Results will be published in the February 2009 issue of Alcoholism: Clinical & Experimental Research and are currently available at Early View.

“Alcohol abuse, often in combination with poor nutrition, is responsible for a great deal of permanent organ damage, and that includes the brain,” explained Michael A. Collins, professor of biochemistry at Loyola University Chicago and corresponding author for the research roundtable. “In fact, studies of alcoholics over the years sometimes indicate that brain damage can develop earlier than liver damage, but it simply is not recognized because there are common clinical lab tests for liver disease but not for subtle cognitive impairment.”

Conversely, Collins added, human studies have indicated that mild or moderate social consumption of alcohol can have beneficial effects on the cardiovascular state and cognitive function. “Alcohol in low to moderate concentrations appears to promote cytoprotective cellular mechanisms,” he said, “which might explain some of these epidemiological findings. It seemed important to bring researchers together in this roundtable, in part to inform the research community about these emerging mechanisms.”

Some of the key points discussed were:
Alcohol appears to have a complex relationship with cardiovascular and neurovascular diseases. These include dose-dependent associations with a lower risk of coronary heart disease (CHD), a higher risk of hemorrhagic stroke throughout a range of drinking, a higher risk of ischemic stroke with heavier drinking, and a possible lower risk of dementia or cognitive decline with aging.

“We need greater insight into how cells in the adult brain and heart, in response to moderate alcohol exposure, are able to achieve a relatively protected state with respect to certain insults or cytotoxins,” said Collins. “Knowing more about these mechanisms might allow us to design ‘non-addictive’ molecules that trigger key cytoprotective biochemical steps, for example. This achievement, however small, potentially could have a significant impact, since – worldwide – heart disease is the major killer, and a new case of dementia from all causes is estimated to develop every seven seconds or so.”

Experimental studies with rodents and cultures indicate that moderate alcohol exposure can promote anti-inflammatory processes involving adenosine receptors, protein kinase C (PKC), nitric oxide synthase, and heat shock proteins that may underlie cardioprotection.

“Like many chemicals that we ingest, alcohol is sort of a classic double-edged sword,” said Collins. “With respect to ‘inflammation,’ alcohol in high binge amounts, either directly or through its metabolism, appears to trigger increases in a number of inflammatory players in many cells that include free radicals and inflammatory protein molecules such as cytokines. These are probably responsible for much of the organ damage of alcoholism.”

Yet alcohol in low to moderate amounts seems to do the opposite. “It increases other factors that are typically anti-inflammatory in their effects” said Collins. “After moderate alcohol exposure, we find higher levels of cellular ‘heat shock’ proteins which are well known to be neuroprotective. Of further relevance to the question of aging-dependent cognitive loss is how this alcohol neuroprotection is exerted against beta-amyloid, a neuroinflammatory protein abnormally increased in Alzheimer’s disease and likely underlying the progressive dementia.”

Additional evidence suggests that alcohol may even help lower the risk for dementia via “preconditioning” mechanisms, that is, inducing neuronal survival pathways through its selective activation of PKC and focal adhesion kinase enzymes, the focal adhesion complex, and stabilization of the cytoskeleton.

“I want to emphasize that none of the researchers on this roundtable panel recommends moderate alcohol consumption as a tried-and-true way of reducing the risks of heart disease or cognitive decline,” said Collins. “And there are situations or conditions when any drinking whatsoever should be discouraged, for example, during pregnancy, during adolescence, or prior to driving. On the other hand, if a responsible adult is doing well socially, psychologically and physically with a stable, non-binge pattern of moderate alcohol ingestion, there is no apparent reason to stop.”

