Rifaximin Efficacious in Moderately Active Crohn Disease.

Twelve weeks of extended-release rifaximin at 800 mg twice daily induced remission in 62% of patients and was both safe and well tolerated.

Many clinicians use antibiotics to treat infection in patients with Crohn disease; some also use them to suppress disease activity, despite mixed evidence to support their efficacy for this purpose. Now, researchers in Europe have conducted a multicenter, double-blind, phase II trial to determine whether an extended intestinal release (EIR) form of rifaximin induces remission in patients with moderately active Crohn disease.

In this manufacturer-funded study, participants (410 adults with Crohn’s Disease Activity Index scores between 220 and 400) were randomized to receive twice-daily rifaximin-EIR (400 mg, 800 mg, or 1200 mg) or placebo for 12 weeks. Patients in remission at the end of the treatment period were followed for an additional 12 weeks. A total of 402 patients received at least one dose of study drug and were included in the full analysis.

At the end of treatment, the remission rate was higher in the 800-mg rifaximin group than in the placebo group (62% vs. 43%; P=0.005). The difference was maintained throughout the follow-up period (at 24 weeks, 45% vs. 29%; P=0.02). Remission rates were 54% in the 400-mg group and 47% in the 1200-mg group and were not significantly different from the placebo group rate. Dropout because of adverse events was significantly more common in the 1200-mg group than in any of the other groups.

Comment: These results support a role for bacteria in the pathogenesis of Crohn disease. The extended-release formulation of rifaximin used in this trial is not yet available in the U.S.

Source: Journal Watch Gastroenterology






Dispatcher-Directed Cardiopulmonary Resuscitation Improves Survival in Pediatric Out-of-Hospital Cardiac Arrest.

In a population-based Japanese study, dispatcher assistance increased 1-month survival but had no effect on neurological outcomes.

In addition to sending help, emergency medical dispatchers provide prearrival instructions for the lay public. Researchers used a nationwide population-based database of all out-of-hospital cardiac arrests in Japan from 2004 through 2008 to analyze the effect of dispatcher assistance on 1-month survival and neurological outcomes in paediatric patients (age, <20 years).

Among 1780 pediatric patients with witnessed collapse, bystanders performed chest compressions in 40% and mouth-to-mouth ventilation in 26%. Dispatchers provided cardiopulmonary resuscitation (CPR) instructions in 28% of cases. Dispatcher assistance was associated with significantly higher rates of bystander-performed chest compressions and ventilations (adjusted odds ratios, 6.04 and 3.10, respectively). Dispatcher assistance was associated with significantly improved 1-month survival rates (AOR, 1.46) but had no effect on rates of favorable neurological outcomes (cerebral performance category 1 or 2). Among adolescents (age range, 12–19 years), but not infants or younger children, survival rates were significantly higher in those with cardiac etiologies than in those with no cardiac etiologies (33% vs. 5%).

Comment: Bystander CPR improves survival, and dispatcher instruction increases the likelihood that CPR is performed. Although no improvement in neurological outcome was noted in this study, the data support dispatcher-directed CPR for pediatric patients and continued advocacy for public CPR training.

Source: Journal Watch Emergency Medicine

Treating Brain Cancer with Nanomedicine.

The race is on to create the best nanomedicine approach for brain cancer. Julia Ljubimova, who directs the research of nanomedicine at Cedars-Sinai Medical Center in Los Angeles, tells me she can’t comment on other people’s work in the field: “It is very competitive.” One nanomedicine company based in Germany refuses to talk to reporters “until next year.”

Perhaps this secrecy is because there is a lot to be gained by developing a new nanomedicine to combat brain cancer (as well as other cancers). Brain cancers are among the most difficult cancers to treat; almost all involve surgery to remove the bulk of the tumor followed by chemotherapy or radiotherapy to remove the last traces of cancer cells.

