Monthly Archives: November 2014

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Joel Saltz lives in a world of numbers. The first chairman of biomedical informatics at Stony Brook recently hit a number that will help him continue to develop a department he arrived to lead last year: $3.2 million. That’s how much the National Cancer Institute pledged to support Saltz’s efforts.

“This grant is related to developing methods and tools for analyzing tissue data, in particular pathology, as it relates to genetics and genomics,” Saltz said. That means he will try to understand more about the complex patterns of interactions between cancer cells, surrounding and distant tissues. By studying these interactions, Saltz and his collaborators hope to help develop diagnostic and treatment methods.

A powerful enemy with ways of evading different kinds of treatment, cancer can present prognoses that vary from one person to another — even when the cancer is in the same area or affects the same organs or systems.

“In some cases, the relationship varies from one part of the tumor to another,” said Saltz. “If one part of the tumor has ‘x,’ they treat it like ‘x,’ but if it has some ‘y,’ the heterogeneity can be indicative of another diagnosis. What you want to do is look at the distribution of proteins or nucleic acids, and then do an image analysis.”

Saltz has programmed computers to scan tumors to get a consistent, quick and reproducible understanding of the underlying cancer or tumors. This effort will provide data that the international community of academic and commercial algorithm developers can study.

This effort to count different types of cells to get a mathematical handle on the type of disease can “reduce the variability from one pathologist to another,” Saltz said. “That is critical for any study.” He also hopes to learn new relationships among various components that may not be obvious.

By understanding the nature of the specific cancer, scientists and doctors hope to get a better handle on a specific treatment for each patient.

Saltz is “working with a number of translational researchers” who have patient populations or are working with animal models of cancer, he said.

The kind of analysis Saltz does in his biomedical informatics world may eventually lead to individualized or precision medicine. At this point, this is a longer-term hope for the effort.

Saltz described the process as taking an image analysis and adding a machine learning component. While convinced of the value of this type of computer-aided analysis, Saltz is not advocating developing a diagnostic or treatment regime by relying exclusively on the analysis of a computer.

“The sort of information a machine can give you complements what two people trained in different parts of the country” conclude, he said. “It can help reduce the level of unanticipated disagreement.”

At this point, these methods are not directly used to treat patients. They are a part of a research effort to improve the quality of the scientific studies.

Saltz credited Ken Kaushansky, the dean of the School of Medicine, with committing Stony Brook to integrate the latest research into improvements in the care and treatment of patients.

Other Stony Brook scientists shared their appreciation for Saltz’s approach. Saltz “brings in unique and urgently needed expertise in cancer informatics,” said Yusuf Hannun, the director of the Stony Brook Cancer Center. “This is a discipline engaged in collating, organizing and analyzing large data sets obtained in the course of cancer studies. Saltz brings internationally recognized expertise in this field.”

Saltz said there were numerous steps researchers needed to take before this approach has a clinical application.

To build out the expertise in biomedical informatics at Stony Brook, Saltz is applying to add a Ph.D., Master’s and certificate program. He said the program will build a bridge between pathology and computer science.

A resident of Huntington, Saltz moved to Long Island with his wife Mary, a clinical associate professor of radiology. The couple have four children, who range in age from 19 to 26.

Saltz said he was impressed with the natural beauty of Long Island. He had visited the area before when his brother, David Saltz, who is now at the Department of Theatre and Film at the University of Georgia, worked at Stony Brook from 1994 to 1996.

As for his work, Saltz said he is “delighted” with the NCI grant. “We’ve got a great team.”

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Good for disease prevention, not so good for weight loss

With the holiday dinners right around the corner, what would be better topic to discuss than exercise? To quell our guilt about Thanksgiving-dinner indiscretions, many of us will resolve to exercise to burn off the calories from this seismic meal and the smaller, calorically dense aftershock meals, whether with a vigorous family football game or with a more modest walk.

Before I go on, let’s take a little quiz. A little knowledge goes a long way in feeling good about your plans to potentially exercise.