###

Alcoholism: Clinical & Experimental Research (ACER) is the official journal of the Research Society on Alcoholism and the International Society for Biomedical Research on Alcoholism. Co-authors of the ACER paper, “Drinking and Alcohol-Related Harm among New Zealand University Students: Findings from a National Web-Based Survey,” were:
Edward J. Neafsey of the Department of Cell Biology, Neurobiology & Anatomy at Loyola University Chicago Stritch School of Medicine; Kenneth J. Mukamal of the Division of General Medicine and Primary Care at Beth Israel Deaconess Medical Center in Boston; Mary O. Gray of the Division of Cardiology at San Francisco General Hospital; Dale A. Parks of the Center for Wine and Cardiovascular Health at the University of Alabama; Dipak K. Das of the Cardiovascular Research Center at the University of Connecticut School of Medicine; and Ronald J. Korthuis of the Department of Medical Pharmacology and Physiology at the University of Missouri School of Medicine. The research and roundtable discussion was funded by the National Institutes of Health, the Loyola University Neuroscience Institute, and the Alcohol Beverage Medical Research Foundation.

Source:
Michael A. Collins, Ph.D.
Loyola University Chicago Stritch School of Medicine

Alcoholism: Clinical & Experimental Research

“Unilever is proud to be playing a major role in this coalition-based, front-of-pack food labeling initiative to help consumers make healthier food and beverage choices, and we commend The Keystone Roundtable for what it has accomplished to date,” said Amanda Sourry, Senior Vice President and General Manager for Foods, Unilever U.S. “As one of the leading food manufacturers and a company whose mission is to deliver ‘Vitality’ by helping people look good, feel good and get more out of life, we have a strong interest and commitment globally to doing so through improved nutrition, and helping consumers make ‘better-for-you’ choices.”

Unilever has played a very active role on the Keystone Food and Nutrition Roundtable, bringing to the table its experience with front-of-pack logo (FOP) programs under its “Eat Smart/Drink Smart” initiative in the U.S. and globally with the Choices Programme. The company joined the Keystone Roundtable in 2007 to be part of a discussion focused on the steady development of science-based strategies for better nutrition via a broad-based, diverse forum with influential thought leaders in the nutrition world.

“We hope that the Smart Choices Program, which follows the same driving principles as the Choices Programme, becomes the standard for FOP nutritional labeling in the United States,” added Sourry. “The end goal is that it will have a positive impact on the nutrition and eating habits of Americans, which could then benefit diet-related health.”

For the companies that voluntarily participate, the Smart Choices Program will replace current systems in the U.S., such as Unilever’s Eat Smart/Drink Smart Program, to create a single and reliable front-of-pack nutrition labeling program. The Smart Choices Program is anticipated to begin appearing on packages in mid-2009.

About Unilever

Unilever’s mission is to add vitality to life. We meet everyday needs for nutrition, hygiene and personal care with brands that help people feel good, look good and get more out of life. Each day, around the world, consumers make 160 million decisions to purchase Unilever products.

In the United States, the portfolio includes major brand icons such as Axe, Ben & Jerry’s, Bertolli, Breyers, Caress, Country Crock, Degree, Dove personal care products, Hellmann’s, Klondike, Knorr, Lipton, Popsicle, Promise, Q-Tips, Skippy, Slim-Fast, Suave, Sunsilk and Vaseline. All of the preceding brand names are registered trademarks of the Unilever Group of Companies. Dedicated to serving consumers and communities where we live, work and play, Unilever employs more than 14,000 people in both the United States and Puerto Rico – generating nearly $10 billion in sales in 2007.

Unilever

“Energy homeostasis may be mediated by both short-term regulators, such as gut hormones, and long-term regulators,” said Takashi Kadowaki of the University of Tokyo. “In this study, we identified, for the first time, a potential long-term regulator that allows energy to be stored efficiently, namely, adiponectin.” The findings offer critical insight into adiponectin’s influence over the central nervous system and suggest that selective inhibition of the chemical in the brain may represent a novel therapeutic strategy for obesity and obesity-linked diseases, he added.

White adipose tissue (WAT) is a major site of energy storage and plays an important role in energy balance, the researchers said. It is also recognized as an important endocrine organ that secretes a number of biologically active signaling proteins, called adipokines. Adiponectin, an adipokine secreted exclusively by WAT, is present at relatively high concentrations in the circulation and has been shown to increase the body’s response to insulin. Studies have also suggested that decreased circulating levels of adiponectin in obesity and type 2 diabetes may contribute to the insulin resistance that characterizes both conditions.

