Tag Archives: medical research

Non-infectious Prion Protein Linked to Alzheimer’s Disease

‘Harmless’ prion protein linked to Alzheimer’s disease

Non-infectious prion proteins found in the brain may contribute to Alzheimer’s disease, researchers have found.
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normal prion proteins produced naturally in the brain interact with the amyloid-Î² peptides that are hallmarks of Alzheimer’s disease. Blocking this interaction in preparations made from mouse brains halted some neurological defects caused by the accumulation of amyloid-Î² peptide. It was previously thought that only infectious prion proteins, rather than their normal, non-infectious counterparts, played a role in brain degeneration.
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Alzheimer’s disease has long been linked to the build-up of amyloid-Î² peptides, first into relatively short chains known as oligomers, and then eventually into the long, sticky fibrils that form plaques in the brain. The oligomeric form of the peptide is thought to be toxic, but exactly how it acts in the brain is unknown.

Researchers Find High-Fructose Corn Syrup Results in More Weight Gain

A Princeton University research team has demonstrated that rats with access to high-fructose corn syrup gained significantly more weight than those with access to table sugar, even when their overall caloric intake was the same. In addition to causing significant weight gain in lab animals, long-term consumption of high-fructose corn syrup also led to abnormal increases in body fat, especially in the abdomen, and a rise in circulating blood fats called triglycerides

Photo of Princeton University research team, including (from left) undergraduate Elyse Powell, psychology professor Bart Hoebel, visiting research associate Nicole Avena and graduate student Miriam Bocarsly, by Denise Applewhite

The first study showed that male rats given water sweetened with high-fructose corn syrup in addition to a standard diet of rat chow gained much more weight than male rats that received water sweetened with table sugar, or sucrose, in conjunction with the standard diet. The concentration of sugar in the sucrose solution was the same as is found in some commercial soft drinks, while the high-fructose corn syrup solution was half as concentrated as most sodas.

The second experiment — the first long-term study of the effects of high-fructose corn syrup consumption on obesity in lab animals — monitored weight gain, body fat and triglyceride levels in rats with access to high-fructose corn syrup over a period of six months. Compared to animals eating only rat chow, rats on a diet rich in high-fructose corn syrup showed characteristic signs of a dangerous condition known in humans as the metabolic syndrome, including abnormal weight gain, significant increases in circulating triglycerides and augmented fat deposition, especially visceral fat around the belly. Male rats in particular ballooned in size: Animals with access to high-fructose corn syrup gained 48 percent more weight than those eating a normal diet. In humans, this would be equivalent to a 200-pound man gaining 96 pounds.

“These rats aren’t just getting fat; they’re demonstrating characteristics of obesity, including substantial increases in abdominal fat and circulating triglycerides,” said Princeton graduate student Miriam Bocarsly. “In humans, these same characteristics are known risk factors for high blood pressure, coronary artery disease, cancer and diabetes.” In addition to Hoebel and Bocarsly, the research team included Princeton undergraduate Elyse Powell and visiting research associate Nicole Avena, who was affiliated with Rockefeller University during the study and is now on the faculty at the University of Florida. The Princeton researchers note that they do not know yet why high-fructose corn syrup fed to rats in their study generated more triglycerides, and more body fat that resulted in obesity.

Engineering Mosquitoes to be Flying Vaccinators

Mosquitoes Engineered Into Flying Vaccinators by Emily Singer

Researchers in Japan have transformed mosquitoes into vaccine-carrying syringes by genetically engineering the insects to express the vaccine for leishmaniasis–a parasitic disease transmitted by the sandfly–in their saliva. According to a study in Insect Molecular Biology, mice bitten by these mosquitoes produced antibodies against the parasite. It’s not yet clear whether the immune response was strong enough to protect against infection.

“Following bites, protective immune responses are induced, just like a conventional vaccination but with no pain and no cost,” said lead researcher Shigeto Yoshida, from the Jichi Medical University in JapanYoshida, in a press release from the journal. “What’s more continuous exposure to bites will maintain high levels of protective immunity, through natural boosting, for a life time. So the insect shifts from being a pest to being beneficial.”