Gliobastoma and medulloblastoma are the most common brain cancers for adults and children, respectively. Doctors call these brain tumors “aggressive” because they are so deadly: After treatment, people with gliobastoma survive at a median of five more months. Of children with medulloblastoma, 70 percent to 80 percent survive to five years or more after treatment.

The follow-up chemotherapy or radiotherapy also comes with nasty side effects, such as nausea and hair loss. Toxic chemotherapy drugs can accumulate in their liver, kidneys, and bone marrow.

Nanomedicines—treatments using materials modified at the atomic or molecular level—have the potential to be game-changers for these patients. For example, some nano-sized molecules can travel through the physiological obstacles to drug treatment: the blood-brain barrier (BBB), a semi-permeable membrane of tightly knit capillary endothelial cells that protects the brain from harmful substances in the blood, and the tumor cell membrane itself. Also, nano-sized particles (between 1 and 100 nanometers) can behave in extraordinary ways—such as reacting to magnetic fields and light—opening up new possibilities for treatment.

Overheating tumor cells

Using nanomedicines to treat brain tumors was first proposed more than three decades ago. Currently there is one nanoparticle treatment available to people with hard brain tumors: Nano-Therm therapy. Available at a clinic in Berlin, the treatment has been through trials in humans to demonstrate its safety and effectiveness. In a study of 59 people with recurring glioblastomapublished in Neuro-Oncology in 2010, those treated with Nano-Therm therapy survived a median time of more than 13 months—more than double the control group. The EU approved the treatment, developed by Magforce, in July 2010.

Nano-Therm uses “thermotherapy,” which involves surgery to insert a liquid containing 15 nanometer-wide magnetic particles into the brain tumor. Next, the person being treated lies in a machine that emits an alternating magnetic field. This causes the nanoparticles, which have an iron oxide core, to oscillate, penetrating the tumor cells. The longer the magnetic field is on, the warmer the nanoparticles grow. Doctors can take the heat up to about 45 degrees Celsius, where the tumor cells are primed for chemotherapy or radiotherapy, or even higher, which can destroy the tumor cells.

“Our vision is to establish this new technology alongside surgery, chemotherapy, and radiation as an additional pillar of cancer therapy,” Magforce’s founder and chief scientific officer Andreas Jordan said in a statement.

Magforce’s already approved nano-treatment is an exception. Most research into nanomedicines for brain cancer is occurring at the level of basic research in the lab or in animal studies.

Trojan horses

Nanoparticles have excellent potential as carriers of drugs, because if they are small enough, they can penetrate the BBB. That way, a treatment could be injected into the bloodstream rather than performing surgery to insert it. Many researchers are exploring using nanoparticles in the manner of a Trojan horse, to carry treatments including chemotherapy, gene therapy, or immune boosters into the brain.

One example of the Trojan horse approach includes a tool called “molecular envelope technology” (MET). Andreas Schatzlein, on the research team at the London School of Pharmacy, says: “What we are trying to do is create an envelope around hydrophobic drugs. This is similar to what a detergent does, but a detergent would destroy cells, so we created a molecule that has the properties of a detergent: a fat-loving part and a water-loving part. This can shield a lipid-based drug from the water, which is what we are made of.”

Research in a 2006 paper in Biomacromolecules [DOI: 10.1021/bm0604000] showed that 10 times more drug is taken up across the blood-brain barrier using these nanoparticles than using conventional suspensions. This experiment was done in mice, and used an anesthetic as the drug, but it shows that drugs encapsulated by MET can get through the BBB.

Research is ongoing into a lipid-based drug that would control cancer growth in the brain; the London researchers have already reported that MET works to control pancreatic cancer growth using an oral peptide drug. “We know we can get a peptide into the brain that is very similar to the one we used in the pancreatic cancer study. We are quite optimistic,” says Schatzlein. He estimates that Phase I (safety) clinical trials could start within two years, depending on funding.