In addition to its peripheral actions on the liver and skeletal muscle, adiponectin has also been reported to have central actions, Kadowaki said. Recently, however, it was reported that adiponectin is undetectable in human cerebrospinal fluid and does not cross the blood-brain barrier, leaving some doubt about its physiological role in the central nervous system, he added.

The researchers now report evidence in mice that adiponectin receptors are present in the hypothalamic region of the brain and that some forms of the chemical enter the cerebrospinal fluid from the blood. Once in the brain, adiponectin enhances the activity of a metabolic enzyme called AMP-activated protein kinase (AMPK) to stimulate greater food consumption. Moreover, the researchers found that adiponectin decreased energy expenditure. They also showed that blood and spinal fluid adiponectin levels in the brain normally increase during fasting and decrease after refeeding, suggesting that adiponectin acts mainly during food shortages.

In adiponectin-deficient mice, AMPK activity in the brain slowed, causing the animals to eat less and expend more energy. That action, in turn, made the animals resistant to becoming obese even on a high-fat diet. Moreover, animals lacking adiponectin lost more fat after 12 hours of fasting than normal mice did.

Blood levels of another fat hormone, leptin, are regulated inversely in relation to serum adiponectin levels, the researchers noted.

“Thus, central adiponectin/leptin signals may represent the physiological pathway by which hypothalamic AMPK activity and food intake are stimulated during fasting and suppressed after refeeding,” they said. “In addition to this short-term regulation of food intake and energy expenditure by adiponectin and leptin, these two adipokines may also participate in the long-term regulation of energy homeostasis. The fundamental roles of leptin and adiponectin seem to be to preserve an adequate fat reserve: leptin acts as a satiety signal, and adiponectin acts as a starvation signal.”

###

The researchers include Naoto Kubota, Iseki Takamoto, and Takashi Kadowaki of the University of Tokyo, CREST, Japan Science and Technology Corporation, and the National Institute of Health and Nutrition in Tokyo, Japan; Wataru Yano, Shinsuke Itoh, Hiroki Kumagai, Hideki Kozono, Hidemi Satoh, Atsushi Tsuchida, Ryozo Nagai, and Kohjiro Ueki of the University of Tokyo in Tokyo, Japan; Tetsuya Kubota of the University of Tokyo, National Institute of Health and Nutrition, and Toho University, Ohashi Hospital in Tokyo, Japan; Toshimasa Yamauchi, Ryo Suzuki, Kazuyuki Tobe of the University of Tokyo, CREST, and Japan Science and Technology Corporation in Tokyo, Japan; Shiki Okamoto, Tetsuya Shiuchi, and Yasuhiko Minokoshi of National Institute for Physiological Sciences in Okazaki, Japan; Masao Moroi and Kaoru Sugi of Toho University, Ohashi Hospital in Tokyo, Japan; Tetsuo Noda of the Japanese Foundation for Cancer Research and Tohoku University School of Medicine in Miyagi, Japan; Hiroyuki Ebinuma of Diagnostics Research Laboratories, Daiichi Pure Chemicals in Ibaraki, Japan; Yoichi Ueta of University of Occupational and Environmental Health in Fukuoka, Japan; Tatsuya Kondo and Eiichi Araki of Kumamoto University in Kumamoto, Japan; Osamu Ezaki of National Institute of Health and Nutrition in Tokyo, Japan; Yasuo Terauchi of Yokohama City University School of Medicine in Kanagawa, Japan.

This work was supported by a Grant-in-Aid for Creative Scientific Research from the Japan Society for the Promotion of Science (10NP0201), a grant from the Juvenile Diabetes Foundation International (1-2003-746), a Grant-in-Aid for the Development of Innovative Technology from the Ministry of Education, Culture, Sports, Science and Technology of Japan, Health Science Research grants (Research on Human Genome and Gene Therapy) from the Ministry of Health and Welfare, a grant for Promotion of Fundamental Studies in Health Science of the Organization for Pharmaceutical Safety and Research (to T. Kadowaki), a grant for Life & Socio-Medical Sciences from the Kanae Foundation, a grant from the Sankyo Foundation of Life Science, and a grant from Astellas Foundation for Research on Metabolic Disorders (to N.K.).

