Computerized tomographic (CT) colonography (CTC), also known as virtual colonoscopy, is comparable to standard colonoscopy in its ability to accurately detectcancer and precancerous polyps in people ages 65 and older, according to a paper published online in Radiology. This is consistent with results of the ACRIN National CT colonography Trial, published in the New England Journal of Medicine in 2008, which demonstrated CT colonography can serve as a primary colorectal cancer screening option for adults ages 50 and older, but did not specifically break out data for participants ages 65 and older included in the overall analysis. The Centers for Medicare and Medicaid Services has deferred coverage for CT colonography primarily citing a lack of data on the exam's performance in Medicare-eligible recipients ages 65 and older.
"Our goal in carrying out this secondary analysis was to determine if the accuracy of CT colonography to detect polyps of clinical concern in patients 65 and older is comparable to the test's accuracy for the 50 and over population studied in the 2008 ACRIN trial. We found no significant difference in the screening exam's performance between the two age groups," said C. Daniel Johnson, MD, of the Mayo Clinic in Scottsdale, AZ and principal investigator of the National CT Colonography Trial and the paper's primary author. "CT colonography is a perfectly viable colorectal cancer screening tool for the traditional Medicare age population. Wider availability made possible by Medicare coverage of CT colonography would attract more seniors to be screened for colorectal cancer - which is so successfully treated when detected early. Making CT colonography more available to seniors ultimately could save lives," summarizes Johnson.
The National CT Colonography Trial recruited 2,600 study participants ages 50 and over from 15 US medical centers to compare the accuracy of state-of-the-art CT colonography to the gold standard of conventional colonoscopy. Ninety percent of the polyps 1 centimeter or larger - the polyps most likely to become cancerous - were detected by CT colonography. Polyps as small as one-half centimeter were also detected by CT colonography with a high degree of accuracy.
In the secondary analysis of the 65 and over cohort, data were available for 477 study participants. The percentage of participants with large polyps was significantly greater among the older participant group (3.7% for aged < 65 vs. 6.9% for > 65); however, even if intermediate-sized polyps of 6mm or larger were targeted for removal with standard colonoscopy, the colonoscopy referral rate would not exceed 12.6 percent.
ACRIN Chair Mitchell J. Schnall, MD, PhD, Matthew J. Wilson Professor of Research Radiology at the University of Pennsylvania, comments, "These results demonstrate the wealth of data that are collected in ACRIN clinical trials that can be used to explore important cancer screening and other research questions. For example, ACRIN has undertaken another study leveraging the National CT Colonography Trial data investigating the prevalence and type of incidental findings reported as part of a CT colonography examination to better understand their impact and to develop guidelines for the reporting and management incidental findings."
CT colonography employs virtual reality technology to produce a three-dimensional visualization that permits a thorough and minimally invasive evaluation of the entire colon and rectum. The ACRIN trial is the largest multi-center study to compare the accuracy of state-of-the-art CT colonography to the gold standard of conventional colonoscopy in patients 50 and older. Colorectal cancer is the third most frequently diagnosed cancer and second leading cause of cancer death in men and women in the United States. Yet, despite the known benefits of screening, studies indicate that millions of Americans age 50 and older are not being screened for the disease.
Saturday, February 25, 2012
Disarming The Botulinum Neurotoxin
Sanford-Burnham researchers determine the first 3-D structure of the botulinum neurotoxin, together with the protein bodyguard that guides it through the body -- revealing weak spots that could be exploited to develop new counterterrorism measures.
Researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) and the Medical School of Hannover in Germany recently discovered how the botulinum neurotoxin, a potential bioterrorism agent, survives the hostile environment in the stomach on its journey through the human body. Their study, published February 24 in Science, reveals the first 3D structure of a neurotoxin together with its bodyguard, a protein made simultaneously in the same bacterium. The bodyguard keeps the toxin safe through the gut, then lets go as the toxin enters the bloodstream. This new information also reveals the toxin's weak spot - a point in the process that can be targeted with new therapeutics.
"Now that we better understand the structure of the bacterial machinery that was designed for highly efficient toxin protection and delivery, we can see more clearly how to break it," said Rongsheng Jin, Ph.D., assistant professor in Sanford-Burnham's Del E. Webb Neuroscience, Aging and Stem Cell Research Center and senior author of the study.
