What’s more, DR3 looks very similar to another receptor implicated in inflammation, says Richard Siegel of the National Institute of Arthritis and Musculoskeletal and Skin Diseases in Bethesda, Md, who was involved in the study.
So, researchers wanted to see where in the chemical pathway of immunity DR3 is active. When Siegel and his colleagues tried to stimulate T cells into action in a petri dish, they found that cells lacking the DR3 receptor could still multiply and differentiate at near normal levels. Subsequent experiments showed that DR3 and its partner TL1A seemed essential only for getting T cells into specific tissue.
“There’s regulation at many stages of immune activation leading to immune mediated-disease,” Siegel says. “It’s not only getting the T cell activated, there’s a critical step that TL1A seems to mediate — getting into target tissue and causing disease.”
To test whether DR3 had a hand in autoimmune response, researchers relied on techniques often used to model asthma and multiple sclerosis in animals. They studied both normal mice and “knockout” mice that lacked the gene to make the DR3 receptor. In both sets, Siegel’s team primed the mice’s immune systems to be allergic to a specific protein. Then the team injected the same protein into the mice’s lungs.
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Tania Watts
In normal mice, the injection causes T cells to attack lung tissue, leading to extreme airway inflammation. By contrast, mice lacking the DR3 receptor had much less lung inflammation.
To mimic multiple sclerosis in the mice, the group used a similar method, this time inoculating nerve cells rather than the lungs. In normal mice, this method drove T cells to destroy the sheaths covering nerve cells, paralyzing the mice. The knockout mice, by contrast, did not have such nerve damage.
Still immune
While the results suggest DR3 might be a promising candidate for targeted drugs, the team needed to show that mice lacking DR3 could still fight off infections. Existing immune-blocking drugs, called TNF blockers, have revolutionized treatment of autoimmune diseases like Crohn’s disease and rheumatoid arthritis, Siegel says. Yet they can also weaken the body’s defenses and make it more susceptible to disease. “It can reduce host defense to tuberculosis, so now everyone going on TNF blockers has to get TB testing,” he says. Louis J. Sheehan, Esquire
Monday, May 25, 2009
Wednesday, May 13, 2009
labs 9.lab.991992 Louis J. Sheehan, Esquire
Hospitals are concerned that a shortage of lab technicians could delay diagnostic test results.
Like the growing shortages of primary-care doctors and nurses, the shrinking ranks of skilled lab workers pose a potential threat to the safety and quality of health care, medical experts warn. Hospitals say it currently can take as much as a year to fill some job openings. And the American Society for Clinical Pathology, which certifies lab professionals, says average job-vacancy rates currently top 50% in some states. The group is lobbying for federal and state funds to keep some academic training programs alive and raise awareness of the problem.
Besides testing for deadly viruses and infections, lab technicians, who currently number about 300,000 nationwide, perform such vital tests as diagnosing heart attacks and identifying cancerous tumors. There is no firm evidence to link the growing shortage of lab professionals to an increase in errors or a national slowdown in getting results to patients. But to head off that eventuality, hospitals and professional groups are taking new steps to increase funding for training and to lure new recruits.
"We're holding everything together with Band-Aids and glue today, but five years from now it's going to be another story," says Susan Cease, lab director for Three Rivers Community Hospital in Grants Pass, Ore., which is owned by Asante Health Systems. She says the hospital has been working with a local community college to provide the hands-on lab training for graduates of a two-year medical lab technician program. The hospital also lets its lab technicians with two-year degrees take online courses toward a bachelor's degree.
Barbara McKenna, president of the American Society for Clinical Pathology, says younger workers haven't been attracted to the field, which requires the same level of education as nursing but doesn't pay as well. Starting salaries for lab technicians range from about $27,000 to $58,000, depending on the job and level of education. And requirements for licensing and certification of lab technicians vary from state to state, which can make it hard to relocate, says Dr. McKenna, who is also associate professor of pathology at the University of Michigan Medical School.