Question #1: I can offset potential weight gain from a calorically dense meal by doing which of the following?

a) Exercising intensely for a short   

    duration

b) Exercising moderately for a long

    duration

c) Exercising lightly for a long
        duration

d) Exercise is unlikely to offset a       

     calorically dense meal

Question #2: Exercise is beneficial for which of the following? Choose all that apply.

a) Chronic kidney disease

b) Rheumatoid arthritis

c) Cognitive decline

d) Risk of falls

Unfortunately, the answer to question one is “d.” Exercise without dietary changes may not actually help many people to lose weight, no matter what the intensity or the duration (1). If it does help, it may only modestly reduce fat mass and weight for the majority of people. However, it may be helpful with weight maintenance. Therefore, it may be more important to think about what you are eating than to succumb to the rationalization that you can eat with abandon during the holidays and work it off later.

Don’t give up on exercise just yet, though. There is very good news: the answer to question two is that exercise has beneficial effects on all of the choices plus many others, including diabetes, cardiovascular disease, osteoporosis, fatigue, insomnia, and depression.

Let’s look at the evidence.

Weight loss attenuated

The well-known weight-loss paradigm in medicine is that when more calories are burned than consumed, we will tip the scale in favor of weight loss. The greater the negative balance with exercise, the greater the loss. However, the results of a recent study say otherwise. They show that in premenopausal women there was neither weight nor fat loss from exercise (2). This involved 81 women over a short duration, twelve weeks. All of the women were overweight to obese, although there was great variability in weight.

However, more than two-thirds of the women (55) gained a mean of 1 kilogram, or 2.2 pounds, of fat mass by the end of the study. There were a few who gained 10 pounds of predominantly fat. Significant variability was seen among the participants, ranging from significant weight loss to substantial weight gain. These women were told to exercise at the American College of Sports Medicine’s optimal level of intensity (3). This is to walk 30 minutes on a treadmill three times a week at 70 percent VO2max — maximum oxygen consumption during exercise— or, in other words, a moderately intense pace. The good news is that the women were in better aerobic shape by the end of the study and that women who had lost weight at the four-week mark were more likely to continue to do so by the end of the study. This was a preliminary study, so no definitive conclusions can be made.

Other studies have shown modest weight loss. For instance, in a meta-analysis involving 14 randomized controlled trials — the gold standard of studies — results showed that there was a disappointing amount of weight loss with exercise alone (4). In six months, patients lost a mean of 1.6 kilograms, or 3.5 pounds, and at 12 months, participants lost 1.7 kilograms, or about 3.75 pounds.

Weight maintenance

However, exercise may be valuable in weight maintenance, according to observational studies. Premenopausal women who exercised at least 30 minutes a day were significantly less likely to regain lost weight (5). When exercise was added to diet, women were able to maintain 30 percent more weight loss than with diet alone after a year in a prospective study (6).

Chronic kidney disease

Chronic kidney disease affects about 1 in 10 people in the United States, according to the Centers for Disease Control and Prevention (7). The U.S. Preventive Services Task Force has indicated that there is insufficient evidence to treat asymptomatic CKD. In fact, the American College of Physicians has said that asymptomatic CKD, which includes stages 3a and 3b, or moderate disease levels, should not be screened for, since the treatment risks outweigh the benefits, and lead to false positive results and unnecessary treatments (8).

However, in a recent trial, the results showed that walking regularly could reduce the risk of kidney replacement therapy and death in patients who have moderate to severe CKD, stages 3-5 (9). Yes, this includes stage 3, which most likely is asymptomatic. There was a 21 percent reduction in the risk of kidney replacement therapy and a 33 percent reduction in the risk of death when walkers were compared to non-walkers.

Walking had such an impressive impact, results were based on a dose-response curve. In other words, the more frequently patients walked in the week, the better the probability of preventing complications. Those who walked between one and two times per week had 17 and 19 percent reductions in death and kidney replacement therapy, respectively, while those who walked at least seven times per week saw 44 and 59 percent reductions in death and kidney replacement. These are substantial results. The authors concluded that the effectiveness of walking on CKD was independent of kidney function, age or other diseases.

