Michele G. Sullivan

Both intensive lifestyle changes and metformin can significantly reduce the risk of diabetes in women with impaired glucose tolerance who have had gestational diabetes, a subanalysis of the Diabetes Prevention Program has concluded.

Both interventions reduced the risk of diabetes progression by about 50% compared with placebo, Dr. Robert Ratner and his colleagues reported in the Journal of Clinical Endocrinology and Metabolism.

However, in women without a history of gestational diabetes, lifestyle changes were significantly more effective than was metformin in preventing diabetes (49% vs. 14%), the investigators wrote (J. Clin. Endocrinol. Metab. 2008; 93:4774–9).

“Our data suggest a differential success of the interventions between those with and without a history of gestational diabetes,” wrote Dr. Ratner of the MedStar Research Institute, Hyattsville, Md. Lifestyle changes were probably not as effective in women who had experienced the disorder because the group had a much harder time losing weight and keeping it off than did those who had never had gestational diabetes, thus equalizing the effect of both treatments, the investigators wrote.

The Diabetes Prevention Program study examined the risk of progression to diabetes in women with impaired glucose tolerance. The study randomized patients to placebo, metformin, or intensive lifestyle changes, which included increasing physical activity at least 1.5 hours per week over baseline for the duration of the 3-year trial.

The substudy examined the risk of progression in 1,766 of these women who had given birth to a live child. Of these, 350 had pregnancies complicated by gestational diabetes mellitus (GDM).

In the placebo group, diabetes developed in 38% of those with a history of GDM and 26% of those without a history—a 71% increased incidence per 100 person-years.

Women without GDM who were randomized to lifestyle therapy experienced a 49% risk reduction compared with placebo; the risk reduction was only 14% in the group randomized to metformin. Women with a history of GDM therapy experienced a 50% risk reduction compared with placebo when randomized to lifestyle therapy and a 53% risk reduction when randomized to metformin.

The pattern of weight loss in the different groups probably impacted the effect of lifestyle therapy in those with a GDM history, the investigators said.

These women lost a mean of 5 kg by 6 months, compared with a mean of 6 kg at 6 months in the comparator group.

Additionally, women who had experienced GDM regained more of their weight, reaching a mean loss of 1.6 kg by the end of the study, compared with 4 kg by the study's end in the comparator group.

Women with a history of GDM also experienced a significantly higher conversion rate to diabetes than did women without a history (15 cases vs. 9 cases per 100 person-years). “Taking into account the treatment effects, we estimate that only five or six women with glucose intolerance and a history of GDM would need to be treated over 3 years with either metformin or lifestyle therapy to prevent one case of diabetes,” the team said. “In women without a history of GDM, the estimated numbers needed to treat to prevent a single case of diabetes over 3 years are 24 [for metformin] and 9 [for lifestyle therapy].”

The Diabetes Prevention Program study was sponsored by the National Institutes of Health. Dr. Ratner was the project's primary investigator.

Women without GDM who received lifestyle therapy had a 49% risk reduction compared with placebo. DR. RATNER

Both intensive lifestyle changes and metformin can significantly reduce the risk of diabetes in women with impaired glucose tolerance who have had gestational diabetes, a subanalysis of the Diabetes Prevention Program has concluded.

Both interventions reduced the risk of diabetes progression by about 50% compared with placebo, Dr. Robert Ratner and his colleagues reported in the Journal of Clinical Endocrinology and Metabolism.

However, in women without a history of gestational diabetes, lifestyle changes were significantly more effective than was metformin in preventing diabetes (49% vs. 14%), the investigators wrote (J. Clin. Endocrinol. Metab. 2008; 93:4774–9).

“Our data suggest a differential success of the interventions between those with and without a history of gestational diabetes,” wrote Dr. Ratner of the MedStar Research Institute, Hyattsville, Md. Lifestyle changes were probably not as effective in women who had experienced the disorder because the group had a much harder time losing weight and keeping it off than did those who had never had gestational diabetes, thus equalizing the effect of both treatments, the investigators wrote.

The Diabetes Prevention Program study examined the risk of progression to diabetes in women with impaired glucose tolerance. The study randomized patients to placebo, metformin, or intensive lifestyle changes, which included increasing physical activity at least 1.5 hours per week over baseline for the duration of the 3-year trial.

The substudy examined the risk of progression in 1,766 of these women who had given birth to a live child. Of these, 350 had pregnancies complicated by gestational diabetes mellitus (GDM).

In the placebo group, diabetes developed in 38% of those with a history of GDM and 26% of those without a history—a 71% increased incidence per 100 person-years.

Women without GDM who were randomized to lifestyle therapy experienced a 49% risk reduction compared with placebo; the risk reduction was only 14% in the group randomized to metformin. Women with a history of GDM therapy experienced a 50% risk reduction compared with placebo when randomized to lifestyle therapy and a 53% risk reduction when randomized to metformin.

The pattern of weight loss in the different groups probably impacted the effect of lifestyle therapy in those with a GDM history, the investigators said.

These women lost a mean of 5 kg by 6 months, compared with a mean of 6 kg at 6 months in the comparator group.

Additionally, women who had experienced GDM regained more of their weight, reaching a mean loss of 1.6 kg by the end of the study, compared with 4 kg by the study's end in the comparator group.

Women with a history of GDM also experienced a significantly higher conversion rate to diabetes than did women without a history (15 cases vs. 9 cases per 100 person-years). “Taking into account the treatment effects, we estimate that only five or six women with glucose intolerance and a history of GDM would need to be treated over 3 years with either metformin or lifestyle therapy to prevent one case of diabetes,” the team said. “In women without a history of GDM, the estimated numbers needed to treat to prevent a single case of diabetes over 3 years are 24 [for metformin] and 9 [for lifestyle therapy].”

The Diabetes Prevention Program study was sponsored by the National Institutes of Health. Dr. Ratner was the project's primary investigator.

Women without GDM who received lifestyle therapy had a 49% risk reduction compared with placebo. DR. RATNER

Both intensive lifestyle changes and metformin can significantly reduce the risk of diabetes in women with impaired glucose tolerance who have had gestational diabetes, a subanalysis of the Diabetes Prevention Program has concluded.

Both interventions reduced the risk of diabetes progression by about 50% compared with placebo, Dr. Robert Ratner and his colleagues reported in the Journal of Clinical Endocrinology and Metabolism.

However, in women without a history of gestational diabetes, lifestyle changes were significantly more effective than was metformin in preventing diabetes (49% vs. 14%), the investigators wrote (J. Clin. Endocrinol. Metab. 2008; 93:4774–9).

“Our data suggest a differential success of the interventions between those with and without a history of gestational diabetes,” wrote Dr. Ratner of the MedStar Research Institute, Hyattsville, Md. Lifestyle changes were probably not as effective in women who had experienced the disorder because the group had a much harder time losing weight and keeping it off than did those who had never had gestational diabetes, thus equalizing the effect of both treatments, the investigators wrote.

The Diabetes Prevention Program study examined the risk of progression to diabetes in women with impaired glucose tolerance. The study randomized patients to placebo, metformin, or intensive lifestyle changes, which included increasing physical activity at least 1.5 hours per week over baseline for the duration of the 3-year trial.

The substudy examined the risk of progression in 1,766 of these women who had given birth to a live child. Of these, 350 had pregnancies complicated by gestational diabetes mellitus (GDM).

In the placebo group, diabetes developed in 38% of those with a history of GDM and 26% of those without a history—a 71% increased incidence per 100 person-years.

Women without GDM who were randomized to lifestyle therapy experienced a 49% risk reduction compared with placebo; the risk reduction was only 14% in the group randomized to metformin. Women with a history of GDM therapy experienced a 50% risk reduction compared with placebo when randomized to lifestyle therapy and a 53% risk reduction when randomized to metformin.

The pattern of weight loss in the different groups probably impacted the effect of lifestyle therapy in those with a GDM history, the investigators said.

These women lost a mean of 5 kg by 6 months, compared with a mean of 6 kg at 6 months in the comparator group.

Additionally, women who had experienced GDM regained more of their weight, reaching a mean loss of 1.6 kg by the end of the study, compared with 4 kg by the study's end in the comparator group.

Women with a history of GDM also experienced a significantly higher conversion rate to diabetes than did women without a history (15 cases vs. 9 cases per 100 person-years). “Taking into account the treatment effects, we estimate that only five or six women with glucose intolerance and a history of GDM would need to be treated over 3 years with either metformin or lifestyle therapy to prevent one case of diabetes,” the team said. “In women without a history of GDM, the estimated numbers needed to treat to prevent a single case of diabetes over 3 years are 24 [for metformin] and 9 [for lifestyle therapy].”

The Diabetes Prevention Program study was sponsored by the National Institutes of Health. Dr. Ratner was the project's primary investigator.

Women without GDM who received lifestyle therapy had a 49% risk reduction compared with placebo. DR. RATNER

Getting six cell-based influenza vaccine manufacturing plants up and running in the United States should be the first of four priorities for the next Secretary of Health and Human Services, advised Secretary Mike Leavitt.

“The highest priority of the next administration should be to expand U.S. production of cell-based technology, so that in a 6-month period, we could generate enough pandemic flu vaccine in this country to protect every American,” Secretary Leavitt said during a Webcast. “We have invested more than $1 billion in this, and now have six companies in various stages of implementing either cell-based manufacturing or expanded egg-based vaccine production. The goal is to complete these contracts by 2011.”

The importance of cell-based vaccine manufacturing can't be overstressed, he said. GlaxoSmithKline, MedImmune Inc., Novartis, DynPort Vaccine Co., Solvay Pharmaceuticals Inc., and Sanofi Pasteur have all received federal grant money to develop vaccines. “There are not enough chickens in the world to get this done in the case of a pandemic. These contracts have to be fulfilled and the factories built.”

Second, the free international sharing of viral samples for vaccine research needs to be addressed, he said. “We need to strongly defend the sample-sharing network against short-term opportunism. For years, nations have freely shared viral samples, and this is now being threatened by nations who want to hold their samples for compensation—they feel the virus is their intellectual property and insist on royalties if anyone makes a vaccine out of it.”

A January 2007 decision by Indonesian authorities to withhold all clinical specimens from suspected cases of human bird flu A (H5N1) fueled this concern. According to the World Health Organization, which manages international sample sharing, the country rescinded this ban in March 2007. But the idea that countries could turn a profit from research samples seems to have taken root in some of the international community, according to a recent report of the European Centre for Disease Prevention and Control.

