Blog Title: BreakThrough Digest - Medical Breakthroughs, Health News and Medical Information About Cancer, Diabetes, Leukemia and more

New mammography technology effective in detecting breast cancer

A study has found that positron emission mammography (PEM), a new technique for imaging the breast, is not affected by either breast density or a woman’s hormonal status, two factors that limit the effectiveness of standard mammography and MRI at detecting cancer. Results will be presented today at the annual meeting of the Radiological Society of North America (RSNA).

“The ability of PEM to detect cancer does not appear to be adversely affected by breast density, hormone replacement therapy or menopausal status,” said lead researcher Kathy Schilling, M.D., director of breast imaging and intervention at the Center for Breast Care at Boca Raton Community Hospital in Florida. “The sensitivity of PEM is equal to or better than breast MRI, and PEM has fewer false-positive results.”

The ability of x-ray mammography, a standard screening tool for breast cancer, to detect lesions is reduced when performed on dense breasts, where tissue is less fatty and more glandular. Breast MRI is effective at detecting cancer in dense breasts and is increasingly being used to screen women at high risk for breast cancer. However, MRI has a high incidence of false-positive test results that indicate cancer is present when it is not. Researchers believe these false positives are due in part to hormonal changes that occur during a woman’s menstrual cycle.

“Unless the MRI is performed on day seven through 14 of a woman’s cycle, reading MRI images is extremely difficult,” Dr. Schilling said. “This is a significant problem with breast MRI.”

Because hormones do not have the same effect on PEM results, Dr. Schilling believes the imaging technique could play a significant role both in preoperatively evaluating breast cancer patients and in screening high-risk patients.

In the study, 208 patients with breast cancer underwent PEM, an application of high-resolution breast positron emission tomography (PET) in which a small amount of radioactive material is injected into the body to measure metabolic activity and determine the presence of disease. The researchers used a PET unit specially developed for the breast and small body parts to perform the PEM exam.

Of 189 malignant lesions imaged, PEM detected 176 for an overall sensitivity rate of 93 percent. Fifteen percent were ductal carcinoma in situ (DCIS), a noninvasive cancer confined to the ducts of the breast; 85 percent were invasive cancer.

PEM successfully detected cancer in 100 percent of fatty breasts, 93 percent of dense breasts, 85 percent of extremely dense breasts, 93 percent of women both with and without a history of hormone replacement therapy, 90 percent of pre-menopausal women and 94 percent of post-menopausal women.

According to Dr. Schilling, PEM is well tolerated by patients, who sit upright during the exam and are not alone or closely confined as they would be during an MRI exam. While breast MRI exams produce more than 2,000 images to be interpreted, PEM produces just 48 images that can be correlated with a woman’s mammogram.

“PEM is easier to use, easier to interpret and easier on the patients than MRI,” Dr. Shilling said.

“It is also ideal for those patients whose MRI is difficult to interpret due to hormonal influences, women with implants, patients with metal in their bodies, or patients who suffer from claustrophobia. It is exciting that we now have a functional imaging approach with high sensitivity that compliments our current anatomic imaging modalities,” she added.

Source: Radiological Society of North America

Mini heart attacks lessen damage from major ones

New class of lipids suggests new treatment approach for heart attacks

Researchers have discovered one potential mechanism by which briefly cutting off, then restoring, blood flow to arteries prior to a heart attack lessens the damage caused, according to a study published today in the journal Cardiovascular Research. The new mechanism points to how future drugs could provide protection ahead of heart attacks and strokes for those at highest risk. In the nearer term, the work may help to prevent damage caused as U.S. heart surgeons temporarily cut off blood flow 450,000 times each year to perform coronary artery bypass graft surgeries. Lastly, the discoveries hold clues to the value of the Mediterranean diet beyond red wine.

