, May 10, 2010, by Chris Bode  –  My mother-in-law moved in with us when she was 82. As her physical condition gradually deteriorated, the number of medications she was taking for various ailments increased: two for high blood pressure, two to promote gastric motility, one for congestive heart failure, one synthetic thyroid hormone, an expectorant, and two inhalers for chronic obstructive pulmonary disease (COPD). In addition, there was the occasional antibiotic for recurrent pneumonia. The drugs were prescribed by at least three different groups of doctors, none of whom communicated with the others. It soon became difficult to tell a new malady from a side effect of one of the drugs, or a potentially harmful interaction between the combinations of chemicals in her system.

A year or two into her time with us, she started to have an irregular heartbeat, an arrhythmia. After EKGs, a Holter monitor, and stress tests, the arrhythmia was diagnosed as a side effect of the cisapride that she was taking for gastric reflux. When her doctors replaced the cisapride with another gastric reflux medication, the drug caused a tremor so pronounced that her primary physician thought she had Parkinson’s disease.

Shortly after she stopped taking cisapride, it was removed from the US market for causing cardiac arrhythmia in a number of patients. But the situation was a little more complicated; the serious, potentially fatal arrhythmia that led to the withdrawal of the drug (following at least 80 reported deaths) was more likely to occur in patients who also took another drug that blocked a liver enzyme that eliminates cisapride from the body. With the natural elimination of cisapride blocked, the body would accumulate the drug to dangerous levels. The problem was that this liver enzyme wasn’t just inhibited by one drug. A wide variety of therapeutics could block it, including common antibiotics such as erythromycin and HIV antiretroviral drugs such as ritonavir. If my mother-in-law had been prescribed erythromycin while she was still taking cisapride, it is likely that she could have died from a stroke or from a fall after fainting.

Physicians have hundreds of drug–drug interactions (DDIs) to keep track of, and even that long list is not complete, generally covering interactions that have been experienced by patients, reported, and recognized for what they were. As more drugs become available for various ailments, the potential for drug interactions increases, especially in retirement-age adults who are the highest consumers of prescription medications per capita.

According to a recent study, about 2.2 million adults in the United States between the ages of 57 and 85 take multiple medications, and could be at risk for drug–drug interactions.1 A patient’s thin line of defense consists of the pharmaceutical companies’ requirement to test for dangerous combinations of drugs before they reach the market. But the tests are limited. For example, there are no methods for testing the interaction of 10 drugs concurrently. Instead, we test specific types of interactions that are the most common and harmful. With prescription patterns becoming more complex, many companies, including ours, have started developing new tests to try to capture other types of interactions before new drugs reach the clinical trial stage of development.

Every drug that makes it to the pharmacist’s shelf has been tested and dosed based on how rapidly and extensively it is absorbed, how quickly it gets to its site of action at an effective concentration, and how long it stays active before being cleared by the liver or kidneys—measures that are collectively called a drug’s pharmacokinetics.

So far, so good for individual drugs. But detecting DDIs is not so straightforward. It is rarely a simple matter of one chemical interfering directly with another; the link between drugs is often indirect and complicated by cellular and biochemical compartmentalization. Before the 1990s, the only way to spot a DDI was in a patient.2

The enzyme involved in the DDI between cisapride and erythromycin was discovered back in the 1980s, when the first nonsedating antihistamine, terfenadine, came on the market. Over the course of several years, clinicians realized that the sudden death of some patients taking terfenadine was associated with the drug’s combination with antibiotics as well as other drugs. Eventually, researchers realized that the antibiotics and other drugs were inhibiting cytochrome P450 (CYP) 3A4, a liver enzyme that oxidizes and inactivates terfenadine as part of the body’s normal metabolism of the antihistamine. The CYP family is a hugely important group of metabolic enzymes involved in the synthesis of hormones, membrane lipids, bile acids, and vitamins. It also eliminates cellular toxins and drugs. With CYP3A4 blocked, the terfenadine build-up resulted in a severe cardiac arrhythmia in many patients.

According to a recent study, about 2.2 million adults in the United States between the ages of 57 and 85 take multiple medications, and could be at risk for drug-drug interactions.

In the 1990s, when researchers realized that CYP inhibition was a property of multiple existing drugs, the FDA responded by requiring a series of preclinical in vitro tests for all investigational new drugs.3,4 One of the most effective testing mechanisms that came out of that guidance was the requirement to use human in vitro systems such as human liver microsomes to test for CYP inhibition. Microsomes are prepared by homogenizing human liver tissue and separating out the subcellular components via high-speed differential centrifugation. The pellet contains the endoplasmic reticulum membranes—the site of CYP-mediated metabolism of drugs. This organelle suspension provides a sensitive and effective system for detecting inhibition of CYPs by a drug, as researchers can readily tell when the concentration of a probe substrate diminishes (with active CYP) or remains constant (with CYP blocked).

Such interactions didn’t preclude drugs from being prescribed together; clinical pharmacologists could develop dosing schemes that took those interactions into account. For example, inhibitors could be classified by the strength of their inhibition of different CYPs, and appropriate dose adjustments could be made to other drugs that were administered at the same time.