The May 2008 report noted that “to date, no other countries have publicly made moves like those of Indonesia, although some others have been considering their positions. Other countries not traditionally concerned have been supporting the Indonesian position; the debate has become politicized internationally and attitudes have hardened.” (See http://ecdc.europa.eu/pdf/ECDC_influenza_briefing.pdf

The international community must take a strong stand against these tactics, Secretary Leavitt said. “Meeting their demands would result in the downfall of our very important sharing strategy. The system would fail and subject the entire world to more danger.”

Third, the new administration will also need to concentrate on countermeasure distribution. “We have an important stockpiling system [of medications and equipment] and we can get massive amounts of supplies anywhere in the U.S. within 2 hours. But getting the pills into the people is our Achilles' heel and it needs work. Not every state is prepared to handle this, and this failure is potentially catastrophic.”

Ultimately, distribution will be a state and local issue. “Public health is a local responsibility because localities are better at accomplishing this mission than the federal government is. Before leaving this administration, I want to release a state-by-state evaluation so people can know if their officials are meeting the standards we need to achieve.”

Tough economic times, Medicaid growth, and a new culture of disaster dependence might interfere with local commitments to pandemic planning, however. “We have to resist the tendency for local and state governments to use budget limitations to upwardly allocate disaster preparedness. Public health is one of a number of important functions being crowded off the budget table by the unconstrained growth of Medicaid eating up state budgets.”

Also, he said, “A cultural change that began with Hurricane Katrina has begun to drive a federalization of public health. But I want to tell you, the state or community that fails to prepare, with the expectation that the federal government will come to the rescue at the last moment, will be tragically disappointed.”

Finally, HHS must keep pandemic preparedness on national and local agendas. “The media buzz about bird flu has died down, but the virus has not,” he said. Publicity is a tightrope act, in that “when we discuss it in advance, we come off as alarmist, but if we don't discuss it until it starts, then none of our preparations will be adequate. We need to speak of this in a way that stimulates discussion, not panic.”

Getting six cell-based influenza vaccine manufacturing plants up and running in the United States should be the first of four priorities for the next Secretary of Health and Human Services, advised Secretary Mike Leavitt.

“The highest priority of the next administration should be to expand U.S. production of cell-based technology, so that in a 6-month period, we could generate enough pandemic flu vaccine in this country to protect every American,” Secretary Leavitt said during a Webcast. “We have invested more than $1 billion in this, and now have six companies in various stages of implementing either cell-based manufacturing or expanded egg-based vaccine production. The goal is to complete these contracts by 2011.”

The importance of cell-based vaccine manufacturing can't be overstressed, he said. GlaxoSmithKline, MedImmune Inc., Novartis, DynPort Vaccine Co., Solvay Pharmaceuticals Inc., and Sanofi Pasteur have all received federal grant money to develop vaccines. “There are not enough chickens in the world to get this done in the case of a pandemic. These contracts have to be fulfilled and the factories built.”

Second, the free international sharing of viral samples for vaccine research needs to be addressed, he said. “We need to strongly defend the sample-sharing network against short-term opportunism. For years, nations have freely shared viral samples, and this is now being threatened by nations who want to hold their samples for compensation—they feel the virus is their intellectual property and insist on royalties if anyone makes a vaccine out of it.”

A January 2007 decision by Indonesian authorities to withhold all clinical specimens from suspected cases of human bird flu A (H5N1) fueled this concern. According to the World Health Organization, which manages international sample sharing, the country rescinded this ban in March 2007. But the idea that countries could turn a profit from research samples seems to have taken root in some of the international community, according to a recent report of the European Centre for Disease Prevention and Control.

The May 2008 report noted that “to date, no other countries have publicly made moves like those of Indonesia, although some others have been considering their positions. Other countries not traditionally concerned have been supporting the Indonesian position; the debate has become politicized internationally and attitudes have hardened.” (See http://ecdc.europa.eu/pdf/ECDC_influenza_briefing.pdf

The international community must take a strong stand against these tactics, Secretary Leavitt said. “Meeting their demands would result in the downfall of our very important sharing strategy. The system would fail and subject the entire world to more danger.”

Third, the new administration will also need to concentrate on countermeasure distribution. “We have an important stockpiling system [of medications and equipment] and we can get massive amounts of supplies anywhere in the U.S. within 2 hours. But getting the pills into the people is our Achilles' heel and it needs work. Not every state is prepared to handle this, and this failure is potentially catastrophic.”

Ultimately, distribution will be a state and local issue. “Public health is a local responsibility because localities are better at accomplishing this mission than the federal government is. Before leaving this administration, I want to release a state-by-state evaluation so people can know if their officials are meeting the standards we need to achieve.”

Tough economic times, Medicaid growth, and a new culture of disaster dependence might interfere with local commitments to pandemic planning, however. “We have to resist the tendency for local and state governments to use budget limitations to upwardly allocate disaster preparedness. Public health is one of a number of important functions being crowded off the budget table by the unconstrained growth of Medicaid eating up state budgets.”

Also, he said, “A cultural change that began with Hurricane Katrina has begun to drive a federalization of public health. But I want to tell you, the state or community that fails to prepare, with the expectation that the federal government will come to the rescue at the last moment, will be tragically disappointed.”

Finally, HHS must keep pandemic preparedness on national and local agendas. “The media buzz about bird flu has died down, but the virus has not,” he said. Publicity is a tightrope act, in that “when we discuss it in advance, we come off as alarmist, but if we don't discuss it until it starts, then none of our preparations will be adequate. We need to speak of this in a way that stimulates discussion, not panic.”

Getting six cell-based influenza vaccine manufacturing plants up and running in the United States should be the first of four priorities for the next Secretary of Health and Human Services, advised Secretary Mike Leavitt.

“The highest priority of the next administration should be to expand U.S. production of cell-based technology, so that in a 6-month period, we could generate enough pandemic flu vaccine in this country to protect every American,” Secretary Leavitt said during a Webcast. “We have invested more than $1 billion in this, and now have six companies in various stages of implementing either cell-based manufacturing or expanded egg-based vaccine production. The goal is to complete these contracts by 2011.”

The importance of cell-based vaccine manufacturing can't be overstressed, he said. GlaxoSmithKline, MedImmune Inc., Novartis, DynPort Vaccine Co., Solvay Pharmaceuticals Inc., and Sanofi Pasteur have all received federal grant money to develop vaccines. “There are not enough chickens in the world to get this done in the case of a pandemic. These contracts have to be fulfilled and the factories built.”

Second, the free international sharing of viral samples for vaccine research needs to be addressed, he said. “We need to strongly defend the sample-sharing network against short-term opportunism. For years, nations have freely shared viral samples, and this is now being threatened by nations who want to hold their samples for compensation—they feel the virus is their intellectual property and insist on royalties if anyone makes a vaccine out of it.”

A January 2007 decision by Indonesian authorities to withhold all clinical specimens from suspected cases of human bird flu A (H5N1) fueled this concern. According to the World Health Organization, which manages international sample sharing, the country rescinded this ban in March 2007. But the idea that countries could turn a profit from research samples seems to have taken root in some of the international community, according to a recent report of the European Centre for Disease Prevention and Control.

The May 2008 report noted that “to date, no other countries have publicly made moves like those of Indonesia, although some others have been considering their positions. Other countries not traditionally concerned have been supporting the Indonesian position; the debate has become politicized internationally and attitudes have hardened.” (See http://ecdc.europa.eu/pdf/ECDC_influenza_briefing.pdf

The international community must take a strong stand against these tactics, Secretary Leavitt said. “Meeting their demands would result in the downfall of our very important sharing strategy. The system would fail and subject the entire world to more danger.”

Third, the new administration will also need to concentrate on countermeasure distribution. “We have an important stockpiling system [of medications and equipment] and we can get massive amounts of supplies anywhere in the U.S. within 2 hours. But getting the pills into the people is our Achilles' heel and it needs work. Not every state is prepared to handle this, and this failure is potentially catastrophic.”

Ultimately, distribution will be a state and local issue. “Public health is a local responsibility because localities are better at accomplishing this mission than the federal government is. Before leaving this administration, I want to release a state-by-state evaluation so people can know if their officials are meeting the standards we need to achieve.”

Tough economic times, Medicaid growth, and a new culture of disaster dependence might interfere with local commitments to pandemic planning, however. “We have to resist the tendency for local and state governments to use budget limitations to upwardly allocate disaster preparedness. Public health is one of a number of important functions being crowded off the budget table by the unconstrained growth of Medicaid eating up state budgets.”

Also, he said, “A cultural change that began with Hurricane Katrina has begun to drive a federalization of public health. But I want to tell you, the state or community that fails to prepare, with the expectation that the federal government will come to the rescue at the last moment, will be tragically disappointed.”

Finally, HHS must keep pandemic preparedness on national and local agendas. “The media buzz about bird flu has died down, but the virus has not,” he said. Publicity is a tightrope act, in that “when we discuss it in advance, we come off as alarmist, but if we don't discuss it until it starts, then none of our preparations will be adequate. We need to speak of this in a way that stimulates discussion, not panic.”

MADRID – Deep brain stimulation shows considerable promise for reducing intractable seizures in patients who are not candidates for epilepsy surgery, even though there have been few large-scale controlled trials to back up the practice.

“We have no idea what the best stimulation parameters are, we don't know whether to stimulate in response to epileptiform activity or continuously, and, of course, the search for the optimal target is ongoing,” Dr. Paul Boon said at the annual congress of the European Federation of Neurological Societies.

“Most of our information has come from uncontrolled studies and case reports, which included about 115 people worldwide.”

Now, data from three new or upcoming studies might help shed light on some of these questions, said Dr. Boon of University Hospital Ghent (Belgium), where he and his colleagues are leaders in researching an epilepsy application for DBS.

Some of the earliest studies, in the 1980s and early 1990s, used the electrodes in the brain's cerebellar regions, but with very little effect, so the cerebellum is no longer considered a target. The caudate nucleus and centromedial nucleus of the thalamus have also been examined as possible targets, but in very small numbers of patients and with varying results, said Dr. Boon.

The most promising approach to date is bilateral stimulation of the anterior thalamic nucleus, he said. Early uncontrolled studies of this application had small patient numbers, but their success led to the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy trial of 110 patients with medically refractory partial-onset seizures.

All of the patients received the implants; for the first 3 months, only half of the patient had their stimulators turned on. After this blinded treatment phase, all of the patients received neurostimulation. By way of detailing his financial conflicts of interest, Dr. Boon said in an interview that Medtronic Inc., the company that makes DBS hardware, has been and is providing devices and electrodes in support of the pilot trial, and has provided an educational grant.

