious diseases. A better understanding of how the body’s own defence mechanism makes use of autophagy will certainly help.”

Publication:
Philipp Wild et al: Phosphorylation of the Autophagy Receptor Optineurin restricts Salmonella growth, Science 26th May 2011 advanced online publication (Science DOI: 10.1126/science.1205405)

Source:
Prof. Ivan Dikic

Goethe University Frankfurt

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Attorneys For Abortion Provider Tiller File Motion Asking For Change Of Presiding Judge

Attorneys representing Kansas abortion provider George Tiller — who has been charged with 19 misdemeanors for allegedly violating a state law that requires an independent, consulting physician to approve some late-term abortions — filed a motion Monday asking that the presiding judge in his case be changed, the AP/Lawrence Journal-World reports (Hegeman, AP/Lawrence Journal-World, 8/14).

State Attorney General Paul Morrison (D) in June filed charges alleging that Tiller, who owns Women’s Health Care Services in Wichita, Kan., received a second opinion from physician Ann Kristin Neuhaus before performing 19 late-term abortions in 2003. Morrison said Neuhaus had financial ties with Tiller. A 1998 Kansas law says that before an abortion of a fetus of 21 weeks’ gestation or more, two physicians must determine if continuation of a pregnancy will lead to death or “substantial and irreversible” harm to a “major bodily function.” The consulting physician agreeing on the necessity of a late-term abortion cannot have legal or financial ties to the abortion provider.

Tillers’ attorneys have entered a not guilty plea to the alleged misdemeanors and filed a motion to dismiss the charges. In the motion, his attorneys argued that the provision requiring two or more doctors to sign off on late-term abortions is unconstitutional because it is vague, it violates a woman’s right to obtain an abortion as outlined in previous court decisions, and it places an undue burden on a physician’s right to practice medicine. If convicted, Tiller could face up to one year in jail and a $2,500 fine for each of the 19 misdemeanor charges.

Judge Assignment
Sedgwick County, Kan., Chief Criminal Judge Gregory Waller on Friday assigned Tiller’s case to Judge Anthony Powell, who served as a Republican state legislator from 1995 to 2002. Powell voted regularly for restrictions on abortion laws, including a 1998 law restricting late-term abortions. Powell in 1998 said Tiller was “defying legal and moral authority” by performing late-term abortions.

Powell on Friday during a hearing for the case said his judgment would not be affected. He also asked attorneys if they objected to his appointment. Tiller attorney Lee Thompson said, “We trust the court’s judgment in that regard” (Kaiser Daily Women’s Health Policy Report, 8/13). Defense attorney Laura Shaneyfelt on Monday said that Thompson’s comments at the hearing were about whether Powell should allow amicus briefs to be filed, not about Powell’s appointment. She also said Thompson meant that he trusted Powell not to be influenced significantly by a brief filed on behalf of his former legislative colleagues.

Thompson on Monday declined to comment on the motion, adding, “Kansas law prohibits us from stating the grounds in the initial motion.” Morrison also declined to comment on the defense motion, Morrison’s spokesperson, Frances Gorman, said, adding that prosecutors have no current plans to ask for Powell’s removal. Powell did not return a message for comment on the motion, the AP/Journal-World reports (AP/Lawrence Journal-World, 8/14).

Related Editorial
Although Powell is capable of “putting aside his personal and political views” and ruling “on the merits” of Tiller’s case, his “high-profile antiabortion past makes him the wrong person to sit in judgment” and “[h]e should recuse himself,” a Wichita Eagle editorial says.

According to the editorial, Powell says his previous statements and legislative past are “irrelevant” to his role as a judge. “Normally, that might be true,” the editorial says, adding, “But other factors here are more personal and compromising: The legislation that Powell helped craft specifically targeted Tiller and his clinic. And Powell made negative statements at the time directed at Tiller, who is now the defendant in his court.”

“Powell should recognize these obvious problems of perception and remove himself from the case,” the editorial says, concluding that the “overriding concern here should not be to give Powell the benefit of the doubt but to give Tiller a fair trial” (Wichita Eagle, 8/14).

“Reprinted with permission from kaisernetwork. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at kaisernetwork/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork, a free service of The Henry J. Kaiser Family Foundation . © 2005 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

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Reducing Cost Of Birth Control For College Women ‘Victory For Common Sense,’ NYT Editorial Says

The fiscal year 2009 omnibus spending bill (H.R. 1105) President Obama signed into law last week includes “a welcome provision designed to make affordable birth control available to millions of women across the country,” a New York Times editorial states, noting that the provision “is not a subsidy and will impose no burden on taxpayers.” The provision restores a “limited exemption from Medicaid pricing rules that was in effect for nearly 20 years” and allows drug companies to supply contraceptives to college health centers, Planned Parenthood offices and other family planning clinics “at an extreme discount that could be passed on to patients,” according to the editorial. The editorial continues that the exemption was eliminated as the result of a “technical drafting error” in the 2005 Deficit Reduction Act and, “until now, efforts to correct the mistake went nowhere, owing to Republican opposition.” According to the editorial, “Washington’s dawdling” in making the correction “has had a stark effect,” pushing the monthly cost of brand-name birth control from $5 to $40 or $50 on some college campuses.