In severely diseased coronary arteries, fatty deposits in blood vessel walls become more likely to rupture, which releases proteins into the blood that cause blood clots and cut off blood flow. When a vessel becomes completely blocked (ischemia) the downstream tissue begins to die for lack of oxygen and nutrients. Worse yet, when blood flow is restored (reperfusion), the returning blood throws off cellular chemistry, creating as a side-product a burst of highly reactive “free radicals” that tear apart cell components and cause cells to self-destruct. Later in the process, the immune system attacks the cardiac tissue damaged by ischemia and reperfusion, causing inflammation which can lead to heart failure.

In 1986 then medical student Chuck Murry at Duke University first described a technique called ischemic preconditioning (IPC), which quickly cuts off then restores blood flow to the heart. He found that IPC somehow protected heart tissue against the damage caused by subsequent, prolonged blood vessel blockages. An emerging theory holds that this natural early warning system of IPC has evolved to protect against heart attack. Labs worldwide are seeking to re-create or strengthen this natural protection against ischemia/reperfusion (IR) injury. In the current study, researchers for the first time determined that IPC caused more of a key molecule, nitro-linoleic acid (LNO2), to be made in ischemic cells.

“LNO2 appears to be important in the mechanism by which IPC triggers the body’s natural defense mechanisms against heart attack before the major attack comes,” said Paul S. Brookes, Ph.D., associate professor of Anesthesiology and of Pharmacology and Physiology at the University of Rochester Medical Center. “Obviously, this natural response, when it follows a major heart attack, is often too little too late. Our hope is that boosting the effect in patients at high risk, perhaps by administering LNO2 beforehand, will reduce heart attack damage in the future. Even sooner, we may be able dramatically reduce reperfusion injury suffered in surgical settings.”

University of Rochester Medical Center

Viral DNA in bacterial genome could hold key to new cystic fibrosis treatments

The bacterium Pseudomonas aeruginosa is well known for its environmental versatility, ability to cause infection in humans, and its capacity to resist antibiotics. P. aeruginosa is the most common cause of persistent and fatal lung infections in cystic fibrosis patients. In a study published online today in Genome Research (www.genome.org), researchers have used genomic techniques to study a particularly virulent strain of P. aeruginosa, uncovering genetic clues to its success that will aid in the design of novel therapeutic strategies.

The Liverpool Epidemic Strain, the most common strain of P. aeruginosa infecting cystic fibrosis patients in the United Kingdom, is characterized by its particular aggressiveness and virulence. Though approximately 90% of the P. aeruginosa genome is shared between different strains, a team of scientist led by Dr. Craig Winstanley of the University of Liverpool set out to investigate the unique genomic features of the Liverpool strain. ”We used genome sequencing to reveal the secrets of the other 10% of the genome, which is likely to include genes contributing to the success of this particular strain,” said Winstanley.

The research group found that many of the genes specific to the Liverpool Epidemic Strain are positioned in clusters, some of which are prophages. A prophage is a set of viral genes that became integrated into the DNA of bacteria infected by a bacterial virus. They then engineered mutations in prophages of the Liverpool strain and tested the pathogenicity of the mutant bacteria in a rat model of chronic lung infection. “We have shown that mutations within these novel prophages and genomic islands can prevent the strain from establishing infections,” Winstanley described. ”This indicates that bacterial viruses may contribute to the ability of bacterial pathogens to adapt to specific environments and to the emergence of particularly successful epidemic bacterial strains.”

Winstanley also explained that this work is especially important in light of the nature of P. aeruginosa lung infections that afflict cystic fibrosis patients. Once an infection has been established, antibiotic therapy is unable to eradicate the bacteria from the lungs. Since antibiotics can be of limited use, the genomic properties of the Liverpool Epidemic Strain characterized in this study will aid in the development of novel strategies for circumventing ineffective antibiotic treatments by preventing infection altogether.


Scientists from the University of Liverpool (Liverpool, UK), Simon Fraser University (Burnaby, BC), Laval University (Quebec City, QC), The Wellcome Trust Sanger Institute (Hinxton, UK), and the University of British Columbia (Vancouver, BC) contributed to this study.