Strong bonds

Another nanotech method to carry therapies into brain cancer cells is called “nanobioconjugates.” These are built around the foundation of a natural polymer, with different chemical “modules” attached (conjugated) by strong covalent bonds. Because the bonds are strong, the molecules are stable; only when they hook onto specific targets will they react. This means that nanobioconjugates do not degrade in blood plasma.

Julia Ljubimova has worked on the creation of a nanobioconjugate that has been shown in mice to inhibit brain tumor growth; that research was published in the Proceedings of the National Academy of Sciences in 2010. Their nanobioconjugate works by including molecules that prevent tumor cell growth by blocking the growth of the blood vessels feeding the tumor.

The Cedars-Sinai nanobioconjugate is still some years away from approval for use in doctor’s offices. Ljubimova says that their data will soon be submitted for FDA approval. She envisions the treatment would be used in combination with surgery to prevent the recurrence of the disease.

Nanoparticles vs nanobioconjugate

Nanobioconjugates targeted at brain cancers do not affect healthy cells; the treatment seems to be nontoxic and does not provoke an immune system response. Ljubimova tells me that nanobioconjugates are “next generation” nanomedicines, better than nanoparticles.

“Nanoparticles, it’s like an eggshell,” she says; the shell is porous and the drug inside can just leak out. “With nanobioconjugate, everything is together. This is like a spaceship: If it goes through the stratosphere, part of the ship is ejected. It is controlled.” The nanobioconjugate targets only specific tumor vessel cells, it is designed to go through the BBB, and also to have an “escape device” to help the conjugate penetrate the tumor cell fluid (explained further here). Some other forms of nanoparticles can be unstable in blood plasma because they have weak chemical bonds.

The BBB is at the nub of the controversy. Ljubimova says of nanoparticles: “Some small molecules can go through BBB, but they go in and they go out with the same speed, and they do not have time to treat cancer. [And] it is difficult for a big molecule to pass through the BBB.”

But that may be an argument for using nanoparticles to cross the BBB rather than nanoconjugates, says Andreas Schatzlein. “One approach is trying to use receptors at the BBB, and then using conjugates with those ligands for receptors at the BBB so that they will be taken up in increased amounts and carried into the brain.” He points out that this can limit the amount of therapy one person can have—if all of the receptors are taken up (filled) no more of the drug could get in.

Hybrid nanotech

Furthermore, there is huge potential to develop hybrid nanomedicines to perform various tasks once inside the body; not only to treat tumors but to help with imaging and diagnosis as well. This is called the “theranostic” approach. For example, nano shells can carry quantum dots or magnetic particles, or nanobioconjugates can carry a tracer dye. This can help show the outline of the tumor more clearly under an MRI scan, which is particularly useful to help diagnosis of tumors compared to infections in the brain, especially when a biopsy cannot be performed.

Sometimes, Ljubimova tells me, an enhanced MRI image can even help discern whether the tissue is part of a primary tumor or a secondary brain tumor, metastasized from lung cancer, for example. This understanding can lead to a different diagnosis and a different treatment. “This is our future,” she says.

Source: http://christineottery.tumblr.com/ 

High Intake of White Rice Associated with Excess Risk for Type 2 Diabetes.

This finding was particularly marked in Asian populations.

White rice — which is almost entirely starch — is the main type of rice eaten worldwide and has a higher glycemic index than other grains. High consumption of foods with high glycemic indexes is associated with excess risk for type 2 diabetes. In this meta-analysis of seven prospective cohort studies, investigators assessed the association between white rice intake and risk for type 2 diabetes mellitus.

Of 352,000 participants, 13,000 developed type 2 diabetes (follow-up range, 4–22 years). Among Asian populations, there was a significant 55% increased risk for type 2 diabetes in the highest category of white rice intake compared with the lowest category. In contrast, among Western populations, a 12% increase in risk was not statistically significant. Combining these populations, each serving per day increment of white rice consumption was associated with an 11% increased risk for type 2 diabetes.