The Janus-faced toxin
The botulinum neurotoxin is two-faced. On one side, it's the most poisonous substance known to man, causing botulism. Accidental botulinum neurotoxin poisoning is usually food-borne, but it's also considered a potential bioterrorism agent. On the other side, botulinum neurotoxin is also used an effective therapy and popular cosmetic, such as in BOTOX.
The neurotoxin accomplishes both the good and the bad using the same trick - paralyzing muscle cells by disrupting their connections with the nerves that tell them how and when to move. But before the neurotoxin can gain access to muscles and the neurons that control them, it must make a remarkable journey through the body - surviving the digestive enzymes and extreme acidic environment in the stomach, penetrating the small intestine, and entering the bloodstream.
Sneaking a peek at the neurotoxin and its bodyguard
This latest study on the botulinum neurotoxin was the result of a close collaboration between the Jin group and a research group at the Institute of Toxicology at the Medical School of Hannover, led by Andreas Rummel, Ph.D., an expert on clostridial neurotoxins. They used a technique called X-ray crystallography, which uses powerful X-ray beams to produce 3D images of proteins at the atomic level, to study a genetically inactivated, nontoxic version of the botulinum neurotoxin.
These experiments helped the team visualize the atomic structure of all three parts of the toxin: 1) the region that recognizes neurons, 2) the enzyme that acts like a pair of scissors to cut human neural proteins and cause paralysis, and 3) the needle that punches holes to help deliver the enzyme to the nerve terminal. What's more, the researchers also captured the toxin's interaction with a second bacterial protein, called nontoxic nonhemagglutinin (NTNHA).
"We were surprised to see that NTNHA, which is not toxic, turned out to be remarkably similar to botulinum neurotoxin. It's composed of three parts, just like a copy of the toxin itself. These two proteins hug each other and interlock with what looks like a handshake," said Jin.
As the toxin moves through the body, NTNHA acts as its bodyguard, keeping it from being degraded when times are tough in the acidic stomach. However, as this study revealed, the toxin has a weak spot: when the toxin/NTNHA complex punches its way out of the small intestine, it's the change in pH that triggers a conformational change, breaks up the duo, and releases only the unprotected toxin into the bloodstream.
Towards prevention and therapy
According to Jin, this new knowledge about how the botulinum neurotoxin and NTNHA balance the need for strong binding and a timely release could be exploited to outsmart them.
"We now hope we might be able to fool the toxin and its bodyguard using a small molecule that sends the wrong signal - mimicking pH change, prematurely breaking up their protective embrace, and leaving the stomach's digestive enzymes and acid to do their job," he said. "We envision this type of therapy - either alone or in combination with other therapies currently in development - could be given preventively at a time when botulinum neurotoxin contamination becomes a public health concern."
Moreover, this type of therapy could be designed for oral delivery, rather than injection, making it easier to treat large numbers of people during an outbreak. A similar strategy could be used to deliver other protein-based drugs that usually need to be injected. "Here, protein drugs could be linked to a botulinum neurotoxin fragment and protected with NTNHA. Then we could possibly take them by mouth," Jin said.
Researchers at Sanford-Burnham Medical Research Institute (Sanford-Burnham) and the Medical School of Hannover in Germany recently discovered how the botulinum neurotoxin, a potential bioterrorism agent, survives the hostile environment in the stomach on its journey through the human body. Their study, published February 24 in Science, reveals the first 3D structure of a neurotoxin together with its bodyguard, a protein made simultaneously in the same bacterium. The bodyguard keeps the toxin safe through the gut, then lets go as the toxin enters the bloodstream. This new information also reveals the toxin's weak spot - a point in the process that can be targeted with new therapeutics.
"Now that we better understand the structure of the bacterial machinery that was designed for highly efficient toxin protection and delivery, we can see more clearly how to break it," said Rongsheng Jin, Ph.D., assistant professor in Sanford-Burnham's Del E. Webb Neuroscience, Aging and Stem Cell Research Center and senior author of the study.