Kubota et al.: “Adiponectin Stimulates AMP-Activated Protein Kinase in the Hypothalamus and Increases Food Intake.” Publishing in Cell Metabolism 6, 55-68, July 2007 DOI 10.1016/j.cmet.2007.06.003 cellmetabolism/

Source: Erin Doonan

Cell Press

University of Queensland researchers working on the world’s longest health study found teens who ate regularly with their family were less likely to be overweight.

Lead researcher, Dr Abdullah Al Mamun from UQ’s School of Population Health said regular family meals could reduce snacking and make for healthier food and social habits.

“Eating together will enable the parent to have better knowledge of the child’s food choices and amount that they tend to eat,” Dr Mamun said of the study, which appears in the latest edition of American journal, Obesity Research.

The study found having a healthy maternal attitude to family eating and diet was more important than the frequency of shared meals.

Even though most mothers said they had a family meal at least once a day, only 43 percent of them said eating together was very or quite important.

The findings have been drawn from the world’s longest running health study – the Mater-University of Queensland Study of Pregnancy, which has followed the progress of Brisbane mothers and their families since 1981.

The survey of 3795 mothers and their teenagers was collected in Brisbane when the teenagers were at age 14, in 1995.

It showed about half the families ate red meat most days and one-fourth had fast food most days or two to three times per week.

Even though more than half of the families had children who played sports four to seven days a week about 40 percent still found enough time to watch five or more hours of TV a day.

Dr Mamun’s paper was co-written, with Mater and University of Bristol researchers and fellow UQ researcher and Mater Study founder, Professor Jake Najman.

The Mater Study was started in 1981 by Professor Najman as a health and social study of 7223 pregnant women.

Researchers have followed the children’s growth over the decades and study was widened to include prenatal, postnatal, childhood and adolescent periods of the child with those babies now in their early 20s.

Dr Abdullah Al Mamun
Research Australia
researchaustralia.au

At the EHU-UPV (University of the Basque Country) Pharmacy Faculty they have been studying the process of the oxidative
degradation of foodstuffs. Research was began with oils, given that these are exclusively (99 %) made up of lipids while, in
subsequent stages, the study will be extended to other foods prone to undergoing processes of oxidative degradation.

Processes of oxidative degradation

Researchers investigated processes of oxidative degradation – notably that caused at 70?C with ventilation – of a broad group
of oils with very wide-ranging compositions. Another degradation process studied was that which is caused by microwave action
that does not heat greater than a temperature of 190 ?C.

In both processes deterioration of the oils takes place. In the first type of process (70 ?C with ventilation) hydroperoxides
are first produced and subsequently aldehydes. In the second kind of process (microwave) it is basically aldehydes produced.
It has to be pointed out that both the oxidative conditions and the composition of the oil determined the velocity of the
degradation and both the nature and concentration of the compounds produced.

These studies have shown, for the first time, that degradation of lipids in foods can produce toxic oxygenated aldehydes.
These compounds, well-known in medical studies for their geno- and cytotoxic activity, considered as markers of oxidative
stress in cells as well as being causal agents of degenerative illnesses, had not previously been detected in foodstuffs.

Researchers have shown that some oils produce these toxic substances in greater quantities and at a greater rate. Virgin
olive oil was, amongst all the oils studied, that which took longer to produce this type of compounds and produced a lower
concentration of them.

The technique

Researchers carried out this investigation, studying the liquid phase of the oil by means of Proton Nuclear Magnetic
Resonance and Fourier Transform Infrarred Spectroscopy, and the gaseous phase of the oil with Solid Phase Microextraccion
techniques followed by Gas Chromatography-Mass Spectrometry. The confirmation of the identity of the aldehydes detected was
carried out with pattern substances and with proton nuclear magnetic resonance spectra for a number of toxic aldehydes
provided by American researchers who are studying the presence of these compounds in damaged cells and tissues.