Researchers consider the project more of a proof of principle experiment than a viable public health option, at least for now.

Very cool.

Statistical Errors in Medical Studies

I have written about statistics, and various traps people often fall into when examining data before (Statistics Insights for Scientists and Engineers, Data Can’t Lie – But People Can be Fooled, Correlation is Not Causation, Simpson’s Paradox). And also have posted about reasons for systemic reasons for medical studies presenting misleading results (Why Most Published Research Findings Are False, How to Deal with False Research Findings, Medical Study Integrity (or Lack Thereof), Surprising New Diabetes Data). This post collects some discussion on the topic from several blogs and studies.

HIV Vaccines, p values, and Proof by David Rind

if vaccine were no better than placebo we would expect to see a difference as large or larger than the one seen in this trial only 4 in 100 times. This is distinctly different from saying that there is a 96% chance that this result is correct, which is how many people wrongly interpret such a p value.
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So, the modestly positive result found in the trial must be weighed against our prior belief that such a vaccine would fail. Had the vaccine been dramatically protective, giving us much stronger evidence of efficacy, our prior doubts would be more likely to give way in the face of high quality evidence of benefit.
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While the actual analysis the investigators decided to make primary would be completely appropriate had it been specified up front, it now suffers under the concern of showing marginal significance after three bites at the statistical apple; these three bites have to adversely affect our belief in the importance of that p value. And, it’s not so obvious why they would have reported this result rather than excluding those 7 patients from the per protocol analysis and making that the primary analysis; there might have been yet a fourth analysis that could have been reported had it shown that all important p value below 0.05.

How to Avoid Commonly Encountered Limitations of Published Clinical Trials by Sanjay Kaul, MD and and George A. Diamond, MD

Trials often employ composite end points that, although they enable assessment of nonfatal events and improve trial efficiency and statistical precision, entail a number of shortcomings that can potentially undermine the scientific validity of the conclusions drawn from these trials. Finally, clinical trials often employ extensive subgroup analysis. However, lack of attention to proper methods can lead to chance findings that might misinform research and result in suboptimal practice.

Why Most Published Research Findings Are False by John P. A. Ioannidis
Continue reading →

Norway Reduces Infections by Reducing Antibiotic Use

Norway conquers infections by cutting use of antibiotics

Twenty-five years ago, Norwegians were also losing their lives to this bacteria. But Norway’s public health system fought back with an aggressive program that made it the most infection-free country in the world. A key part of that program was cutting back severely on the use of antibiotics.

Now a spate of new studies from around the world prove that Norway’s model can be replicated with extraordinary success, and public health experts are saying these deaths — 19,000 in the U.S. each year alone, more than from AIDS — are unnecessary.

“It’s a very sad situation that in some places so many are dying from this, because we have shown here in Norway that Methicillin-resistant Staphylococcus aureus [MRSA] can be controlled, and with not too much effort,” said Jan Hendrik-Binder, Oslo’s MRSA medical advisor. “But you have to take it seriously, you have to give it attention and you must not give up.”

The World Health Organization says antibiotic resistance is one of the leading public health threats on the planet. A six-month investigation by The Associated Press found overuse and misuse of medicines has led to mutations in once curable diseases like tuberculosis and malaria, making them harder and in some cases impossible to treat.

Now, in Norway’s simple solution, there’s a glimmer of hope.

Antibiotics Breed Superbugs Faster Than Expected

We continue to endanger ourselves by using antibiotics inappropriately. This is one of many things that happen when the public at large is ignorant about science and ignores scientific evidence. I don’t believe people want to put other people’s lives in danger. But our behavior in the face of the evidence has us doing just that. I believe because we don’t value science rather than because we don’t care about putting others (and ourselves) in danger. Antibiotics Breed Superbugs Faster Than Expected

Bacteria don’t just develop resistance to one drug at a time, but to many — and at accelerated rates. That’s because antibiotics boost bacterial production of free-radical oxygen molecules that damage bacterial DNA. Repairs to the DNA cause widespread mutations, giving bacteria more chances to randomly acquire drug-resistant traits.
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Drug resistance is a serious public health concern. According to the federal Centers for Disease Control and Prevention, 70 percent of 1.7 million infections acquired in hospitals every year are resistant to at least one drug. Those infections annually kill 99,000 Americans — more than double the number that die in car crashes.

