Day: 02/17/2012

Dabigatran and Acute Coronary Syndromes: Meta-Analysis Confirms RE-LY Findings

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Dabigatran increases risk for acute coronary syndromes but decreases mortality.

Several alternatives to warfarin for prevention of venous thromboembolism and stroke are already approved for clinical use, and several more are in development. The principal advantage of these agents is their ease of use. Yet they also have known disadvantages — such as the lack of a rapid reversal agent and cost — and, possibly, unknown toxicities. By contrast, warfarin has been in use for millions of patient-years, and its effects (both beneficial and adverse) are very familiar.

Dabigatran was FDA-approved for treatment of atrial fibrillation after the landmark RE-LY study . A secondary finding from RE-LY showed a significant increase in myocardial infarction with dabigatran. To find out more, investigators conducted a meta-analysis of seven dabigatran studies. Control agents in the studies included warfarin, enoxaparin, and placebo.

The rate of acute coronary syndromes (including infarction) was significantly higher in the 20,000 dabigatran patients than in the 10,514 control patients (1.19% vs. 0.79%). These results were largely driven by RE-LY, which contributed 59% of the cohort and 74% of the events. Unlike the RE-LY trial, in which a decrease in overall mortality with dabigatran did not quite achieve statistical significance (P=0.051), the meta-analysis demonstrated a significant reduction in mortality with dabigatran (5.02% vs. 4.83%; P=0.04).

Comment: The confirmation of one adverse endpoint in the RE-LY study does not diminish the fact that dabigatran reduces the rates of venous thromboembolism and stroke. However, this meta-analysis does underline the need for continuing postapproval study of any new drug. I suspect that as data accumulate from registry and other observational studies, warfarin will fare poorly in overall safety comparisons with dabigatran and other new competitors.

Source: Journal Watch Cardiology

IM Administration of Benzodiazepines as Good as IV for Epileptic Seizures En Route to Hospital .

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Paramedics caring for patients with prolonged epileptic seizures have as much success ending the seizures with intramuscular midazolam as they do with intravenous lorazepam.

In a noninferiority study, some 900 patients in status epilepticus who had been convulsing for longer than 5 minutes received either intramuscular midazolam or intravenous lorazepam. The primary outcome, the termination of seizures before arrival in the emergency department, was 73% with the intramuscular benzodiazepine and 63% with the intravenous one.

Writing in the New England Journal of Medicine, the authors point out that their study showed not only that intramuscular midazolam was equal to intravenous lorazepam, but that the differences clearly favored the superiority of intramuscular midazolam.

Dr. J. Stephen Bohan concludes in Journal Watch Emergency Medicine: “Prehospital protocols should instruct use of intramuscular midazolam as the primary treatment for prolonged seizure activity not caused by a correctable condition, such as hypoglycemia.”

Source: NEJM

Timing of Biomarker Changes in Alzheimer Disease Process.

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Abnormal amyloid biomarker levels may be seen before abnormal tau biomarker levels in patients progressing toward Alzheimer disease.

Alzheimer disease (AD) is associated with neuronal plaques and neurofibrillary tangles, which result from abnormal amyloid and tau processing, respectively. To explore the relative timing and rates of these changes during the AD process, researchers analyzed levels of one amyloid biomarker (cerebrospinal fluid [CSF] amyloid-beta1-42 [Aβ1-42]) and of two tau biomarkers (CSF total tau [T-tau] and adjusted hippocampal volume [AHV]) in 116 elderly patients with normal cognition, 196 with mild cognitive impairment (MCI), and 89 with dementia. To distinguish normal from abnormal biomarker levels, the researchers used cutoff values from separate autopsy cohorts of those who met clinical criteria for low- or high-probability of AD pathology.

Each biomarker became more abnormal across the clinical diagnostic spectrum, from normal to MCI to dementia. Significantly greater proportions of each clinical diagnostic group had abnormal CSF Aβ1-42] levels (<192 pg/mL) than abnormal CSF T-tau levels (>92 pg/mL) or AHV (<0.48). The proportion with abnormal Aβ42 levels did not change from baseline to 12 months in any group. Among cognitively normal patients, the proportion with abnormal CSF T-tau levels increased significantly at 12 months. By contrast, in the MCI group, the proportion of patients with abnormal AHV increased at 12 months, whereas the proportion with abnormal T-tau levels did not. The authors conclude that decreased CSF Aβ42 levels appear early in the disease process and may be seen in cognitively normal patients, whereas increased CSF T-tau and decreased AHV appear later and are primarily associated with clinical symptoms of MCI and dementia. Further, they conclude that abnormal CSF T-tau levels precede abnormal AHV and that AHV changes more rapidly as clinical symptoms progress.