This work was supported by the Wellcome Trust, the Canadian Institutes of Health Research, the Canadian Cystic Fibrosis Foundation, the US Cystic Fibrosis Foundation, the Michael Smith Foundation for Health Research, the Big Lottery Fund, and the UK Cystic Fibrosis Trust.

Over 100 Medicines and Vaccines Now in Development for HIV/AIDS

America’s pharmaceutical research companies are testing 109 medicines and vaccines to treat or prevent HIV/AIDS and related conditions, according to a report released today by the Pharmaceutical Research and Manufacturers of America (PhRMA). December 1 marks the 20th anniversary of “World AIDS Day” - a global awareness campaign that originated at the 1988 World Summit of Ministers of Health on Programmes for AIDS Prevention.

New Stapling Treatment May Help Reverse Childhood Scoliosis

New Treatment Alternative at Morgan Stanley Children’s Hospital Frees Children With Scoliosis From Restrictive Back Braces

Morgan Stanley Children’s Hospital of NewYork-Presbyterian is one of only a few hospitals in the country to offer spinal stapling, a new treatment alternative for young people with scoliosis, an abnormal curvature of the spine that is painful and can restrict breathing. The Center for Early Onset Scoliosis, led by Dr Michael Vitale, sees about 400 patients per year under the age of 5 with the condition. Spinal stapling is one of a number of new techniques that promise improved outcomes.

Tens of thousands of children in the U.S. are diagnosed with scoliosis each year. When the curvature is moderate, spinal braces can be used to slow or decrease the chance of progression. Until now, however, there was no way to reverse progression and straighten the spine.

Spinal stapling is a two-hour minimally invasive surgery that involves implanting inch-long metallic staples across the growth plates of the spine. Made of a high-tech temperature-sensitive metal alloy, the staples are implanted using a camera called a thoracoscope with a very limited incision and minimal scar. The procedure is available to children with progressive moderate scoliosis (less than 30) who are still growing (girls up to age 14 and boys up to age 16).

“Stapling not only stops scoliosis from getting worse, but can even correct the curve,” says Dr. Michael Vitale, chief of pediatric spine and scoliosis surgery at Morgan Stanley Children’s Hospital of NewYork-Presbyterian and the Ana Lucia Associate Professor of Clinical Pediatrics and Orthopaedic Surgery at Columbia University College of Physicians and Surgeons. “While most children do well with spinal fusion, we are on the cusp of a new era in the treatment of scoliosis. For the first time, we have a way to potentially reverse the scoliosis. ”

Braces can be uncomfortable and embarrassing for children, notes Dr. Vitale. The custom-made plastic corset is usually worn all but one or two hours a day, and its tight fit presses against the stomach, making eating and any sports difficult.

Spinal fusion, too, has its drawbacks. “We recently presented evidence that spinal fusion in young children can lead to significant issues in quality of life and pulmonary function over the long term,” says Dr. Vitale, who presented the findings at the International Conference on Early Onset Scoliosis in Montreal. The study followed 27 patients who received spinal fusion, which permanently connects several vertebrae. After 10 years, their pulmonary function, measured by lung volume, and reported quality of life were significantly less than that of a healthy child.

“While stapling is very new,” adds Dr. Vitale “it promises to have a major effect on how we treat young people with scoliosis.” Additional therapies may include:

VEPTR. The Vertical Expandable Prosthetic Titanium Rib (VEPTR) straightens the spine and opens a larger space for the lungs and other internal organs to grow by placing a titanium brace between two ribs to push them apart. VEPTR can be expanded as the patient grows through an outpatient procedure.

Growing Rod. Attached to the spine and affixed to vertebrae at the top and the bottom, growing rods are expanded over time using a mechanism that allows the lengthening to be performed in a simple outpatient surgery. The approach minimizes spinal deformity, and most importantly allows lung development to occur to preserve a normal life span for the patient.