The editorial cites comments from Rep. Joseph Crowley (D-N.Y.), who noted that the fix will reduce a financial burden for college and low-income women as well as help to reduce the number of unintended pregnancies. It continues, “This victory for common sense follows a string of positive steps already taken by President Obama to dismantle his predecessor’s assault on women’s reproductive health and freedom.” For example, Obama “has lifted the odious gag rule that former President George W. Bush imposed on international family planning groups and moved to rescind an 11th-hour Bush regulation aimed at hindering women’s access to abortion, contraceptives and the information necessary to make decisions about their own health.” The editorial concludes, “There is much more to be done, but the shift in momentum is refreshing” (New York Times, 3/14).

Reprinted with kind permission from nationalpartnership. You can view the entire Daily Women’s Health Policy Report, search the archives, or sign up for email delivery here. The Daily Women’s Health Policy Report is a free service of the National Partnership for Women & Families, published by The Advisory Board Company.

© 2009 The Advisory Board Company. All rights reserved.

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Several new bird flu outbreaks in China

As several new outbreaks of bird flu are reported across China, China’s battle with bird flu (avian flu) is intensifying.

One third of China’s regions (12 provinces) have suspected cases of bird flu. There are 17 new cases.

Four other outbreaks have been confirmed as the deadly H5N1 virus. Tests are being conducted to confirm the other areas.

The first case of bird flu (reported case) appeared only a week ago. The Chinese authorities have moved quickly to slaughter the affected animals and quarantine surrounding areas.

The World Health Organisation says it has requested information on the surveillance and vaccination efforts but nothing has been forthcoming.

No human cases of the virus have been reported in China.

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Seventh Annual Gastrointestinal Cancers Symposium Press Program Announced

Four studies from the seventh annual Gastrointestinal (GI) Cancers Symposium Press Program will be highlighted in an embargoed presscast (press briefing via live webcast) on Wednesday, January 20, from 12:00-1:30 PM (EST). The featured studies will focus on advances in the detection and treatment of colorectal, gastric and pancreatic cancers.

During the presscast, researchers will present four featured studies, including:

– Findings on the effectiveness of a simple CD24 blood test for detecting colorectal cancer and polyps. CD24 is a protein involved in colorectal cancer cell adhesion and metastasis.

– Results of a study evaluating the PAM4 antibody assay for detecting early-stage pancreatic cancer.

– A randomized, phase III trial evaluating the effectiveness of capecitabine (Xeloda) and oxaliplatin (Eloxatin) with 5-fluorouracil plus leucovorin (5-FU/LV) for stage III colon cancer; the study also assessed whether treatment efficacy is influenced by patient age.

– A study examining the influence of a variation in the CD44 gene on clinical outcome in people with localized gastric cancer.

This year’s Symposium will take place from January 22 through January 24, 2010, at the Orlando World Center Marriott in Florida, and will feature more than 500 abstracts on a variety of gastrointestinal cancers including cancers of the esophagus, stomach, hepatobiliary, pancreas, small bowel, colon, and rectum. There are approximately 275,000 cases and more than 135,000 deaths due to these cancers in the U.S. every year.

Four leading medical specialty societies co-sponsor the three-day, multidisciplinary symposium, including the American Gastroenterological Association (AGA), the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO) and the Society of Surgical Oncology (SSO).

Source
ASCO

View drug information on Eloxatin; Xeloda.

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Fertile? Not Without The Brain

There are many causes of infertility. The fact that nerve cells can also play a role is little known. The hormone estrogen regulates the activity of neurons that give the starting signal for ovulation. Collaborating with international research groups, scientists at the German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ) have studied this signaling pathway in detail and have discovered new causes of infertility.

The time of a woman’s monthly ovulation depends on how far the egg is matured and on the brain being informed about this. Estrogen, a hormone produced in the ovaries, transmits this message to the brain around the 14th day of the fertility cycle. In response, the stimulated neurons trigger increased release of another hormone called gonadotropin from the pituitary gland and, thus, give the signal for ovulation. “The better we understand how estrogens work and what may go wrong in the interaction with neurons, the more possibilities we will have to counteract infertility,” says Professor G?nther Sch?tz, head of the Division of Molecular Biology of the Cell I at the German Cancer Research Center. Sch?tz and his co-workers, collaborating with Professor Allan Herbison in New Zealand and two research groups in the U.S., demonstrated that only a specific group of neurons in the brain receive the hormone signal. These cells need to have the estrogen receptor alpha in order to recognize the message and subsequently trigger production of the necessary sex hormones.

Estrogen receptors are specialized on perceiving the estrogen hormone. Two types of estrogen receptors, alpha and beta, are found in the nervous system. It has been known that female animals suffer from lesions in the ovaries, mammary glands and uterus when they lack the estrogen receptor alpha. “Every single one of these defects is sufficient to make the animals infertile,” says biochemist Dr. Tim Wintermantel. Moreover, there were indications suggesting that estrogen receptor beta is also relevant for fertility. The scientists performed several experiments to find out more about the role played by the two estrogen receptors in the activation of neurons in the brain.

They studied mice who lacked the estrogen receptor alpha only in nerve cells. Additional estrogen given to these animals failed to trigger the hormone signal for ovulation. Furthermore, the investigators administered synthetic molecules developed and provided by Schering AG, Berlin, to healthy female mice. These substances activated exclusively the estrogen receptor alpha. This alone was sufficient to increase hormone production substantially. “Both experiments led to corresponding results,” explains Tim Wintermantel. “The estrogen receptor alpha needs to be not only present but also activated.”