Rheumatoid arthritis

Unfortunately, more than three quarters of patients with rheumatoid arthritis are affected with varying degrees of hand dysfunction. Well, it turns out that in a randomized controlled trial that included supervised (physiotherapist or occupational therapist) exercise for six sessions and exercise at home showed more than twice the improvement in hand function than those in the usual care group over a 12-month period (10). There were no changes in drug therapies or pain.

Therefore, while it is important to enjoy the holidays, it is food choices that will have the greatest impact on our weight and body composition. Exercise will not be the solution for most of us to overcome holiday weight gain. However, exercise is extremely beneficial for preventing progression of chronic disorders, such as CKD. Improved functioning of the hand with exercise in rheumatoid arthritis patients reduces disability.

So, by all means, exercise during the holidays, but also focus on more nutrient-dense foods. At the least, strike a balance rather than eating purely calorically dense foods. They are unlikely to be rationalized with exercise.

References

(1) update.com. (2) J Strength Cond Res. Online Oct. 28, 2014. (3) ACSM.org. (4) Am J Med. 2011;124(8):747. (5) Obesity (Silver Spring). 2010;18(1):167. (6) Int J Obes Relat Metab Disord. 1997;21(10):941. (7) cdc.gov. (8) Ann Intern Med. online October 21, 2013. (9) Clin J Am Soc Nephrol. 2014 Jul;9(7):1183-9. (10) Lancet. online Oct. 9, 2014.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, go to the website www.medicalcompassmd.com and/or consult your personal physician.

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While the United States was celebrating Independence Day two years ago, a group of people were cheering the discovery of something they had spent almost half a century seeking. Physicists around the world were convinced the so-called Higgs boson particle existed, but no one had found clear-cut evidence of it.

At a well-attended press conference, scientists hailed the discovery, while recognizing the start of a new set of experiments and questions.

As a part of the ATLAS team, Marc-Andre Pleier knew what the group was set to announce. He was very excited “to see the signal confirmed by an independent measurement.” Two years later, Pleier, a physicist at Brookhaven National Laboratory and a part of a group of more than 3,000 scientists from around the world, are tackling the next set of questions.

The discovery “points to the Standard Model [of particle physics] being correct, but to know this we need to understand this new particle and its properties a lot better than we do now.”

According to the Standard Model of particle physics, the Big Bang beginning to the universe should have created equal parts matter and antimatter. If it did, the two opposite energies would have annihilated each other into light. An imbalance, however, resulted in a small fraction of matter surviving, forming the visible universe. The origin of this imbalance, however, is unknown, Pleier said.

“We know the Standard Models is incomplete,” he said, because there are observations of dark matter, dark energy and the antimatter/matter asymmetry in the universe that can’t be explained by this model. “We can test this” next chapter.

The process Pleier studies allows him to test whether the particle is doing its job as expected. In addition to analyzing data, Pleier also has “major responsibility in upgrading the detector,” said Hong Ma, a group leader in the Physics Department at BNL who recruited Pleier to join BNL in 2009.

Scientists at the Hadron Collider in Switzerland and at BNL and elsewhere are studying interactions that are incredibly rare among particles.

Pleier is searching for interactions of vector bosons, which have spin values of one and are extremely large in the world of bosons. He is looking for cases where two W bosons interact with each other.

“Only one event out of a hundred trillion events will be of interest to me,” said Pleier. Comparing those numbers to the world of biology, Pleier likened that to finding a single cell in an entire human body.

In 2012, the Hadron Collider produced 34 such interactions. The collider produces about 40 million pictures per second. To find the ones that might hold promising information, scientists like Pleier need to use a computing grid. BNL is one of only 10 tier 1 centers for ATLAS and the only one in the United States. Thus far, scientists have been able to look at these collisions from energies at 8 trillion electron volts. They hope to measure similar data at 13 trillion electron volts next year.

Ma said the increased energy of the collider will “put the Standard Model to an unprecedented level of tests,” allowing scientists to “measure the properties of Higgs boson to a higher precision.”

Growing up in Germany, Pleier said he loved playing with Legos to see how things worked. He helped fix his own toys. When he was older, he worked to repair a motor bike his uncle had.