Scoliosis
Scoliosis is a musculoskeletal condition that primarily affects children and adolescents, in which there is an abnormal lateral curvature of the spine, causing the spinal column to bend to the left or right. The name is derived from the Greek word “skoliosis,” which means “crookedness.” Scoliosis affects approximately 3 percent of the population. The Adam’s bend test is performed to gauge the amount of curvature a scoliosis patient has. Scoliotic curve is said to exist when the angle of the curve measure is at least 10 degrees. Curves of more than 40 degrees are considered severe. Most patients are diagnosed between ages 10 and 15, although those with severe cases may be detected earlier. Dr. Vitale is a proponent of school screening of adolescents for scoliosis, and authored an informational statement on the subject that was published in the January 2008 issue of the Journal of Bone and Joint Surgery. His position is shared by American Academy of Orthopaedic Surgeons (AAOS), the Scoliosis Research Society (SRS), the Pediatric Orthopaedic Society of North America (POSNA) and the American Academy of Pediatrics (AAP).

For more information, patients may call (866) NYP-NEWS or visit www.nyp.org.

Heart disease halted in mice - human trials a few years away

A promising treatment has reportedly allowed scientists to halt the advance of heart disease in mice - and even reversed some of its effects. they used a chemical on the mice which blocked microRNA-21, and found that not only that this pathway was interrupted, but that cardiac function in the animals improved. This, they wrote, proved its potential as a new target for drugs in heart diseased humans.

The study provides hard evidence that tiny pieces of genetic material called microRNA can play a key role in the development of heart disease. The therapy, featured in the journal Nature, targets and blocks microRNA in heart cells. A US specialist said that, with trials under way in other animals, human tests may be only a few years away. The researchers found that cells in a failing heart had higher levels of this microRNA, and linked it to a chemical signalling pathway which leads to the tissue damage found in the condition.

The importance of microRNAs to heart disease - and a host of other diseases - has already been suggested by other scientists. Their job is to regulate the activity of our genes, but with many different types present in the cell, scientists are trying to establish which plays the biggest role. US and German scientists are focusing on one type labelled microRNA-21, and their role in a type of heart cell called the cardiac fibroblast, which helps provide the structure of the organ, and plays a critical role in the progressive scarring which stops it working properly in heart disease. Until recently, that process was thought to be an irreversible one.

Combining targeted therapy drugs may treat previously resistant tumors

Blocking 2 cell signalling pathways leads to dramatic shrinkage of K-Ras-mutated tumors in animal model

A team of cancer researchers from several Boston academic medical centers has discovered a potential treatment for a group of tumors that have resisted previous targeted therapy approaches. In their Nature Medicine report, which is receiving early online release, investigators from Dana-Farber Cancer Institute (DFCI), Massachusetts General Hospital (MGH) Cancer Center, and Beth Israel Deaconess Medical Center (BIDMC) Cancer Center report that combining two different kinase inhibitors drugs that interfere with specific cell-growth pathways led to significant tumor shrinkage in mice with lung cancer driven by mutations in the K-Ras gene. In addition to their association with nearly 30 percent of cases of non-small-cell lung cancer the leading cause of cancer deaths in the U.S. K-Ras mutations are involved in many cases of colon cancer and most pancreatic cancers, which are extremely resistant to treatment.

“Finding a way to effectively treat K-Ras-mutated cancers would be a huge advance in solid tumor oncology, since these mutations are common in several incurable cancers,” says Jeffrey Engelman, MD, PhD, of the MGH Cancer Center, one of the report’s co-lead authors. “Cancers with K-Ras mutations have been resistant to all targeted therapies to date, and it is exciting to learn that a combination of PI3K and MEK inhibitors, two families of drugs currently in clinical development, may be highly effective in these cancers.”

The current study began with a focus on the PI3K signaling pathway, which is key to cell survival and known to control cellular motility and adhesion. PI3K mutations have caused tumor development in laboratory studies, but their role had not yet been studied in an animal model. The research team developed a transgenic mouse in which administration of the drug doxycycline induces the expression of cancer-associated PI3K mutations, leading to development of lung tumors.