Today we know that we also have to take the inhibiting drug’s mechanism of action into account: is it a reversible vs. irreversible inhibitior? Reversible inhibitors block CYP function only as long as the inhibitor is present in the bloodstream, whereas irreversible inhibitors inactivate an enzyme permanently, knocking out its function until the cell produces more enzyme, which could take hours or days.

The FDA relied on these and other in vitro tests, saying that results indicating no interaction are sufficient to rule out the need for a clinical DDI study. Positive or borderline in vitro results, on the other hand, indicate the need for such a clinical study in healthy human volunteers. While these assays, which remain the industry standard today, were certainly an improvement over discovering DDIs in patients, they still fall short of catching all of the clinically observed interactions.

By the year 2000, researchers thought they had a pretty good handle on which metabolizing enzymes had to be tested for DDIs. The FDA required in vitro data on the interactions with human drug-metabolizing enzymes, with the understanding that members of the CYP superfamily were involved in most cases. But metabolizing enzymes were not the only mechanism for eliminating drugs from the body.

One clue, although nobody knew it at the time, was the discovery in 1976 that drug-resistant mutants of a mammalian cell line expressed more of a membrane-bound protein called P-glycoprotein (P-gp) than wild-type cells. Before long, it became clear that P-gp was an efflux transporter that ejected drugs from a cell and played a role in the resistance of cancer cells to chemotherapeutic drugs. The human gene encoding that protein was named MDR1 in recognition of its role in multidrug resistance in cancer.5 A number of other mammalian efflux transporters, or pumps, have since been discovered, first in cancer cells and eventually in normal cells. These pumps are important for drug uptake, distribution, and clearance (collectively called a drug’s “disposition”), specifically in pharmacologically crucial organs such as the small intestine, blood–brain barrier, liver, and kidneys.

Once researchers appreciated the central role played by overexpression of P-gp and other transporters in drug-resistant tumors, they turned a spotlight on this class of proteins. Soon drug companies were looking for ways to block the activities of the efflux pumps in order to retain the chemotherapeutic agents in the tumor cells longer—thus improving the efficacy of the drug. In a sense, they were trying to create an intentional drug–drug interaction. The problem was that, due to the fact that P-gp is expressed in multiple pharmacokinetically important locations, the concentration of the chemotherapeutic agent increased everywhere in the body, leading to side effects so intolerable that an increase in therapeutic efficacy became a moot point. To this day, no company has successfully developed a P-gp inhibitor that achieves the desired effect on tumors without the undesirable systemic effects.

It gradually became clear that these proteins played a role in the disposition of many types of drugs by the body—not just chemotherapies—which meant that they could also play a role in unintentional drug–drug interactions, and might be a way to explain interactions that had to date gone unidentified.

Drug Metabolizing Enzymes
Researchers first learned the role of metabolizing enzymes in drug-drug interactions when some patients died from the combined administration of an antihistamine and an antibiotic. The antihistamine terfenadine was normally metabolized by the enzyme cytochrome P 450 (CYP) 3A4—a fact taken into account to establish a safe dose. But when certain antibiotics—or other drugs—were administered at the same time, they blocked CYP3A4 activity, which caused a dangerous buildup of terfenadine.

Surprisingly, it’s often difficult to tell whether a transporter is involved in a DDI and, if so, to what degree. The few examples of a purely transporter-mediated DDI have involved drugs with a narrow therapeutic range (NTR) that are not metabolized by CYP3A4. NTR drugs have a very small window of efficacy—if the dose is too low, there is no effect and if the dose is even slightly beyond a threshold level, serious side effects can result. In these cases, inhibition of a transporter, resulting in even a slight alteration of the circulating concentration of the drug, could have severe consequences. The best example is digoxin, a drug taken for heart failure and atrial fibrillation. If exposure to the drug is increased by as little as 25% to 50%, side effects including cardiac arrest, nausea, vomiting and diarrhea can occur (with other drugs, increases in exposure of less than 100% aren’t generally considered significant to the patient). When digoxin is taken with a drug such as quinidine (an anti-arrhythmic), which inhibits P-glycoprotein, plasma concentrations of the drug increase on the order of 150%, enough to cause a digoxin overdose in some patients.6

But there may be other transporter-mediated interactions we haven’t pinned down yet. One example is the interaction that occurs in organ transplant recipients. In these patients, cyclosporine is given to prevent immune rejection in combination with statin drugs, which are administered to combat the hypercholesterolemia that is a frequent consequence of organ transplantation. Cyclosporine inhibits both CYP3A4, which metabolizes some statins, and multiple uptake transporters that some statins rely on for entry into liver cells. When taken together, the exposure to the statin can increase as much as 20-fold, with the consequences ranging from muscle discomfort to the potentially fatal condition, rhabdomyolysis—the rapid breakdown of muscle fiber.