The medial temporal lobe and the hippocampus are other potential targets. Last year, Dr. Boon and his colleagues published a study of 12 patients with refractory temporal lobe epilepsy, who were also candidates for surgery. Instead of implanting recording electrodes during the presurgical period, they implanted DBS electrodes in the medial temporal lobe.

“We aimed to adjust the simulation parameters to get a 50% reduction in spikes for 7 consecutive days,” he said. “If the patient achieved that, then we went to chronic stimulation, and if they did not achieve that, then we adjusted the parameters until we met those criteria. If the patient still didn't achieve the reduction, then we removed the electrodes and proceeded to surgery.”

Of the 12 patients, 10 underwent long-term DBS and 2 had the resection. After a mean follow-up of 31 months, both of the surgical patients were seizure free. One of the DBS patients had a seizure reduction of more than 90%; five had a reduction of at least 50%, and two had a reduction of 30%–40% (Epilepsia 2007;48:1551–60).

“We got a 70% response rate, with no significant adverse events or changes in memory,” he said. “This shows that DBS of the medial temporal lobe is safe, feasible, and effective.”

Dr. Boon and his group are also seeking to recruit 45 patients for a study comparing DBS of the hippocampus with medial temporal lobe resection or with hippocampal DBS delayed for 6 months after implantation. The 1-year trial will also be sponsored by Medtronic.

Researchers believe that DBS controls seizures by desynchronizing synchronized high-voltage cortical discharges. During chronic DBS, the stimulation is applied constantly to the epileptogenic focus, regardless of the area's own discharge.

However, there is some evidence that stimulation only in response to epileptiform activity might be more effective. This “closed-loop” stimulation would require a device that could read and analyze brain waves and then “decide” what type of stimulation to deliver.

Early external devices were tested in small numbers of patients in the late 1990s and early 2000s. More recently, a California-based company, NeuroPace Inc., has developed the RNS System, which includes fully implantable intracranial components as well as external products, Dr. Boon said.

The device consists of an implanted neurostimulator with one or two strip leads that can be placed in different areas of the brain to allow activity to be monitored and controlled.

An external programming device allows the stimulator to detect predetermined electrographic patterns; the physician can also program the type of response that the device delivers.

MADRID – Deep brain stimulation shows considerable promise for reducing intractable seizures in patients who are not candidates for epilepsy surgery, even though there have been few large-scale controlled trials to back up the practice.

“We have no idea what the best stimulation parameters are, we don't know whether to stimulate in response to epileptiform activity or continuously, and, of course, the search for the optimal target is ongoing,” Dr. Paul Boon said at the annual congress of the European Federation of Neurological Societies.

“Most of our information has come from uncontrolled studies and case reports, which included about 115 people worldwide.”

Now, data from three new or upcoming studies might help shed light on some of these questions, said Dr. Boon of University Hospital Ghent (Belgium), where he and his colleagues are leaders in researching an epilepsy application for DBS.

Some of the earliest studies, in the 1980s and early 1990s, used the electrodes in the brain's cerebellar regions, but with very little effect, so the cerebellum is no longer considered a target. The caudate nucleus and centromedial nucleus of the thalamus have also been examined as possible targets, but in very small numbers of patients and with varying results, said Dr. Boon.

The most promising approach to date is bilateral stimulation of the anterior thalamic nucleus, he said. Early uncontrolled studies of this application had small patient numbers, but their success led to the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy trial of 110 patients with medically refractory partial-onset seizures.

All of the patients received the implants; for the first 3 months, only half of the patient had their stimulators turned on. After this blinded treatment phase, all of the patients received neurostimulation. By way of detailing his financial conflicts of interest, Dr. Boon said in an interview that Medtronic Inc., the company that makes DBS hardware, has been and is providing devices and electrodes in support of the pilot trial, and has provided an educational grant.

The medial temporal lobe and the hippocampus are other potential targets. Last year, Dr. Boon and his colleagues published a study of 12 patients with refractory temporal lobe epilepsy, who were also candidates for surgery. Instead of implanting recording electrodes during the presurgical period, they implanted DBS electrodes in the medial temporal lobe.

“We aimed to adjust the simulation parameters to get a 50% reduction in spikes for 7 consecutive days,” he said. “If the patient achieved that, then we went to chronic stimulation, and if they did not achieve that, then we adjusted the parameters until we met those criteria. If the patient still didn't achieve the reduction, then we removed the electrodes and proceeded to surgery.”

Of the 12 patients, 10 underwent long-term DBS and 2 had the resection. After a mean follow-up of 31 months, both of the surgical patients were seizure free. One of the DBS patients had a seizure reduction of more than 90%; five had a reduction of at least 50%, and two had a reduction of 30%–40% (Epilepsia 2007;48:1551–60).

“We got a 70% response rate, with no significant adverse events or changes in memory,” he said. “This shows that DBS of the medial temporal lobe is safe, feasible, and effective.”

Dr. Boon and his group are also seeking to recruit 45 patients for a study comparing DBS of the hippocampus with medial temporal lobe resection or with hippocampal DBS delayed for 6 months after implantation. The 1-year trial will also be sponsored by Medtronic.

Researchers believe that DBS controls seizures by desynchronizing synchronized high-voltage cortical discharges. During chronic DBS, the stimulation is applied constantly to the epileptogenic focus, regardless of the area's own discharge.

However, there is some evidence that stimulation only in response to epileptiform activity might be more effective. This “closed-loop” stimulation would require a device that could read and analyze brain waves and then “decide” what type of stimulation to deliver.

Early external devices were tested in small numbers of patients in the late 1990s and early 2000s. More recently, a California-based company, NeuroPace Inc., has developed the RNS System, which includes fully implantable intracranial components as well as external products, Dr. Boon said.

The device consists of an implanted neurostimulator with one or two strip leads that can be placed in different areas of the brain to allow activity to be monitored and controlled.

An external programming device allows the stimulator to detect predetermined electrographic patterns; the physician can also program the type of response that the device delivers.

MADRID – Deep brain stimulation shows considerable promise for reducing intractable seizures in patients who are not candidates for epilepsy surgery, even though there have been few large-scale controlled trials to back up the practice.

“We have no idea what the best stimulation parameters are, we don't know whether to stimulate in response to epileptiform activity or continuously, and, of course, the search for the optimal target is ongoing,” Dr. Paul Boon said at the annual congress of the European Federation of Neurological Societies.

“Most of our information has come from uncontrolled studies and case reports, which included about 115 people worldwide.”

Now, data from three new or upcoming studies might help shed light on some of these questions, said Dr. Boon of University Hospital Ghent (Belgium), where he and his colleagues are leaders in researching an epilepsy application for DBS.

Some of the earliest studies, in the 1980s and early 1990s, used the electrodes in the brain's cerebellar regions, but with very little effect, so the cerebellum is no longer considered a target. The caudate nucleus and centromedial nucleus of the thalamus have also been examined as possible targets, but in very small numbers of patients and with varying results, said Dr. Boon.

The most promising approach to date is bilateral stimulation of the anterior thalamic nucleus, he said. Early uncontrolled studies of this application had small patient numbers, but their success led to the Stimulation of the Anterior Nucleus of the Thalamus for Epilepsy trial of 110 patients with medically refractory partial-onset seizures.

All of the patients received the implants; for the first 3 months, only half of the patient had their stimulators turned on. After this blinded treatment phase, all of the patients received neurostimulation. By way of detailing his financial conflicts of interest, Dr. Boon said in an interview that Medtronic Inc., the company that makes DBS hardware, has been and is providing devices and electrodes in support of the pilot trial, and has provided an educational grant.

The medial temporal lobe and the hippocampus are other potential targets. Last year, Dr. Boon and his colleagues published a study of 12 patients with refractory temporal lobe epilepsy, who were also candidates for surgery. Instead of implanting recording electrodes during the presurgical period, they implanted DBS electrodes in the medial temporal lobe.

“We aimed to adjust the simulation parameters to get a 50% reduction in spikes for 7 consecutive days,” he said. “If the patient achieved that, then we went to chronic stimulation, and if they did not achieve that, then we adjusted the parameters until we met those criteria. If the patient still didn't achieve the reduction, then we removed the electrodes and proceeded to surgery.”

Of the 12 patients, 10 underwent long-term DBS and 2 had the resection. After a mean follow-up of 31 months, both of the surgical patients were seizure free. One of the DBS patients had a seizure reduction of more than 90%; five had a reduction of at least 50%, and two had a reduction of 30%–40% (Epilepsia 2007;48:1551–60).

“We got a 70% response rate, with no significant adverse events or changes in memory,” he said. “This shows that DBS of the medial temporal lobe is safe, feasible, and effective.”

Dr. Boon and his group are also seeking to recruit 45 patients for a study comparing DBS of the hippocampus with medial temporal lobe resection or with hippocampal DBS delayed for 6 months after implantation. The 1-year trial will also be sponsored by Medtronic.

Researchers believe that DBS controls seizures by desynchronizing synchronized high-voltage cortical discharges. During chronic DBS, the stimulation is applied constantly to the epileptogenic focus, regardless of the area's own discharge.

However, there is some evidence that stimulation only in response to epileptiform activity might be more effective. This “closed-loop” stimulation would require a device that could read and analyze brain waves and then “decide” what type of stimulation to deliver.

Early external devices were tested in small numbers of patients in the late 1990s and early 2000s. More recently, a California-based company, NeuroPace Inc., has developed the RNS System, which includes fully implantable intracranial components as well as external products, Dr. Boon said.

The device consists of an implanted neurostimulator with one or two strip leads that can be placed in different areas of the brain to allow activity to be monitored and controlled.

An external programming device allows the stimulator to detect predetermined electrographic patterns; the physician can also program the type of response that the device delivers.

The first family-based genome-wide association study for Alzheimer's disease has identified four new genes that may significantly affect the risk of developing the disease.

The gene with the strongest association lies on chromosome 14, not far from the early-onset familial Alzheimer's gene presenilin-1, Dr. Rudolph Tanzi said in an interview. “What we don't know yet, is whether this is a coincidence or whether there is some interaction going on with that gene.”

Dr. Tanzi, director of the Massachusetts General Hospital's genetics and aging research unit in Boston, and his coinvestigators published the results of their study in the November issue of the American Journal of Human Genetics (doi:10.1016/j.ajhg.2008.10.008).