Treatment of those animals with an investigational PI3K inhibitor did lead to rapid tumor regression. Since previous studies suggested that PI3K inhibition might also block K-Ras-induced tumor development, the investigators also tested the PI3K inhibitor in mice with K-Ras-stimulated tumors. That treatment was ineffective, but since K-Ras also activates the MEK/ERK signalling pathway, the researchers treated the animals with an investigational MEK inhibitor and with a combination of both drugs. Treatment with the MEK inhibitor alone caused only a modest reduction in tumor size, but combined treatment with both agents caused the K-Ras-stimulated lung tumors to virtually disappear.

“For several years we have known that K-Ras activates two major pathways the PI3K pathway and the MEK/MAPK pathway and that these pathways have many redundant functions in tumor growth and survival,” says Lewis Cantley, PhD, of the BIDMC Cancer Center, one of the study’s co-corresponding authors. “Inhibitors of both of these pathways are now in clinical trials, and in this paper we show that, while either agent alone has a minor effect on K-Ras-driven tumors in mice, combining inhibitors of both pathways eradicates these tumors with minimal toxicity.”

Kwok-Kin Wong, MD, PhD, of DFCI, also a co-corresponding author, adds, “The results of our study are truly remarkable and provide a strong and compelling scientific rationale to test this combination therapy in human phase 1 and 2 trials. This work would not have been possible without the highly productive collaboration between our laboratories at Mass. General, Beth Israel-Deaconess and Dana-Farber.” Wong is an assistant professor of Medicine at Harvard Medical School, where Engelman is also an assistant professor in Medicine, and Cantley is the Castle Professor of Medicine.

The researchers are hoping to advance towards clinical trials by testing combination therapy against other models of K-Ras-mutated cancer, including those that involve additional mutations in other tumor-associated genes, and to investigate whether K-Ras-associated tumors will become resistant to combination therapy, a problem that has plagued other targeted cancer therapies.

The co-lead author of the Nature Medicine report is Liang Chen of Dana Farber Cancer Institute. Additional co-authors are Youngchul Song, and Ramneet Kaur, MGH Cancer Center; Alexander Guimaraes, Rabi Upadhyay, Ralph Weissleder and Umar Mahmood, MGH Center for Molecular Imaging Research; Xiaohong Tan, Kate McNamara and Samanthi Perera, DFCI; Timothy Li, BIDMC; Katherine Crosby, Angela Lightbown and Jessica Simendinger, Cell Signaling Technology; Michel Maira and Carlos Garcia-Echeverria, Novartis Institutes for Biomedical Research; Lucian Chirieac and Robert Padera, Brigham and Women’s Hospital.

The study was supported by grants from the National Institutes of Health, the American Association for Cancer Research, the International Association for the Study of Lung Cancer, the Joan Scarangello Foundation to Conquer Lung Cancer, the Cecily and Robert Harris Foundation, the Flight Attendant Medical Research Institute and several Dana-Farber/Harvard Cancer Center Specialized Program of Research Excellence grants.

Massachusetts General Hospital (www.massgeneral.org), the original and largest teaching hospital of Harvard Medical School, conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million.

Scientists find key to keeping killer T cells in prime shape for fighting infection, cancer

Like tuning a violin to produce strong, elegant notes, researchers at The Wistar Institute have found multiple receptors on the outside of the body’s killer immune system cells which they believe can be selectively targeted to keep the cells in superb infection- and disease-fighting condition.

In a study published online November 30 in Nature Immunology, the researchers describe their discovery of seven different receptors on T cells that can tamp down immune responses during a prolonged battle with an infectious pathogen or against developing cancer.

Chronic over-stimulation of the immune system can lead to poor control of infections and cancer, so the results explain why it is that these key immune cells gradually become “exhausted” and ineffective over time, says the study’s lead author, E. John Wherry, Ph.D., an assistant professor in Wistar’s Immunology Program.

Wherry had recently been involved in discovering a single receptor involved in turning off T cells but this new study shows that at least six more receptors can also restrain or negatively regulate immune responses. According to Wherry, a key finding is that these new receptors likely control different aspects of T cell responses, such as division or expansion, controlling viral replication, and local killing of infected cells versus secretion of long-range active antiviral proteins.