One of the reasons that so few DDIs have been confirmed to be transporter mediated is that the in vitro tools available to study them have been less than definitive. A limited number of assay systems and cell lines exist, but each is problematic. For example, human cell lines contain multiple transporters, making it impossible to pinpoint a single receptor. Nonhuman cell lines that overexpress a single human transporter, on the other hand, function on a backdrop of animal transporters, which can also obscure findings, as animal and human transporters interact differently with some substrates and inhibitors. Another problem is that when one transporter is knocked out in a cell, another will often take over its function. In fact, because of the redundant function of many transporters, there may never be a toolbox of specific probe substrates and inhibitors of transporters, comparable to those available for drug-metabolizing enzymes.

Without information about which specific transporter is responsible for a given DDI, drug developers can’t design a definitive clinical trial to assess the implications of co-administration of drugs in a human. This is very different from the situation with drug-metabolizing enzymes of the CYP superfamily, where many drugs and other chemicals act as highly specific probe substrates or inhibitors to isolate the offending CYP enzyme.

Drug Transporters
Rather than metabolize drugs, transporter proteins simply shuttle them either into (uptake) or out of (efflux) a cell. For example, the efflux transporter P-gp shuttles digoxin—a drug given to patients with heart failure—from kidney cells into urine at a particular rate. When the transporter is blocked by the anti-arrhythmic quinidine, the renal clearance of digoxin is reduced, potentially resulting in an overdose.

In recognition of its clinical importance, the FDA has announced that it “expects” in vitro P-gp interaction data as part of any new drug application filed as of September 2006.4 Not that P-gp is the only important transporter; in fact, a new white paper from an international panel of experts, including some from the FDA, indicates the importance of a number of other key transporters.7 This is the next step in the evolution and eventual finalization of the FDA’s guidance on this topic, which has been in draft form since 2006.

In response, a number of companies—including our own, Absorption Systems—are developing better ways to define the role played by transporters in DDIs. Our approach tackles the problem of trying to identify the most important efflux transporter in a particular interaction by multiple-choice elimination. We start with a human intestinal cell line, in this case one called Caco-2, in which the expression and function of multiple efflux transporters is well characterized. When cultured under appropriate conditions, the cells differentiate into a polarized monolayer that mimics the epithelial cells lining the human small intestine. On the apical surface (i.e., the surface that would be facing the intestinal lumen in vivo), three efflux transporters are expressed: P-gp, BCRP and MRP2. By means of RNA gene silencing, we have knocked down the expression of one efflux transporter at a time.8 Unlike typical in vitro RNA interference, the “transporter knockdown” phenotype is long-lasting and stable. As a result, we now have a panel of cell lines, in each of which the expression of one efflux transporter is reduced.

The utility of this system, which we call CellPort Technologies®, was demonstrated recently to help explain a clinical DDI that was partially responsible for the decision to withdraw ximelagatran, an anticoagulant, from the market. The study identified P-gp as the efflux transporter responsible for pumping ximelagatran and its active metabolite, melagatran, into bile.9 Co-administration of the common antibiotic erythromycin inhibited the transporter, leading to elevated levels of ximelagatran and melagatran, which was associated with liver damage.

While these assays were certainly an improvement over discovering DDIs in patients, they still fall short of catching all of the clinically observed interactions.

By knocking down one transporter at a time, we can test a new drug candidate in the parental cell line and each of the knockdown lines in turn, and by process of elimination see which of the three targeted transporters is responsible for efflux of the drug. Another advantage is that the results don’t rely on the available toolbox of transporter inhibitors, which are nondefinitive. Furthermore, it is an all-human system, unlike several other commonly used cell lines in which a given human transporter is overexpressed in a nonhuman cell line.

CellPort Technologies, as it currently stands, is not perfect. It won’t necessarily enable us to test for interactions among multiple drugs at one time (a feat no current assay system achieves), but it does offer the opportunity to screen for another class of interactions. As the number of drugs that the elderly take inevitably increases, and the more tools we have to interrogate potential drug interactions, the more capable we’ll be to catch interactions before they occur in patients.

It was frustrating to watch my once-vibrant mother-in-law decline, to watch as she was shuttled from one doctor to the next for test after test. By the time we reach our 80s, it is practically inevitable that we will be taking multiple drugs for what ails us. The more we know about how each of those drugs interacts with the transporters and enzymes that process drugs and toxins, the less likely it is we’ll be treating the side effect rather than the disease.

Chris Bode is a pharmacologist and the vice president of Corporate Development at Absorption Systems. He has been associated with the pharmaceutical industry for more than 20 years.


1. D.M. Qato et al., “Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States,” JAMA, 300:2867–78, 2008.

2. B.P. Monahan et al., “Torsades de pointes occurring in association with terfenadine use,” JAMA, 264:2788–90, 1990.

3. U.S. Department of Health and Human Services, Food and Drug Administration, 1997. “Guidance for Industry, Drug metabolism/drug interaction studies in the drug development process: studies in vitro”; available online at…

4. U.S. Department of Health and Human Services, Food and Drug Administration, 2006. “Guidance for Industry, Drug interaction studies—Study design, data analysis, and implications for dosing and labeling”; available online at…

5. R.L. Juliano and V. Ling, “A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants,” Biochim Biophys Acta, 455:152–62, 1976.