The Janus-faced toxin
The botulinum neurotoxin is two-faced. On one side, it's the most poisonous substance known to man, causing botulism. Accidental botulinum neurotoxin poisoning is usually food-borne, but it's also considered a potential bioterrorism agent. On the other side, botulinum neurotoxin is also used an effective therapy and popular cosmetic, such as in BOTOX.
The neurotoxin accomplishes both the good and the bad using the same trick - paralyzing muscle cells by disrupting their connections with the nerves that tell them how and when to move. But before the neurotoxin can gain access to muscles and the neurons that control them, it must make a remarkable journey through the body - surviving the digestive enzymes and extreme acidic environment in the stomach, penetrating the small intestine, and entering the bloodstream.
Sneaking a peek at the neurotoxin and its bodyguard
This latest study on the botulinum neurotoxin was the result of a close collaboration between the Jin group and a research group at the Institute of Toxicology at the Medical School of Hannover, led by Andreas Rummel, Ph.D., an expert on clostridial neurotoxins. They used a technique called X-ray crystallography, which uses powerful X-ray beams to produce 3D images of proteins at the atomic level, to study a genetically inactivated, nontoxic version of the botulinum neurotoxin.
These experiments helped the team visualize the atomic structure of all three parts of the toxin: 1) the region that recognizes neurons, 2) the enzyme that acts like a pair of scissors to cut human neural proteins and cause paralysis, and 3) the needle that punches holes to help deliver the enzyme to the nerve terminal. What's more, the researchers also captured the toxin's interaction with a second bacterial protein, called nontoxic nonhemagglutinin (NTNHA).
"We were surprised to see that NTNHA, which is not toxic, turned out to be remarkably similar to botulinum neurotoxin. It's composed of three parts, just like a copy of the toxin itself. These two proteins hug each other and interlock with what looks like a handshake," said Jin.
As the toxin moves through the body, NTNHA acts as its bodyguard, keeping it from being degraded when times are tough in the acidic stomach. However, as this study revealed, the toxin has a weak spot: when the toxin/NTNHA complex punches its way out of the small intestine, it's the change in pH that triggers a conformational change, breaks up the duo, and releases only the unprotected toxin into the bloodstream.
Towards prevention and therapy
According to Jin, this new knowledge about how the botulinum neurotoxin and NTNHA balance the need for strong binding and a timely release could be exploited to outsmart them.
"We now hope we might be able to fool the toxin and its bodyguard using a small molecule that sends the wrong signal - mimicking pH change, prematurely breaking up their protective embrace, and leaving the stomach's digestive enzymes and acid to do their job," he said. "We envision this type of therapy - either alone or in combination with other therapies currently in development - could be given preventively at a time when botulinum neurotoxin contamination becomes a public health concern."
Moreover, this type of therapy could be designed for oral delivery, rather than injection, making it easier to treat large numbers of people during an outbreak. A similar strategy could be used to deliver other protein-based drugs that usually need to be injected. "Here, protein drugs could be linked to a botulinum neurotoxin fragment and protected with NTNHA. Then we could possibly take them by mouth," Jin said.
Nighttime Or Daily Dialysis May Improve Patients' Health And Survival
Frequent and longer dialysis treatments may provide more benefits for patients than conventional dialysis treatments, according to several studies appearing in upcoming issues of the Journal of the American Society Nephrology (JASN). The findings suggest that daily or nightly dialysis sessions at home or in the clinic are viable - and perhaps superior - alternatives for some patients with kidney failure.
Most kidney failure patients who undergo dialysis receive treatments at outpatient facilities three times per week, for three to four hours per visit. Researchers suspect that more frequent and longer treatments might be more effective, but these would be inconvenient for most patients and would take up too much of their time. Therefore, nighttime dialysis while patients sleep (at home or in a clinic) or daily treatments at home might be good options.
Several groups of researchers set out to test these alternatives. Their findings are summarized below.
Most kidney failure patients who undergo dialysis receive treatments at outpatient facilities three times per week, for three to four hours per visit. Researchers suspect that more frequent and longer treatments might be more effective, but these would be inconvenient for most patients and would take up too much of their time. Therefore, nighttime dialysis while patients sleep (at home or in a clinic) or daily treatments at home might be good options.
Several groups of researchers set out to test these alternatives. Their findings are summarized below.