“This amount of control over T cells’ response is remarkable. It suggests that layers of negative regulation exist on exhausted T cells from co-expression of multiple inhibitory receptors,” he says. “My bet is that these receptors inhibit different aspects of the T cells’ response, but that the net result of their activation is to turn specific T cell populations off.

“We are starting to see a picture emerging of a really tuneable array of inhibitory receptors expressed on T cells,” Wherry says. “That suggests it may be possible to not only dramatically enhance antiviral or antitumor T cell responses, but also to fine tune which response you want to enhance in order to reverse T cell exhaustion and continue fighting an infection or disease.

“This presents us with a great clinical opportunity,” Wherry says. “T cells have a lot of weapons at their disposal to control viral infection and most of them are disarmed when these cells become exhausted. It may be possible to selectively rearm T cells while generally reinvigorating them.”

The researchers made their discoveries in a mouse model of chronic infection with lymphocytic choriomeningitis virus. They had earlier found that a receptor known as programmed death-1 (PD-1) was highly expressed by exhausted T cells from chronically infected mice but not from mice that had cleared the infection. In a study published September 15 in the Proceedings of the National Academy of Sciences (PNAS), the researchers extended previous studies on the role of the PD-1 pathway in regulating T cell exhaustion. In these studies, blocking PD-1 increased T cell response, but not completely, so the researchers suspected other negative regulatory pathways were activated as well.

In the newest report in Nature Immunology, Wherry and colleagues compared the global patterns of gene expression for exhausted killer T cells compared to other types of T cells (nave, effector and memory). A “nearest neighbor” analysis to PD-1 revealed up-regulation of six other inhibitory receptor genes. They are LAG3, 2B4, CD160, CTLA-4, PIR-B and GP49. While the function of many of these receptors has been characterized, they had not been known to play a role in chronic viral infection. LAG-3, for example, is associated with an antitumor response. These observations may explain why PD-1 blockade did not completely restore T cell responses in previous work.

The investigators discovered that the severity of chronic infection correlated with the number and intensity of inhibitory receptor expression, suggesting a cumulative impact of inhibitory receptor expression. They also found that blocking both PD-1 and LAG-3 together led to substantially greater improvement in T cell responses and viral control compared to either blockade alone.

“The goal now is to understand the pathways the receptors control, and then to learn how to fine tune reversal of exhaustion by targeting pathways that selectively control the desired type of T cell response,” Wherry says.

Source: The Wistar Institute

Study supports value of advanced CT scans to check for clogged arteries

Catheterization still gold standard, but 64-row scanners now shown equally useful in diagnosis
In a development that researchers say is likely to quell concerns about the value of costly computed tomography (CT) scans to diagnose coronary artery blockages, an international team led by researchers at Johns Hopkins reports solid evidence that the newer, more powerful 64-CT scans can easily and correctly identify people with major blood vessel disease and is nearly as accurate as invasive coronary angiography.

Reporting in the New England Journal of Medicine online Nov. 26, researchers at nine medical centers say the faster, 64-CT scans were 93 percent as precise as invasive, conventional imaging, better known as cardiac catheterization and virtually 100 percent accurate in detecting people with at least one artery dangerously clogged by the buildup of cholesterol and plaque.

Comparison of CT and catheterization results also showed for the first time that they were equally useful in patients with heart attack symptoms, such as chest pain and shortness of breath, for predicting the need for cardiac bypass surgery or angioplasty to restore their blood flow. The CT scans accurately predicted 84 percent of invasive procedures performed, and catheterization predicted 82 percent. More than a quarter-million Americans undergo coronary bypass surgery each year, and another 1.2 million people undergo angioplasty.

Announcement of the latest findings is timed to coincide with the annual meeting of the Radiological Society of North America being held this week in Chicago, after initial results were reported last year at an annual meeting of cardiologists.