What he’s doing now, he said, is exploring the fundamental building blocks of matter and their interactions. He likened it to examining the “construction kit” for the universe. While he’s a physicist, Pleier explained that he’s a Christian. “Some people think it has to be in conflict, but, for me, it clearly is not,” he said. “Each discovery adds to my admiration for God’s creation.”

A resident of Middle Island, Pleier lives with his wife Heather, an English teacher who is staying home for now to take care of their three children.

Pleier and Ma emphasized that the work at the collider is a collaborative effort involving scientists from institutions around the world.

Michael Kobel, a professor at TU Dresden, head of the Institute for Particle Physics and Dean of Studies in the Department of Physics who has known Pleier for about nine years, likened the process of studying the high energy particles to exploring a cave, where scientists “get more light to look deeper” into areas that were in the dark before. Researchers, he said, are just entering this cave of knowledge, with “a lot of corners yet to be explored.”

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Some medications contribute to fall risk

With winter’s icy conditions around the corner, our risk for falls is about to go up. When we were younger, falls usually did not result in significant consequences. However, when we reach middle age and chronic diseases become more prevalent, falls become more substantial. And, unfortunately, falls are a serious concern for older patients, where consequences can be devastating. They can include brain injuries, hip fractures, a decrease in functional ability, and a decline in physical and social activities (1). Ultimately, falls can lead to loss of independence (2).

Of those over the age of 65, between 30 and 40 percent will fall annually (3). Most of the injuries that involve emergency room visits are due to falls in this older demographic (4).

What can increase the

risk of falls?

A multitude of factors contribute to fall risk. A personal history of falling in the recent past is the most prevalent. But there are many other significant factors, such as age; female gender; drugs like antihypertensive medications used to treat high blood pressure; and psychotropic medications used to treat anxiety, depression, and insomnia. Chronic diseases, including arthritis, as an umbrella term; history of stroke; cognitive impairment and Parkinson’s disease can also contribute. Circumstances that predispose us to falls also involve weakness in upper and lower body strength, decreased vision, hearing disorders and psychological issues, such as anxiety and depression (5).

How do we prevent falls?

Fortunately, there are ways to modify many risk factors and ultimately reduce the risk of falls. Of the utmost importance is exercise. But what do we mean by “exercise?” Exercises involving balance, strength, movement, flexibility and endurance, whether home-based or in groups, all play significant roles in fall prevention (6). We will go into more detail below.

Many of us in the northeast suffer from low vitamin D, which strengthens muscle and bone. This is an easy fix with supplementation. Obviously, footwear needs to be addressed. Non-slip shoes, if last year is any indication, are of the utmost concern because of ice, especially black ice. Inexpensive changes in the home can also make a big difference.

Medications that exacerbate fall risk

There are a number of medications that may heighten fall risk. As I mentioned earlier, psychotropic drugs top the list. Ironically, they also top the list of the best-selling drugs. But what other drugs might have an impact?

High blood pressure medications have recently been investigated. A recent propensity-matched sample study (a notch below an RCT in terms of quality) showed an increase in fall risk in those who were taking high blood pressure medication (7). Surprisingly, those who were on moderate doses of blood pressure medication had the greatest risk of serious injuries from falls, a 40 percent increase. One would have expected those on the highest levels of BP medication to have the greatest increase in risk, but this was not the case.

While blood pressure medications may contribute to fall risk, they have significant benefits in reducing the risks of cardiovascular disease and events. Thus, we need to tread lightly before considering stopping a medication; we need to weigh the risk-benefit ratio, specifically in older patients. When it comes to treating high blood pressure, lifestyle modifications may also play a significant role in treating this disease (8).

Where does arthritis fit into this paradigm?

In those with arthritis, compared to those without, there is an approximately two-times increased risk of two or more falls and, additionally, a two-times increased risk of injury resulting from falls, according to the CDC (1). This survey encompassed a significantly large demographic; arthritis was an umbrella term including those with osteoarthritis, rheumatoid arthritis, gout, lupus, and fibromyalgia. Therefore, the amount of participants with arthritis was 40 percent. Of these, about 13 percent had one fall and, interestingly, 13 percent experienced two or more falls in the previous year. Unfortunately, almost 10 percent of the participants sustained an injury from a fall. Patients 45 and older were as likely to fall as those 65 and older.