- Eric Weinhandl (Minneapolis Medical Research Foundation) and his co-investigators compared survival of 1,873 daily home dialysis patients using the NxStage System One - a portable hemodialysis machine for use in the home - between 2005 and 2008 with 9,365 thrice-weekly in-center hemodialysis patients. Over an average period of 1.7 to 1.8 years, daily home dialysis patients were 13% less likely to die than thrice-weekly clinic patients, and the survival benefit of daily home dialysis appeared to apply to all types of patients (different sexes, races, weights, etc.). "Whether these results apply to all hemodialysis patients needs further study because patients in our analysis were generally younger and less sick," said Weinhandl.
- Gihad Nesrallah, MD, Rita Suri, MD (University of Western Ontario, in London, Canada), and their team compared 338 patients who received intensive home hemodialysis (during the day or night) for an average of 4.8 sessions per week and an average treatment time of 7.4 hours per session with 1,388 patients who received conventional hemodialysis. After following patients for an average of 1.8 years, the researchers found that patients receiving intensive dialysis were 45% less likely to die than patients receiving conventional dialysis. "Whether this improvement in survival is due to increased intensity of dialysis itself or due to the fact that the intensive dialysis patients performed their own dialysis treatments at home is not yet clear," said Dr. Suri.
- Eduardo Lacson, Jr., MD (Fresenius Medical Care North America) and his colleagues studied the health of 746 patients who received hemodialysis treatments at a clinic for three nights per week and for an average of eight hours per night, compared with 2,062 similar patients who received conventional hemodialysis treatments. During a two-year follow-up period, patients who received nighttime dialysis had a 25% reduced risk of dying compared with conventional dialysis. Nighttime dialysis patients also experienced improvements in certain measures such as lower weight, blood pressure, and blood phosphorous levels. "This comparison primarily evaluated the impact of the length of treatment time on hemodialysis because patients were all dialyzed in the center and at the same frequency of three times per week," said Dr. Lacson. "Longer treatment time allows for removal of fluid and waste products at a slower pace, but with the added benefit of potentially removing larger quantities from the body."
- Finally, John Daugirdas, MD (University of Illinois at Chicago) and his team analyzed data from two studies, the Frequent Hemodialysis Network Daily and Nocturnal Trials, which compared frequent (six times per week) treatments received during the day or at night, with conventional dialysis. Daugirdas and his colleagues looked to see if more frequent dialysis treatments could help lower patients' blood phosphorus levels. (Traditionally, dialysis patients often have high levels, which puts them at risk of developing various complications such as heart disease.) Compared with conventional dialysis treatments, daily or nightly dialysis treatments for 12 months lowered patients' phosphorus levels and reduced their need for phosphorus-lowering medications.
Only 9 Percent Of Israeli Firefighters Do Not Exhibit Symptoms Of PTSD
A new study on the prevalence of Post Traumatic Stress Disorder (PTSD) among firefighters in Israel indicates that approximately 90 percent show some form of full or partial symptoms.
According to the study by Ben-Gurion University of the Negev's Dr. Marc Lougassi, a firefighter himself, 24 percent of active firefighters in Israel suffer from full PTSD, 67 percent display partial PTSD while only nine percent showed no symptoms.
PTSD can occur after exposure to serious injury to oneself or another, or another's death and then result in recurring stress symptoms such as nightmares, trouble sleeping and other difficulties for over a month.
According to Dr. Lougassi, "Professional firefighters are frequently exposed to extreme stress during their work in emergency situations. In addition to the physical challenges of firefighting, they must evacuate burned and injured victims or bodies. Their involvement in traumatic events exposes them not only to the pressures stemming from the traumatic event itself, but also to post-traumatic emotional expressions that result in secondary traumatization."
"As far as Israeli firefighters are concerned, there has been no documented evidence of PTSD prevalence, despite the fact that they are exposed to additional traumas such as war and terror strikes," says Lougassi about the first of its kind study.
Approximately 342 active firefighters were recruited for this study, from all age groups, marital statuses (single, married, divorced), educational backgrounds, seniority levels (over two years), roles (firefighter, crew leader, officer, service commander, etc.). Firefighters with a psychiatric background, head injuries (loss of consciousness and neurological disturbances), in psychiatric and/or psychological treatment, with chronic diseases and those taking medications on a regular basis were excluded from the sample.