The presence of toxic oxygenated aldehydes in fats and oils subjected to thermal treatment highlights the need to control the
manufacture and preparation processes of foodstuffs as well as the fatty material employed, given their capacity to generate
these oxygenated aldehydes responsible for degenerative illnesses. This research opens new lines of investigation and
perspectives in the field of food safety.

Contact: Garazi Andonegi
garazielhuyar
34-433-3040
Elhuyar Fundazioa
basqueresearch

The study followed 192 people with Alzheimer’s disease in New York for an average of four and a half years. During that time, 85 of the people died. Researchers found that those who most closely followed a Mediterranean diet were 76 percent less likely to die during the study period than those who followed the diet the least.

“The more closely people followed the Mediterranean diet, the more they reduced their mortality,” said study author Nikos Scarmeas, MD, MSc, of Columbia University Medical Center in New York, and member of the American Academy of Neurology. “For example, Alzheimer’s patients who adhered to the diet to a moderate degree lived an average 1.3 years longer than those people who least adhered to the diet. And those Alzheimer’s patients who followed the diet very religiously lived an average four years longer.” Previous research by Scarmeas and his colleagues demonstrated that healthy people who eat a Mediterranean diet lower their risk of developing Alzheimer’s disease. Studies have also shown that healthy people who follow a Mediterranean diet live longer than those who eat a more traditional Western diet, higher in saturated fat and meats and lower in fruits and vegetables.

“New benefits of this diet keep coming out,” said Scarmeas. “We need to do more research to determine whether eating a Mediterranean diet also helps Alzheimer’s patients have slower rates of cognitive decline, maintain their daily living skills, and have a better quality of life.”

The Mediterranean diet includes a high intake of vegetables, legumes, fruits, cereals, fish, monounsaturated fatty acids; a low intake of saturated fatty acids, dairy products, meat and poultry; and a mild to moderate amount of alcohol.

The study was supported by grants from the National Institute on Aging and the Taub Institute for Research on Alzheimer’s Disease and the Aging Brain at Columbia University.

The American Academy of Neurology, an association of more than 20,000 neurologists and neuroscience professionals, is dedicated to improving patient care through education and research. A neurologist is a doctor with specialized training in diagnosing, treating and managing disorders of the brain and nervous system such as stroke, Alzheimer’s disease, epilepsy, Parkinson’s disease, and multiple sclerosis.

American Academy of Neurology

The international, multi-center trial will compare the best standard treatments — surgical removal of the tumor, radiotherapy or chemotherapy — to that treatment combined with a new, noninvasive therapy that provides alternating electrical fields directly to the surface of the head.

“This therapy is a totally novel approach that is, in concept, relatively simple,” said Dr. Herbert Engelhard, associate professor of neurosurgery and site investigator for the trial at UIC.

Following a baseline MRI to determine the location of the tumor, several electrodes are placed on the patient’s shaved head. The electrodes are connected to a medical device with alternating electric fields powered by a portable battery. The patient remains on the portable device for 22 hours a day, indefinitely, while continuing his or her daily activities at home.

“Research has shown that these electrical fields rupture the cancer cells as they divide,” Engelhard said.

While likely not a cure for the deadly tumor, called glioblastoma multiforme, the therapy, Engelhard says, may extend life for some people. In an earlier small-scale study, the therapy more than doubled survival for glioblastoma patients.

Glioblastoma multiforme is the most deadly of all intracranial tumors. Standard therapy does not provide a cure and often results in side effects that compromise a patient’s quality of life. Despite attempts to improve outcome, the current three-year survival is only 6 percent.

“Patients with recurrent glioblastoma whose tumor progresses despite radiation treatment and chemotherapy do not have many options,” Engelhard said. “Therefore, it’s critical that we consider new therapies for the treatment of this disease.”

Fifty-one-year-old Daniel Torres of Chicago is a pioneer, according to Engelhard. Torres is the first person in the United States randomized to receive the novel therapy.

On Nov. 15 Torres had 36 electrodes placed on his head to emit very low intensity, intermediate frequency electric fields called tumor-treating fields. He was kept in the hospital overnight for observation and discharged the next day.