Drugs that once destroyed almost any bacteria now kill only a few, or don’t work at all. In the case of some drugs, like Cipro, the decline is dramatic: Where in 1999 it worked against 95 percent of E. coli, it treated only 60 percent by 2006. Against lung infection-causing Acinobacter, its effectiveness fell by 70 percent in just four years.

Though drug resistance is ultimately inevitable, conventional wisdom holds that antibiotics consumed at suboptimum doses hasten the process. Bugs that would have succumbed to a larger dose live to multiply, pushing the strain as a whole closer to resistance. That happens when a prescription goes unfinished, or when antibiotics used on farms enter food and water at low levels.
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Of the 35 million pounds of antibiotics consumed annually in the United States, 80 percent goes to farm animals. Much of it is used to treat diseases spread by industrial husbandry practices, or simply to accelerate growth. As a result, farms have become giant petri dishes for superbugs, especially multidrug-resistant Staphylococcus aureus, or MRSA, which kills 20,000 Americans every year – more than AIDS.

Alarming cases of farm-based MRSA and other diseases led to a proposed Congressional law restricting the use of agricultural antibiotics. That bill, supported by the American Medical Association and American Public Health Association, is opposed by farm lobbyists and remains stuck in committee.

Researchers Find Switch That Allows Cancer Cells to Spread

Researchers discovered of a specific protein called disabled-2 (Dab2) that switches on the process that releases cancer cells from the original tumor and allows the cells to spread and develop into new tumors in other parts of the body.

The process called epithelial-mesenchymal transdifferientiation (EMT) has been known to play a role in releasing cells (epithelial cells) on the surface of the solid tumor and transforming them into transient mesenchymal cell: cells with the ability to start to grow a new tumor.

This is often the fatal process in breast, ovarian, pancreatic and colon-rectal cancers.

Searching to understand how the EMT process begins, Ge Jin, who has joint appointments at the Case Western Reserve University School of Dental Medicine and the Lerner Research Institute at the Cleveland Clinic, began by working backwards from EMT to find its trigger. The researchers found that a compound called transforming growth factor-ÃŸ (TGF-ÃŸ) triggers the formation of the Dab2 protein. It was this protein, Dab2, that activated the EMT process.

He discovered that when the researchers knocked out Dab2, EMT was not triggered. “This is the major piece in cancer research that has been missing,” Jin said. Most tumors are epithelial in origin and have epithelial markers on their surface. The EMT process takes place when some of those cells dislodge from the surface and undergo a transformation into a fibrous mesenchymal cell maker with the ability to migrate.

“EMT is the most important step in this process,” said Jin. He was part of a six-member research team, led by Philip Howe from the Department of Cancer Biology at the Lerner Research Institute in a National Institute of Cancer-funded study. The research group studied the biological processes that initiated the cancer spread by using cancer cells in animal models.

“If we can understand the signaling pathway for modulating EMT, then we can design drugs to delay or halt EMT cells and control tumor progression,” Jin said. Beyond cancer, Jin said. “The process we discovered may lead to understanding how other diseases progress.”

Microbes Flourish In Healthy People

Bugs Inside: What Happens When the Microbes That Keep Us Healthy Disappear? by Katherine Harmon

The human body has some 10 trillion human cells—but 10 times that number of microbial cells. So what happens when such an important part of our bodies goes missing?
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“Someone who didn’t have their microbes, they’d be naked,” says Martin Blaser, a professor of microbiology and chair of the Department of Medicine at New York University Langone Medical Center in New York City.
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Even though it is such an apparently integral and ancient aspect of human health, scientists are still grasping for better ways to study human microbiota—before it changes beyond historical recognition. Borrowing models from outside of medicine has helped many in the field gain a better understanding of this living world within us. “The important concept is about extinctions,” Blaser says. “It’s ecology.”
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The first step in understanding these systems is simply taking stock of what archaea, bacteria, fungi, protozoa and viruses are present in healthy individuals. This massive micro undertaking has been ongoing since 2007 through the National Institutes of Health’s (NIH) Human Microbiome Project. So far it has turned up some surprisingly rich data, including genetic sequencing for some 205 of the different genera that live on healthy human skin.