Why is exercise critical?

All exercise has value. A meta-analysis of a group of 17 trials showed that exercise significantly reduced the risk of a fall (9). If their categories are broken down, exercise had a 37 percent reduction in falls that resulted in injury and a 30 percent reduction in those falls requiring medical attention. But even more impressive was a 61 percent reduction in fracture risk. Remember, the lower the fracture risk, the more likely you are to remain physically independent. Thus, the author summarized that exercise not only helps to prevent falls, but also fall injuries. The weakness of this study was that there was no consistency in design of the trials included in the meta-analysis. Nonetheless, the results were impressive.

What specific types of exercise are useful?

Many times exercise is presented as a word that defines itself. In other words: just do any exercise and you will get results. But some exercises may be more valuable or have more research behind them. Tai chi, yoga and aquatic exercise have been shown to have benefits in preventing falls and injuries from falls.

A randomized controlled trial (RCT), the gold standard of studies, showed that those who did an aquatic exercise program (HydrOS) had a significant improvement in the risk of falls (10). Results showed a reduction in the number of falls from a mean of 2.00 to a fraction of this level — a mean of 0.29. There was no change in the control group.

Both groups were given equal amounts of vitamin D and calcium supplements. The aim of the aquatic exercise was to improve balance, strength and mobility. Also, there was a 44 percent decline in the number of patients who fell. This study’s duration was six months and involved 108 post-menopausal women with an average age of 58. This is a group that is more susceptible to bone and muscle weakness. The good news is that many patients really like aquatic exercise.

Thus, our best line of defense against fall risk is prevention. Does this mean stopping medications? Not necessarily. But for those 65 and older, or for those who have “arthritis” and are at least 45 years old, it may mean reviewing your medication list with your doctor. Before considering changing your BP medications, review the risk-to-benefit ratio with your physician. The most productive and least dangerous way to prevent falls is through lifestyle modifications.

References

(1) MMWR. 2014;63(17):379-83. (2) J Gerontol A Biol Sci Med Sci. 1998;53(2):M112. (3) J Gerontol. 1991;46(5):M16. (4) MMWR Morb Mortal Wkly Rep. 2003;52(42):1019. (5) JAMA. 1995;273(17):1348. (6) Cochrane Database Syst Rev. 2012;9:CD007146. (7) JAMA Intern Med. 2014 Apr;174(4):588-95. (8) JAMA Intern Med. 2014;174(4):577-87. (9) BMJ. 2013;347:f6234. (10) Menopause. 2013;20(10):1012-1019.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management. For further information, go to the website www.medicalcompassmd.com and/or consult your personal physician.

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Human mistakes occur everywhere, from a driver who runs a red light to a professional athlete who literally drops a ball, to an accountant who adds the wrong numbers. Even scientists, with their lab coats, their scientific method and their careful review process make errors.

So it was, in 2013, when scientists in Switzerland published a research paper suggesting that boron could exhibit a similar behavior to a topological insulator. If true, that could have implications for nanotechnology.

Recently, however, postdoctoral student Xiang-Feng Zhou at Stony Brook University, working with his lab director Artem Oganov, discovered that their fellow researchers had made a mistake. The Swiss scientists had “suggested metallicity for boron’s surface and this turned out to be an incorrect suggestion,” said Oganov.

Typically, topological insulators are made up of heavier elements. The Swiss scientists believed that the surface atom rearrangements in boron would enable the lighter element to exhibit the same conducting properties.

Zhou was able to test this theory by using a high-powered computer system created by Oganov and his colleagues. Called USPEX, for Universal Structure Predictor: Evolutionary Xtallogaraphy, the prediction code uses a set of principals driven by quantum mechanics.

Zhou and Oganov, who is a professor of theoretical crystallography at Stony Brook University, published their results recently in the journal Physical Review Letters, a journal of the American Physical Society.

“Topological insulators must include heavy elements and metallicity of their surfaces does not come from structural reconstructions,” Oganov said. “For boron, a similar effect was predicted (as we now know, incorrectly) due to the reconstruction of the surface.”