Comment: The use of biomarkers may increase the certainty that clinical symptoms of those with MCI and dementia are caused by AD pathology. These findings suggest that cognitively normal patients with abnormal Aβ42 levels may develop the clinical changes associated with AD, and other biomarkers such as CSF T-tau and AHV may assist in identifying patients in need of closer follow-up. A clinical-biomarker profile should be developed that can identify both asymptomatic patients who have an increased risk for developing symptoms of AD and candidates for future clinical trials of disease-modifying therapy.

Source:Journal Watch Neurology

Chipping Away at Bone: Proton-Pump Inhibitors and Smoking.

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Long-term PPI use was associated with excess risk for postmenopausal hip fractures, especially in smokers.

Proton-pump inhibitors (PPIs) suppress gastric acid production and, consequently, calcium absorption. Thus, long-term PPI use may reduce bone density and raise fracture risk. Using data from the Nurses’ Health Study (NHS) and prior studies, investigators assessed the association between long-term PPI use and risk for hip fracture in postmenopausal women.

Among 80,000 women in the NHS (age range at entry, 30–55), PPI use rose from 7% in 2000 to 19% in 2008. Absolute risk for hip fracture was 2.0 events per 1000 person-years among regular PPI users and 1.5 events per 1000 person-years among nonusers. Adjusted for multiple factors (e.g., body-mass index, calcium intake, osteoporosis history, use of hormone therapy), risk for hip fracture among women who used PPIs regularly for 2 years was 40% higher than among nonusers and rose with duration of PPI use. Among previous or current smokers, PPI use was associated with a 50% increased risk for hip fracture, whereas among never-smokers, PPI use was not associated with excess risk. In a meta-analysis involving 11 studies and 1.5 million participants, PPI use was associated with a 30% increased risk for hip fracture.

Comment: Notably, proton-pump inhibitor use also has been associated with excess risks for vertebral, forearm, and wrist fractures . The finding that chronic PPI use is associated with excess risk for hip fracture, especially in women with histories of smoking, suggests that long-term PPI use in women should be critically evaluated.

Source: Journal Watch General Medicine

Amoxicillin Has No Effect on Acute, Uncomplicated Bacterial Rhinosinusitis .

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Amoxicillin doesn’t ameliorate the severity of acute, uncomplicated bacterial rhinosinusitis any better than placebo, according to a JAMA study.

Some 160 patients with clinically confirmed disease (purulent nasal discharge and maxillary pain or facial tenderness) were randomized to receive either 1500 mg/day of amoxicillin or placebo for 10 days. In addition, all received a supply of symptomatic treatments (e.g., acetaminophen) for use as needed.

Patients’ assessment of improvement in 16 sinus-related symptoms did not differ between groups at day 3 or at day 10. (While symptom scores did favor antibiotics at day 7, the authors judge the difference to be “too small to represent any clinically important change.”)

In his Journal Watch HIV and ID Observations blog, Dr. Paul Sax says the study reminds us that “most of the common community-acquired infections resolve spontaneously.”

Source: JAMA

 

 

Vitamin C proven to help protect Fukushima victims from radiation poisoning, cancer .

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Pretreatment with intravenous vitamin C and other oral antioxidants has been demonstrated once again to provide significant protection against radiation poisoning and cancer. Dr. Atsuo Yanagisawa, M.D., Ph.D., from the Japanese College of IV Therapy recently conducted a study which found that Fukushima workers who underwent a high-dose vitamin C pretreatment prior to handling radioactive debris during cleanup efforts were protected against DNA damage and cancer.

The Orthomolecular Medicine News Service (OMNS) reports that Dr. Yanagisawa evaluated 16 men between the ages of 32 and 59 that worked between five and six weeks in a high-radiation area of Fukushima. Some of the men received 25,000 milligrams (mg) of intravenous vitamin C therapy along with oral intake of other powerful antioxidants like alpha-lipoic acid and vitamin E prior to entering the contaminated area, while the others received no pretreatment at all.