An additional 42 firefighters from flight firefighting services at Ben-Gurion Airport constituted the control group, since firefighters are not exposed to similar events. Only five percent of the control group showed signs of PTSD.
"These results support the hypothesis that increased exposure to recurring traumatizing events is a significant factor contributing to PTSD development," according to Lougassi.
"The findings of this study can help researchers and the Israeli Firefighting Service improve the firefighters' abilities to cope with extended exposure to traumatizing events through professional intervention programs," he suggests.
"Moreover, these results can help the Israeli Firefighting Services develop appropriate screening tools to be used during the recruiting process of new firefighters, in order to assure their future psychological safety."
According to the study by Ben-Gurion University of the Negev's Dr. Marc Lougassi, a firefighter himself, 24 percent of active firefighters in Israel suffer from full PTSD, 67 percent display partial PTSD while only nine percent showed no symptoms.
PTSD can occur after exposure to serious injury to oneself or another, or another's death and then result in recurring stress symptoms such as nightmares, trouble sleeping and other difficulties for over a month.
According to Dr. Lougassi, "Professional firefighters are frequently exposed to extreme stress during their work in emergency situations. In addition to the physical challenges of firefighting, they must evacuate burned and injured victims or bodies. Their involvement in traumatic events exposes them not only to the pressures stemming from the traumatic event itself, but also to post-traumatic emotional expressions that result in secondary traumatization."
"As far as Israeli firefighters are concerned, there has been no documented evidence of PTSD prevalence, despite the fact that they are exposed to additional traumas such as war and terror strikes," says Lougassi about the first of its kind study.
Approximately 342 active firefighters were recruited for this study, from all age groups, marital statuses (single, married, divorced), educational backgrounds, seniority levels (over two years), roles (firefighter, crew leader, officer, service commander, etc.). Firefighters with a psychiatric background, head injuries (loss of consciousness and neurological disturbances), in psychiatric and/or psychological treatment, with chronic diseases and those taking medications on a regular basis were excluded from the sample.
An additional 42 firefighters from flight firefighting services at Ben-Gurion Airport constituted the control group, since firefighters are not exposed to similar events. Only five percent of the control group showed signs of PTSD.
"These results support the hypothesis that increased exposure to recurring traumatizing events is a significant factor contributing to PTSD development," according to Lougassi.
"The findings of this study can help researchers and the Israeli Firefighting Service improve the firefighters' abilities to cope with extended exposure to traumatizing events through professional intervention programs," he suggests.
"Moreover, these results can help the Israeli Firefighting Services develop appropriate screening tools to be used during the recruiting process of new firefighters, in order to assure their future psychological safety."
Physical Activity Keeps Workers Mentally Fit
Obesity can be a dangerous risk to our physical health, but according to a Tel Aviv University researcher, avoiding the gym can also take a toll on our mental health, leading to depression and greater burnout rates at work.
Dr. Sharon Toker of TAU's Recanati Faculty of Management, working with Dr. Michal Biron from the University of Haifa, discovered that employees who found the time to engage in physical activity were less likely to experience a deterioration of their mental health, including symptoms of burnout and depression. The best benefits were achieved among those exercising for four hours per week - they were approximately half as likely to experience deterioration in their mental state as those who did no physical activity.
Drs. Toker and Biron say that employers will benefit from encouraging the physical fitness of their employees. If the fight against obesity isn't enough of an incentive, inspiring workers to be physically active lessens high heath costs, reduces absenteeism, and increases productivity in the workplace. Their research was recently published in the Journal of Applied Psychology.
Preventing a downward spiral
Though depression and burnout are connected, they are not the same entity, says Dr. Toker. Depression is a clinical mood disorder, and burnout is defined by physical, cognitive, and emotional exhaustion. But both contribute towards a "spiral of loss" where the loss of one resource, such as a job, could have a domino effect and lead to the loss of other resources such as one's home, marriage, or sense of self-worth.
Originally designed to examine the relationship between depression and burnout, the study assessed the personal, occupational, and psychological states of 1,632 healthy Israeli workers in both the private and public sectors. Participants completed questionnaires when they came to medical clinics for routine check-ups and had three follow-up appointments over a period of nine years.