Comment: Although this meta-analysis showed that high intake of white rice was associated with excess risk for type 2 diabetes in Asian populations, the association does not prove that rice is more diabetogenic than other starches. For example, mean white rice intake in Asian populations was far higher (3–4 servings daily) than in Western populations (1–2 servings weekly), and rice comprises a smaller proportion of overall glycemic load in Western than in Asian populations. In any case, people should limit their intake of starchy foods and employ other measures (e.g., exercise, weight control) to lower their risk for type 2 diabetes.

Source: Journal Watch General Medicine

Tenecteplase for Acute Stroke?

An investigational drug shows promise in a phase IIB study.

For more than a decade, intravenous tissue plasminogen activator (TPA) has been the only approved pharmacological treatment for acute ischemic stroke. Tenecteplase, an investigational drug, is a modified version of TPA with greater fibrin specificity and a longer half-life. Researchers conducted this randomized, phase IIB trial to compare standard TPA with two doses of tenecteplase (0.1 mg/kg or 0.25 mg/kg) for patients seen at one of three centers within 6 hours of stroke onset. Inclusion criteria were standard clinical criteria, a computed tomography (CT) perfusion deficit at least 20% greater than the infarct core, and CT angiography evidence of occlusion in the anterior, middle, or posterior cerebral arteries. The two primary endpoints were radiologic evidence of reperfusion at 24 hours and improvement on the NIH Stroke Scale (NIHSS) from before treatment to 24 hours after treatment. The two tenecteplase groups were pooled for analysis of the primary results.

Of 2768 patients screened, 75 met both clinical and CT criteria. The 75 participants were enrolled at a mean of 2.9 hours after stroke onset and had a mean NIHSS score of 14.4. Tenecteplase was significantly better than TPA with regard to radiologic reperfusion (79% vs. 55%) and with regard to clinical improvement (8-point vs. 3-point improvement on the NIHSS). At 3 months, 72% of the higher-dose tenecteplase patients had an excellent outcome, compared with 40% of the TPA group, a significant difference. The rates of hemorrhagic complications did not differ significantly between the TPA and tenecteplase groups.

Comment: This trial showed better short-term radiologic and clinical outcomes with tenecteplase than with TPA for acute ischemic stroke. The trial was not powered to assess 3-month outcomes, but the higher-dose tenecteplase patients had better 3-month outcomes than the TPA patients. A previous dose-ranging study of tenecteplase was inconclusive; the trial was terminated because of slow enrollment (Stroke 2010; 41:707).

This innovative study required additional radiologic criteria for thrombolysis treatment (CT perfusion and CT angiography), in addition to the standard clinical criteria. These criteria make pathophysiological sense, but they also restricted enrollment. A larger phase III study of tenecteplase should be considered, but the authors should also consider altering the enrollment criteria (e.g., by removing some of the exclusion criteria used in the current study) to make the treatment more broadly applicable to the acute ischemic stroke population. Until these further studies are complete, tenecteplase should not be used to treat ischemic stroke.

Source:Journal Watch Neurology


GIST patients taking Novartis drug Glivec .



Study in JAMA reports significant survival benefit in certain GIST patients taking Novartis drug Glivec® for three years after surgery


  • First large Phase III study to demonstrate significant survival benefits of extending treatment with Glivec for three years compared to one year following surgery
  • Important finding for treatment of KIT+ GIST patients who are at risk of recurrence following complete resection of primary tumor
  • Publication follows European Commission approval of new label based on these data


The Journal of the American Medical Association (JAMA) today published a Phase III study that showed significant survival benefits for patients meeting the study inclusion criteria who received three years of treatment with Glivec® (imatinib)[1] after surgery to remove KIT (CD117)-positive gastrointestinal stromal tumors (KIT+ GIST) compared to one year of treatment[1]. The study results were first presented at the 47th Annual Meeting of the American Society of Clinical Oncology (ASCO) plenary session in June 2011[2].