Senior study investigator and Johns Hopkins cardiologist Joo Lima, M.D., says 64-CT scans are not a substitute for catheterization, but the scans, which take between five and 10 seconds to perform, are “an alternative diagnostic tool” physicians can use to “rule in or rule out” coronary blockages when other, more indirect tests for reduced blood flow, such as cardiac stress testing, are unclear or unsafe for a particular patient.

Cardiac catheterization, which also checks the function of heart valves and muscle, takes longer, between 30 minutes and 45 minutes to perform, and requires more than an hour for recovery. Potential complications from the invasive procedure include infection, heart attack and stroke; however, these events are rare.

Lima, a professor of medicine and radiology at The Johns Hopkins University School of Medicine and its Heart and Vascular Institute, says the 64-CT scans, first introduced to the United States and tested at Hopkins in 2005, could reduce as much as one-fifth of the 1.3 million cardiac catheterizations performed each year nationwide that show no blockages.

CT scans for heart disease, although not yet covered by many private health plans, could also serve as an alternative to cardiac stress testing, which generally cannot safely be performed on the weak and elderly because the test uses hard exercise to speed up blood flow and measure heart function.

Lima says previous research had shown that older, less-powerful 16-CT scans were only a quarter to a third as precise as the newer tests, “fuelling much heated debate as to whether or not use of the technology could ever be justified.

“But our latest findings weigh heavily in favor of the more advanced 64-CT scans,” he adds, citing additional study results showing that the scans could pinpoint with 91 percent certainty the precise artery blocked. At four times the strength of the more widely available 16-CT scanner, Lima says the 64-CT scans “provided our first real view of the whole picture of what is going on in the artery, precisely where the blockage is, even if it is only a partially obstructed.”

Lead study investigator and interventional cardiologist Julie Miller, M.D., says the advanced scanners are so good that physicians can for the first time measure blockages in blood vessels as small as 1.5 millimeters in diameter. Older 16-CT scanners, she says, are best suited for looking inside bigger arteries, those greater in diameter than 2 millimeters.

Each of the 291 men and women, all over the age of 40, selected to participate in the new study were already scheduled to have cardiac catheterization to check for blocked arteries. Every participant had a 64-CT scan prior to catheterization and was then monitored through regular check-ups, starting in 2005 and set to continue through 2009, to identify who developed or did not develop any heart problems, who required subsequent bypass surgery or angioplasty, and who did not need any procedure.

Researchers found that 90 percent of the patients without any major blockages were correctly diagnosed with 64-CT scans.

The disadvantages of using 64-CT, Miller says, are radiation exposure and the rare potential in some people to have an allergic reaction or to develop kidney problems resulting from the contrast dyes injected into the body to enhance the images.

“CT technology has come a long way in the last decade,” says Miller, the leader of angiographic research and an assistant professor at Hopkins. She cites improvements that cut the average amount of radiation exposure and time required for a CT scan to less than 20 millisieverts with 16-CT scanners (which took about 12 seconds to perform), on average, to less than 15 millisieverts with 64-CT devices (at close to 6 seconds), and less than 6 millisieverts with the 320-CT (at less than a second.)

She says the cost of the newer CT scans approximately $700 compares favorably with that of current nuclear stress testing for reduced blood flow, in which radioactive dyes are used to detect arterial clogs, at nearly $1,000.

In cardiac catheterization, a thin tube is threaded into a blood vessel in the groin area to the heart’s arteries, where a dye is released to produce a clear X-ray image of the beating heart and its arterial blood supply. The procedure usually costs in excess of $1,500.

In CT imaging, computer-driven machinery passes X-rays through the body, producing digitized signals from multiple angles that are detected and reconstructed for a precise picture.

Miller points out that early detection of blockages is critical to preempting a heart attack, allowing time for drug therapy, angioplasty or heart bypass surgery to be used to keep arteries open. In coronary artery disease, hardened bits of fat and dead tissue, called plaque, build up along the inside wall of the blood vessels, impeding the body’s natural blood flow and leaving the narrowed opening more vulnerable to formation of blood clots.