Findings indicate that an increase in depression predicts an increase in job burnout over time, and vice versa. But for the first time, the researchers also considered the participants' levels of physical activity, defined as any activity that increases the heart rate and brings on a sweat. The participants were divided into four groups: one that did not engage in physical activity; a second that did 75 to 150 minutes of physical activity a week; a third that did 150 to 240 minutes a week; and a fourth that did more than 240 minutes a week.
Depression and burnout rates were clearly the highest among the group that did not participate in physical activity. The more physical activity that participants engaged in, the less likely they were to experience elevated depression and burnout levels during the next three years. The optimal amount of physical activity was a minimum of 150 minutes per week, where its benefits really started to take effect.
In those who engaged in 240 minutes of physical activity or more, the impact of burnout and depression was almost nonexistent. But even 150 minutes a week will have a highly positive impact, says Dr. Toker, helping people to deal with their workday, improving self-efficacy and self-esteem, and staving off the spiral of loss.
Fighting stress at work
If they're feeling stressed at work, employees can always ask the boss to effect changes, such as providing more opportunities for emotional support in the workplace. But if the organization is unwilling to change, workers can turn to physical activities in their leisure time as an effectivestress management tool.
Far-sighted employers can benefit by building a gym on company grounds or subsidizing memberships to gyms in the community, and by allowing for flexible work hours to encourage employees to make physical activity an integral part of their day, suggests Dr. Toker. Such a strategy pays business dividends in the long run.
Dr. Sharon Toker of TAU's Recanati Faculty of Management, working with Dr. Michal Biron from the University of Haifa, discovered that employees who found the time to engage in physical activity were less likely to experience a deterioration of their mental health, including symptoms of burnout and depression. The best benefits were achieved among those exercising for four hours per week - they were approximately half as likely to experience deterioration in their mental state as those who did no physical activity.
Drs. Toker and Biron say that employers will benefit from encouraging the physical fitness of their employees. If the fight against obesity isn't enough of an incentive, inspiring workers to be physically active lessens high heath costs, reduces absenteeism, and increases productivity in the workplace. Their research was recently published in the Journal of Applied Psychology.
Preventing a downward spiral
Though depression and burnout are connected, they are not the same entity, says Dr. Toker. Depression is a clinical mood disorder, and burnout is defined by physical, cognitive, and emotional exhaustion. But both contribute towards a "spiral of loss" where the loss of one resource, such as a job, could have a domino effect and lead to the loss of other resources such as one's home, marriage, or sense of self-worth.
Originally designed to examine the relationship between depression and burnout, the study assessed the personal, occupational, and psychological states of 1,632 healthy Israeli workers in both the private and public sectors. Participants completed questionnaires when they came to medical clinics for routine check-ups and had three follow-up appointments over a period of nine years.
Findings indicate that an increase in depression predicts an increase in job burnout over time, and vice versa. But for the first time, the researchers also considered the participants' levels of physical activity, defined as any activity that increases the heart rate and brings on a sweat. The participants were divided into four groups: one that did not engage in physical activity; a second that did 75 to 150 minutes of physical activity a week; a third that did 150 to 240 minutes a week; and a fourth that did more than 240 minutes a week.
Depression and burnout rates were clearly the highest among the group that did not participate in physical activity. The more physical activity that participants engaged in, the less likely they were to experience elevated depression and burnout levels during the next three years. The optimal amount of physical activity was a minimum of 150 minutes per week, where its benefits really started to take effect.
In those who engaged in 240 minutes of physical activity or more, the impact of burnout and depression was almost nonexistent. But even 150 minutes a week will have a highly positive impact, says Dr. Toker, helping people to deal with their workday, improving self-efficacy and self-esteem, and staving off the spiral of loss.
Fighting stress at work
If they're feeling stressed at work, employees can always ask the boss to effect changes, such as providing more opportunities for emotional support in the workplace. But if the organization is unwilling to change, workers can turn to physical activities in their leisure time as an effectivestress management tool.
Far-sighted employers can benefit by building a gym on company grounds or subsidizing memberships to gyms in the community, and by allowing for flexible work hours to encourage employees to make physical activity an integral part of their day, suggests Dr. Toker. Such a strategy pays business dividends in the long run.
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