The initial portion of the study included a genome-wide screen of more than 1,400 DNA samples taken from 410 families with at least three Alzheimer's-affected members. This analysis revealed five candidate genes: one closely linked to the apolipoprotein E gene, variations of which are associated with late-onset Alzheimer's, and four previously unknown single nucleotide polymorphisms (SNPs), said Dr. Tanzi.

“We took these top hits and screened another 900 families for them, and after correcting for all the possible variables, we still had overall genome-wide significance with all of them, with the best hit in the novel chromosome 14 gene.”

The second-best-associated gene is involved in innate immune response. “This was quite a surprise, to see a gene involved with response to bacterial and viral infection implicated in Alzheimer's,” Dr. Tanzi said. “This now has us thinking more about the possible role of infection in Alzheimer's etiology.”

The third novel SNP resides in the gene that causes spinocerebellar ataxia, a neurodegenerative movement disorder. “Although none of our Alzheimer's samples had spinocerebellar ataxia, the location of this gene near the cause of another neurodegenerative disease is interesting. Perhaps a different mutation in this gene might cause Alzheimer's,” Dr. Tanzi said.

The final SNP is located in a gene that produces a synaptic protein–a logical association given the role of synaptic dysfunction in Alzheimer's.

At this point, it's impossible to predict the extent of influence these genetic variants may confer on Alzheimer's risk, Dr. Tanzi said. “We refrain from making a big deal about odds ratios in family studies, because those numbers are only specific to those families–the odds ratio in the population at large could be less impressive. But if I had to guess, for our best hit I'd say it might end up to be a doubling of risk in the general population.”

The study opens a new door in genetic research, Dr. Tanzi said. New genome chips capable of scanning almost the entire code at once are taking some of the guesswork out of genetic studies. “Much of what we have done in the past is look for variants in a gene that we picked based on a favorite hypothesis. This adds an element of bias to your results. The beauty of this is that these results are totally unbiased. With the gene chip, you just see what falls out as significant and wait to be surprised.”

Dr. Tanzi's lab has been involved in genetic analysis of Alzheimer's since the 1980s, codiscovering all three early-onset genes out of the four total genes known for the disease. “We also learned that the four genes only account for 30% of the genetics of Alzheimer's disease,” while twin studies suggest that at least 80% of cases involve some inherited factor.

“Look at how much we've learned with only 30% of the genetics solved and imagine what we could learn if we knew the other 70%.”

The first family-based genome-wide association study for Alzheimer's disease has identified four new genes that may significantly affect the risk of developing the disease.

The gene with the strongest association lies on chromosome 14, not far from the early-onset familial Alzheimer's gene presenilin-1, Dr. Rudolph Tanzi said in an interview. “What we don't know yet, is whether this is a coincidence or whether there is some interaction going on with that gene.”

Dr. Tanzi, director of the Massachusetts General Hospital's genetics and aging research unit in Boston, and his coinvestigators published the results of their study in the November issue of the American Journal of Human Genetics (doi:10.1016/j.ajhg.2008.10.008).

The initial portion of the study included a genome-wide screen of more than 1,400 DNA samples taken from 410 families with at least three Alzheimer's-affected members. This analysis revealed five candidate genes: one closely linked to the apolipoprotein E gene, variations of which are associated with late-onset Alzheimer's, and four previously unknown single nucleotide polymorphisms (SNPs), said Dr. Tanzi.

“We took these top hits and screened another 900 families for them, and after correcting for all the possible variables, we still had overall genome-wide significance with all of them, with the best hit in the novel chromosome 14 gene.”

The second-best-associated gene is involved in innate immune response. “This was quite a surprise, to see a gene involved with response to bacterial and viral infection implicated in Alzheimer's,” Dr. Tanzi said. “This now has us thinking more about the possible role of infection in Alzheimer's etiology.”

The third novel SNP resides in the gene that causes spinocerebellar ataxia, a neurodegenerative movement disorder. “Although none of our Alzheimer's samples had spinocerebellar ataxia, the location of this gene near the cause of another neurodegenerative disease is interesting. Perhaps a different mutation in this gene might cause Alzheimer's,” Dr. Tanzi said.

The final SNP is located in a gene that produces a synaptic protein–a logical association given the role of synaptic dysfunction in Alzheimer's.

At this point, it's impossible to predict the extent of influence these genetic variants may confer on Alzheimer's risk, Dr. Tanzi said. “We refrain from making a big deal about odds ratios in family studies, because those numbers are only specific to those families–the odds ratio in the population at large could be less impressive. But if I had to guess, for our best hit I'd say it might end up to be a doubling of risk in the general population.”

The study opens a new door in genetic research, Dr. Tanzi said. New genome chips capable of scanning almost the entire code at once are taking some of the guesswork out of genetic studies. “Much of what we have done in the past is look for variants in a gene that we picked based on a favorite hypothesis. This adds an element of bias to your results. The beauty of this is that these results are totally unbiased. With the gene chip, you just see what falls out as significant and wait to be surprised.”

Dr. Tanzi's lab has been involved in genetic analysis of Alzheimer's since the 1980s, codiscovering all three early-onset genes out of the four total genes known for the disease. “We also learned that the four genes only account for 30% of the genetics of Alzheimer's disease,” while twin studies suggest that at least 80% of cases involve some inherited factor.

“Look at how much we've learned with only 30% of the genetics solved and imagine what we could learn if we knew the other 70%.”

The first family-based genome-wide association study for Alzheimer's disease has identified four new genes that may significantly affect the risk of developing the disease.

The gene with the strongest association lies on chromosome 14, not far from the early-onset familial Alzheimer's gene presenilin-1, Dr. Rudolph Tanzi said in an interview. “What we don't know yet, is whether this is a coincidence or whether there is some interaction going on with that gene.”

Dr. Tanzi, director of the Massachusetts General Hospital's genetics and aging research unit in Boston, and his coinvestigators published the results of their study in the November issue of the American Journal of Human Genetics (doi:10.1016/j.ajhg.2008.10.008).

The initial portion of the study included a genome-wide screen of more than 1,400 DNA samples taken from 410 families with at least three Alzheimer's-affected members. This analysis revealed five candidate genes: one closely linked to the apolipoprotein E gene, variations of which are associated with late-onset Alzheimer's, and four previously unknown single nucleotide polymorphisms (SNPs), said Dr. Tanzi.

“We took these top hits and screened another 900 families for them, and after correcting for all the possible variables, we still had overall genome-wide significance with all of them, with the best hit in the novel chromosome 14 gene.”

The second-best-associated gene is involved in innate immune response. “This was quite a surprise, to see a gene involved with response to bacterial and viral infection implicated in Alzheimer's,” Dr. Tanzi said. “This now has us thinking more about the possible role of infection in Alzheimer's etiology.”

The third novel SNP resides in the gene that causes spinocerebellar ataxia, a neurodegenerative movement disorder. “Although none of our Alzheimer's samples had spinocerebellar ataxia, the location of this gene near the cause of another neurodegenerative disease is interesting. Perhaps a different mutation in this gene might cause Alzheimer's,” Dr. Tanzi said.

The final SNP is located in a gene that produces a synaptic protein–a logical association given the role of synaptic dysfunction in Alzheimer's.

At this point, it's impossible to predict the extent of influence these genetic variants may confer on Alzheimer's risk, Dr. Tanzi said. “We refrain from making a big deal about odds ratios in family studies, because those numbers are only specific to those families–the odds ratio in the population at large could be less impressive. But if I had to guess, for our best hit I'd say it might end up to be a doubling of risk in the general population.”

The study opens a new door in genetic research, Dr. Tanzi said. New genome chips capable of scanning almost the entire code at once are taking some of the guesswork out of genetic studies. “Much of what we have done in the past is look for variants in a gene that we picked based on a favorite hypothesis. This adds an element of bias to your results. The beauty of this is that these results are totally unbiased. With the gene chip, you just see what falls out as significant and wait to be surprised.”

Dr. Tanzi's lab has been involved in genetic analysis of Alzheimer's since the 1980s, codiscovering all three early-onset genes out of the four total genes known for the disease. “We also learned that the four genes only account for 30% of the genetics of Alzheimer's disease,” while twin studies suggest that at least 80% of cases involve some inherited factor.

“Look at how much we've learned with only 30% of the genetics solved and imagine what we could learn if we knew the other 70%.”

CHICAGO – Methylphenidate appears to improve the symptoms of apathy in patients with early Alzheimer's, benefiting both patients and caregivers, according to a small prospective trial.

After taking the drug for 12 weeks, patients showed significantly reduced frequency and severity of apathy, while their caregivers reported significantly reduced distress, Dr. Prasad Padala said at the International Conference on Alzheimer's Disease.

“Apathy is the most common behavioral and psychiatric symptom of dementia, occurring in up to 90% of patients, and it's one of the earliest symptoms to appear,” said Dr. Padala of the University of Nebraska Medical Center, Omaha.

“Apathy also causes the caregivers a lot of stress, and it has a very high impact on functional status. Patients with apathy are three times more likely to be dependent on caregivers for their activities of daily living than are patients without apathy.”

It's thought that dysregulation of both the dopaminergic and noradrenergic systems contribute to apathy, and methylphenidate works on both of these systems.

The study enrolled 20 patients (mean age 70 years) at the Veterans Affairs Medical Center, Omaha. All had early Alzheimer's disease, with a mean Mini-Mental State Examination score of 23 and a score above 30 on the Apathy Evaluation Scale, indicating significant apathy.

At baseline, patients were assessed with the Neuropsychiatric Inventory's apathy subscale. This system scores apathy on a 1- to 4-point scale for frequency and on a 1- to 3-point scale for severity. The score is a product of the two ratings. Caregivers rate their distress on a 1–5 scale, with 5 being the greatest.

Patients were started on 5 mg methylphenidate twice daily, and titrated up to 10 mg twice daily. Follow-up visits were conducted at 4, 8, and 12 weeks. After 12 weeks of treatment, patients significantly improved in their total item score from baseline (5 vs. 1.6), as well as their frequency/severity score (9 vs. 2). Caregiver distress also improved significantly, decreasing from 3.25 to 1.

“Caregivers noted substantial improvements in the patients, such as increased energy, spontaneity, motivation, and ambition,” Dr. Padala said at the meeting, sponsored by the Alzheimer's Association.

Two patients needed reductions in methylphenidate dosing: one for loss of appetite and the other because of a blood pressure increase, said Dr. Padala, who had no financial disclosures with regard to the study drug.