6. W. Doering, “Quinidine-digoxin interaction: Pharmacokinetics, underlying mechanism and clinical implications,” N Engl J Med, 301:400–4, 1979.

7. K. Giacomini et al., “Membrane transporters in drug development,” Nature Rev Drug Disc, 9:215–36, 2010.

8. W. Zhang et al., “Silencing the breast cancer resistance protein expression and function in Caco-2 cells using lentiviral vector-based short hairpin RNA,” Drug Metab Disp, 37:737–44, 2009.

9. M. Darnell et al., “Investigation of the involvement of P-gp and MRP2 in the efflux of ximelagatran and its metabolites by using short hairpin RNA knockdown in Caco-2 cells,” Drug Metab Dispos, 38:491–97, 2010.

Read more: Dangerous Liaisons – The Scientist – Magazine of the Life Sciences

Different types of stem cells in the brain of mature mice. (Credit: Verdon Taylor (from: Lugert et al., Cell Stem Cell, May 7th, 2010))

ScienceDaily (May 9, 2010) — After birth the brain loses many nerve cells and this continues throughout life — most neurons are formed before birth, after which many excess neurons degenerate. However, there are some cells that are still capable of division in old age — in the brains of mice, at least. According to scientists from the Max Planck Institute of Immunobiology in Freiburg, different types of neuronal stem cells exist that can create new neurons. While they divide continuously and create new neurons in young animals, a large proportion of the cells in older animals persist in a state of dormancy. However, the production of new cells can be reactivated, for example, through physical activity or epileptic seizures. What happens in mice could also be applicable to humans as neurons that are capable of dividing also occur in the human brain into adulthood.

The research is published in the journal Cell Stem Cell.

You can’t teach an old dog new tricks. The corresponding view that the brain loses learning and memory capacity with advancing age prevailed for a long time. However, neuronal stem cells exist in the hippocampus — a region of the brain that plays a central role in learning and memory functions — that can produce new nerve cells throughout life. It is known from tests on mice that the newly formed cells are integrated into the existing networks and play an important role in the learning capacity of animals. Nonetheless, the formation of new cells declines with age and the reasons for this were unknown up to now.

Together with colleagues from Dresden and Munich, the Freiburg researchers have now succeeded in explaining for the first time why fewer new neurons are formed in the adult mouse brain. They managed to identify different populations of neuronal stem cells, thereby demonstrating that the hippocampus has active and dormant or inactive neuronal stem cells. “In young mice, the stem cells divide four times more frequently than in older animals. However, the number of cells in older animals is only slightly lower. Therefore, neuronal stem cells do not disappear with age but are kept in reserve,” explains Verdon Taylor from the Max Planck Institute of Immunobiology.

The precise factors that influence the reactivation of dormant stem cells are not yet clear. The cells can, however, be stimulated to divide again. The scientists observed more newborn hippocampal neurons in physically active mice than in their inactive counterparts. “Consequently, running promotes the formation of new neurons,” says Verdon Taylor. Pathological brain activity, for example that which occurs during epileptic seizures, also triggers the division of the neuronal stem cells.

Horizontal and radial stem cells

The different stem cell populations are easy to distinguish under the microscope. The first group comprises cells which lie perpendicular to the surface of the hippocampus. Most of these radial stem cells are dormant. As opposed to this, over 80% of the cells in the group of horizontal stem cells — cells whose orientation runs parallel to the hippocampus surface — continuously form new cells; the remaining 20% are dormant but sporadically become activated. The activity of genes such as Notch, RBP-J and Sox2 is common to all of the cells.

Radial and horizontal stem cells differ not only in their arrangement, apparently they also react to different stimuli. When the animals are physically active, some radial stem cells abandon their dormant state and begin to divide, while this has little influence on the horizontal stem cells. The result is that more radial stem cells divide in active mice. The horizontal stem cells, in contrast, are also influenced by epileptic seizures.

It would appear that neuronal stem cells are not only found in the brains of mice. The presence of neurons that are formed over the course of life has also been demonstrated in the human hippocamus. Therefore, scientists suspect that different types of active and inactive stem cells also arise in the human brain. It is possible that inactive stem cells in humans can also be activated in a similar way to inactive stem cells in mice. “There are indicators that the excessive formation of new neurons plays a role in epilepsy. The use of neuronal brain stem cells in the treatment of brain injuries or degenerative diseases like Alzheimers may also be possible one day,” hopes Verdon Taylor.

DNA microarrayImage: Wikimedia commons, Guillaume Paumier, April/May 2010, by Megan Scudellari  –  Cancer, obesity, and even atherosclerosis share a common set of differentially expressed genes, suggesting a diverse number of human diseases share the same disrupted biological pathways, according to new research published this week in Cancer Cell.

The genetic link also suggests that drugs currently used for the treatment of metabolic and cardiovascular diseases might also be used against cancer, researchers say.

“In any year, there are probably ten big papers in a field that help push a concept forward,” said Reuben Shaw, an HHMI investigator at the Salk Institute in California who was not involved in the research. “I think this is one of them.”