Torres, a father of four, ages 6 to 16, says the therapy may offer him a second chance at life. He has had three surgeries, chemotherapy, radiation and radiotherapy since he was first diagnosed with glioblastoma multiforme nearly three years ago.

He says he is hopeful for himself, but also for future patients who may benefit from the study.

The trial will enroll 236 patients at 10 U.S. centers and seven in Europe. Half the patients will receive continuous therapy with the NovoTTF-100A in addition to standard treatment and will be evaluated every four weeks; the other half will receive the standard treatment alone. All patients in the study will be evaluated for disease progression.

Funding for the study is provided by NovoCure, Ltd.

The principal investigator of the multi-center trial in the United States is Dr. Philip Gutin at Memorial Sloan Kettering Cancer Center in New York. The principal investigator in Europe is Dr. Roger Stupp at the University of Lausanne in Switzerland.

University of Illinois at Chicago
601 S. Morgan St. MC 288
Chicago, IL 60607-7113
United States
uic.edu/index.html/

A group led by Dr. James M. Musser at the Center for Molecular and Translational Human Infectious Diseases Research of The Methodist Hospital Research Institute in Houston, Texas has demonstrated that the cytotoxin Paton-Valentine leukocidin (PVL) does not affect methicillin-resistant Staphlococcus aureus (MRSA)-induced pneumonia. Their report can be found in the March 2010 issue of The American Journal of Pathology.

Community-associated-MRSA causes a wide spectrum of infections, ranging from mild skin problems to fatal invasive diseases. MRSA spreads rapidly from initial topical symptoms to affect vital organs, often resulting in widespread infection, toxic shock, and ‘flesh eating’ pneumonia. MRSA is resistant to traditional anti-staphylococcal beta-lactam antibiotics and is therefore much more difficult to treat.

The cytolytic toxin PVL is a CA-MRSA virulence factor that has been epidemiologically associated with the development of invasive, and sometimes fatal, pneumonia in affected patients and has therefore become a target for new therapeutics. To explore the role of PVL in invasive MRSA, Olsen et al examined both wild-type and PVL-deficient MRSA in a model of CA-MRSA pneumonia. They found no effect of PVL on virulence in MRSA-associated pneumonia, as a PVL-mutated strain caused similar lower respiratory tract pathology as a wild-type strain. These data highlight the importance of context in the pathogenesis of MRSA-associated pneumonia.

Additional studies are underway by Dr. Musser and colleagues “to test the hypothesis that PVL enhances pathogenesis during influenza virus co-infection. These studies are especially important in the context of the recent global spread of a H1N1 influenza strain and widespread concerns about a detrimental effect on human health.”

Olsen RJ, Kobayashi SD, Ayeras AA, Ashraf M, Graves SF, Ragasa W, Humbird T, Greaver JL, Long D, Cantu C, Swain JL, Jenkins L, Blasdel T, Cagle P, Gardner DJ, DeLeo FR, Musser JM: Lack of a major role of Staphylococcus aureus Panton-Valentine leukocidin in lower respiratory tract infection in non-human primates. Am J Pathol 2010, 176: 1346-56

Novel Inhibitor of Tumor Angiogenenesis

Dr. Suneel S. Apte and colleagues at the Lerner Research Institute, Cleveland Clinic Foundation in Cleveland, OH have discovered that the metalloprotease ADAMTS9 inhibits tumor angiogenesis. They present these findings in the March 2010 issue of The American Journal of Pathology.

Angiogenesis, or the growth of new blood vessels, is a critical step in the transition of tumors from dormant to malignant. Therefore, angiogenesis inhibitors form a major therapeutic approach to cancer treatment.

The metalloprotease ADAMTS9 functions as a tumor suppressor in throat and nose cancer. Mice partially deficient for Adamts9 spontaneously form new blood vessels, suggesting that it may play an inhibitory role in tumor angiogenesis. Koo et al found that capillary cells in both healthy tissue and tumors expressed ADAMTS9. Moreover, mice that lack one copy of Adamts9 had a greater level of new vessel formation in tumors than wild-type mice, and blocking ADAMTS9 in vitro resulted in increased signs of vessel formation. Indeed, ADAMTS9 inhibits angiogenesis through a different mechanism than a similar molecule, ADAMTS1.