CHICAGO – Methylphenidate appears to improve the symptoms of apathy in patients with early Alzheimer's, benefiting both patients and caregivers, according to a small prospective trial.

After taking the drug for 12 weeks, patients showed significantly reduced frequency and severity of apathy, while their caregivers reported significantly reduced distress, Dr. Prasad Padala said at the International Conference on Alzheimer's Disease.

“Apathy is the most common behavioral and psychiatric symptom of dementia, occurring in up to 90% of patients, and it's one of the earliest symptoms to appear,” said Dr. Padala of the University of Nebraska Medical Center, Omaha.

“Apathy also causes the caregivers a lot of stress, and it has a very high impact on functional status. Patients with apathy are three times more likely to be dependent on caregivers for their activities of daily living than are patients without apathy.”

It's thought that dysregulation of both the dopaminergic and noradrenergic systems contribute to apathy, and methylphenidate works on both of these systems.

The study enrolled 20 patients (mean age 70 years) at the Veterans Affairs Medical Center, Omaha. All had early Alzheimer's disease, with a mean Mini-Mental State Examination score of 23 and a score above 30 on the Apathy Evaluation Scale, indicating significant apathy.

At baseline, patients were assessed with the Neuropsychiatric Inventory's apathy subscale. This system scores apathy on a 1- to 4-point scale for frequency and on a 1- to 3-point scale for severity. The score is a product of the two ratings. Caregivers rate their distress on a 1–5 scale, with 5 being the greatest.

Patients were started on 5 mg methylphenidate twice daily, and titrated up to 10 mg twice daily. Follow-up visits were conducted at 4, 8, and 12 weeks. After 12 weeks of treatment, patients significantly improved in their total item score from baseline (5 vs. 1.6), as well as their frequency/severity score (9 vs. 2). Caregiver distress also improved significantly, decreasing from 3.25 to 1.

“Caregivers noted substantial improvements in the patients, such as increased energy, spontaneity, motivation, and ambition,” Dr. Padala said at the meeting, sponsored by the Alzheimer's Association.

Two patients needed reductions in methylphenidate dosing: one for loss of appetite and the other because of a blood pressure increase, said Dr. Padala, who had no financial disclosures with regard to the study drug.

CHICAGO – Methylphenidate appears to improve the symptoms of apathy in patients with early Alzheimer's, benefiting both patients and caregivers, according to a small prospective trial.

After taking the drug for 12 weeks, patients showed significantly reduced frequency and severity of apathy, while their caregivers reported significantly reduced distress, Dr. Prasad Padala said at the International Conference on Alzheimer's Disease.

“Apathy is the most common behavioral and psychiatric symptom of dementia, occurring in up to 90% of patients, and it's one of the earliest symptoms to appear,” said Dr. Padala of the University of Nebraska Medical Center, Omaha.

“Apathy also causes the caregivers a lot of stress, and it has a very high impact on functional status. Patients with apathy are three times more likely to be dependent on caregivers for their activities of daily living than are patients without apathy.”

It's thought that dysregulation of both the dopaminergic and noradrenergic systems contribute to apathy, and methylphenidate works on both of these systems.

The study enrolled 20 patients (mean age 70 years) at the Veterans Affairs Medical Center, Omaha. All had early Alzheimer's disease, with a mean Mini-Mental State Examination score of 23 and a score above 30 on the Apathy Evaluation Scale, indicating significant apathy.

At baseline, patients were assessed with the Neuropsychiatric Inventory's apathy subscale. This system scores apathy on a 1- to 4-point scale for frequency and on a 1- to 3-point scale for severity. The score is a product of the two ratings. Caregivers rate their distress on a 1–5 scale, with 5 being the greatest.

Patients were started on 5 mg methylphenidate twice daily, and titrated up to 10 mg twice daily. Follow-up visits were conducted at 4, 8, and 12 weeks. After 12 weeks of treatment, patients significantly improved in their total item score from baseline (5 vs. 1.6), as well as their frequency/severity score (9 vs. 2). Caregiver distress also improved significantly, decreasing from 3.25 to 1.

“Caregivers noted substantial improvements in the patients, such as increased energy, spontaneity, motivation, and ambition,” Dr. Padala said at the meeting, sponsored by the Alzheimer's Association.

Two patients needed reductions in methylphenidate dosing: one for loss of appetite and the other because of a blood pressure increase, said Dr. Padala, who had no financial disclosures with regard to the study drug.

The amyloid hypothesis is not dead, but it seems to be limping a bit in the race for an Alzheimer's cure.

Some researchers who predicted 5 years ago that an antiamyloid disease-modifying therapy was imminent are now re-evaluating that optimism–including the geneticist who first suggested the pathologic link between amyloid plaque deposition and Alzheimer's disease.

“I accept that criticism of myself; it's definitely what I thought,” John Hardy, Ph.D., said in an interview. “Everything is taking a lot longer than I thought it would, there's no question about that.”

In 1991, Dr. Hardy, a professor of neuroscience at University College London, postulated that β-amyloid deposition was the root of a pathologic cascade that resulted in Alzheimer's disease. The concurrent discovery that a mutation in the amyloid precursor protein (APP) gene caused early-onset Alzheimer's, coupled with the association of plaque deposition and early Alzheimer's in Down syndrome patients, added weight to the theory (Trends Pharmicol. Sci. 1991;12:383–8). A new research boom was born.

The protein was a near-ideal therapeutic target because there are many ways to get at it: immunotherapy to break up existing plaques, compounds to prevent formation of the sticky β-amyloid-42, and antiaggregants to prevent the protein from clumping into neurotoxic plaques. But the first phase III trials of antiamyloid have brought no good news.

Tramiprosate, a β-amyloid antagonist, was the disappointment of 2007; tarenflurbil, a gamma-secretase modulator, this year's downer. And although bapineuzumab, a passive immunotherapy, made it to phase II last summer, positive findings in its phase II trial were slim. A post hoc analysis showed that some patients with mild-moderate Alzheimer's, with no genetic risk factors, had cognitive improvement after getting the vaccine.

Apparently, the finding was enough for Elan Pharmaceuticals Inc., and Wyeth Pharmaceuticals, but maybe not for Dr. Hardy. “The data right now are neither positive nor negative. At this point, the only thing we can say about bapineuzumab is that it's not going to be a miracle therapy,” he said.

A long-term follow-up study of patients enrolled in the early AN-1792 immunotherapy trial “doesn't look great for amyloid, either,” he said. The AN-1792 trial was halted early, in 2002, when some of the patients developed encephalitis after getting the vaccine. The follow-up, published last summer, showed that the vaccine did clear plaques, but that clearance did not affect cognition or survival (Lancet 2008;372:216–23).

Dr. Hardy doesn't think that slow progress on antiamyloid drugs negates the theory's basic truth, though–at least for a subset of patients. “A much more open debate is whether the same process is at work in the typical Alzheimer's patient.”

But drug companies must target this larger population to create a financially successful therapy, and lack of progress has them fidgeting, he said. “Every drug company is worried now and wondering if they should widen to other therapies, including tau-targeted drugs.”

The essential mystery of amyloid further complicates things, Dr. Hardy said: The protein has not yielded up all its secrets, despite years of research. “The thing that keeps me up at night is that we don't really know if amyloid has a function. It could be that amyloid is a response to vascular damage. We all ignore the fact that amyloid deposition occurs to a large extent in the vasculature. There must be a reason for this.”

That worry also plagues Mark A. Smith, Ph.D., professor of pathology and an Alzheimer's researcher at Case Western Reserve University, Cleveland. “We have said for a long time that amyloid is doing something important in the brain. It could be acting like a vascular sealant in areas of injury. It forms structural scaffolding for blood vessels, and if you start getting rid of that scaffold, you'll see problems in the blood-brain barrier.” This reaction probably caused the brain inflammation seen in the AN-1792 trial, he said.

Dr. Smith, a paid consultant for several companies investigating non-amyloid-related therapies, is among a minority of researchers who resist the amyloid theory. The amyloid research momentum, he said, is so strong right now that only more high-profile failures will begin to temper it. “People still can't believe it's not working, and they're waiting for the results of the phase III vaccine trial,” as well as new data on β-secretase inhibitors, theorized to reduce the buildup of plaque-forming AB-42, he said.

Dr. Rachelle Doody, director of the Alzheimer's Disease and Memory Disorders Center at Baylor College of Medicine, Houston, thinks that the failure of antiamyloid drugs illustrates not a failure of the theory, but the failure of specific drugs and possibly the failure of drug companies to follow a comprehensive and logical phase II plan.

“Companies want their drug to be labeled as a disease-modifying agent as soon as possible,” she said in an interview. And because they are going for that, they are designing phase II trials that are long and costly but don't give them all the information they need.”

Ideally, when any agent finishes phase II, there should be clear evidence that it is safe and effective in the primary end point. “Neither tramiprosate nor tarenflurbil had a clear signal in phase II, and neither did bapineuzumab, although it at least had some signal,” she said.

Companies could also modify their research track to prove first that a drug confers symptomatic benefit, and then examine its possible disease-modifying properties. That is the path Medivation Inc. is following with dimebon–the only bright note in late-stage clinical trials this year. The obscure Russian antihistamine, thought to boost mitochondrial function, succeeded where the antiamyloids failed, significantly improving cognition, behavior, and function in Alzheimer's patients, although it did not modify disease progression.

“Dimebon probably is a disease-modifying drug, but proving this requires long-term studies,” said Dr. Doody, primary investigator on the phase II trial. “But many pharmaceutical companies fear that a drug will be priced too low if they go for symptomatic approval first without the disease-modifying work up front.”

Dr. Marwan Sabbagh, chief medical and scientific officer of Sun Health Research Institute, Sun City, Ariz., suspects that researchers might be looking at antiamyloids through the wrong end of the lens. Rather than a one-step cure, the compounds may be best used in primary prevention. “The problem is, we may be approaching it too late,” he said in an interview. “By the time you clinically manifest dementia, it might be too late for the drugs to help, even if they clear the plaques.”

Dr. Rachelle Doody says the phase II trial of bapineuzumab “at least had some signal” that the agent is safe and effective. Agapito Sanchez Jr./Baylor College of Medicine

The amyloid hypothesis is not dead, but it seems to be limping a bit in the race for an Alzheimer's cure.

Some researchers who predicted 5 years ago that an antiamyloid disease-modifying therapy was imminent are now re-evaluating that optimism–including the geneticist who first suggested the pathologic link between amyloid plaque deposition and Alzheimer's disease.