Nevertheless, a gap in the researchers’ model became apparent: The neurons that are critical for the release of the messenger substance gonadotropin do not have the estrogen receptor alpha. How do the gonadotropin producers receive the signal to increase hormone release if they are unable to receive the estrogen message? The researchers discovered that a second group of neurons in the hypothalamus transmits the message. They demonstrated that these mediators are equipped with the alpha antenna and that they use long cellular extensions to connect with the cells that induce gonadotropin production in the pituitary gland.

G?nther Sch?tz is convinced that this regulatory cycle is not the only one that estrogen uses to control the activity of neurons. “This could be important, for example, for patients who lack a specific receptor on the gonadotropin producing cells and who are infertile because of this,” he says. Therefore, the medical researcher plans to investigate further signaling pathways of estrogen in the brain with his co-workers in future.

About the DEUTSCHES KREBSFORSCHUNGSZENTRUM

The Deutsches Krebsforschungszentrum (DKFZ) Heidelberg was founded as a non-profit organization and supraregional research center by the Land (state) Baden-Wuerttemberg in 1964. It was constituted as a foundation of public law. Since 1975, it has been a Gro?forschungseinrichtung (National Research Center). It is mainly funded by the Bundesforschungsministerium (Federal Ministry for Research and Technology) (90 %) and by the Ministerium fuer Forschung und Wissenschaft (Ministry for Research and Sciences) of the Land Baden-Wuerttemberg (10 %). Additional funding is obtained by other public and private sources e.g. the Deutsche Forschungsgemeinschaft (German Science Association), special projects of the European Union (EU), of Federal and State ministries as well as cooperations with the industry and also private donations to the foundation. In accordance with its Statutes and Articles, it is the task of the Center to engage in cancer research. “Cancer research”, a term which every discipline defines quite differently. In a center with a multi-disciplinary structure, the discussion about the research program is a continuous balancing process.

DEUTSCHES KREBSFORSCHUNGSZENTRUM
Im Neuenheimer Feld 280
69120 Heidelberg
dkfz.de/

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Pico-Tesla Starts Pilot Study Of Magneceutical(R) Therapy For Fibromyalgia

Pico-Tesla, The Magneceutical® Company, announced that it has commenced a randomized, double-blind, placebo-controlled pilot study of 30 patients who have fibromyalgia. The pilot study seeks to determine whether the application of magnetic fields generated by Pico-Tesla’s patented Resonator™ system can be effective as an adjunctive therapy to oral medications in ameliorating the symptoms of fibromyalgia.

The study will be coordinated by Miguel Trevino, M.D., Medical Director, Innovative Research of West Florida, Clearwater, Fla. Dr. Trevino is certified to practice medicine by the American Board of Internal Medicine. Innovative Research of West Florida is a leading Clinical Research Site.

“We are excited about expanding the clinical indications for Magneceutical® Therapy, and pleased to have Dr. Trevino coordinating our pilot study to establish the clinical potential of Magneceutical® Therapy for fibromyalgia patients,” said Allen Braswell, CEO of Pico-Tesla.

Fibromyalgia (pronounced fy-bro-my-AL-ja) is a common and complex chronic pain disorder that affects people physically, mentally and socially. Fibromyalgia, which has also been referred to as fibromyalgia syndrome, fibromyositis and fibrositis, is characterized by chronic widespread pain, multiple tender points, abnormal pain processing, sleep disturbances, fatigue and often psychological distress. For those with severe symptoms, fibromyalgia can be extremely debilitating and interfere with basic daily activities. (Source: National Fibromyalgia Association)

Pico-Tesla’s Magneceutical® Therapy involves the use of an extremely low-level electromagnetic field (EMF) applied by a specially designed device-the Resonator™, invented by Dr. Jerry I. Jacobson, along with proprietary therapeutic protocols-intended to improve a number of the signs and symptoms of fibromyalgia and other disorders and diseases, including atrial fibrillation, Parkinson’s disease, Alzheimer’s disease and osteoarthritis.

Source:

Pico-Tesla, The Magneceutical® Company

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Highlights From The Journal Of Clinical Investigation April, 2006

Using stem cells to repair torn tendons

Weekend athletes who overexert themselves running or playing basketball may one day reap the benefits of research that shows adult stem cells can make new tendon tissue. Researchers Dan Gazit and colleagues at Hadassah Medical Center in Israel engineered mouse mesenchymal stem cells (MSCs), which reside in the bone marrow and fat tissue, to express a protein called Smad8 and another called BMP2, each involved in the formation of bone and cartilage. When the researchers filled small sponges with these cells and implanted the sponges into torn Achilles tendons of rats, they found that the cells not only survived the implantation process, but were recruited to the site of the injury and able to repair the tendon for at least 7 weeks after implantation. The cells changed their appearance to look more like tendon cells (tenocytes), and significantly increased production of collagen, a protein critical for creating strong yet flexible tendons and ligaments. Tendon tissue was detected using a special type of imaging known as proton DQF MRI, which recognizes differences among collagen-containing tissue such as tendon, bone, skin, and muscle. The authors note that BMP and Smad proteins are involved in other tissues such as nerve and liver, suggesting that this type of delivery technology may be helpful for other degenerative diseases. The study appears in the April issue of the Journal of Clinical Investigation.

In an accompanying commentary, Dwight A. Towler and Richard Gelberman from Washington University School of Medicine in St. Louis, states that “given our limited understanding of how MSCs become tenocytes, the recent progress demonstrated in these studies is quite remarkable and may be potentially useful in cell-based therapeutic approaches to musculoskeletal injuries.”