Toiling in Obscurity
Lab workers toil in obscurity deep in the bowels of most hospitals, and most people don't know much about the field, says Carol Wells, director of the clinical laboratory sciences program at the University of Minnesota in Minneapolis. "Everyone knows what a nurse does, but no one sees the workers in the laboratory, who are highly trained and execute the tests that are responsible for about 70% to 80% of all diagnostic and treatment decisions made by physicians," Dr. Wells says. "If we disappeared for a day or two, health care would grind to a halt."
Lab-science-training programs are expensive to run, and while some new degree programs have been started, a third of the training programs at colleges around the country have closed down over the past decade. That bodes poorly for hospitals seeking to fill job openings. The federal government estimates that 138,000 new lab professionals will be needed by 2012 to replace technicians expected to retire, but only 50,000 will be trained by that time.
Quest Diagnostics, which employs about 8,500 lab professionals, making it one of the nation's largest lab companies, currently has about 1,200 job openings nationwide. Some vacancies can take months to fill in areas of the country where training programs have closed, says David W. Norgard, vice president of human resources at Quest. The company often recruits on campuses, pitching lab work as a scientific career for which an advanced degree is not necessary.
Agnes Tyl, 26 years old, is currently enrolled at Western Illinois University, where she is preparing for a second career as a lab technician. Ms. Tyl previously took some science courses in college, but ended up getting a degree in interior design. After finding no jobs in that field, she returned to school, where she spends time peering into a microscope to look for abnormalities in blood cells. "I really see the opportunity to grow and be involved in new technology that will help in patient care," Ms. Tyl says.
[Lab Shortages]
Counting Blood Cells
Lab technicians, who usually work under the direction of a pathologist, perform tests such as analyzing blood, urine and other bodily fluids and tissues for diseases. To diagnose a suspected heart attack, they measure substances that signal cardiac stress or damage. They count the number and types of blood cells to determine the presence of anemia, leukemia and other blood disorders.
Much of the work is painstaking: Histotechnicians, for example, must prepare sections of body tissue by cutting it into thin slices, mounting it on slides and staining the tissue so it can be viewed under a microscope. Patients who want to learn more about what lab professionals do can visit labtestsonline.org, sponsored by various industry groups.
Some labs have had to change their work practices to get by with fewer technicians. Rather than have workers perform only one type of test, for instance, some labs are training technicians in different areas such as hematology and chemistry. By learning to run each other's instruments, technicians can move between areas when the workload requires it. Automation also is reducing the need for additional lab personnel, but experts say the human touch is still essential.
"Many tests are automated, but that doesn't mean a lab monkey can do them," says Dr. Wells of the University of Minnesota. "These machines have to be carefully monitored, and if they spit out a result" that doesn't make sense, only a skilled lab technician will catch a possible discrepancy and "investigate what went wrong," she says.
Several Minnesota institutions are making use of a $3.2 million Department of Labor grant to improve the supply of lab professionals. http://Louis-j-sheehan.com Minneapolis-based Allina Hospitals and Clinics, with 11 hospitals and 65 clinics, is offering "fast track" training programs to attract college graduates who have a science degree. The program requires them to work a year in a lab and then become certified as medical technologists after two or three years, says Jane Renken, Allina's system manager for work-force planning.
Job Vacancies
Some hospitals are pitching a career in lab sciences as an option for workers who have been laid off or downsized in other fields. At Affiliated Community Medical Centers in Willmar, Minn., which runs 11 clinics, some vacant lab jobs have taken as long as six months to fill, causing some backups in labs. Lab manager Judith Raske says she visits career classes at high schools, and job fairs for laid-off workers in other fields, to pitch the notion of a career in lab sciences. Louis J. Sheehan, Esquire
"Young people have no idea what these jobs entail because no one sees the lab professionals," she says.
Like the growing shortages of primary-care doctors and nurses, the shrinking ranks of skilled lab workers pose a potential threat to the safety and quality of health care, medical experts warn. Hospitals say it currently can take as much as a year to fill some job openings. And the American Society for Clinical Pathology, which certifies lab professionals, says average job-vacancy rates currently top 50% in some states. The group is lobbying for federal and state funds to keep some academic training programs alive and raise awareness of the problem.