After taking blood samples from all the men and evaluating them for whole blood count and chemistry, as well as for plasma levels of free DNA and 47 cancer-related gene expressions, Dr. Yanagisawa and his team found that those who received the vitamin C therapy experienced no increase in cancer risk or change in free DNA. Those who did not receive the treatment, on the other hand, had significantly increased cancer risk.

Those who did not receive pretreatment, but that received a post-treatment intervention with the same regimen for two months, however, saw their heightened free DNA levels return to normal. Their overall cancer risk score also returned back to normal, illustrating the incredible power of vitamin C and other antioxidants to protect against, and even reverse, the damage caused by radiation.

“This important clinical demonstration confirms research done nearly 20 years ago showing that pretreatment with vitamin C, by oral intake or injection, increased sperm head survival after the injection of radioactive Iodine-131 in mice,” says the OMNS report.

Vitamin C is one of the most powerful nutrients in protecting against cell-damaging free radicals. And while ascorbic acid, the popular isolated version of vitamin C, has its demonstrable therapeutic uses, the camu camu berry is one of the most powerful vitamin C-rich superfoods for gaining the same health benefits naturally. The acerola cherry is also another vitamin C-dense superfood with amazing radio-protective abilities.
Source:Nature.

 

Physicists Predict The Existence of Time Crystals.

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If crystals exist in spatial dimensions, then they ought to exist in the dimension of time too, says Nobel prize-winning physicist

One of the most powerful ideas in modern physics is that the Universe is governed by symmetry. This is the idea that certain properties of a system do not change when it undergoes a transformation of some kind.

For example, if a system behaves the same way regardless of its orientation or movement in space, it must obey the law of conservation of momentum.

If a system produces the same result regardless of when it takes place, it must obey the law of conservation of energy.

We have the German mathematician, Emmy Noether, to thank for this powerful way of thinking. According to her famous theorem, every symmetry is equivalent to a conservation law. And the laws of physics are essentially the result of symmetry.

Equally powerful is the idea of symmetry breaking. When the universe displays less symmetry than the equations that describe it, physicists say the symmetry has been broken.

A well known example is the low energy solution associated with the precipitation of a solid from a solution—the formation of crystals, which have a spatial periodicity. In this case the spatial symmetry breaks down.

Spatial crystals are well studied and well understood. But they raise an interesting question: does the universe allow the formation of similar periodicities in time?

Today, Frank Wilczek at the Massachussettsi Institute of Technology and Al Shapere at the University of Kentucky, discuss this question and conclude that time symmetry seems just as breakable as spatial symmetry at low energies.

This process should lead to periodicities that they call time crystals. What’s more, time crystals ought to exist, probably under our very noses.

Let’s explore this idea in a bit more detail. First, what does it mean for a system to break time symmetry? Wilczek and Shapere think of it like this. They imagine a system in its lowest energy state that is completely described, independently of time.

Because it is in its lowest energy state,  this system ought to be frozen in space. Therefore, if the system moves, it must break time symmetry. This is equivalent tot he idea that the lowest energy state has a minimum value on a curve on space rather than at a single isolated point

That’s actually not so extraordinary. Wilczek points out that a superconductor can carry a current—the mass movement of electrons—even in its lowest energy state.

The rest is essentially mathematics. In the same way that the equations of physics allow the spontaneous formation of  spatial crystals, periodicities in space, so they must also allow the formation of periodicities in time or time crystals.

In particular, Wilczrek considers spontaneous symmetry breaking in a closed quantum mechanical system. This is where the mathematics become a little strange. Quantum mechanics forces physicists to think about imaginary values of time or iTime, as Wilczek calls it.

He shows that the same periodicities ought to arise in iTime and that this should manifest itself as periodic behaviour of various kinds of thermodynamic properties.

That has a number of important consequences. First up is the possibility that this process provides a mechanism for measuring time, since the periodic behaviour is like a pendulum. “The spontaneous formation of a time crystal represents the spontaneous emergence of a clock,” says Wilczek.

Another is the possibility that it may be possible to exploit time crystals to perform computations using zero energy. As Wilczek puts it, “it is interesting to speculate that a…quantum mechanical system whose states could be interpreted as a collection of qubits, could be engineered to traverse a programmed landscape of structured states in Hilbert space over time.”