Despite the flood of new data, Foxman laughs when asked if there is any hope for a final report from the Human Microbiome Project any time soon. “This is the very, very beginning,” she says, comparing this project with the NIH’s Human Genome Project, which jump-started a barrage of new genetic research. “There are basic, basic questions that we don’t know the answers to,” she says, such as how different microbiota are between random individuals or family members; how much microbiota change over time; or how related the microbiota are to each other on or inside a person’s body.

Printing Bone, Muscle and More

A Pittsburgh-based research team has created and used an innovative ink-jet system to print “bio-ink” patterns that direct muscle-derived stem cells from adult mice to differentiate into both muscle cells and bone cells.

The custom-built ink-jet printer, developed at Carnegie Mellon’s Robotics Institute, can deposit and immobilize growth factors in virtually any design, pattern or concentration, laying down patterns on native extracellular matrix-coated slides (such as fibrin). These slides are then placed in culture dishes and topped with muscle-derived stem cells (MDSCs). Based on pattern, dose or factor printed by the ink-jet, the MDSCs can be directed to differentiate down various cell-fate differentiation pathways (e.g. bone- or muscle-like).

“This system provides an unprecedented means to engineer replacement tissues derived from muscle stem cells,” said Johnny Huard, professor of orthopedic surgery at the University of Pittsburgh School of Medicine and director of the Stem Cell Research Center at Children’s Hospital of UPMC. Huard has long-standing research findings that show how muscle-derived stem cells (MDSCs) from mice can repair muscle in a model for Duchenne Muscular Dystrophy, improve cardiac function following heart failure, and heal large bone and articular cartilage defects.

Weiss and Campbell, along with graduate student Eric Miller, previously demonstrated the use of ink-jet printing to pattern growth factor “bio-inks” to control cell fates. For their current research, they teamed with Phillippi, Huard and biologists of the Stem Cell Research Center at Children’s Hospital to gain experience in using growth factors to control differentiation in populations of MDSCs from mice.

The team envisions the ink-jet technology as potentially useful for engineering stem cell-based therapies for repairing defects where multiple tissues are involved, such as joints where bone, tendon, cartilage and muscle interface. Patients afflicted with conditions like osteoarthritis might benefit from these therapies, which incorporate the needs of multiple tissues and may improve post-treatment clinical outcomes.

The long-term promise of this new technology could be the tailoring of tissue-engineered regenerative therapies. In preparation for preclinical studies, the Pittsburgh researchers are combining the versatile ink-jet system with advanced real-time live cell image analysis developed at the Robotics Institute and Molecular Biosensor and Imaging Center to further understand how stem cells differentiate into bone, muscle and other cell types.

Prion Proteins, Without Genes, Can Evolve

‘Lifeless’ prion proteins are ‘capable of evolution’

scientists transferred prion populations from brain cells to other cells in culture and observed the prions that adapted to the new cellular environment out-competed their brain-adapted counterparts. When returned to the brain cells, the brain-adapted prions again took over the population.

Charles Weissmann, head of Scripps Florida’s department of infectology who led the study, said: “On the face of it, you have exactly the same process of mutation and adaptive change in prions as you see in viruses.

“This means that this pattern of Darwinian evolution appears to be universally active. “In viruses, mutation is linked to changes in nucleic acid sequence that leads to resistance.

“Now, this adaptability has moved one level down- to prions and protein folding – and it’s clear that you do not need nucleic acid (DNA or RNA) for the process of evolution.”
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He said: “The prion protein is not a clone, it is a quasi-species that can create different protein strains even in the same animal. “The abnormal prion proteins multiply by converting normal prion proteins.

“The implication of Charles Weissmann’s work is that it would be better to cut off that supply of normal prion proteins rather than risk the abnormal prion adapting to a drug and evolving into a new more virulent form.