Lima says the team’s next steps are head-to-head comparison studies using either CT or nuclear stress testing, which gauges reduced blood flow in parts of the heart to reveal clogging arteries. Included in the next analysis will be scans performed using an even more advanced scanner, the 320-CT. The latest imaging device was also tested at Johns Hopkins in 2006, and it can obtain images in less than a second, with significant reductions in radiation exposure.

According to researchers, nearly 5,000 64-CT scanners are installed worldwide, but not all of the centers are equipped to perform and read cardiac CTs. Miller notes that special training and certification are required by technicians and physicians to accurately perform, read and interpret the scanned images. The American Heart Association and the American College of Cardiology Foundation in 2005 jointly established training guidelines.

Source: Johns Hopkins Medical Institutions

Experimental TB drug explodes bacteria from the inside out

Research advance may lead to new ways to attack latent TB and other bacteria

An international team of biochemists has discovered how an experimental drug unleashes its destructive force inside the bacteria that cause tuberculosis (TB). The finding could help scientists develop ways to treat dormant TB infections, and suggests a strategy for drug development against other bacteria as well.

A report describing the research, led by Clifton E. Barry, III, Ph.D., of the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, is published in the Nov. 28 issue of Science. Dr. Barry’s collaborators included scientists from NIAID and from the Novartis Institute for Tropical Diseases in Singapore.

One-third of the world’s population is infected with Mycobacterium tuberculosis (M. tb), the bacteria that cause TB. “Currently, there are no drugs available that specifically target latent tuberculosis infections in which bacteria are present but are not actively dividing,” notes NIAID Director Anthony S. Fauci, M.D. “Dr. Barry and his colleagues have now given us a detailed picture of how the candidate TB drug PA-824 is metabolized inside Mycobacterium tuberculosis. Their discovery is a promising step towards developing effective drugs against latent TB as well as other bacteria.”

Previously, Dr. Barry and his collaborators found that M. tb mutants lacking a specific bacterial enzyme were resistant to PA-824, but at that time, they did not know the function of the enzyme.

“It took several years, but at last we were able to recreate in the test tube what happens inside mycobacterial cells when the bacterial enzyme, which we named Ddn, and a second bacterial component called a cofactor, interact with PA-824,” says Dr. Barry. The key event in PA-824 metabolism, they found, is the production of nitric oxide (NO) gas. “This highly reactive molecule,” he adds, “is akin to a bomb blast that kills the bacteria from within.”

NO gas is produced naturally by certain immune system cells after they engulf M. tb or other bacteria. This is one way that people with healthy immune systems can contain M. tb infection. However, this natural immune response is not always enough to completely rid the body of TB bacteria. In essence, PA-824 performs similarly to the NO-producing immune cells–but the drug’s effect is more specific and triggered only after it enters the bacteria.

The non-dividing M. tb bacteria characteristic of latent TB infections are walled off by immune cells that aggregate around the bacteria to form a body called a granuloma. Oxygen levels are low inside granulomas. In their latest research, the scientists observed that NO-generation during PA-824 metabolism is greatest when oxygen levels are low. This observation suggests how PA-824 may work against non-dividing M. tb.

PA-824 was originally designed to work best under aerobic, or oxygenated, conditions. With this new understanding of how the bacterial enzyme and cofactor act on PA-824 under low-oxygen conditions, Dr. Barry says, scientists can design drugs with a chemical structure similar to PA-824 but optimize them from the start to behave best under low-oxygen conditions. This work is already proceeding in the laboratory at NIAID and in partnership with collaborators from the Novartis Institute for Tropical Diseases in Singapore as well as with scientists from the Genomics Institute of the Novartis Research Foundation in San Diego.

Because humans have neither the bacterial cofactor nor any enzymes equivalent to Ddn, PA-824 has no effect on human cells. Conversely, many bacteria have enzymes in the same family as Ddn. Thus, says Dr. Barry, it is possible to envision new kinds of NO-generating drugs designed to interact with enzymes associated with other disease-causing bacteria as well.

Source: NIH/National Institute of Allergy and Infectious Diseases