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The Importance Of Increasing Our Knowledge Of Placebo Neurophysiology

There has been an ongoing debate about placebos on SBM, both in the articles and in the comments. What does it mean that a treatment has been shown to be “no better than placebo?”  If our goal is for patients to feel better and they feel better with placebos, why not prescribe them? Do placebos actually do anything useful? What can science tell us about why a patient might report diminished pain after taking an inert sugar pill? The subject is complex and prone to misconceptions. A recent podcast interview offers a breakthrough in understanding.

On her Brain Science Podcast Dr. Ginger Campbell interviewed Dr. Fabrizio Benedetti, a physician and clinical neurophysiologist who is one of the world’s leading researchers on the neurobiology of placebos. A transcript of the interview [PDF] is available on her website for those who prefer reading to listening. The information Dr. Benedetti presents and the expanded remarks by Dr. Campbell after the interview go a long way towards explaining the placebo phenomenon and its consequences for clinical medicine. Dr. Campbell also includes a handy list of references. I’ll try to provide a summary of the main points, but I recommend reading or listening to the original.

A common misconception is that Read more »

*This blog post was originally published at Science-Based Medicine*

Insect-Killing Fungus May Provide Basis For New Multiple Sclerosis Treatment

A very well-written review of an orally-active drug for multiple sclerosis has just appeared in the April 25th issue of the Journal of Natural Products, a joint publication of the American Chemical Society and the American Society of Pharmacognosy.

The review, Fingolimod (FTY720): A Recently Approved Multiple Sclerosis Drug Based on a Fungal Secondary Metabolite, is co-authored by Cherilyn R. Strader, Cedric J. Pearce, and Nicholas H. Oberlies. In the interest of full disclosure, the latter two gentlemen are research collaborators of mine from Mycosynthetix, Inc. (Hillsborough, NC) and the University of North Carolina at Greensboro. My esteemed colleague and senior author, Dr. Oberlies, modestly deflected my request to blog about the publication of this review.

So, I am instead writing this post to promote the excellent work of his student and first author, Cherilyn Strader. As of [Wednesday] morning, this review article is first on the list of most-read articles in the Journal. This status is noteworthy because the review has moved ahead of even the famed David Newman and Gordon Cragg review of natural product-sourced drugs of the last 25 years, the JNP equivalent of Pink Floyd’s The Dark Side of the Moon (the album known for its record 14-year stay on the Billboard music charts.). Read more »

*This blog post was originally published at Science-Based Medicine*

Inflammation: It’s Not Always A Bad Thing

A number of buzz-words appear repeatedly in health claims, such as natural, antioxidants, organic, and inflammation. Inflammation has been implicated in a number of chronic diseases, including diabetes, Parkinson’s, rheumatoid arthritis, allergies, atherosclerosis, and even cancer. Inflammation has been demonized, and is usually thought of as a bad thing. But it is not all bad.

In a study in Nature Medicine in September 2011, a research group led by Dr. Umut Ozcan at Children’s Hospital Boston (a teaching hospital affiliated with Harvard Medical School) reported that two proteins activated by inflammation are crucial to maintaining normal blood sugar levels in obese and diabetic mice. This could be the beginning of a new paradigm. Ozcan says Read more »

*This blog post was originally published at Science-Based Medicine*

The First Stem Cell-Derived Organ Transplant: A Rat’s Tooth

The individual in the photo is not displaying his newly acquired gold tooth bling, but rather something more precious: the first fully functioning 3D organ derived from stem cells, described in PNAS as “a successful fully functioning tooth replacement in an adult mouse achieved through the transplantation of bioengineered tooth germ into the alveolar bone in the lost tooth region.”

More from The Wall Street Journal:

Researchers used stem cells to grow a replacement tooth for an adult mouse, the first time scientists have developed a fully functioning three-dimensional organ replacement, according to a report in the Proceedings of the National Academy of Sciences. The researchers at the Tokyo University of Science created a set of cells that contained genetic instructions to build a tooth, and then implanted this “tooth germ” into the mouse’s empty tooth socket. The tooth grew out of the socket and through the gums, as a natural tooth would. Once the engineered tooth matured, after 11 weeks, it had a similar shape, hardness and response to pain or stress as a natural tooth, and worked equally well for chewing. The researchers suggested that using similar techniques in humans could restore function to patients with organ failure.

Press release from the Tokyo University of Science (in Japanese)…

Full story in WSJ: From Stem Cells to Tooth In the Mouth of a Mouse…

Takashi Tsuji Lab…

*This blog post was originally published at Medgadget*

New Technique Images Rotavirus Interacting With Immune System

vi342.jpgDirectly imaging dynamic biomolecular processes can reveal secrets which scientists have been trying to uncover in indirect ways. The interaction between various virus species and the immune system is one of those topics that would benefit from novel visualization techniques. Now researchers from the Howard Hughes Medical Institute have imaged, with considerable detail, a rotavirus as it is grabbed by an immune system molecule. The technique may allow the development of better vaccines against not only rotavirus, but open a large range of research possibilities in the life sciences.

In the new experiments, Howard Hughes Medical Institute (HHMI) researchers have mapped the structure of an antiviral antibody clamped onto a protein called VP7 that stipples the surface of rotavirus. The structural map reveals intimate new details about how the antibody interferes with VP7, a protein that helps the virus infect cells. The information may be useful in designing a new generation of rotavirus vaccines that could be easier to store and administer than current vaccines, said the researchers.