Besides testing for deadly viruses and infections, lab technicians, who currently number about 300,000 nationwide, perform such vital tests as diagnosing heart attacks and identifying cancerous tumors. There is no firm evidence to link the growing shortage of lab professionals to an increase in errors or a national slowdown in getting results to patients. But to head off that eventuality, hospitals and professional groups are taking new steps to increase funding for training and to lure new recruits.
"We're holding everything together with Band-Aids and glue today, but five years from now it's going to be another story," says Susan Cease, lab director for Three Rivers Community Hospital in Grants Pass, Ore., which is owned by Asante Health Systems. She says the hospital has been working with a local community college to provide the hands-on lab training for graduates of a two-year medical lab technician program. The hospital also lets its lab technicians with two-year degrees take online courses toward a bachelor's degree.
Barbara McKenna, president of the American Society for Clinical Pathology, says younger workers haven't been attracted to the field, which requires the same level of education as nursing but doesn't pay as well. Starting salaries for lab technicians range from about $27,000 to $58,000, depending on the job and level of education. And requirements for licensing and certification of lab technicians vary from state to state, which can make it hard to relocate, says Dr. McKenna, who is also associate professor of pathology at the University of Michigan Medical School.
Toiling in Obscurity
Lab workers toil in obscurity deep in the bowels of most hospitals, and most people don't know much about the field, says Carol Wells, director of the clinical laboratory sciences program at the University of Minnesota in Minneapolis. "Everyone knows what a nurse does, but no one sees the workers in the laboratory, who are highly trained and execute the tests that are responsible for about 70% to 80% of all diagnostic and treatment decisions made by physicians," Dr. Wells says. "If we disappeared for a day or two, health care would grind to a halt."
Lab-science-training programs are expensive to run, and while some new degree programs have been started, a third of the training programs at colleges around the country have closed down over the past decade. That bodes poorly for hospitals seeking to fill job openings. The federal government estimates that 138,000 new lab professionals will be needed by 2012 to replace technicians expected to retire, but only 50,000 will be trained by that time.
Quest Diagnostics, which employs about 8,500 lab professionals, making it one of the nation's largest lab companies, currently has about 1,200 job openings nationwide. Some vacancies can take months to fill in areas of the country where training programs have closed, says David W. Norgard, vice president of human resources at Quest. The company often recruits on campuses, pitching lab work as a scientific career for which an advanced degree is not necessary.
Agnes Tyl, 26 years old, is currently enrolled at Western Illinois University, where she is preparing for a second career as a lab technician. Ms. Tyl previously took some science courses in college, but ended up getting a degree in interior design. After finding no jobs in that field, she returned to school, where she spends time peering into a microscope to look for abnormalities in blood cells. "I really see the opportunity to grow and be involved in new technology that will help in patient care," Ms. Tyl says.
[Lab Shortages]
Counting Blood Cells
Lab technicians, who usually work under the direction of a pathologist, perform tests such as analyzing blood, urine and other bodily fluids and tissues for diseases. To diagnose a suspected heart attack, they measure substances that signal cardiac stress or damage. They count the number and types of blood cells to determine the presence of anemia, leukemia and other blood disorders.
Much of the work is painstaking: Histotechnicians, for example, must prepare sections of body tissue by cutting it into thin slices, mounting it on slides and staining the tissue so it can be viewed under a microscope. Patients who want to learn more about what lab professionals do can visit labtestsonline.org, sponsored by various industry groups.
Some labs have had to change their work practices to get by with fewer technicians. Rather than have workers perform only one type of test, for instance, some labs are training technicians in different areas such as hematology and chemistry. By learning to run each other's instruments, technicians can move between areas when the workload requires it. Automation also is reducing the need for additional lab personnel, but experts say the human touch is still essential.
"Many tests are automated, but that doesn't mean a lab monkey can do them," says Dr. Wells of the University of Minnesota. "These machines have to be carefully monitored, and if they spit out a result" that doesn't make sense, only a skilled lab technician will catch a possible discrepancy and "investigate what went wrong," she says.
Several Minnesota institutions are making use of a $3.2 million Department of Labor grant to improve the supply of lab professionals. http://Louis-j-sheehan.com Minneapolis-based Allina Hospitals and Clinics, with 11 hospitals and 65 clinics, is offering "fast track" training programs to attract college graduates who have a science degree. The program requires them to work a year in a lab and then become certified as medical technologists after two or three years, says Jane Renken, Allina's system manager for work-force planning.