“I accept that criticism of myself; it's definitely what I thought,” John Hardy, Ph.D., said in an interview. “Everything is taking a lot longer than I thought it would, there's no question about that.”

In 1991, Dr. Hardy, a professor of neuroscience at University College London, postulated that β-amyloid deposition was the root of a pathologic cascade that resulted in Alzheimer's disease. The concurrent discovery that a mutation in the amyloid precursor protein (APP) gene caused early-onset Alzheimer's, coupled with the association of plaque deposition and early Alzheimer's in Down syndrome patients, added weight to the theory (Trends Pharmicol. Sci. 1991;12:383–8). A new research boom was born.

The protein was a near-ideal therapeutic target because there are many ways to get at it: immunotherapy to break up existing plaques, compounds to prevent formation of the sticky β-amyloid-42, and antiaggregants to prevent the protein from clumping into neurotoxic plaques. But the first phase III trials of antiamyloid have brought no good news.

Tramiprosate, a β-amyloid antagonist, was the disappointment of 2007; tarenflurbil, a gamma-secretase modulator, this year's downer. And although bapineuzumab, a passive immunotherapy, made it to phase II last summer, positive findings in its phase II trial were slim. A post hoc analysis showed that some patients with mild-moderate Alzheimer's, with no genetic risk factors, had cognitive improvement after getting the vaccine.

Apparently, the finding was enough for Elan Pharmaceuticals Inc., and Wyeth Pharmaceuticals, but maybe not for Dr. Hardy. “The data right now are neither positive nor negative. At this point, the only thing we can say about bapineuzumab is that it's not going to be a miracle therapy,” he said.

A long-term follow-up study of patients enrolled in the early AN-1792 immunotherapy trial “doesn't look great for amyloid, either,” he said. The AN-1792 trial was halted early, in 2002, when some of the patients developed encephalitis after getting the vaccine. The follow-up, published last summer, showed that the vaccine did clear plaques, but that clearance did not affect cognition or survival (Lancet 2008;372:216–23).

Dr. Hardy doesn't think that slow progress on antiamyloid drugs negates the theory's basic truth, though–at least for a subset of patients. “A much more open debate is whether the same process is at work in the typical Alzheimer's patient.”

But drug companies must target this larger population to create a financially successful therapy, and lack of progress has them fidgeting, he said. “Every drug company is worried now and wondering if they should widen to other therapies, including tau-targeted drugs.”

The essential mystery of amyloid further complicates things, Dr. Hardy said: The protein has not yielded up all its secrets, despite years of research. “The thing that keeps me up at night is that we don't really know if amyloid has a function. It could be that amyloid is a response to vascular damage. We all ignore the fact that amyloid deposition occurs to a large extent in the vasculature. There must be a reason for this.”

That worry also plagues Mark A. Smith, Ph.D., professor of pathology and an Alzheimer's researcher at Case Western Reserve University, Cleveland. “We have said for a long time that amyloid is doing something important in the brain. It could be acting like a vascular sealant in areas of injury. It forms structural scaffolding for blood vessels, and if you start getting rid of that scaffold, you'll see problems in the blood-brain barrier.” This reaction probably caused the brain inflammation seen in the AN-1792 trial, he said.

Dr. Smith, a paid consultant for several companies investigating non-amyloid-related therapies, is among a minority of researchers who resist the amyloid theory. The amyloid research momentum, he said, is so strong right now that only more high-profile failures will begin to temper it. “People still can't believe it's not working, and they're waiting for the results of the phase III vaccine trial,” as well as new data on β-secretase inhibitors, theorized to reduce the buildup of plaque-forming AB-42, he said.

Dr. Rachelle Doody, director of the Alzheimer's Disease and Memory Disorders Center at Baylor College of Medicine, Houston, thinks that the failure of antiamyloid drugs illustrates not a failure of the theory, but the failure of specific drugs and possibly the failure of drug companies to follow a comprehensive and logical phase II plan.

“Companies want their drug to be labeled as a disease-modifying agent as soon as possible,” she said in an interview. And because they are going for that, they are designing phase II trials that are long and costly but don't give them all the information they need.”

Ideally, when any agent finishes phase II, there should be clear evidence that it is safe and effective in the primary end point. “Neither tramiprosate nor tarenflurbil had a clear signal in phase II, and neither did bapineuzumab, although it at least had some signal,” she said.

Companies could also modify their research track to prove first that a drug confers symptomatic benefit, and then examine its possible disease-modifying properties. That is the path Medivation Inc. is following with dimebon–the only bright note in late-stage clinical trials this year. The obscure Russian antihistamine, thought to boost mitochondrial function, succeeded where the antiamyloids failed, significantly improving cognition, behavior, and function in Alzheimer's patients, although it did not modify disease progression.

“Dimebon probably is a disease-modifying drug, but proving this requires long-term studies,” said Dr. Doody, primary investigator on the phase II trial. “But many pharmaceutical companies fear that a drug will be priced too low if they go for symptomatic approval first without the disease-modifying work up front.”

Dr. Marwan Sabbagh, chief medical and scientific officer of Sun Health Research Institute, Sun City, Ariz., suspects that researchers might be looking at antiamyloids through the wrong end of the lens. Rather than a one-step cure, the compounds may be best used in primary prevention. “The problem is, we may be approaching it too late,” he said in an interview. “By the time you clinically manifest dementia, it might be too late for the drugs to help, even if they clear the plaques.”

Dr. Rachelle Doody says the phase II trial of bapineuzumab “at least had some signal” that the agent is safe and effective. Agapito Sanchez Jr./Baylor College of Medicine

The amyloid hypothesis is not dead, but it seems to be limping a bit in the race for an Alzheimer's cure.

Some researchers who predicted 5 years ago that an antiamyloid disease-modifying therapy was imminent are now re-evaluating that optimism–including the geneticist who first suggested the pathologic link between amyloid plaque deposition and Alzheimer's disease.

“I accept that criticism of myself; it's definitely what I thought,” John Hardy, Ph.D., said in an interview. “Everything is taking a lot longer than I thought it would, there's no question about that.”

In 1991, Dr. Hardy, a professor of neuroscience at University College London, postulated that β-amyloid deposition was the root of a pathologic cascade that resulted in Alzheimer's disease. The concurrent discovery that a mutation in the amyloid precursor protein (APP) gene caused early-onset Alzheimer's, coupled with the association of plaque deposition and early Alzheimer's in Down syndrome patients, added weight to the theory (Trends Pharmicol. Sci. 1991;12:383–8). A new research boom was born.

The protein was a near-ideal therapeutic target because there are many ways to get at it: immunotherapy to break up existing plaques, compounds to prevent formation of the sticky β-amyloid-42, and antiaggregants to prevent the protein from clumping into neurotoxic plaques. But the first phase III trials of antiamyloid have brought no good news.

Tramiprosate, a β-amyloid antagonist, was the disappointment of 2007; tarenflurbil, a gamma-secretase modulator, this year's downer. And although bapineuzumab, a passive immunotherapy, made it to phase II last summer, positive findings in its phase II trial were slim. A post hoc analysis showed that some patients with mild-moderate Alzheimer's, with no genetic risk factors, had cognitive improvement after getting the vaccine.

Apparently, the finding was enough for Elan Pharmaceuticals Inc., and Wyeth Pharmaceuticals, but maybe not for Dr. Hardy. “The data right now are neither positive nor negative. At this point, the only thing we can say about bapineuzumab is that it's not going to be a miracle therapy,” he said.

A long-term follow-up study of patients enrolled in the early AN-1792 immunotherapy trial “doesn't look great for amyloid, either,” he said. The AN-1792 trial was halted early, in 2002, when some of the patients developed encephalitis after getting the vaccine. The follow-up, published last summer, showed that the vaccine did clear plaques, but that clearance did not affect cognition or survival (Lancet 2008;372:216–23).

Dr. Hardy doesn't think that slow progress on antiamyloid drugs negates the theory's basic truth, though–at least for a subset of patients. “A much more open debate is whether the same process is at work in the typical Alzheimer's patient.”

But drug companies must target this larger population to create a financially successful therapy, and lack of progress has them fidgeting, he said. “Every drug company is worried now and wondering if they should widen to other therapies, including tau-targeted drugs.”

The essential mystery of amyloid further complicates things, Dr. Hardy said: The protein has not yielded up all its secrets, despite years of research. “The thing that keeps me up at night is that we don't really know if amyloid has a function. It could be that amyloid is a response to vascular damage. We all ignore the fact that amyloid deposition occurs to a large extent in the vasculature. There must be a reason for this.”

That worry also plagues Mark A. Smith, Ph.D., professor of pathology and an Alzheimer's researcher at Case Western Reserve University, Cleveland. “We have said for a long time that amyloid is doing something important in the brain. It could be acting like a vascular sealant in areas of injury. It forms structural scaffolding for blood vessels, and if you start getting rid of that scaffold, you'll see problems in the blood-brain barrier.” This reaction probably caused the brain inflammation seen in the AN-1792 trial, he said.

Dr. Smith, a paid consultant for several companies investigating non-amyloid-related therapies, is among a minority of researchers who resist the amyloid theory. The amyloid research momentum, he said, is so strong right now that only more high-profile failures will begin to temper it. “People still can't believe it's not working, and they're waiting for the results of the phase III vaccine trial,” as well as new data on β-secretase inhibitors, theorized to reduce the buildup of plaque-forming AB-42, he said.

Dr. Rachelle Doody, director of the Alzheimer's Disease and Memory Disorders Center at Baylor College of Medicine, Houston, thinks that the failure of antiamyloid drugs illustrates not a failure of the theory, but the failure of specific drugs and possibly the failure of drug companies to follow a comprehensive and logical phase II plan.

“Companies want their drug to be labeled as a disease-modifying agent as soon as possible,” she said in an interview. And because they are going for that, they are designing phase II trials that are long and costly but don't give them all the information they need.”

Ideally, when any agent finishes phase II, there should be clear evidence that it is safe and effective in the primary end point. “Neither tramiprosate nor tarenflurbil had a clear signal in phase II, and neither did bapineuzumab, although it at least had some signal,” she said.

Companies could also modify their research track to prove first that a drug confers symptomatic benefit, and then examine its possible disease-modifying properties. That is the path Medivation Inc. is following with dimebon–the only bright note in late-stage clinical trials this year. The obscure Russian antihistamine, thought to boost mitochondrial function, succeeded where the antiamyloids failed, significantly improving cognition, behavior, and function in Alzheimer's patients, although it did not modify disease progression.