Kevin Struhl and colleagues at Harvard Medical School compared the transcription profiles of two genetically identical human mammary epithelial cell lines from the same individual — one normal and one cancerous, or transformed, through the addition of an oncoprotein — to determine which genes were differentially expressed in the transformed cells. They then performed the same experiment with human fibroblasts, and juxtaposed the two models to identify 343 genes that were differentially expressed in both models — a common “cancer gene signature.”

“The use of the two systems made a huge difference,” said Struhl. With a single model, researchers isolate thousands of genes that appear to be expressed differently in cancerous cells versus normal cells. But by comparing data sets from two totally different cell models, mammary cells and fibroblasts, “it cut down the list of genes from thousands to hundreds. And hundreds is something you can really work with,” added Struhl.

Once the team had a list of 343 genes, they set out to identify them. Using basic bioinformatics techniques, they identified several families of transcription factors involved in inflammation and lipid metabolism. “I was completely stunned,” said Struhl. A significant amount of research links inflammation and cancer, but the association between metabolic disease and cancer is much less understood. Scanning the literature, the researchers found that many of the 343 genes they implicated in cancer have already been implicated in diabetes, obesity, heart disease, and other top killers.

To validate those metabolic genes that had not previously been linked to cancer, Struhl and his team knocked down the genes prior to transformation and found seven of eleven were important to the development of cancer in both experimental models. In additional work, they demonstrated that low-density lipoprotein (LDL) and its receptor (OLR1), both highly involved in atherosclerosis, also play a role in cancer. “That seems very novel, very unexpected,” said Shaw, who studies genes at the interface between cancer and diabetes. “This further illustrates how broadly some of these proteins are involved in different disease states.”

Looking at the results, Struhl believes there may be common molecular pathways underlying many disparate diseases. “The idea is that there’s essentially a diseased cell state, but the specific phenotype and disease you get depends on what cell type it is,” said Struhl. It’s a broad idea, he admitted, which may be part of the reason it took him two years to get the paper published.

As a crude test of that idea, the team tested drugs for other diseases — including metformin (diabetes), celecoxib (arthritis), and simvastatin (atherosclerosis) — against cancerous cells. “If all these diseases have some common pathways, then drugs against these diseases should also work against cancer,” said Struhl. Eleven out of thirteen drugs inhibited cancer development in the cell lines.

The drugs had a dramatic effect on the cancer cells, said Sam Hanash, a molecular diagnostician at the Fred Hutchinson Cancer Research Center who was not part of the study. “The findings are very interesting, and we should give more consideration to those agents in developing strategies for chemoprevention,” he said. Last October, Struhl published additional results in Cancer Research demonstrating that metformin selectively killed cancer stem cells in four different types of breast cancer.

“A lot of work is going on concerning the role of metabolism in cancer development,” said Hanash. “I think we will see more and more similar studies.”

A new study suggests that being overweight is implicated in up to 10% of all cancers in non-smokers.
Email: SPIS MedWire –
News from The Scientist 2001, 2(1):20010517-02


17 May 2001


Obesity is the single most important cause of cancer among non-smokers, concludes a major review of research carried out over the last 50 years. But the nature of the relationship remains unclear and the benefits of dieting are unknown.

In 17 May Nature Julian Peto from the Institute of Cancer Research, Surrey points out that tobacco remains the biggest health risk by far, causing cancer in 60% of smokers. Other causes include alcohol, sunlight and air pollution, each responsible for about 1% of cancers. Microorganisms such as human papilloma virus and Helicobacter pylori are also identified as important causes of cancer. But around 10% of cancers in non-smoking Americans and 7% in Europeans can be directly attributed to obesity.

Peto observed that being overweight is strongly associated with cancers of the breast, endometrium, gall bladder and kidney, aside from its link with heart disease. He added that he found the strength of the association surprising. ‘I really had not appreciated that the influence of being overweight was so strong,’ he said. ‘It is not at all clear what you can do if you are fat because it is very hard to study the impact of losing weight when one of the main reasons for losing weight is becoming very ill.’

He added: ‘If you are a smoker, nothing else matters two hoots in relation to smoking but if you are a non-smoker, the two things that really matter are being overweight and the viruses that cause stomach and cervical cancer.’

Read more: Obesity weighs in as major cancer cause – The Scientist – Magazine of the Life Sciences

Musclebound: Rings made from protein-based hydrogels are shown in ultraviolet light (top) and normal light (bottom).   Credit: Nature

Researchers create a protein-based material that flexes just like the real thing.

MIT Technology Review, May 10, 2010, by Corinna Wu  –  Many research groups are trying to develop materials with similar properties to muscles. One of the big difficulties is creating anything with just the right muscle-like elasticity–its ability to change shape while withstanding a large strain. Now researchers at the University of British Columbia (UBC) in Vancouver, Canada, have synthesized a protein-based material that stretches exactly like the real thing.