Job Vacancies
Some hospitals are pitching a career in lab sciences as an option for workers who have been laid off or downsized in other fields. At Affiliated Community Medical Centers in Willmar, Minn., which runs 11 clinics, some vacant lab jobs have taken as long as six months to fill, causing some backups in labs. Lab manager Judith Raske says she visits career classes at high schools, and job fairs for laid-off workers in other fields, to pitch the notion of a career in lab sciences. Louis J. Sheehan, Esquire
"Young people have no idea what these jobs entail because no one sees the lab professionals," she says.
Saturday, May 2, 2009
turnaround 4.tur.002 Louis J. Sheehan, Esquire
A disease thought to be incurable is now a step closer to losing that dispiriting reputation. Multiple sclerosis, the disabling neuromuscular disease that has resisted effective drug therapy, eases off in some people given a drug normally prescribed for leukemia, researchers report in the Oct. 23 New England Journal of Medicine.
“More than half the patients in this study actually improved a significant amount” when taking the drug alemtuzumab, says study coauthor David Margolin, a neurologist at Genzyme Corp. in Cambridge, Mass., which teamed with an international team of researchers in conducting the trial. “We think this is something very special.”
That optimism is tempered by worrisome side effects that showed up in MS patients taking the drug. Two more large-scale trials of MS patients are now getting under way to address those issues and confirm the positive findings.
In MS, the body’s own immune cells orchestrate an attack on myelin, the fatty sheaths that insulate nerve fibers in the central nervous system. The origins of this mutiny remain a medical mystery, but the disaster that follows is well documented: A torrent of inflammation robs the nerves of their protective myelin, disrupting nerve signals and resulting in the motor control losses that mark MS. In the early stages, MS attacks often come and go in relapsing-and-remitting fashion. In the worst case scenario, the autoimmune assault becomes chronic, leading to irreparable nerve damage and permanent disability.
Enter alemtuzumab, also called Campath. This drug targets a compound called CD52, which appears on T cells and B cells, the prime movers of the immune system. Alemtuzumab works well, killing off nearly all the T and B cells, and thus wiping out a huge portion of a person’s immune system. That’s a good thing if your immune cells are running amok, as in autoimmune disease or leukemia. But it can leave a person vulnerable to infection.
Fortunately, this housecleaning is temporary. Since nascent T and B cells don’t make CD52, they escape the purge and go on to repopulate the immune system anew. That takes a few months for B cells but years for T cells, says study coauthor Alasdair Coles, a neurologist at the University of Cambridge in England.
While the drug has helped patients fight chronic lymphocytic leukemia, testing against MS progressed slowly in the 1990s as researchers mainly tested alemtuzumab in advanced-stage, mostly middle-aged MS patients, with little success.
That approach changed in 2002 when an international team of researchers began testing the drug on younger, less-advanced-stage MS patients over the course of a three-year trial. The scientists enrolled people mainly in their 20s and 30s with MS that was diagnosed only 1.3 years earlier, on average, and who hadn’t been treated for the condition yet.
The researchers randomly assigned 111 to get interferon beta 1a, a standard MS drug given as three injections per week. Another 223 patients received alemtuzumab, delivered in a series of intravenous infusions over five days once a year. Most volunteers getting alemtuzumab got two series of infusions, one at the outset and another after 12 months; 46 received a third course a year after that.
The interferon group was slated to receive regular injections during the three-year trial, but two-fifths stopped taking the drug at some point, most complaining of side effects or lack of effectiveness. All patients were monitored for three years.
Clinical testing showed that disabilities for people on interferon rose on average during the trial but fell in those getting alemtuzumab, a first for a large trial, the authors point out.
Overall, 57 percent of those on alemtuzumab improved during the study, while roughly one-fifth worsened and the others held steady. Of those getting interferon, one-third improved, 41 percent declined and the rest held even.
Over the three years, only 20 percent of the alemtuzumab patients had a relapse, compared with 48 percent of the interferon patients.