“Dimebon probably is a disease-modifying drug, but proving this requires long-term studies,” said Dr. Doody, primary investigator on the phase II trial. “But many pharmaceutical companies fear that a drug will be priced too low if they go for symptomatic approval first without the disease-modifying work up front.”

Dr. Marwan Sabbagh, chief medical and scientific officer of Sun Health Research Institute, Sun City, Ariz., suspects that researchers might be looking at antiamyloids through the wrong end of the lens. Rather than a one-step cure, the compounds may be best used in primary prevention. “The problem is, we may be approaching it too late,” he said in an interview. “By the time you clinically manifest dementia, it might be too late for the drugs to help, even if they clear the plaques.”

Dr. Rachelle Doody says the phase II trial of bapineuzumab “at least had some signal” that the agent is safe and effective. Agapito Sanchez Jr./Baylor College of Medicine

BARCELONA — The antidepressants milnacipran and trazodone appear to relieve pain and improve sleep and overall quality of life for fibromyalgia patients.

Neither drug is approved in the United States for fibromyalgia, but the Food and Drug Administration is considering a New Drug Application for milnacipran jointly submitted by Forest Laboratories Inc. and Cypress Bioscience, Anne Cazorla said at the annual congress of the European College of Neuropsychopharmacology.

“If this is approved, as we expect, then U.S. physicians will have a third approved choice for treating patients with fibromyalgia,” said Ms. Cazorla, a manager with Pierre-Fabre Medicament, Boulogne, France, developer of the drug.

The results of the large European randomized, controlled trial were presented in a poster. The mean age of the 884 patients was 49 years; 94% were female. They were randomized to placebo or 200 mg/day milnacipran.

Patients taking milnacipran reported significant improvements in pain, quality of life, fatigue, sleep quality, and cognition.

“For all parameters, the efficacy of milnacipran vs. placebo was observed as soon as the first on-treatment assessment visit at week 4 and was maintained up to the end of treatment,” wrote principal investigator Dr. Jaime C. Branco, chief of rheumatology at the Hospital Egas Moniz, Lisbon.

Trazodone, a drug fibromyalgia patients usually receive to improve sleep, also appears to have an impact on a wide range of fibromyalgia symptoms, Rocio Molina-Barea concluded in another poster. But the drug's side effects made the researcher question its clinical usefulness in fibromyalgia.

Patients who received the drug had an “unusually high frequency of palpitations,” wrote Mr. Molina-Barea, a researcher at the University of Granada, Spain. “Globally, our data do seem to support the use of trazodone in fibromyalgia management.”

The 12-week open-label study included 44 patients with a mean age of 50 years. Patients were started on 25 mg trazodone given at bedtime; the final dose ranged from 50 to 300 mg/day.

By the study's end, patients experienced significant improvements in sleep, pain, and global pain interference with daily activities. Both depression and anxiety showed significant improvements.

At the end of the study, 51% of patients reported mild improvement and 15% reported much or very much improvement.

Mr. Molina-Barea reported that he had no conflicts to declare.

BARCELONA — The antidepressants milnacipran and trazodone appear to relieve pain and improve sleep and overall quality of life for fibromyalgia patients.

Neither drug is approved in the United States for fibromyalgia, but the Food and Drug Administration is considering a New Drug Application for milnacipran jointly submitted by Forest Laboratories Inc. and Cypress Bioscience, Anne Cazorla said at the annual congress of the European College of Neuropsychopharmacology.

“If this is approved, as we expect, then U.S. physicians will have a third approved choice for treating patients with fibromyalgia,” said Ms. Cazorla, a manager with Pierre-Fabre Medicament, Boulogne, France, developer of the drug.

The results of the large European randomized, controlled trial were presented in a poster. The mean age of the 884 patients was 49 years; 94% were female. They were randomized to placebo or 200 mg/day milnacipran.

Patients taking milnacipran reported significant improvements in pain, quality of life, fatigue, sleep quality, and cognition.

“For all parameters, the efficacy of milnacipran vs. placebo was observed as soon as the first on-treatment assessment visit at week 4 and was maintained up to the end of treatment,” wrote principal investigator Dr. Jaime C. Branco, chief of rheumatology at the Hospital Egas Moniz, Lisbon.

Trazodone, a drug fibromyalgia patients usually receive to improve sleep, also appears to have an impact on a wide range of fibromyalgia symptoms, Rocio Molina-Barea concluded in another poster. But the drug's side effects made the researcher question its clinical usefulness in fibromyalgia.

Patients who received the drug had an “unusually high frequency of palpitations,” wrote Mr. Molina-Barea, a researcher at the University of Granada, Spain. “Globally, our data do seem to support the use of trazodone in fibromyalgia management.”

The 12-week open-label study included 44 patients with a mean age of 50 years. Patients were started on 25 mg trazodone given at bedtime; the final dose ranged from 50 to 300 mg/day.

By the study's end, patients experienced significant improvements in sleep, pain, and global pain interference with daily activities. Both depression and anxiety showed significant improvements.

At the end of the study, 51% of patients reported mild improvement and 15% reported much or very much improvement.

Mr. Molina-Barea reported that he had no conflicts to declare.

BARCELONA — The antidepressants milnacipran and trazodone appear to relieve pain and improve sleep and overall quality of life for fibromyalgia patients.

Neither drug is approved in the United States for fibromyalgia, but the Food and Drug Administration is considering a New Drug Application for milnacipran jointly submitted by Forest Laboratories Inc. and Cypress Bioscience, Anne Cazorla said at the annual congress of the European College of Neuropsychopharmacology.

“If this is approved, as we expect, then U.S. physicians will have a third approved choice for treating patients with fibromyalgia,” said Ms. Cazorla, a manager with Pierre-Fabre Medicament, Boulogne, France, developer of the drug.

The results of the large European randomized, controlled trial were presented in a poster. The mean age of the 884 patients was 49 years; 94% were female. They were randomized to placebo or 200 mg/day milnacipran.

Patients taking milnacipran reported significant improvements in pain, quality of life, fatigue, sleep quality, and cognition.

“For all parameters, the efficacy of milnacipran vs. placebo was observed as soon as the first on-treatment assessment visit at week 4 and was maintained up to the end of treatment,” wrote principal investigator Dr. Jaime C. Branco, chief of rheumatology at the Hospital Egas Moniz, Lisbon.

Trazodone, a drug fibromyalgia patients usually receive to improve sleep, also appears to have an impact on a wide range of fibromyalgia symptoms, Rocio Molina-Barea concluded in another poster. But the drug's side effects made the researcher question its clinical usefulness in fibromyalgia.

Patients who received the drug had an “unusually high frequency of palpitations,” wrote Mr. Molina-Barea, a researcher at the University of Granada, Spain. “Globally, our data do seem to support the use of trazodone in fibromyalgia management.”

The 12-week open-label study included 44 patients with a mean age of 50 years. Patients were started on 25 mg trazodone given at bedtime; the final dose ranged from 50 to 300 mg/day.

By the study's end, patients experienced significant improvements in sleep, pain, and global pain interference with daily activities. Both depression and anxiety showed significant improvements.

At the end of the study, 51% of patients reported mild improvement and 15% reported much or very much improvement.

Mr. Molina-Barea reported that he had no conflicts to declare.

Psychological distress is a significant driver of cardiovascular disease, mostly because of poor health behaviors associated with chronic stress, according to the findings of a prospective study.

Psychologically distressed individuals were at a significantly elevated risk of having a stroke, heart attack, and invasive cardiovascular interventions. And the relationship between stress and cardiovascular disease, in particular, was a linear one. However, most of the relationship between distress and disease was apparently caused by poor health behaviors, Mark Hamer, Ph.D., of University College London, and his colleagues reported.

“Our data suggest that the behavioral factors of smoking and physical activity made the largest contribution to increased risk, with C-reactive protein and hypertension making a modest contribution,” the investigators wrote (J. Am. Coll. Cardiol. 2008;52:2156–62).

The team analyzed data from the Scottish Health Survey, a national survey that includes a representative sample of all households in Scotland. The analysis included data from the 1998 and 2003 cohorts of 6,576 adults aged 30 years and older, none of whom had cardiovascular disease at baseline. The baseline assessment included demographics, health behaviors, and a 12-item measure of psychological distress.

The mean follow-up time was 7 years; measured outcomes (MI, coronary artery bypass, percutaneous coronary angioplasty, stroke, and heart failure) were assessed from records contained in the national patient database.

At baseline, 15% of participants were classified as psychologically distressed. Compared with nondistressed individuals, they were younger and more likely to be female, to have poorer health behaviors, to have hypertension, and to have higher levels of inflammatory and hemostatic markers.

A multivariate analysis determined that smoking, physical activity, alcohol consumption, C-reactive protein, and hypertension were significantly associated with being psychologically distressed.

After 7 years, there were 223 cardiovascular events; 63 were fatal. Psychologically distressed individuals were 54% more likely to have experienced an event than were nondistressed participants. With every standard deviation increment in the health questionnaire score indicating psychological distress, the investigators found a 7% increase in the risk of an event, even after adjusting for age and gender.

Further analysis concluded that 83% of the association between distress and disease could be explained by health behaviors, inflammatory markers, or hypertension. “When behavioral factors were modeled separately, smoking accounted for 41%, physical activity for 22%, and alcohol for about 2% of the variance,” the investigators wrote.

“The further addition of pathophysiological factors accounted for a further modest proportion of the variance (hypertension explained 13% and CRP, 5%).”

The associations were similar among men and women, although weaker in older participants than in younger ones.

There were 247 deaths of any cause during the follow-up period. The investigators found that participants with psychological distress were 88% more likely than were nondistressed individuals to have died, even after adjustment for age, gender, and socioeconomic status. The risk was still elevated, although attenuated, after adjustment for behavioral and pathopsychological risk factors (hazard ratio 1.36).

The findings should spur providers to adopt an integrated approach to cardiovascular disease prevention strategies, Dr. Roland von Känel wrote in a commentary (J. Am. Coll. Cardiol. 2008;52:2163–5).

“Specifically, behavioral interventions targeting smoking cessation and increasing physical exercise, as well as blood pressure-lowering techniques and inflammation-lowering relaxation techniques, are best delivered in combination with psychotherapeutic and psychopharmacologic means aimed at directly alleviating psychological distress,” wrote Dr. von Känel of the University Hospital Bern (Switzerland).