Gastrointestinal stromal tumors are a rare, life-threatening cancer of the gastrointestinal tract. The major cause of GIST is an abnormal form of the protein KIT which causes cells to grow uncontrollably and become cancerous[3]. Patients with GIST are at risk of recurrence following complete resection of primary GIST[4].


According to data published in JAMA from this international, multicenter, open-label Phase III clinical trial, at five years, 66% of patients taking Glivec for three years after surgery for KIT+ GIST remained free of recurrence (RFS) compared to 48% who had received Glivec for only one year after surgery (p<0.001; HR 0.46, 95% CI 0.32-0.65). In addition, at five years, 92% of patients taking Glivec for three years after surgery were alive (OS) compared to 82% who had received Glivec for only one year after surgery (p=0.02; HR 0.45, 95% CI 0.22-0.89). Four hundred patients entered the study. Median patient follow-up was 54 months[1].


Based on this data, in February 2012, the European Commission approved an update to the Glivec label to include three years of treatment after surgery for adults with KIT+ GIST.


“This study shows a significant recurrence-free survival benefit in adults with KIT+ GIST from adjuvant treatment with Glivec and provides important evidence to inform the clinical care of these patients after surgery,” said Heikki Joensuu, M.D., Ph.D., Professor, Oncology, University of Helsinki. “These data are likely to result in a new standard of care for these patients.”


About the SSG Phase III trial

This multicenter, prospective, randomized study for the evaluation of adjuvant treatment with Glivec of histologically confirmed KIT+ GIST was conducted by the Scandinavian Sarcoma Group (SSG) and the Sarcoma Group of the Arbeitsgemeinschaft Internistische Onkologie (AIO)[5]. The primary endpoint was to compare, within the first five years, recurrence-free survival in patients with a greater than 50% estimated risk of GIST disease recurrence, following diagnosis and treatment with adjuvant Glivec for either 12 or 36 months. The secondary endpoints included overall survival and treatment safety[2].


Inclusion criteria for risk of recurrence was defined as tumor diameter >5.0 cm and mitotic count >5/50 high power fields (HPFs); or tumor diameter >10.0 cm; or tumor of any size with a mitotic count >10/50 HPFs; or tumors ruptured into the peritoneal cavity.


Almost all patients experienced side effects while taking Glivec. Glivec was generally well tolerated. The proportion of patients who discontinued Glivec during the assigned treatment period for reasons other than GIST recurrence was 25.8% in the 36-month group and 13% in the 12-month group[2].


Novartis provided the study drug and supported the study financially. Additional funding was received from the Academy of Finland, Cancer Society of Finland, Sigrid Juselius Foundation and Helsinki University Research Funds.


About Glivec (imatinib)

Glivec® (imatinib) is approved in more than 110 countries for the treatment of all phases of Ph+ CML, for the treatment of adult patients with KIT (CD117)-positive gastrointestinal stromal tumors (GIST), which cannot be surgically removed and/or have metastasized and for the treatment of adult patients following complete surgical removal of KIT+ GIST.

Source: Novartis Release.


The Bigger Your Brain, the More Friendships You Can Manage.

Professor Robin Dunbar is best known for his work related to how many stable social relationships the human brain can manage. In earlierresearch, he argued that the optimal number of active relationships is 150 — now famously known as the “Dunbar Number.”

Dunbar is once again delving into the brain’s social capacity, but this time he’s focused on the size of the orbital prefrontal cortex (aka, the frontal lobe), the part of the brain involved in high-level thinking that sits just above our eyes.  Dunbar and collegues have found that the size of this brain area correlates with the number of friendships a person is capable of managing.

The study suggests that we need to employ a set of cognitive skills to maintain a large number of friends, known in psychology circles as “mentalizing” or “mind-reading”– an ability to understand what another person is thinking, which is crucial to our ability to handle our complex social world, including the ability to hold conversations with one another.