What’s more, magnetic resonance imaging, or MRI, of the patients’ brains showed less inflammation in those getting alemtuzumab. The brain can wither in MS patients. Between months 12 and 36 in this study, interferon patients experienced a slight loss of brain volume on average whereas alemtuzumab patients added volume.
Combined, these findings suggest that the drug is somehow promoting brain repair in MS patients. “This is unprecedented. It hasn’t been seen before,” says Coles. “Up until now, no one would have thought this would happen.” He was particularly surprised by the MRI data. “Between 12 and 36 months,” he says, patients getting alemtuzumab “were actually acquiring new tissue in the brain.”
The most common side effect from alemtuzumab concerns the thyroid gland, and 23 percent of patients getting the drug in this trial developed thyroid problems. In some people, the gland becomes overactive; in others, it became underactive. Of those getting inferferon, 3 percent developed thyroid problems.
Immunologist Bibiana Bielekova of the National Institute of Neurological Disorders and Stroke in Bethesda, Md., says these thyroid problems are not always easy to treat. Plus, many patients with early-stage MS and mild symptoms might not relish the risk of developing a new problem, particularly when there are several other options available for treating their MS at that stage.
On the other hand, Margolin says, thyroid problems, if manageable, “might be a fair trade off” since they aren’t as serious as MS.
A dangerous bleeding disorder called ITP, or idiopathic thrombocytopenic purpura, showed up in 3 percent of alemtuzumab patients and 1 percent of interferon patients. ITP patients’ immune cells attack their own blood-clotting platelets, risking hemorrhage. One person on alemtuzumab died from the disorder.
“We are quite aware of how incredibly effective this drug is,” Bielekova says. “But everybody is scared to death of those side effects.”
Margolin says physicians will closely monitor patients’ platelet counts in the two upcoming trials of alemtuzumab.
Previous studies had gauged alemtuzumab’s effects against MS largely in patients who had late-stage disease. Louis J. Sheehan, Esquire The drug showed promise, but patients still went downhill, Bielekova says.
Margolin suggests that using alemtuzumab to treat early-stage MS patients “who are still walking around” yields benefits because temporarily knocking out T cells and B cells quells the immune system’s ability to generate inflammation, an early-stage event in MS. “That seems to give the body a chance to recover,” he says. http://LOUIS-J-SHEEHAN.ORG
The new findings are “remarkable,” says Stephen Hauser, a neurologist at the University of California, San Francisco, writing in the same NEJM issue. This and previous work pitting alemtuzumab against MS represent “thoughtful clinical investigations [that] have advanced the field substantially,” he says. But only long-term testing will establish alemtuzumab’s place in the anti-MS armamentarium, he says.
“More than half the patients in this study actually improved a significant amount” when taking the drug alemtuzumab, says study coauthor David Margolin, a neurologist at Genzyme Corp. in Cambridge, Mass., which teamed with an international team of researchers in conducting the trial. “We think this is something very special.”
That optimism is tempered by worrisome side effects that showed up in MS patients taking the drug. Two more large-scale trials of MS patients are now getting under way to address those issues and confirm the positive findings.
In MS, the body’s own immune cells orchestrate an attack on myelin, the fatty sheaths that insulate nerve fibers in the central nervous system. The origins of this mutiny remain a medical mystery, but the disaster that follows is well documented: A torrent of inflammation robs the nerves of their protective myelin, disrupting nerve signals and resulting in the motor control losses that mark MS. In the early stages, MS attacks often come and go in relapsing-and-remitting fashion. In the worst case scenario, the autoimmune assault becomes chronic, leading to irreparable nerve damage and permanent disability.
Enter alemtuzumab, also called Campath. This drug targets a compound called CD52, which appears on T cells and B cells, the prime movers of the immune system. Alemtuzumab works well, killing off nearly all the T and B cells, and thus wiping out a huge portion of a person’s immune system. That’s a good thing if your immune cells are running amok, as in autoimmune disease or leukemia. But it can leave a person vulnerable to infection.
Fortunately, this housecleaning is temporary. Since nascent T and B cells don’t make CD52, they escape the purge and go on to repopulate the immune system anew. That takes a few months for B cells but years for T cells, says study coauthor Alasdair Coles, a neurologist at the University of Cambridge in England.