The new material achieves the elasticity of muscle by mimicking the microscopic structure of a giant muscle protein called titin. The structure of titin resembles a string with beads–globules of folded protein sequences are connected by floppy, unstructured sequences. Hongbin Li, a chemist at the UBC, and his colleagues constructed the new material that imitates this structure. They chose a mechanically stable protein sequence that folds in on itself to form globules, and another protein called resilin to serve as the floppy connectors.

The result was a “mini-titin”–a protein that resembled titin structurally but is much smaller, Li says. The researchers chemically linked the individual protein strands together to form a hydrogel–a light, solid material that consists mostly of water–and then tested the material’s mechanical properties. The team describes the work in a recent issue of the journal Nature.

When they tested the material, Li and his colleagues found that it behaved much like real muscle tissue. When stretched a little bit, it bounces back like an elastic rubber band. If stretched more vigorously, the beadlike protein domains unfold, and it dissipates some energy before returning to its original state.

“It’s a nice progression along the lines of building an artificial muscle,” says physicist David Weitz of Harvard University, whose group studies the structure of muscle protein networks. Other groups are working on creating electroactive polymers, which contract when stimulated by an electric signal, so that the “muscle” can be controlled. The current material does not have this feature, but adding that would be “the next step,” Weitz says.

Artificial muscles could one day be used as scaffolds for growing muscle to repair damage in patients; in biologically compatible devices for medical applications; even to control robots without using motors. However, since proteins tend to unravel at high temperatures and under harsh environmental conditions, this does not make them ideal for industrial applications.

Adolescents, Young Adults Lack Knowledge of Acetaminophen’s Toxicity, by Brian Hoyle, May 11, 2010 (Vancouver, British Columbia) — A study of more than 250 teenagers and young adults by researchers at the University of Rochester, in New York, has found that more than 60% do not know what acetaminophen is, even though a third are users of acetaminophen-containing over-the-counter (OTC) pain-relieving products. Nearly 25% misuse the medications, researchers announced here at the Pediatric Academic Societies 2010 Annual Meeting.

“Acetaminophen toxicity is a big deal, but we know a lot more [about its effects] in adults than we do in adolescents. The adolescent age group is what is new about this work,” said study presenter Laura Shone, DrPH, MSW, associate professor of pediatrics and clinical nursing, Department of Pediatrics, University of Rochester Medical Center, in an interview with Medscape Pediatrics.

The problem is huge, Dr. Shone said. Published studies have documented that overdoses of acetaminophen are the cause of more acute liver failure in the United States than viral hepatitis. Furthermore, one half to two thirds of these overdoses are unintentional and result from taking excessive doses of OTC medication.

At the heart of this problem is a lack of awareness about medications being consumed (health literacy). Agencies such as the National Academy of Sciences (NAS) have weighed in on the issue. Estimates are that up to half of American adults have problems with health literacy, which, according to a 2004 NAS report, is “the ability to find, understand, and use health information to communicate and make health decisions and function successfully as a patient.”

The situation for adolescents is far less clear, particularly concerning the understanding of OTC medications and label instructions for their use, explained Dr. Shone.

“Health literacy in regard to OTC meds is truly lacking in the adolescent age group, because the medication managers prior to these years were the adults in the home. Now, there is capability and access without knowledge, in combination with teenage behavior and thoughts — a combination of [the attitude that] nothing is going to hurt me, impulsive thinking, and risk-taking behaviors — that are all in play,” Germaine Defendi, MD, associate clinical professor, Department of Paediatrics, Olive View/UCLA Medical Center, Los Angeles, told Medscape Pediatrics.

In the study, conducted in 2008 and 2009, 266 youth (age range, 16 to 23 years; mean age, 18.6 ± 2 years; 56% female) from Monroe County, New York, were anonymously recruited, passively during visits to clinics or more actively during health information sessions at schools and elsewhere. The health literacy of the participants was determined using the Rapid Estimate of Adult Literacy (REALM) or REALM-Teen surveys. Limited health literacy was a REALM score of 60 or below, or a REALM-Teen score of 62 or below.

Of the 266 participants, 96 (36%) had limited health literacy and 170 (64%) had adequate health literacy.

A survey solicited information about knowledge of acetaminophen as the active ingredient in OTC pain relief medications, the ability to identify acetaminophen-containing OTC products, and the ability to identify the one-time and daily dosage limits of acetaminophen.

Fully 63% of the participants had no knowledge of acetaminophen, even though 33% of them had used an acetaminophen-containing OTC product within the previous month. The majority displayed limited health literacy.

Multivariate analysis pegged inadequate health literacy as the main reason for taking too few or too many pills per dose, for incorrect frequency of use, and for incorrect maximum daily dose. Even 77% of those identified as health literate did not know the maximum daily dose of acetaminophen.

“I truly think that this is a worthwhile study addressing the lack of knowledge in teens about OTC medication. Kids know that there are things that they can easily purchase OTC that are medicines. But a true understanding of the medications and what they are used for and what they do is lacking,” Dr. Germaine told Medscape Pediatrics.

Dr. Shone and the other study authors suggest that providers of OTC drugs have “a critical role” to play in conveying information in a way that is meaningful and relevant to adults and adolescents alike.