TITLE: Neotendon formation induced by manipulation of the Smad8 signaling pathway in mesenchymal stem cells

AUTHOR CONTACT: Dan Gazit
Hebrew University-Hadassah Medical Center, Jerusalem, Israel

Phone: 972-2-6757627; Fax: 972-2-6757628; E-mail: dgazcc.huji.ac.il

View the PDF of this article at: https://www.the-jci/article.php?id=22689

ACCOMPANYING COMMENTARY:

TITLE: The alchemy of tendon repair: a primer for the (S)mad scientist

AUTHOR CONTACT: Dwight A. Towler
Washington University School of Medicine, St. Louis, Missouri, USA

Phone: (314) 454-7434; Fax: (314) 454-8434; E-mail: dtowlerim.wustl.edu

View the PDF of this article at: https://www.the-jci/article.php?id=28320

CARDIOLOGY

No more Mr. Nice Guy: why having a big heart is dangerous to your health

Increased signaling through a protein called Gq in heart cells (called myocytes) is thought to be involved in the formation of an enlarged heart (hypertrophy) and the resulting heart failure. Thus it is surprising that patients with high blood pressure who receive drugs that block alpha1-adrenergic (alpha1A/B) receptors, which signal through Gq, demonstrate a two-fold higher risk of developing heart failure, compared to patients taking a diuretic. Now, in a new study in the April issue of the Journal of Clinical Investigation, researcher Paul C. Simpson and colleagues at the San Francisco VA Medical Center in California examine how this occurs, by studying cardiac hypertrophy development in mice genetically modified to no longer express alpha1A/B receptors. The researchers found that, compared to normal mice, these alpha1A/B “knockout” (ABKO) mice demonstrated rapid heart failure and death following a surgical procedure to induce heart failure. In addition, the ABKO animals that did survive demonstrated higher rates of myocyte death as well as elevated fibrosis, or scarring, of the heart tissue. The study suggests that alpha1A/B and Gq signaling are specifically necessary for a normal response to increased pressure on the heart, and is part of a molecular signaling program used by the heart to adapt to stress.

In an accompanying commentary, Stephen B. Liggett from the University of Maryland School of Medicine in Baltimore notes that, “although previous studies have suggested that approaches that decrease this signaling might be protective against the development of heart failure or be beneficial in treatment, the data obtained from this study of alpha1A/B knockout mice provide support for the potential deleterious effects of alpha1-adrenergic blockade.”

TITLE: alpha1-Adrenergic receptors prevent a maladaptive cardiac response to pressure overload

AUTHOR CONTACT: Paul C. Simpson
San Francisco VA Medical Center, San Francisco, California, USA

Phone: (415) 221-4810 ext. 3200; Fax: (415) 379-5570; E-mail: paul.simpsonucsf.edu

View the PDF of this article at: https://www.the-jci/article.php?id=22811

ACCOMPANYING COMMENTARY:

TITLE: Cardiac 7-transmembrane-spanning domain receptor portfolios: diversify, diversify, diversify

AUTHOR CONTACT: Stephen B. Liggett
University of Maryland School of Medicine, Baltimore, Maryland, USA

Phone: (410) 706-6256; Fax: (410) 706-6262; E-mail: sligg001umaryland.edu

View the PDF of this article at: https://www.the-jci/article.php?id=28234

CARDIOLOGY

The heart teams with the kidney to control blood pressure

To control blood pressure, the kidney has evolved a mechanism called the renin-angiotensin system (RAS), in which the protein angiotensinogen is sequentially cleaved by renin (then by another enzyme called ACE) to form the biologically active peptide, angiotensin II (AngII). The secretion of renin is tightly linked to salt intake and the pressure inside the kidney, suggesting that the RAS is central to controlling body fluid volume and blood pressure. Now, in a study appearing in the April issue of the Journal of Clinical Investigation, researcher Roberto Levi and colleagues at Weill Medical College of Cornell University, New York report that cells called mast cells, known to be involved in asthma and allergy, also produce renin. The authors studied isolated guinea pig hearts and found that cardiac mast cells can release renin, and that this release results in the formation of angiotensin in sufficient amounts to cause disease-associated events such as release of norepinephrine (a stress hormone involved in the “fight or flight” response) and cardiac arrythmias (irregular heartbeat). The researchers confirmed that the angiotensin was formed through the action of renin by treating the hearts with an inhibitor of renin, which abolished angiotenisn formation. The researchers confirmed these results using hearts obtained from mice. Production of renin by cardiac mast cells represents a novel mechanism for regulating RAS. The authors note that these findings imply that mast cell-derived renin may be a useful therapeutic target for cardiac dysfunctions associated with arrhythmias, cardiac death, heart attack, and heart failure.

In an accompanying commentary, Thomas M. Coffman from the Durham VA Medical Center in North Carolina states that “although the precise basis for control of renin in mast cells is not clear, this will be a critical area for future research. This discovery suggests a distinct pathway for activation of the RAS that may have a particular impact in the pathogenesis of chronic tissue injury as well as more acute pathology such as arrhythmias in the heart.” He summarizes by stating that, “the finding that mast cells produce renin raises the possibility of an alternate mechanism for regulation of the RAS, controlled by inflammatory mechanisms likely to be quite different from those that regulate renin production in the kidney.”