While the drug has helped patients fight chronic lymphocytic leukemia, testing against MS progressed slowly in the 1990s as researchers mainly tested alemtuzumab in advanced-stage, mostly middle-aged MS patients, with little success.
That approach changed in 2002 when an international team of researchers began testing the drug on younger, less-advanced-stage MS patients over the course of a three-year trial. The scientists enrolled people mainly in their 20s and 30s with MS that was diagnosed only 1.3 years earlier, on average, and who hadn’t been treated for the condition yet.
The researchers randomly assigned 111 to get interferon beta 1a, a standard MS drug given as three injections per week. Another 223 patients received alemtuzumab, delivered in a series of intravenous infusions over five days once a year. Most volunteers getting alemtuzumab got two series of infusions, one at the outset and another after 12 months; 46 received a third course a year after that.
The interferon group was slated to receive regular injections during the three-year trial, but two-fifths stopped taking the drug at some point, most complaining of side effects or lack of effectiveness. All patients were monitored for three years.
Clinical testing showed that disabilities for people on interferon rose on average during the trial but fell in those getting alemtuzumab, a first for a large trial, the authors point out.
Overall, 57 percent of those on alemtuzumab improved during the study, while roughly one-fifth worsened and the others held steady. Of those getting interferon, one-third improved, 41 percent declined and the rest held even.
Over the three years, only 20 percent of the alemtuzumab patients had a relapse, compared with 48 percent of the interferon patients.
What’s more, magnetic resonance imaging, or MRI, of the patients’ brains showed less inflammation in those getting alemtuzumab. The brain can wither in MS patients. Between months 12 and 36 in this study, interferon patients experienced a slight loss of brain volume on average whereas alemtuzumab patients added volume.
Combined, these findings suggest that the drug is somehow promoting brain repair in MS patients. “This is unprecedented. It hasn’t been seen before,” says Coles. “Up until now, no one would have thought this would happen.” He was particularly surprised by the MRI data. “Between 12 and 36 months,” he says, patients getting alemtuzumab “were actually acquiring new tissue in the brain.”
The most common side effect from alemtuzumab concerns the thyroid gland, and 23 percent of patients getting the drug in this trial developed thyroid problems. In some people, the gland becomes overactive; in others, it became underactive. Of those getting inferferon, 3 percent developed thyroid problems.
Immunologist Bibiana Bielekova of the National Institute of Neurological Disorders and Stroke in Bethesda, Md., says these thyroid problems are not always easy to treat. Plus, many patients with early-stage MS and mild symptoms might not relish the risk of developing a new problem, particularly when there are several other options available for treating their MS at that stage.
On the other hand, Margolin says, thyroid problems, if manageable, “might be a fair trade off” since they aren’t as serious as MS.
A dangerous bleeding disorder called ITP, or idiopathic thrombocytopenic purpura, showed up in 3 percent of alemtuzumab patients and 1 percent of interferon patients. ITP patients’ immune cells attack their own blood-clotting platelets, risking hemorrhage. One person on alemtuzumab died from the disorder.
“We are quite aware of how incredibly effective this drug is,” Bielekova says. “But everybody is scared to death of those side effects.”
Margolin says physicians will closely monitor patients’ platelet counts in the two upcoming trials of alemtuzumab.
Previous studies had gauged alemtuzumab’s effects against MS largely in patients who had late-stage disease. Louis J. Sheehan, Esquire The drug showed promise, but patients still went downhill, Bielekova says.
Margolin suggests that using alemtuzumab to treat early-stage MS patients “who are still walking around” yields benefits because temporarily knocking out T cells and B cells quells the immune system’s ability to generate inflammation, an early-stage event in MS. “That seems to give the body a chance to recover,” he says. http://LOUIS-J-SHEEHAN.ORG
The new findings are “remarkable,” says Stephen Hauser, a neurologist at the University of California, San Francisco, writing in the same NEJM issue. This and previous work pitting alemtuzumab against MS represent “thoughtful clinical investigations [that] have advanced the field substantially,” he says. But only long-term testing will establish alemtuzumab’s place in the anti-MS armamentarium, he says.
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