Altogether this is a simple argument. But simplicity is often  deceptively powerful. Of course, there will be disputes over some of the issues this raises. One of them is that the motion that breaks time symmetry seems a little puzzling. Wilczek and Shapere acknowledge this: “Speaking broadly speaking, what we’re looking for looks perilously close to perpetual motion.”

That will need some defending. But if anyone has the pedigree to push these ideas forward, it’s Wilczek, who is a Nobel prize winning physicist.

Source:Physics

 

 

 

New study finds ingested nanoparticles more dangerous than previously thought.

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Billions of engineered nanoparticles in foods and pharmaceuticals are ingested by humans daily and new Cornell research warns they may be more harmful to health than previously thought. A research collaboration led by Michael Shuler, the Samuel B. Eckert Professor of Chemical Engineering and the James and Marsha McCormick Chair of Biomedical Engineering, studied how large doses of polystyrene nanoparticles — a common, FDA-approved material found in substances from food additives to vitamins — affected how well chickens absorbed iron, an essential nutrient, into their cells. The results were reported online Feb. 12 in the journal Nature Nanotechnology. According to the study, high-intensity, short-term exposure to the particles initially blocked iron absorption, whereas longer-term exposure caused intestinal cell structures to change, allowing for a compensating uptick in iron absorption. The researchers tested both acute and chronic nanoparticle exposure using human gut cells in petri dishes as well as live chickens and reported matching results. They chose chickens because these animals absorb iron into their bodies similarly to humans, and they are also similarly sensitive to micronutrient deficiencies, explained Gretchen Mahler, Ph.D. ’08, the paper’s first author and former Cornell graduate student and postdoctoral associate. The researchers used commercially available, 50-nanometer polystyrene carboxylated particles that are generally considered safe for human consumption. They found that following acute exposure, a few minutes to a few hours after consumption, both the absorption of iron in the in vitro cells and the chickens decreased. But following exposure of 2 milligrams per kilogram for two weeks — a slower, more chronic intake — the structure of the intestinal villi began to change and increase in surface area. This was an effective physiological remodeling that led to increased iron absorption. “This was a physiological response that was unexpected,” Mahler said. Shuler noted that in some sense this intestinal villi remodeling was positive because it shows the body adapts to challenges. But it serves to underscore how such particles, which have been widely studied and considered safe, cause barely detectable changes that could lead to, for example, over-absorption of other, harmful compounds. Human exposure to nanoparticles is only increasing, Shuler continued. “Nanoparticles are entering our environment in many different ways,” Shuler said. “We have some assurance that at a gross level they are not harmful, but there may be more subtle effects that we need to worry about.”
Source:Physics

 

 

 

 

The More Active Kids Are, the Better Their Health — Regardless of Sedentary Time .

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Children who are more physically active have healthier cardiometabolic risk profiles than less-active children — regardless of the amount of time they also spend being sedentary — according to a JAMA meta-analysis.

Researchers examined data from 14 studies comprising nearly 21,000 children (aged 4 through 18 years) whose physical activity was measured with accelerometers. They found that higher levels of moderate-to-vigorous physical activity were associated with healthier cardiometabolic risk factors, including waist circumference, blood pressure measurements, and insulin, triglyceride, and HDL levels. These associations persisted after adjustment for sedentary time. Sedentary time, on the other hand, was not independently associated with any cardiometabolic risk factor.

The researchers conclude: “Children should be encouraged to increase their participation in physical activity of at least moderate intensity rather than reducing their overall sedentary time as this appears more important in relation to cardiometabolic health.”

Soure: JAMA

FDA Warns of Counterfeit Bevacizumab .

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A counterfeit version of the cancer drug bevacizumab (Avastin) may have been used by physicians in the U.S, the FDA warns. The counterfeit version does not contain the active ingredient and may be “unsafe or ineffective.”

The agency sent a warning letter to 19 medical practices that had purchased unapproved cancer drugs — possibly including the counterfeit Avastin — from Quality Specialty Products, a foreign supplier also known as Montana Health Care Solutions.

Packages may be counterfeit if:

  • Roche is listed as the manufacturer on the packaging or vials;
  • batch numbers start with B6010, B6011, or B86017.

Source:FDA