TITLE: Cardiac mast cell-derived renin promotes local angiotensin formation, norepinephrine release, and arrhythmias in ischemia/ reperfusion

AUTHOR CONTACT: Roberto Levi
Weill Medical College of Cornell University, New York, New York USA

Phone: (212) 746-6223; Fax: (212) 746-8835; E-mail: rlevimedrnell.edu

View the PDF of this article at: https://www.the-jci/article.php?id=25713

ACCOMPANYING COMMENTARY:

TITLE: A new cardiac MASTer switch for the renin-angiotensin system

AUTHOR CONTACT: Thomas M. Coffman
VA Medical Center, Durham, North Carolina, USA

Phone: (919) 286-6947; Fax: (919) 286-6879; Email: tcoffmanacpub.duke.edu

View the PDF of this article at: https://www.the-jci/article.php?id=28312

ENDOCRINOLOGY

Why girls will be girls: molecular safeguards for female sexual development

In the first trimester of human fetal development, the male and female external genitalia are identical. However, although boy and girl babies begin their development as girls, male genital development will occur if high levels of the male steroid hormone testosterone are present at 7-12 weeks, which occurs in female fetuses deficient in an enzyme called CYP21, involved in the production of cortisol. This increase in cortisol is the direct result of a related defect called congenital adrenal hyperplasia, essentially an enlargement of the adrenal glands above the kidneys. Interestingly, if the mother is given a cortisol-like drug called dexamethasone at this point in the pregnancy, the fetal genitalia can be restored back to the female form. Now, in a study appearing in the April issue of the Journal of Clinical Investigation, researcher Neil A. Hanley and colleagues at the Southampton General Hospital in the United Kingdom, report that the reason for this dexamethasone-mediated reversal is due to the drug’s suppression of fetal levels of male hormones (adrenal androgens) produced by a critical determinant of gender known as the “hypothalamic-pituitary-adrenal” (HPA) axis. The researchers analyzed adrenal tissue from 121 human fetuses (following ethical approval from their research ethics committee), and found that although the adrenal gland increased in size over the course of 8-10 weeks of development, the content of cortisol dropped by approximately 50%. Further, the authors found that individual adrenal glands from first trimester fetuses were able to produce several different androgens, including testosterone, and that this androgen production was responsive to ACTH (a hormone of the anterior pituitary). Together these data suggest that the adrenal cortex participates in the production of cortisol and androgens during the first trimester of human development, and that adrenocortical activity is correlated to that of the anterior pituitary, and identify an important mechanism for safeguarding female sexual development.

In an accompanying commentary, Perrin C. White from the UT Southwestern Medical Center in Dallas states that “by demonstrating that there is indeed a functioning fetal HPA axis when the external genitalia are differentiating, the present work provides a rationale for prenatal treatment of congenital adrenal hyperplasia due to CYP21 deficiency.” In addition, he comments that “this study implies that high doses of dexamethasone are most necessary in the relatively narrow time window when cortisol levels would normally be high and the genitalia are differentiating.”

TITLE: In humans, early cortisol biosynthesis provides a mechanism to safeguard sexual development

AUTHOR CONTACT: Neil A. Hanley
Southampton General Hospital, Southampton, United Kingdom

Phone: 44-23-8079-5040; Fax: 44-23-8079-4264; E-mail:N.A.Hanleysoton.ac

View the PDF of this article at: https://www.the-jci/article.php?id=25091

ACCOMPANYING COMMENTARY:

TITLE: Ontogeny of adrenal steroid biosynthesis: why girls will be girls

AUTHOR CONTACT: Perrin C. White
UT Southwestern Medical Center, Dallas, Texas, USA

Phone: (214) 648-3501; Fax: (214) 648-9772; E-mail: Perrin.whiteutsouthwestern.edu

View the PDF of this article at: https://www.the-jci/article.php?id=28296

AUTOIMMUNITY

Antibodies in arthritis: reacting to self

Rheumatoid arthritis (RA) is a painful inflammatory disorder of the joints. Now, in a study appearing in the April issue of the Journal of Clinical Investigation, researcher V. Michael Holers and colleagues at the University of Colorado Health Sciences Center in Denver examine the pathogenic role of antibodies known as “anti-CCP antibodies,” which react against joint proteins that have been “citrullinated” or modified by the addition of a citrulline peptide. The researchers induced arthritis in mice by injecting them with a collagen protein that had been isolated from cows. This procedure resulted not only in the onset of RA in the mice, but also was associated with the production of both anti-collagen and anti-CCP antibodies in the blood. The authors found that sera (blood proteins) from the experimental mouse model of RA and sera from a patient with RA contained antibodies that specifically recognized citrullinated forms of fibrinogen and filaggrin, proteins in the joint tissue. To understand whether these anti-CCP antibodies were a marker of RA, or were involved directly in the destructive process that takes place within the joint during RA disease, the authors delivered to mice antibodies against citrullinated fibrinogen (another protein in the joint), which resulted in an increase in the symptoms of arthritis such as inflammation in the joint, cartilage destruction, bone destruction, as well as changes in the overall appearance of the tissue, including joint swelling. Importantly, animals that were made tolerant (or resistant) to the citrullinated proteins showed a reduced severity of RA. Together, these results demonstrate that antibodies against citrullinated proteins are centrally involved in the pathogenesis of autoimmune rheumatoid arthritis. The authors suggest that future therapeutics which inhibit these antibodies or their development may reduce the severity of disease in patients with active disease, or perhaps even prevent the onset of clinically significant arthritis.

In an accompanying commentary, Cornelia M. Weyand from Emory University School of Medicine in Atlanta states that “the authors deserve praise for these elegant studies, since the study design settles the question of whether anti-CCP antibodies are merely a part of chronic immune stimulation or participate in tissue damage.”