Dr. Apte and colleagues conclude that “ADAMTS9 may be of broad relevance to all angiogenesis-dependent cancers through its novel and constitutive expression in capillary [endothelial cells] and physiological anti-angiogenic role.”

Koo B-H, Coe DM, Dixon LJ, Somerville RPT, Nelson CM, Wang LW, Young ME, Lindner DJ, Apte SS: ADAMTS9 is a cell-autonomously acting, anti-angiogenic metalloprotease expressed by microvascular endothelial cells. Am J Pathol 2010 176, 1494-1504

New Pathway in the Development of Colon Cancer

Researchers led by Dr. Dalila Darmoul of the Institut National de la Sant?© et de la Recherche M?©dicale (INSERM) in Paris, France have found that Kallikrein-related peptidase 4 (KLK4) may activated protease-activated receptors (PARs), promoting the development of colon cancer. They report their data in the March 2010 issue of The American Journal of Pathology.

Colon cancer causes 655,000 deaths worldwide per year and is the fifth most common form of cancer in the United States. Colon cancers arise from usually benign polyps in the colon, which may develop into cancer over time.

Proteases promote cancer progression both by degrading the extracellular matrix and by signaling through PARs, which can induce proliferation and motility in colon cancer cells. The physiological activators of PARs in colon cancer remain unknown. Gratio et al hypothesized that KLKs, which have been shown to function as PAR activators in vitro and in vivo, may activate PARs in colon cancer. They found that KLK-4 was expressed in colon adenocarcinomas, but absent from normal endothelium, and that KLK-4 expression resulted in loss of PAR1 and PAR2 in a colon cancer cell line. Taken together, these results suggest that KLK-4 may be an endogenous ligand for PAR activation in colon cancer and therefore may provide a novel therapeutic target.

Dr. Darmoul’s group indicates that “concomitant upregulation of KLK4 and PAR1 in colonic tumors would suggest that KLK4-mediated PAR1 activation could play an important role in colon tumorigenesis.”

Gratio V, Beaufort N, Seiz L, Maier J, Virca GD, Debela M, Grebenchtchikov N, Magdolen V, Darmoul D: Kallikrein-related peptidase 4 (KLK4): a new activator of the aberrantly expressed protease-activated receptor 1 in colon cancer cells. Am J Pathol 2010, 176 1452-1461.

Reversing Remodeling in Chronic Inflammation

Dr. Li-Chin Yao and colleagues of the University of California, San Francisco, CA have discovered that remodeling of lymphatic vessels may be more persistent than blood vessel remodeling as a result of inflammation. These results are presented in the March 2010 issue of The American Journal of Pathology.

Vessel remodeling plays a pathogenic role in a number of chronic inflammatory diseases, including asthma, chronic obstructive pulmonary disease, rheumatoid arthritis, Crohn’s disease, and skin lesions in psoriasis. Reversal of such remodeling could prevent long-term complications from these diseases.

Yao et al used mice infected with the bacteria Mycoplasma pulmonis to induce vessel remodeling as a result of inflammation; these mice were then treated with the anti-inflammatory corticosteroid dexamethasone to examine the reversibility of vessel remodeling. In the absence of dexamethasone, both blood and lymphatic vessel remodeling occurred, whereas concurrent dexamethasone treatment prevented this remodeling. In contrast, dexamethasone treatment after two weeks of remodeling reversed blood vessel changes but not lymphangiogenesis; it also decreased the number of lymphocytes but not neutrophils and macrophages. Thus, lymphatic remodeling may be more persistent than blood vessel remodeling and may play a larger role in future inflammatory episodes.

The study by Yao et al shows that “changes in blood vessels and lymphatics are easier to prevent than to reverse in chronic inflamed airways. … A better understanding of the role of distinct growth and maintenance factors that first induce the growth of blood and lymphatic vessels and then protect them from regression in chronic inflammatory disease may provide insight to the vascular contribution to the course of inflammatory disease.”