“Label information . . . is not as simple as it may seem. Providers can help prepare adolescents to safely self-administer,” Dr. Shone told Medscape Pediatrics.

The study was funded by the National Institute for Child Health and Human Development and the Centers for Disease Control and Prevention, Office of the Director. The authors have disclosed no relevant financial relationships.

Pediatric Academic Societies (PAS) 2010 Annual Meeting: Poster session 1476.250. Presented May 1, 2010.

Read more about the danger of too much acetaminophen…, by Kathryn Foxhall, 2009/2010 — The FDA should put new restrictions on acetaminophen, an advisory committee recommended Tuesday, saying the move would protect people from the potential toxicity that can cause liver failure and even death.

The FDA does not have to follow its advisory committees’ recommendations, but it usually does. It will likely be months before the FDA makes a final decision on the drug.

One of the nation’s top drugs for pain relief, acetaminophen is found in many over-the-counter products — including Tylenol, aspirin-free Anacin, Excedrin, and numerous cold medicines. It’s also found in many prescription drugs.

Billions of doses of acetaminophen are used safely every year. But acetaminophen-related overdoses cause 56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths annually, according to studies done between 1990 and 1998.

Some people inadvertently take more than is recommended. Others — such as people with underlying liver disease — are more at risk of liver injury from acetaminophen use. Because acetaminophen is in so many products, people sometimes take two or more products containing acetaminophen without realizing it. That risk extends to children, who may be poisoned because they swallow the medication. Sometimes caregivers mistakenly give children too much acetaminophen.

Acetaminophen: Limiting Dosage Amounts

The advisory committee voted that the single adult acetaminophen dose should be no more than 650 milligrams, significantly less that the current 1,000 milligrams often contained in two tablets of certain over-the-counter pain products. The panel of 37 doctors and other experts also said that the maximum total dose for 24 hours, now at 4,000 milligrams, should be decreased.

Some advisory committee members said the move should help lower the overall amounts of acetaminophen that people take. Some on the panel said they were influenced by research indicating there are changes in liver function in some people who had taken only the currently recommended levels.

Call to Eliminate Some Acetaminophen Products

In a recommendation that would be a real change for the prescription industry, the committee voted 20 to 17 that prescription products that combine acetaminophen with other medications should be eliminated. Today, billions of doses of products are prescribed in which acetaminophen is combined with narcotics, according to the FDA. Some brand-name pain prescriptions containing acetaminophen include Vicodin, Lortab, Maxidone, Norco, Zydone, Tylenol with codeine, Percocet, Endocet, and Darvocet.

The combination of hydrocodone and acetaminophen, for instance, has been the most frequently dispensed drug since 1997, according to the FDA.

Richard DeNisco, MD, MPH, medical officer at the National Institute of Drug Abuse and a panel member, said that so much acetaminophen is going out to people in hydrocodone/acetaminophen mixes that he is uncertain why there is not more liver damage.

Prohibiting these combined products “would rock the system,” he said, but the two products should be prescribed separately, if necessary.

The combination prescription products, which have rapidly increased in use in the last five years, are clearly the biggest cause of the acetaminophen overdose, said Marie Griffin, MD, professor of preventive medicine at Vanderbilt University. But she worried that people will simply turn to plain narcotics, if the combinations are eliminated. “We need a broader answer to chronic pain, because these drugs are being used extensively in the older population,” Griffin said during the meeting. “And I am not sure that practitioners feel like they have many other choices.”

On the other hand, the committee declined to vote for eliminating combination acetaminophen products that are sold over the counter.

Karl Lorenz, MD, who is with the VA Los Angeles Healthcare System, said that many people are being creative in managing low level chronic pain. “I just think we have to be cautious about eliminating an entire category of products that many people find useful,” he said.

Black Box Warning Advised for Acetaminophen Combination Products

The advisory committee also voted overwhelmingly to recommend that the FDA require a boxed warning — often called a black box warning — on the labels of prescription acetaminophen combination products, with members noting this is considered the highest precaution the agency can give.

They also called for limiting formulations of liquid over-the-counter acetaminophen to only one concentration level in order to reduce confusion when people give the medicine to children.

Linda Suydam, president of the Consumer Healthcare Products Association, which represents companies that make over-the-counter products, objected to the committee’s recommendations for new limits on acetaminophen in over-the-counter products.

“CHPA strongly believes that patients and physicians need to have a wide range of dosing available for patients who need their acetaminophen-containing products,” she said, asserting there is little data to support the idea that patients are harmed at current levels.


FDA Options Paper and Memo.

Richard DeNisco, MD, MPH, medical officer, National Institute of Drug Abuse.

Marie Griffin, MD, professor of preventive medicine, Vanderbilt University.

Karl Lorenz, MD, VA Los Angeles Healthcare System.

Linda Suydam, president, Consumer Healthcare Products Association.

In the latest 2009 rankings, 4,861 hospitals were considered of which only 174 were ranked in any one of 16 specialities. Twenty-one hospitals ranked highly enough within at least 6 specialties to qualify them for the Honor Roll.