TITLE: Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis

AUTHOR CONTACT: V. Michael Holers
University of Colorado Health Sciences Center, Denver, Colorado, USA

Phone: (303) 315-7952; Fax: (303) 315-5540; E-mail: michael.holersuchsc.edu

View the PDF of this article at: https://www.the-jci/article.php?id=25422

ACCOMPANYING COMMENTARY:

TITLE: Pathomechanisms in rheumatoid arthritis –time for a string theory?

AUTHOR CONTACT: Cornelia M. Weyand
Emory University School of Medicine, Atlanta, Georgia, USA

Phone: (404) 727-7310; Fax: (404) 727-7371; E-mail: cweyandemory.edu

View the PDF of this article at: https://www.the-jci/article.php?id=28300

IMMUNOLOGY

Protection from infection: how antioxidant signaling pathways can help

In a study appearing in the April issue of the Journal of Clinical Investigation, researcher Shyam Biswal and colleagues at the Johns Hopkins University in Baltimore report that mice that fail to express Nrf2, a protein involved in the expression of various antioxidant genes, are dramatically more susceptible to death following acute exposure to a bacterial cell wall sugar called LPS and to surgically-induced sepsis. The authors examined post-LPS-treatment lung inflammation in the mice and found that Nrf2-deficient animals had significantly higher levels of inflammatory cells called neutrophils, as well as higher levels of immune cells called macrophages, as soon as 6 hours after LPS exposure. The treatments also stimulated greater development of pulmonary edema, accompanied by elevated blood levels of the early-phase proinflammatory protein TNF-alpha in the Nrf2-deficient mice, compared to normal mice. Examination of antioxidants revealed that Nrf2-deficient mice expressed severely depressed levels of the tissue-protective enzyme glutathione, suggesting that Nrf2 plays a central role in controlling the body’s proper immune response during infection. The authors note that these results provide insight into the immune system’s response to sepsis and septic shock, and provide avenues for designing novel therapies that could minimize mortality.

In an accompanying commentary, Jay K. Kolls from the Children’s Hospital of Pittsburgh in Pennsylvania, puts the work by Biswal and colleagues into the context of a pressing public health need, when he informs us that “despite decades of advances in antibiotic treatment, sepsis remains an elusive killer, with over 750,000 cases per year in North America, with 40-50% mortality in adults.” In addition, he notes that these studies “confirm the critical role of the cellular redox state in regulating the immune system and support the contention that antioxidants are critical in regulating the cellular response to external stressors.”

TITLE: Nrf2 is a critical regulator of the innate immune response and survival during experimental sepsis

AUTHOR CONTACT: Shyam Biswal
Johns Hopkins University, Baltimore, Maryland, USA

Phone: (410) 955-4728; Fax: (410) 955-0116; E-mail: sbiswaljhsph.edu

View the PDF of this article at: https://www.the-jci/article.php?id=25790

ACCOMPANYING COMMENTARY:

TITLE: Oxidative stress in sepsis: a redox redux

AUTHOR CONTACT: Jay K. Kolls
Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA

Phone: (412) 648-7457; Fax: (412) 692-6645; E-mail: jay.kollschp.edu

View the PDF of this article at: https://www.the-jci/article.php?id=28111

IMMUNOLOGY

Transforming T cells into tumors takes time and tax

Infection with human T cell leukemia virus type 1 (HTLV-1) leads to an aggressive disease called adult T cell leukemia/lymphoma (ATLL) or a related condition called HAM/TSP, following an asymptomatic period of 30 years. HTLV-1 infects blood cells called CD4+ and CD8+ T cells, but only the CD4+ subset becomes leukemic. To better understand why, researchers Eric Wattel and colleagues at the Universit? Claude Bernard in France isolated T cells from patients with HAM/TSP. The authors found that although both subsets of HTLV-1-infected T cells had higher growth rates than uninfected cells, the mechanisms were different: while CD4+ cells were recruited to enter an active process of cell division called the cell cycle, CD8+ cells were prevented from dying. In addition, although the HTLV-1 viral protein called “tax” was present in both subsets of infected cells, only CD4+ T cells displayed abnormalities in their appearance and defects in a type of cell division called cytokinesis. Thus, the effects of HTLV-1 infection are distinct for each T cell subset. Further study showed that the increased cell cycling (as seen in infected CD4+ cells), but not the reduction in cell death (as seen in infected CD8+ cells), correlated with tax levels, suggesting that tax is a critical determinant of the sensitivity of CD4+ cells to leukemia. The study appears in the April issue of the Journal of Clinical Investigation.

In an accompanying commentary, O. John Semmes from Eastern Virginia Medical School in Norfolk, writes that this study will allow researchers to better identify a postinfection, nonmalignant cell-based on some of the cell’s behavior. He further notes that, “the determination of the molecular events that occur between virus infection and disease development has been a particularly challenging area of research.”