Yao L-C, Baluk P, Feng J, McDonald DM: Steroid-resistant lymphatic remodeling in chronically inflamed mouse airways. Am J Pathol 2010, 176: 1525-1541

Source:
Angela Colmone, Ph.D.
American Journal of Pathology

“What’s unique in this study is that brain-processing activities seemed to help aspects of memory that were not directly exercised by the program – a new finding in memory research,” says Glenn Smith, Ph.D., Mayo Clinic neuropsychologist and lead researcher on the study.

The research, a controlled, multisite, double-blind study, will be published in the April issue of the Journal of the American Geriatrics Society. A copy is available online Feb. 9, 2009.

For an hour a day, five days a week for eight weeks, study participants worked on computer-based activities in their homes. The participants, from Minnesota and California, were age 65 or older. No one had a diagnosis of cognitive impairment, such as early Alzheimer’s disease.

The control group, with 245 adults, watched educational videos on art, history and literature topics. They completed quizzes on the content.

The experimental therapy group, with 242 adults, completed six auditory exercises designed to help the brain improve the speed and accuracy of processing. For example, participants were asked to distinguish between high- and low-pitched sounds. To start, the sounds were slow and distinct. Gradually, the speed increased and separation disappeared.

“The sounds go faster and faster, until it ends up sounding almost like a click,” says Dr. Smith. The difficulty increases only as participants master each step with 85 percent accuracy. Other exercises, such as matching or distinguishing between similar-sounding words, for example, pop and pot, also were part of the skill building.

The commercially available program was developed by Posit Science, a San Francisco company that financed the research. Mayo Clinic researchers do not have financial ties to this business.

At the end of eight weeks, researchers used a standardized tool to measure participants’ memory changes. Called the Repeatable Battery for the Assessment of Neuropsychological Status, it includes tasks such as repeating words or numbers after hearing them once.

“We found that the improvement in these skills was significantly greater in the experimental group – about double,” says Dr. Smith.

Participants in the experimental group self-reported memory improvement, too, indicating the change was noticeable in day-to-day tasks.

While the study results are statistically significant, Dr. Smith says it is important to understand the extent of the memory boost. Collectively, the experimental group’s memory function increased about 4 percent over the baseline measured at the study’s onset. The control group’s overall memory gain was about 2 percent.

But, Dr. Smith says, because participants were in generally good health, the results don’t offer insights on preventing Alzheimer’s or other forms of dementia.

Results indicate that aging adults may be able to make better-informed decisions about ways to improve memory. “Brain processing speed slows as we age,” says Dr. Smith. “The study indicates that choosing a memory-enhancing approach that focuses on improving brain processing speed and accuracy, rather than memory retention, may be helpful.”

There’s no harm in trying other approaches – mnemonics, workshops or even doing crosswords or playing piano, he says, but there’s little evidence these methods sustain benefits in memory.

Other researchers involved in this study include: Patricia Housen, Ph.D., and Elizabeth Zelinski, Ph.D., both with Leonard Davis School of Gerontology, University of Southern California, Los Angeles; Kristine Yaffe, M.D., University of California, San Francisco; Ronald Ruff, Ph.D., Stanford University, Stanford, Calif.; Robert Kennison, Ph.D., California State University, Los Angeles; and Henry Mahncke, Ph.D., Posit Science Corporation, San Francisco. His affiliation with this company is noted in the journal article.

Mayo Clinic
mayoclinic

Huckabee Announces Candidacy
In related news, former Arkansas Gov. Mike Huckabee (R) on Sunday announced that he has formed a presidential campaign exploratory committee for 2008. Huckabee said he supports an expansion of health insurance for children, adding, “Some of us Republicans actually like kids” (Lawrence, USA Today, 1/29). According to the Los Angeles Times, Huckabee might “be best known nationally for his efforts to promote health and for his own dramatic 110-pound weight loss” (Serrano, Los Angeles Times, 1/29).

“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.