According to Professor Dunbar, as reported by Science Daily,’”Mentalizing” is where one individual is able to follow a natural hierarchy involving other individuals’ mind states. For example, in the play ‘Othello’, Shakespeare manages to keep track of five separate mental states: he intended that his audience believes that Iago wants Othello to suppose that Desdemona loves Cassio. Being able to maintain five separate individuals’ mental states is the natural upper limit for most adults.”

The researchers took brain scans of 40 volunteers to measure the size of the prefrontal cortex. Participants were then asked to make a list of everyone they had had social (not professional) contact with over the previous seven days. They also took a test to determine their competency in mentalizing.

Dunbar adds, “We found that individuals who had more friends did better on mentalizing tasks and had more neural volume in the orbital frontal cortex. Understanding this link between an individual’s brain size and the number of friends they have helps us understand the mechanisms that have led to humans developing bigger brains than other primate species. The frontal lobes of the brain, in particular, have enlarged dramatically in humans over the last half million years.”

The study was published in The Proceedings of the Royal Academy of Biological Sciences.





Scientists investigate mystery of telephone cord buckles.

Ranging in thickness from a few nanometers to several micrometers, thin films and coatings play a role in a wide variety of applications. The reflective metal layer on a mirror, the coatings on low-emissivity or colored windows, and the thin silicon layers on thin-film solar cells all consist of thin films. When thin films are compressed with enough force, they can buckle and delaminate under compressive stress. Starting from defects, the buckles propagate, delaminating the film substrate interface on their way. Buckles can be straight, circular, or even take the three-dimensional coiled shape of a telephone cord. Although researchers have studied telephone cord buckling in thin films for decades, they still don’t fully understand their propagation mechanisms. A new study now sheds some light on this area.

A team of researchers from France, Jean-Yvon Faou, Sergey Grachev, and Etienne Barthel from CNRS/Saint-Gobain in Paris, and Guillaume Parry from SIMaP (Grenoble Institute of Technology), have published their study on the formation of telephone cord buckles in thin films in a recent issue of Physical Review Letters.

The propagation of telephone cord buckles is more complex than that of other buckling shapes. In experiments, scientists have observed telephone cord buckle formation, assumed to be starting from initial defects. At some point, the propagation front begins to rotate. The rotating buckle sags slightly, and the sagging is immediately followed by a change in the rotation direction. These steps repeat, and the telephone cord buckling grows.

Although scientists can observe these buckles occurring over and over in different thin-film materials, an understanding of the physical mechanisms that cause this coiled morphology to form has remained elusive. Now for the first time, the researchers have developed a simulation of telephone cord buckling that mimics very closely the way that the buckling occurs in experiments.

“The problem is highly non-linear,” Parry and Faou told PhysOrg.com. “It actually mixes the mechanical non-linearity of plates (the buckling thin film) and the physical non-linearity of adhesion. Non-linearities make it difficult to find solutions. In this work we had precise experimental results which helped identify exactly where to look for a solution.”

What makes the problem even trickier, they explain, is that the compression that causes telephone cord buckling is often the same kind of compression that causes other types of buckles.

“In non-linear problems, various solutions may coexist under the same conditions!,” the scientists explain. “So basically it is the same kind of compressive loadings which leads to the different types of buckles. However, a first parameter affecting the morphology is possible stress asymmetry in the plane, while details in the interface energy will also affect buckle patterns.”

The scientists built their simulation based on a suggestion from a previous study that the telephone cord morphology arises from an instability at the buckle front. The new simulation shows that, during the sagging of the buckle, such an instability can cause the sagged area to pin the front of the buckle. This pinning causes the buckle front to collapse, which induces the counter-rotation in the buckle, the defining feature of the telephone cord morphology.

By better understanding telephone cord buckling in thin films, researchers may find ways to minimize or avoid this unwanted buckling in applications.