Rank Hospital Name Location Points in specialties
1 Johns Hopkins Hospital Baltimore, MD 30 points in 15 specialties
2 Mayo Clinic Rochester, MN 28 points in 15 specialties
3 UCLA Medical Center Los Angeles, CA 26 points in 15 specialties
4 Cleveland Clinic Cleveland, OH 26 points in 13 specialties
5 Massachusetts General Hospital Boston, MA 25 points in 13 specialties
6 New York-Presbyterian University Hospital of Columbia and Cornell New York, NY 24 points in 13 specialties
7 University of California San Francisco Medical Center San Francisco, CA 21 points in 11 specialties
8 Hospital of the University of Pennsylvania Philadelphia, PA 19 points in 12 specialties
9 Barnes-Jewish Hospital / Washington University in St. Louis St. Louis, MO 17 points in 12 specialties
10 Brigham and Women’s Hospital Boston, MA 17 points in 10 specialties
10 Duke University Medical Center Durham, NC 17 points in 10 specialties
12 University of Washington Medical Center Seattle, WA 16 points in 8 specialties
13 UPMC (University of Pittsburgh Medical Center) Pittsburgh, PA 13 points in 8 specialties
14 University of Michigan Hospitals and Health Centers Ann Arbor, MI 12 points in 8 specialties
15 Stanford Hospital and Clinics Stanford, CA 11 points in 7 specialties
16 Vanderbilt University Medical Center Nashville, TN 11 points in 6 specialties
17 NYU Medical Center New York, NY 10 points in 7 specialties
17 Yale-New Haven Hospital New Haven, CT 10 points in 7 specialties
19 Mount Sinai Medical Center New York, NY 9 points in 7 specialties
20 The Methodist Hospital Houston, TX 8 points in 7 specialties
21 Ohio State University Hospital Columbus, OH 7 points in 6 specialties

The CEO of Eni would like to see new, cheaper solar technologies.

MIT Technology Review, May 10, 2010, by David Rotman  –  As CEO of Eni, the Italian oil and natural gas giant, Paolo Scaroni heads one of the world’s largest petroleum companies. Eni’s commercial portfolio of energy technologies does not currently include solar power, but Scaroni came to MIT this week with an eye on longer-term opportunities, helping to officially open the Eni-MIT Solar Frontiers Center.

Eni has committed $50 million to MIT energy research, including $25 million for the solar center, which was originally announced in 2008. And Scaroni was clearly interested in seeing what the company was getting for its money. On display were the center’s recent inventions, including the first solar cell printed on paper. Scaroni said he believes that existing alternative-energy technologies are not yet ready for wide-scale deployment, and that eventual success in replacing petroleum will depend on the development of new technologies and devices. “If only 10 percent of what I have seen [at the MIT center] materializes,” he suggested, “it would change the world.”

After Scaroni toured the MIT labs, Technology Review‘s editor, David Rotman, asked him what opportunities and challenges he sees with renewable energies.

TR: You don’t think solar power is ready to make a significant impact in replacing petroleum?

Paolo Scaroni: I’m not very familiar with U.S. numbers. I’m more familiar with the European numbers. In order to make commercially sellable solar energy, you have to pay, depending on the country and the situation, between four and six times what you pay for thermal energy. Which means that if in a European country all the electricity comes from solar, the bill would be between four to six times higher than it is today.

TR: So it’s not economically practical?

PS: No, it is not practical, with the price of the technology.

TR: Eni currently has no existing business in solar power.

PS: Solar energy in the world is less than 1 percent. So it is still really a minute number.

TR: You’re waiting for a breakthrough?

PS: We need a breakthrough. And I think the breakthrough will be around replacing silicon. Silicon is expensive, heavy, and has a conversion of around 12 percent, which is not bad. But if we can improve it, it would change completely the whole commercial perspective. There is also the problem of density, because you need to cover a large surface to produce a fairly small amount of energy [with solar power]. When you have a thermal power station, with a small surface area, you produce a lot of energy.

TR: Do you think, however, that consumers will be willing to pay more for alternative energies?

PS: I’m not sure about that. Of course, it depends very much on the price of oil. Cheap oil is the biggest enemy of renewables. We need to have a price of oil which is in the region of $80, $90 a barrel to make the price of renewables acceptable–still expensive but acceptable. Of course, if oil prices go to $30 a barrel, then renewables would be killed.

TR: Any other alternative energies besides solar that interest you?

PS: In some countries wind is certainly a good alternative. But of course to produce wind energy, you need wind. People tend to forget you need constant wind for many hours a day. And normally in the countries or in the regions where you have a lot of constant wind, there is not a lot of population because people don’t like to live in places where there is a lot of wind. So you have the additional problem of transporting the electricity from where you produce it to where you use it. But where you have constant wind, such as places like the U.K., Spain, some parts of Denmark, wind is an alternative. But the key issue around all renewables is storage. If we don’t solve the problem of storage, we’re going nowhere. Solar is fantastic but what happens during the night or what happens if you have no sun? So storage research is key.

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