The Swiss scientists knew that breaking a solid causes a cleaving of many bonds, Oganov said. Atoms near the surface try to compensate for the lost bonds. Often, this results in unusual chemistry, he continued. The Swiss scientists thought this would lead to metallicity, he said.

Using their computer model, Zhou and Oganov found that boron would have a much more stable structure if it avoided a metallic state. Instead, it forms a semiconducting surface.

When Zhou, who is also an associate professor of physics at Nankai University in Tianjin, China, and Oganov sent their results for publication, the editors at Physical Review Letters did what they always do: they sent the paper to several experts in the field for review. One of the groups overseeing the analysis of the Stony Brook scientists’ results was the original team from Switzerland. Oganov wasn’t sure how they’d react.

“Usually, people are upset when their results are disproven,” Oganov said. “They checked our calculations and found that our result is correct. They gracefully admitted a mistake. Often, people would fight even knowing they are wrong.”

The Swiss scientists said they didn’t find the right surface because they didn’t have enough computing power, Oganov said. They suggested to Oganov that they finished their calculations “too soon.”

Another reviewer confirmed the result was correct, while a third one suggested the result might not even be worth publishing because it was something a scientist might be able to come up with using a pencil and paper.

“I take this as a compliment,” said Oganov. “Simple and beautiful are sometimes hard to come by. Heavy computations like the ones we have done are often the best way to find the simple reality. Reality is not always simple.”

Oganov credits Zhou, whom he met over five years ago and recruited to join his lab on one of his annual trips to China, with pursuing this work.

What Zhou found was “absolutely surprising and unexpected. I couldn’t expect the Swiss paper would be so far from the solution. I give [Zhou] credit for his inquisitiveness. It is hard and beautiful work.” Zhou said he met Oganov when he was a Ph.D. student. He found that the two of them had similar interests. “I love predicting crystal structures,” Zhou said.

Oganov was born in the Ukraine and raised and educated in Russia. He has worked in the UK, Switzerland and the United States. While science has a discipline and approach that keeps researchers from making unsupported claims, scientists still make mistakes. “Nobody,” he offered, “is insured from making mistakes.”

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PPIs may not prevent esophageal cancer

I recently watched “The Caine Mutiny,” a wonderful 1954 film starring Humphrey Bogart. I encourage those who have not seen the movie to watch it, but this is not a film review. Sadly, Humphrey Bogart died at 57 from esophageal cancer. It got me thinking: what might prevent this cancer? I thought of proton pump inhibitors. This class of medication includes Nexium (omeprazole), Prilosec (pantoprazole), and Prevacid (lansoprazole). As I am sure you know, PPIs can be found in both prescription and over-the-counter forms.

What are PPIs?

PPIs are acid-reducing medications that work by blocking the gastric proton pump (H+/K+ ATPase) of parietal cells in the lining of the stomach. They are used to treat GERD reflux; Barrett’s esophagus, a potential consequence of reflux; esophagitis (inflammation of the esophagus); and ulcers in the stomach and small intestines (1). Barrett’s can potentially lead to esophageal cancer.

Are PPIs effective?

The prevailing thought is that, by treating reflux disease with PPIs, you reduce the risk of esophageal cancer in those who have Barrett’s esophagus. However, the effectiveness has been called into question by a Danish study, which I will explain in more detail below.

How common are PPIs?

According to the FDA, there were 21 million prescriptions filled in 2009 for this class of medication (2). PPIs were the fifth most common drugs prescribed in the U.S. in 2011 (3). The median length of use is six months.

Do PPIs have significant

side effects?

Unfortunately, PPIs have side effects, and with chronic use, we seem to be seeing more side effects. The FDA warns of infections, both community-acquired pneumonia and Clostridium difficile, a bacterial infection that causes watery diarrhea and substantial discomfort; potential absorption issues with vitamins and minerals such as magnesium, calcium and B12; drug interactions with Plavix (clopidegril); increased bone fracture risk; and negative effects in older patients in general (2). Note that none of these side effects has been definitively tied to this class of drugs, but it should make you think twice.