“It is usually seen as a flaw,” Parry and Faou said. “We like telephone cord buckles because, on the other hand, we hope we can understand adhesion better from the analysis of the buckle morphologies. In addition, the idea of pinning is interesting: we may think that if we understand buckles accurately enough, we could find ways to really pin them down, thus suppressing propagation. This would require specific interface designs.”

Source: PhysOrg.com. 




Vitamins doing gymnastics: Scientists capture first full image of vitamin B12 in action.

But when it gets inside your body, new research suggests, B12 turns into a gymnast.

In a paper published recently in the journal Nature, scientists from the University of Michigan Health System and the Massachusetts Institute of Technology report they have created the first full 3-D images of B12 and its partner molecules twisting and contorting as part of a crucial reaction called methyltransfer.


That reaction is vital both in the cells of the human body and, in a slightly different way, in the cells of bacteria that consume carbon dioxide and carbon monoxide. That includes bacteria that live in the guts of humans, cows and other animals, and help with digestion. The new research was done using B12 complexes from another type of carbon dioxide-munching bacteria found in the murky bottoms of ponds.


The 3-D images produced by the team show for the first time the intricate molecular juggling needed for B12 to serve its biologically essential function. They reveal a multi-stage process involving what the researchers call an elaborate protein framework – a surprisingly complicated mechanism for such a critical reaction.

U-M Medical School professor and co-author Stephen Ragsdale, Ph.D., notes that this transfer reaction is important to understand because of its importance to human health. It also has potential implications for the development of new fuels that might become alternative renewable energy sources.


“Without this transfer of single carbon units involving B12, and its partner B9 (otherwise known as folic acid), heart disease and birth defects might be far more common,” explains Ragsdale, a professor of biological chemistry. “Similarly, the bacteria that rely on this reaction would be unable to consume carbon dioxide or carbon monoxide to stay alive – and to remove gas from our guts or our atmosphere. So it’s important on many levels.”


In such bacteria, called anaerobes, the reaction is part of a larger process called the Wood-Ljungdahl pathway. It’s what enables the organisms to live off of carbon monoxide, a gas that is toxic to other living things, and carbon dioxide, which is a greenhouse gas directly linked to climate change. Ragsdale notes that industry is currently looking at harnessing the Wood-Ljungdahl pathway to help generate liquid fuels and chemicals.


In addition to his Medical School post, Ragsdale is a member of the faculty of the U-M Energy Institute.

In the images created by the team, the scientists show how the complex of molecules contorts into multiple conformations — first to activate, then to protect, and then to perform catalysis on the B12 molecule. They had isolated the complex from Moorella thermoacetica bacteria, which are used as models for studying this type of reaction.

The images were produced by aiming intense beams of X-rays at crystallized forms of the protein complex and painstakingly determining the position of every atom inside.


“This paper provides an understanding of the remarkable conformational movements that occur during one of the key steps in this microbial process, the step that involves the generation of the first in a series of organometallic intermediates that lead to the production of the key metabolic intermediate, acetyl-CoA,” the authors note.

Senior author Catherine L. Drennan from MIT and the Howard Hughes Medical Institute, who received her Ph.D. at the U-M Medical School, adds, “We expected that this methyl-handoff between B vitamins must involve some type of conformational change, but the dramatic rearrangements that we have observed surprised even us.”


Source: University of Michigan

Two studies show promising, durable results for renal denervation.

The Symplicity renal denervation system provided reductions in blood pressurethat were sustained for up to 3 years in patients with treatment-resistant hypertension, according to data from two clinical trials presented at the American College of Cardiology’s 61st Scientific Sessions.