Rotaviruses replicate mainly in the gut, where they infect cells in the small intestine. The virus has a triple-layered protein coat, which allows it to resist being chewed up by digestive enzymes or the gut’s acidic environment. Rotavirus does not have an envelope covering its protein shell. A virus’ envelope helps it enter host cells, and viruses without envelopes face significant hurdles in penetrating the membrane of the cells they infect. “Since they have no membrane of their own, they must therefore perforate a cellular membrane to gain access to the cytoplasm (the interior of the cell),” [HHMI investigator Stephen C. Harrison] said.

The new research shows that as rotavirus matures inside an infected cell, it assembles a kind of “armor” coating made principally of VP7 and a “spike” protein called VP4. When the mature virus particle exits one cell to infect a new cell, it perforates the endosomal membrane of the target cell by thrusting in its VP4 spike like a grappling hook.

The virus’ ability to infect cells depends on a critical structural change that quickly removes the coat from the interconnected VP7 proteins — an event that unleashes the spike protein. Although researchers still do not know precisely what triggers the uncoating of VP7, they do know that it appears to happen when the virus senses a lowered concentration of calcium in its environment.

“VP7 sort of closes over VP4 locking it in place like the metal grills that surround a tree planted on a city sidewalk,” explained Harrison. “And it is the loss of VP7 in the uncoating step that triggers VP4 to carry out its task.”

To get a closer look at how antibodies latch onto VP7 and neutralize the virus, Harrison and his colleagues used x-ray crystallography to examine the molecular architecture of VP7 in the grasp of a fragment of the antibody. X-ray crystallography is a powerful tool for “seeing” the orientation of atoms and the distances separating them within the molecules.

Before Harrison’s team could use x-ray crystallography, however, they first had to crystallize VP7 in complex with the antibody fragment. Only after that step was completed, could they move on to bombarding those crystallized proteins with x-rays. Computers helped capture the diffraction patterns that emerged as the x-rays scattered from the crystal lattice. By rotating the crystallized protein complexes through multiple exposures, the researchers could record enough data to calculate three-dimensional models, which exposed the underlying architecture of VP7 and the antibody fragment.

The resulting detailed structural map of the VP7-antibody protein complex revealed that the antibody neutralizes the virus by preventing the VP7 proteins from dissociating, said Harrison. “Normally, calcium creates a bridge between VP7 molecules that holds them in place until uncoating,” he said. “Our structure revealed that the antibody makes an additional bridge, cementing the subunits together, making the virus resistant to the uncoating trigger and preventing it from infecting cells.”

Current rotavirus vaccines consist of weakened live virus that triggers the immune system to produce neutralizing antibodies. However, the new structural findings suggest how researchers might engineer a different type of rotavirus vaccine consisting only of immune-triggering protein, said Harrison. This protein-only vaccine could be made of a chemically linked complex of VP7 molecules that would stimulate the immune system more vigorously to produce anti-rotavirus antibodies.

While live-virus-based vaccines have been effective, said Harrison, they have drawbacks that a protein-based vaccine might overcome. The virus-based vaccines are perishable and require refrigeration, but vaccines based on proteins are more stable and can be stored at room temperature. Another benefit, said Harrison, is that protein-based vaccines could be combined with other protein vaccines in a “cocktail” that would cut down on the number of clinic visits since blending cannot be done so readily with virus-based vaccines. These advantages could make protein vaccines especially useful in developing countries that lack an extensive public health infrastructure and where the vast majority of childhood deaths from rotavirus occur, Harrison said.

HHMI press release: New Images May Improve Vaccine Design for Deadly Rotavirus

Abstract in Science: Structure of Rotavirus Outer-Layer Protein VP7 Bound with a Neutralizing Fab

*This blog post was originally published at Medgadget*

Latest Interviews

IDEA Labs: Medical Students Take The Lead In Healthcare Innovation

It’s no secret that doctors are disappointed with the way that the U.S. healthcare system is evolving. Most feel helpless about improving their work conditions or solving technical problems in patient care. Fortunately one young medical student was undeterred by the mountain of disappointment carried by his senior clinician mentors…

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How To Be A Successful Patient: Young Doctors Offer Some Advice

I am proud to be a part of the American Resident Project an initiative that promotes the writing of medical students residents and new physicians as they explore ideas for transforming American health care delivery. I recently had the opportunity to interview three of the writing fellows about how to…

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Latest Book Reviews

Book Review: Is Empathy Learned By Faking It Till It’s Real?

I m often asked to do book reviews on my blog and I rarely agree to them. This is because it takes me a long time to read a book and then if I don t enjoy it I figure the author would rather me remain silent than publish my…

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The Spirit Of The Place: Samuel Shem’s New Book May Depress You

When I was in medical school I read Samuel Shem s House Of God as a right of passage. At the time I found it to be a cynical yet eerily accurate portrayal of the underbelly of academic medicine. I gained comfort from its gallows humor and it made me…

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Eat To Save Your Life: Another Half-True Diet Book

I am hesitant to review diet books because they are so often a tangled mess of fact and fiction. Teasing out their truth from falsehood is about as exhausting as delousing a long-haired elementary school student. However after being approached by the authors’ PR agency with the promise of a…

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