Let’s look at the evidence.

Do PPIs prevent esophageal cancer?

The answer is probably not, and they may even increase risk. In a newly published Danish study, the surprising results showed that PPIs did not decrease the risk of esophageal cancer or high-grade dysplasia (abnormal growth of tissue) in patients who had Barrett’s esophagus (4). One precursor of cancer of the esophagus is Barrett’s esophagus, which can develop from chronic reflux disease. The risk of esophageal cancer in long-term users was greater in those who were more adherent than in those who had lower adherence with PPI use, but both had significantly increased risk of cancer development, 3.4 times and 2.2 times, respectively. This study involved 9,883 patients over a 10-year duration.

This study was observational, so the results are suggestive and require further studies to confirm these results. The authors surmise that the reason for this increased risk is that reflux disease involves other factors besides stomach acid production, and PPIs may increase the proportion of bile acids that are prone to cause cancer. Another reason may be that gastrin (which initiates secretion of stomach juices) production increases with the use of PPIs and may be responsible for the increased risk.

Do PPIs really increase
the risk of infection?

There are two scary diseases that are a potential result of PPIs: pneumonia and Clostridium difficile.

Pneumonia risk

PPIs may increase our risk of the most common type of bacterial pneumonia, Streptococcus pneumoniae. In an observational prospective (forward-looking) study, those who used PPIs were at two times the increased risk of developing this type of pneumonia compared to those not using these drugs (5). There were 463 patients involved in this study.

Fortunately, the severity of pneumonia was the same whether it was potentially caused by PPIs or not. In other words, PPIs did not make the pneumonia worse. The researchers surmise that PPIs may increase the risk of pneumonia because of potential bacterial overgrowth in esophagus due to a decrease in gut acid production and from modulation of the immune system.

In a meta-analysis (a group of nine studies), results showed that PPIs increased the risk of developing pneumonia (6). The most interesting part of this study was that those at higher risk were patients who used PPIs for less than 30 days. These patients had a 65 percent increased risk. Those who used high doses of the therapies were at a 50 percent increased risk. Interestingly, patients who had been using the PPIs for over six months did not show an increased risk of pneumonia. So it may not always relate to just long-term or chronic use.

Clostridium difficile risk

The infection by a bacterium Clostridium difficile may cause mild to severe watery diarrhea and abdominal pain. It is typically precipitated by antibiotic use. However, PPIs might also be implicated. In a meta-analysis (a group of 42 observational studies), results showed that PPIs increased the risk of Clostridium difficile infection by 74 percent compared to those who did not use these medications (7). And those who used both PPIs and antibiotics were at an even greater risk of 96 percent. There were 313,000 patients involved in this meta-analysis. No definitive conclusions can be made, though, since these results were based on observational trials; however, it makes you ponder the use of these drugs.

Aspirin and PPIs

Many people take daily low-dose (75 to 325 mg) aspirin to prevent a heart attack, stroke or even potentially cancer. Well, when it comes to taking two of the most common drugs together, aspirin and PPIs, this may not be a good combination. In a recent observational study, the results showed that PPI use in those patients who take low-dose aspirin prompted a more than twofold greater risk of causing a break in the mucosa, or lining of the small bowel (8). This study involved 198 patients. The researchers used video capsule endoscopy to confirm the rupture of the mucosa.

Bone Fracture and PPIs

While the results with bone fracture are mixed, it seems that the longer the use and the higher the dose, the greater the risk (9).

Does the lack of efficacy with preventing serious consequences of esophageal cancer mean that the drugs are ineffective? The answer is no. This class of drugs is still valuable for treating heartburn symptoms. In addition, there needs to be randomized controlled trials before we can even consider making a definitive statement about the risks. The problem is that most of the trials are post-marketing studies and there is a lower probability of funding for side effect trials that will be large enough to be useful.

Therefore, be cautious with the use of PPIs. Just because they are over the counter does not mean they are harmless. GI doctors have the most experience with the drugs. Do not change your use of the medications without talking to your doctor.