TITLE: HTLV-1 propels untransformed CD4+ lymphocytes into the cell cycle while protecting CD8+ cells from death

AUTHOR CONTACT: Eric Wattel
Universite Claude Bernard, Lyon Cedex, France

Phone: 33-478-78-26-69; Fax: 33-478-78-27-17; E-mail: wattellyon.fnclcc.fr

View the PDF of this article at: https://www.the-jci/article.php?id=27198

ACCOMPANYING COMMENTARY:

TITLE: Adult T cell leukemia: a tale of 2 T cells

AUTHOR CONTACT: O. John Semmes
Eastern Virginia Medical School, Norfolk, Virginia, USA

Phone: (757) 446-5904; Fax: (757) 446-5766; E-mail: semmesojevms.edu

View the PDF of this article at: https://www.the-jci/article.php?id=28140

Contact: Brooke Grindlinger
press_releasesthe-jci
Journal of Clinical Investigation

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Molecular Insight Pharmaceuticals Presents AzedraTM 12-Month Efficacy Data From Phase I Clinical Trial In Neuroendocrine Tumors

Molecular Insight Pharmaceuticals, Inc. (NASDAQ: MIPI) reported one-year follow-up data from a Phase I dose-escalation clinical study of Azedra™ demonstrating a positive safety profile and durable objective tumor responses in patients with neuroendocrine cancers, pheochromocytoma and paraganglioma. The study was designed to evaluate the safety and identify the maximum tolerated dose (MTD) of Azedra, as well as to collect clinical data on efficacy. These data were presented on October 2, 2009, at the North American Neuroendocrine Tumor Society (NANETS) 2009 Neuroendocrine Tumor Symposium in Charlotte, North Carolina. Azedra (Ultratrace™ iobenguane I 131) is Molecular Insight’s lead oncology targeted radiotherapeutic using the Company’s proprietary radiolabeling technology platform.

In 12-month data reported today, a single dose of Azedra was shown to be well tolerated by patients, and toxicities were predictable and manageable. Additionally, Azedra demonstrated clinical benefit, stabilizing or reducing tumor volumes in a majority of patients. Twenty-one patients were treated at escalating dose levels from 6 to 9 mCi/kg. Objective tumor response according to Response Criteria in Solid Tumors (RECIST) was obtained every three months. Best confirmed overall response per RECIST was partial response (PR) for three patients (14%), stable disease for 14 (67%), progressive disease for two (10%), and not evaluable for two (10%) who had no follow-up scans. All three patients with PR demonstrated this response at the first post-therapy visit at three months and sustained the response through 12 months.

“Currently, there are no approved treatments in the United States for patients with metastatic neuroendocrine tumors, so a targeted radiotherapeutic such as Azedra that could provide a more potent, effective therapy would be a significant therapeutic advancement,” commented R. Edward Coleman, M.D., of Duke University Medical Center, an author and investigator on the study. “These results at one year after therapy demonstrate that Azedra therapy may potentially benefit many patients who have metastatic pheochromocytoma or paraganglioma.”

Data reported today provide long-term confirmation of preliminary Phase I clinical findings presented at the 2008 American Society of Clinical Oncology (ASCO) Annual Meeting. In June 2009, Molecular Insight Pharmaceuticals initiated a single-arm, pivotal Phase 2 clinical trial for Azedra for the treatment of malignant pheochromocytoma under a Special Protocol Assessment (SPA) by the U.S. Food and Drug Administration (FDA). In addition, Azedra has been granted Orphan Drug designation and Fast Track status by the FDA. Under these programs, Molecular Insight plans to file a New Drug Application (NDA) based on the Phase 2 data and anticipates expedited FDA review of its application.

Phase I Study Overview

The Phase I dose-escalation study was designed to identify the maximum tolerated dose (MTD) of Azedra and to evaluate the safety and efficacy in patients with pheochromocytoma/ paraganglioma. The study results reported today support a maximum tolerated dose of 8 mCi/kg (maximum 600 mCi). Related adverse events were primarily hematologic or gastrointestinal, as expected.

Patient evaluations were scheduled at 3, 6, 9, and 12 months. Long-term follow-up will continue every six months through 5 years after treatment with Azedra. In addition to RECIST criteria, other efficacy evaluations included tumor biomarker response. Hypertension measurement was performed as part of safety evaluations and anti-hypertensive medication taper, discontinuation or changes were not a pre-specified endpoint in this study. Since hypertension typically occurs in more than 90 percent of pheochromocytoma/paraganglioma patients, changes in anti-hypertensive medication from baseline use, as a measure of clinical benefit and tumor response, were also evaluated.

While tumor markers in these patients are known to show frequent and considerable variability in values, many patients with elevated baseline tumor markers showed decreases, with many having normalization of these levels at a post-therapy visit that was consistent with preliminary findings reported previously [ASCO, 2008]. For example, at six months post-therapy, vanillylmandelic acid levels were normalized or decreased by at least 50% for four of the 11 evaluable patients with elevated baseline values. Furthermore, five of 15 (33%) patients on anti-hypertensive medications at time of therapy reduced or discontinued use of these medications following treatment.

Significant side effects observed in the trial were thrombocytopenia, neutropenia, dry mouth, salivary gland pain, nausea, vomiting, fatigue and anorexia. The dose-limiting toxicities were neutropenia (2), febrile neutropenia (1), and thrombocytopenia (1). Two patients died within the 12-month efficacy follow-up (hepatic failure, pulmonary embolism), while three died during long-term follow-up; all deaths were considered by the study investigator to be unrelated to Azedra. In this study, the drug demonstrated favorable dosimetry and a predictable safety profile at all doses tested. Per protocol, 8 mCi/kg (maximum 600 mCi) was confirmed as a tolerable dose in adult patients with pheochromocytoma.

For the study abstract, please visit the Company’s website.

Neuroendocrine Tumors

Neuroendocrine Tumors (NETs) are rare tumors of the nervous and endocrine systems. Until becoming metastatic, they are typically slowly growing and difficult to diagnose. Functional NETs secrete excess hormone, leading to a variety of clinical syndromes, some life threatening and all adversely affecting quality of life.