Paul A. Sobotka, MD, professor of medicine and cardiology at the Ohio State University, presented 3-year results from Symplicity HTN-1, a series of pilot studies that enrolled 153 patients with treatment-resistant hypertension at sites in Australia, Europe and the United States. Eligible patients in this study had systolic BP ≥160 mm Hg despite use of at least three antihypertensive drugs, including a diuretic, at target or maximal tolerated doses. Exclusion criteria included an estimated glomerular filtration rate <45 mL/min/m2 or type 1 diabetes.

One-year results from Symplicity-HTN-1 indicated that patients who crossed over to denervation after previous pharmacologic therapy also achieved sustained reductions in BP.

“A sustained significant BP reduction has been observed through 36 months,” Sobotka said during an oral session. “There is no evidence of reversal or regression of BP advantage bestowed early on.”

Nonresponders were defined, arbitrarily, according to Sobotka, as patients with failure to reduce BP more than 10 mm Hg.

“At 1 month, the responder rate was 0%, but by 36 months, the full cohort responded with reductions of 10 mm Hg.

Sobotka also discussed “late responders,” or patients who had no response at 1 month.

“Of 45 patients who had no clinical response at 1 month, 58% had a 10 mm Hg drop in BP at 3 months, and at 36 months, we are seeing all patients with a clinical response to the initial renal denervation.”

Reductions in diastolic and systolic BP were observed in patients aged older than 65 years or younger than 65 years, according to Sobotka.

“Age does not discriminate the time course, durability or magnitude of the response itself,” he said.

The treatment was also durable in terms of BP behavior regardless of diabetes status, according to Sobotka.

“On the basis of renal function, we bifurcated the group with patients who had estimated glomerular filtation rates between 45 and 60 mL/min/m2, and those who had estimated glomerular filtation rates of greater than 60 mL/min/m2,” Sobotka said. “By 12, 24 and 36 months, there is no significant difference to the systolic and diastolic reductions in BP on the basis of preceding renal status.”

Sobotka also reported no significant changes in renal function at any time interval.

Regarding safety, Sobotka reported one progression of preexisting stenosis unrelated to the current treatment and one moderate stenosis that was not hemodynamically relevant. There were three deaths, none of which were related to the treatment. There were no catheter or generator malfunctions and no major complications.

Murray D. Esler, MD, of the Baker IDI Heart and Diabetes Institute in Melbourne, Australia, reported 1-year results from the international, multicenter, prospective, randomized, controlled Symplicity HTN-2 trial. Fifty-two patients were assigned to renal denervation treatment and 54 patients to a control group that remained on previous therapy. At 6 months, patients in the control group were allowed to cross over to denervation treatment. Esler presented results on 35 crossover patients.

Patients who crossed over at 6 months had a similar significant drop in BP as patients receiving immediate denervation.

“At 12 months post denervation, the reduction in BP was similar to the initially denervated group,” Esler said.

He noted that long-term safety outcomes were “good,” with three hypertensive events reported in two patients in the crossover group. No deaths occurred.

“There may be significant costs associated with delaying denervation,” Esler said. “These patients were treated with 6 months of medication that was essentially ineffective.”

The novel Symplicty renal denervation system (Medtronic) is not currently approved by the FDA for distribution in the United States.

For more information:

Disclosure: Dr. Esler reports research funds and is a consultant and on the speaker’s bureau for Ardian and Medtronic. Dr. Sobotka is an employee of Medtronic.



We now have two valuable pieces of information. One, we now know that patients defined as nonresponders actually are responders if you wait long enough. We do not necessarily understand why, but they do. Two, there is good proof of durability at least going out to 3 years. Beyond that we don’t know. Some people have projected that it could be as long as 10 years before those nerves grow back. At least now we have assurances that at 3 years it will happen. My conjecture is that depending on how good a job the denervation procedure does, it would not shock me if they remained denervated for 10 years. In fact, it would shock me if it was less than 5 years. That would tell me that the nerves were either not fully ablated, or that they were growing back faster than would be expected.

George Bakris, MD
Endocrine Today Editorial Board member

Source: Endocrine Today