References

(1) uptodate.com. (2) FDA.gov. (3) imshealth.com. (4) Aliment Pharmacol Ther. 2014 May;39(9):984-91. (5) Aliment Pharmacol Ther. 2012;36(10):941-49. (6) Expert Rev Clin Pharmacol. 2012 May;5(3):337-44. (7) Am J Gastroenterol. 2012;107(7):1011. (8) Gastrointest Endosc online May 13, 2014. (9) JAMA. 2006;296(24):2947.

Dr. Dunaief is a speaker, author and local lifestyle medicine physician focusing on the integration of medicine, nutrition, fitness and stress management.  For further information, go to the website www.medicalcompassmd.com and/or consult your personal physician.

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Picture a child on a bike circling the neighborhood. If the bike path has hills and valleys, the child needs to pedal harder to climb the hills, and can coast down to the valleys. When the child stops pedaling and lets the bike stop on its own, it is likely to rest at the bottom of a valley, the way an apple that falls from a tree at the top of a hill will come to a stop after rolling to the bottom.

Jin Wang applies the same logic to cells and cancer. A faculty member in the Chemistry Department and an adjunct faculty member in Physics at Stony Brook University, Wang said the interaction between the contours of a landscape and the energy to move around that space affects a cell’s fate.

“We have been looking at the underlying gene regulatory networks of cancer,” Wang said. “The normal cell, a cancer state, and apoptosis (or cell death) are all represented by valleys.”

Wang has been looking at the influence on the driving force from individual genes and gene regulations, or links between genes. He is planning to consider multiple genes and gene regulations.

“The way the genes are connected influences the shape of the underlying landscape, making it more or less likely to enter a particular phase,” he said. A deeper cancer valley could make it easier to get into that state and tougher to get out.

A physicist by training, Wang doesn’t have a lab where he does experiments at a bench. He collaborates with other researchers, develops mathematical models and analyzes the results.

Wang and his post doctoral student, Chunhe Li, recently published a paper on the hills and valleys in cancer in the Journal of the Royal Society Interface.

Wang said the cancer state is already present in many people’s genes, but they don’t necessarily get there because it is shallower with a lower probability, the barrier is too high or the force pushing in that direction is not enough. A mutation or the environment can change the shape of the landscape, tilting it towards cancer.

Wang also published work he’s done on something basic to the life of a cell, called the cell cycle. Cancer corrupts the speed of the cell cycle, often causing cells to grow and divide at a rate that is faster than normal.

In the cell cycle, a cell goes through several well-documented stages before it divides in two. During the interphase, the cell has a G1 period, where it prepares to copy its genes, or DNA. In the S phase, it builds a genetic twin, and in the G2 period, it goes through a stage where it checks to make sure the process worked correctly. At the end of G2, it goes into the M stage, where it divides.

Wang, Li and collaborators in China explored the landscape as the cell moves from one period to another. “We have a three dimensional shape of the cell cycle,” he said.

What drives the cell through these stages is a combination of the depth of the valleys and the nutrition in the cell. “The underlying landscape for the cell cycle for cancer and the normal state is different,” he said. “The hills between valleys for cancer may be lower so that traveling through the different valleys is easier.”Wang and Li published their paper in the Proceedings of the National Academy of Sciences.

Li, who has worked with Wang since 2012, called the approach Wang has taken with landscape and flux “original.”

“The landscape shape can be used as a potential way to design anti-cancer strategies, by targeting multiple genes and gene regulation patterns,” Li explained. “These findings shed light on the understanding of cancer mechanisms and provide some insight on cancer treatment.”

Wang explained that his framework for understanding the combination of a driving force and a contoured environment could also have applications in other arenas, such as psychology, where people have natural steady-state valleys which require different levels of energy to change.

Wang grew up in China, where both of his parents were chemists. He has been on Long Island for a decade. He has an appreciation for something many residents take for granted. “I like to watch the clouds moving,” he said. “Because Long Island is in a special geographic location, the water keeps vaporizing and going out” to form clouds of different shapes and speeds.

Wang sees other arenas to apply his framework, including in psychology and decision making. Future questions could include, he said, “How do you make a decision from an undecided valley to a decided valley?”

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