Pheochromocytomas are NETs that arise from sympathetic nervous system cells in the adrenal gland and often produce catecholamines, resulting in hypertension and other signs and symptoms in many patients. Extra-adrenal pheochromocytomas are called paragangliomas. Approximately 10-15% of patients with pheochromocytoma (pheo)/paraganglioma (para) develop malignant disease with some reports noting >30% of pheos as being malignant. The five-year survival rate for malignant pheo is reported at 50% while patients with metastatic pheochromocytoma have a five-year survival reported between 20-60% with an average of about 35%. Prognosis is worse in patients with metastatic liver or lung lesions where survival is usually less than 2 years. No treatments for pheo/para have been approved in the United States for these rare tumors.

About Azedra and Molecular Insight Pharmaceuticals’ Oncology Pipeline

Azedra recognizes this norepinephrine transporter molecular target that is over-expressed in neuroendocrine tumor cells allowing targeted accumulation at these tumor sites. Azedra, developed using Molecular Insight’s proprietary Ultratrace™ technology, which permits more efficient and high specific activity labeling with the therapeutically active Iodine-131 isotope, permits maximum delivery of the therapeutic potential of iobenguane I 131, a radiotherapeutic currently marketed in Europe to treat neuroendocrine tumors. At a given therapeutic dose, Azedra — high specific activity 131 iobenguane — minimizes the amount of non-radioactive iobenguane molecules administered to the patient, thereby reducing pharmacologic toxicities, especially cardiovascular events or toxicity, and enabling safe, better tolerated and effective treatment.

Azedra is one of two clinical-stage oncology candidates that Molecular Insight is developing for the treatment of neuroendocrine tumors. The Company also is developing Onalta™ (90Y-edotreotide), a radiolabeled somatostatin analog, initially for the treatment of pancreatic neuroendocrine and carcinoid tumors whose symptoms are not controlled by conventional somatostatin analog therapy.

Source
Molecular Insight Pharmaceuticals, Inc.

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Autism – Early failure to pay attention to faces, speech may influence later development

A leading scientist trying to understand and treat autism suspects that a failure to engage in such normal social
activities as looking at a parent’s face or listening to speech sounds early in life may help explain the profound
impairments in social and language development shown by most children with the disorder.

Geraldine Dawson, director of the Autism Center at the University of Washington, will deliver the keynote address today at
the 4th International Meeting for Autism Research being held at the Marriott Boston Copley Place. The meeting will attract
leading scientists from around the world, who will discuss research on genetic factors, brain research, new treatments and
potential environmental factors involved in the development of autism.

Dawson, also a UW psychology professor, said her team has begun testing a new intervention program for toddlers with autism
that not only has a dual focus on language and cognitive development but also promotes the emotional relationship between a
child and other people.

“We are examining whether this very early intervention that focuses on social engagement alters the course of development,”
she said. “As part of our outcomes, we will be examining the child’s brain responses to social stimuli. We hope to find that
our intervention not only affects behavior but also alters the trajectory of early brain development toward a more normal
one.”

Most interventions for children with autism are designed for children of preschool age or older, and there are few such
programs for toddlers. The UW program, however, treats children as young as the researchers can reliably diagnosis with
autism, some just 18 months of age. The program was designed with the assistance of Sally Rogers, a professor of psychiatry
at the University of Colorado Health Sciences Center.

The intervention program is intensive, running 25 to 30 hours per week over a two-year period. It involves cognitive and
motor skills, and also has a strong focus on emotional and social relationships, Dawson said. The intervention includes such
things as children playing games that encourage social activities with their parents or a therapist. The games are modeled
after typical parent-infant games, such as patty-cake, that focus on shared communication and enjoyment.

Previous studies by Dawson and her colleagues have shown that preschool-age children with autism do not show typical brain
responses to faces and speech sounds, but they do have normal responses toward objects. By 7 or 8 months of age a typically
developing a baby’s brain waves register differences between two speech sounds and between familiar and unfamiliar faces.
Children with autism, however, do not show such differences at 3 and 4 years of age.

Other research has shown that normal development of the brain systems involved in speech and face perception requires early
stimulation. Dawson said that a study of American infants exposed to the sounds of Mandarin Chinese that was led by colleague
Patricia Kuhl, co-director of the UW’s Institute for Learning and Brain Sciences, has important implications for
understanding autism.

In that study, groups of 9-month-old infants were shown exactly the same material in Mandarin. One group had the material
presented in person by a Mandarin speaker with whom they could interact socially. The other group saw the speaker only on a
videotape. Only the brains of children exposed to the speaker with whom they could interact socially learned to distinguish
different sounds in Mandarin.

Similarly, children with autism are not able to distinguish English sounds, according to Dawson.

“For speech perception to develop normally, a baby not only must hear speech sounds, but the baby also must be actively
engaged in social interaction that involves speech. In other words, the emotional and social relationship is critical for
normal social and language brain development to occur. The infant or toddler with autism appears to lack a normal preference
or interest for social and language information and fails to actively attend to other people,” she said.

Dawson hopes that by teaching toddlers with autism how to interact socially, this will influence the way the children’s brain
process language and facial information.

For more information, contact Dawson at (206) 543-1051 or dawsonu.washington.edu

On the web, depts.washington.edu/uwautism

Contact: Joel Schwarz
joelsu.washington.edu
206-543-2580
University of Washington
uwnews

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