Psychological distress is a significant driver of cardiovascular disease, mostly because of poor health behaviors associated with chronic stress, according to the findings of a prospective study.

Psychologically distressed individuals were at a significantly elevated risk of having a stroke, heart attack, and invasive cardiovascular interventions. And the relationship between stress and cardiovascular disease, in particular, was a linear one. However, most of the relationship between distress and disease was apparently caused by poor health behaviors, Mark Hamer, Ph.D., of University College London, and his colleagues reported.

“Our data suggest that the behavioral factors of smoking and physical activity made the largest contribution to increased risk, with C-reactive protein and hypertension making a modest contribution,” the investigators wrote (J. Am. Coll. Cardiol. 2008;52:2156–62).

The team analyzed data from the Scottish Health Survey, a national survey that includes a representative sample of all households in Scotland. The analysis included data from the 1998 and 2003 cohorts of 6,576 adults aged 30 years and older, none of whom had cardiovascular disease at baseline. The baseline assessment included demographics, health behaviors, and a 12-item measure of psychological distress.

The mean follow-up time was 7 years; measured outcomes (MI, coronary artery bypass, percutaneous coronary angioplasty, stroke, and heart failure) were assessed from records contained in the national patient database.

At baseline, 15% of participants were classified as psychologically distressed. Compared with nondistressed individuals, they were younger and more likely to be female, to have poorer health behaviors, to have hypertension, and to have higher levels of inflammatory and hemostatic markers.

A multivariate analysis determined that smoking, physical activity, alcohol consumption, C-reactive protein, and hypertension were significantly associated with being psychologically distressed.

After 7 years, there were 223 cardiovascular events; 63 were fatal. Psychologically distressed individuals were 54% more likely to have experienced an event than were nondistressed participants. With every standard deviation increment in the health questionnaire score indicating psychological distress, the investigators found a 7% increase in the risk of an event, even after adjusting for age and gender.

Further analysis concluded that 83% of the association between distress and disease could be explained by health behaviors, inflammatory markers, or hypertension. “When behavioral factors were modeled separately, smoking accounted for 41%, physical activity for 22%, and alcohol for about 2% of the variance,” the investigators wrote.

“The further addition of pathophysiological factors accounted for a further modest proportion of the variance (hypertension explained 13% and CRP, 5%).”

The associations were similar among men and women, although weaker in older participants than in younger ones.

There were 247 deaths of any cause during the follow-up period. The investigators found that participants with psychological distress were 88% more likely than were nondistressed individuals to have died, even after adjustment for age, gender, and socioeconomic status. The risk was still elevated, although attenuated, after adjustment for behavioral and pathopsychological risk factors (hazard ratio 1.36).

The findings should spur providers to adopt an integrated approach to cardiovascular disease prevention strategies, Dr. Roland von Känel wrote in a commentary (J. Am. Coll. Cardiol. 2008;52:2163–5).

“Specifically, behavioral interventions targeting smoking cessation and increasing physical exercise, as well as blood pressure-lowering techniques and inflammation-lowering relaxation techniques, are best delivered in combination with psychotherapeutic and psychopharmacologic means aimed at directly alleviating psychological distress,” wrote Dr. von Känel of the University Hospital Bern (Switzerland).

Psychological distress is a significant driver of cardiovascular disease, mostly because of poor health behaviors associated with chronic stress, according to the findings of a prospective study.

Psychologically distressed individuals were at a significantly elevated risk of having a stroke, heart attack, and invasive cardiovascular interventions. And the relationship between stress and cardiovascular disease, in particular, was a linear one. However, most of the relationship between distress and disease was apparently caused by poor health behaviors, Mark Hamer, Ph.D., of University College London, and his colleagues reported.

“Our data suggest that the behavioral factors of smoking and physical activity made the largest contribution to increased risk, with C-reactive protein and hypertension making a modest contribution,” the investigators wrote (J. Am. Coll. Cardiol. 2008;52:2156–62).

The team analyzed data from the Scottish Health Survey, a national survey that includes a representative sample of all households in Scotland. The analysis included data from the 1998 and 2003 cohorts of 6,576 adults aged 30 years and older, none of whom had cardiovascular disease at baseline. The baseline assessment included demographics, health behaviors, and a 12-item measure of psychological distress.

The mean follow-up time was 7 years; measured outcomes (MI, coronary artery bypass, percutaneous coronary angioplasty, stroke, and heart failure) were assessed from records contained in the national patient database.

At baseline, 15% of participants were classified as psychologically distressed. Compared with nondistressed individuals, they were younger and more likely to be female, to have poorer health behaviors, to have hypertension, and to have higher levels of inflammatory and hemostatic markers.

A multivariate analysis determined that smoking, physical activity, alcohol consumption, C-reactive protein, and hypertension were significantly associated with being psychologically distressed.

After 7 years, there were 223 cardiovascular events; 63 were fatal. Psychologically distressed individuals were 54% more likely to have experienced an event than were nondistressed participants. With every standard deviation increment in the health questionnaire score indicating psychological distress, the investigators found a 7% increase in the risk of an event, even after adjusting for age and gender.

Further analysis concluded that 83% of the association between distress and disease could be explained by health behaviors, inflammatory markers, or hypertension. “When behavioral factors were modeled separately, smoking accounted for 41%, physical activity for 22%, and alcohol for about 2% of the variance,” the investigators wrote.

“The further addition of pathophysiological factors accounted for a further modest proportion of the variance (hypertension explained 13% and CRP, 5%).”

The associations were similar among men and women, although weaker in older participants than in younger ones.

There were 247 deaths of any cause during the follow-up period. The investigators found that participants with psychological distress were 88% more likely than were nondistressed individuals to have died, even after adjustment for age, gender, and socioeconomic status. The risk was still elevated, although attenuated, after adjustment for behavioral and pathopsychological risk factors (hazard ratio 1.36).

The findings should spur providers to adopt an integrated approach to cardiovascular disease prevention strategies, Dr. Roland von Känel wrote in a commentary (J. Am. Coll. Cardiol. 2008;52:2163–5).

“Specifically, behavioral interventions targeting smoking cessation and increasing physical exercise, as well as blood pressure-lowering techniques and inflammation-lowering relaxation techniques, are best delivered in combination with psychotherapeutic and psychopharmacologic means aimed at directly alleviating psychological distress,” wrote Dr. von Känel of the University Hospital Bern (Switzerland).

Prophylactic antibiotics don't appear to protect children with a first febrile urinary tract infection from a recurrence, whether or not they have primary, nonsevere vesicoureteral reflux.

“Our study shows that prophylaxis does not reduce the rate of febrile urinary tract infection recurrence during the 12 months after the first episode,” wrote Dr. Giovanni Montini of Padua (Italy) University, and his colleagues (Pediatrics 2008;122:1064-71).

The randomized controlled trial was conducted at 22 centers and included 338 patients (mean age 15 months); 69% were girls. All the children received antibiotic treatment for their initial urinary tract infection (UTI), and were placed on prophylactic treatment until a voiding cystourethrogram was conducted.

After the test, children were randomized to either no prophylaxis or to prophylaxis with either co-trimoxazole 15 mg/kg a day or co-amoxiclav 15 mg/kg a day, for 12 months. They underwent monthly urine cultures for the first 6 months, and then every other month during the study period. At the end of the study, they all underwent a 99-mTc dimercaptosuccinic acid scan to determine the extent of any renal scarring.

Recurrent febrile UTIs occurred in 12 (9%) of the control group patients and in 15 (7%) of the prophylaxis group patients—not a significant difference. The difference remained nonsignificant even when the two groups were stratified by degree of vesicoureteral reflux (VUR). Recurrence rates among those with VUR grade I were 9% in the control group vs. 5% in the prophylaxis group. The rates in those with VUR II were 9% in the control group and 8% in the prophylaxis group. Among those with VUR III, the rate of recurrence was 43% in the prophylaxis group and 23% in the control group, although the difference was not significant.

In a bivariate analysis, younger age and VUR grade were associated with recurrence. The mean age among patients with recurrence was 7 months, compared with 15 months among those without recurrence. The rate of recurrence increased with VUR grade, from 4% among patients without VUR to 7% in those with VUR I, 9% of those with VUR II, and 30% of those with VUR III.

Most of the children (87%) underwent the renal scan at the end of the follow-up period. A new renal scar occurred in only four patients—just over 1%. Two scars were found in each treatment group.

During the study, 2,422 urinalyses were performed. Most of the 27 recurrences were from Escherichia coli infections (70%). Other infective agents included Proteus mirabilis and Enterobacter (7% each), and Pseudomonas aeruginosa, Klebsiella pneumoniae, and Citrobacter (4% each).

Antibiotic-resistant bacteria caused nine infections; eight of those occurred in the prophylaxis group, and the ninth in a child who was switched from the control to the prophylaxis group after developing two recurrences.

Ten percent more repeat positive urine cultures occurred in the control arm, but that finding doesn't necessarily indicate the need for antibiotics, the authors said. “This has been the driving force behind the use of prophylactic antibiotics; however, we believe that repeat positive urine cultures in the absence of fever or other symptoms of parenchymal localization of the infection are not clinically relevant and do not produce renal scars.”

Adverse events—mostly gastrointestinal—occurred in 25 children, all of whom were taking prophylactic therapy.

Dr. Andrew Kirsch, a professor of urology at Emory University, Atlanta, said the study was well designed but did not go far enough in identifying VUR status and its possible impact on recurrent infection. “Voiding cystourethrograms were not cyclic, and they probably underestimated the incidence of VUR,” he said in an interview. “Even in cases with VUR resolution, up to 20% may show VUR on a subsequent cystourethrogram, which was not done here. A second cycle may identify VUR in those not identified in the first cycle.”

Prophylactic antibiotics don't appear to protect children with a first febrile urinary tract infection from a recurrence, whether or not they have primary, nonsevere vesicoureteral reflux.

“Our study shows that prophylaxis does not reduce the rate of febrile urinary tract infection recurrence during the 12 months after the first episode,” wrote Dr. Giovanni Montini of Padua (Italy) University, and his colleagues (Pediatrics 2008;122:1064-71).

The randomized controlled trial was conducted at 22 centers and included 338 patients (mean age 15 months); 69% were girls. All the children received antibiotic treatment for their initial urinary tract infection (UTI), and were placed on prophylactic treatment until a voiding cystourethrogram was conducted.

After the test, children were randomized to either no prophylaxis or to prophylaxis with either co-trimoxazole 15 mg/kg a day or co-amoxiclav 15 mg/kg a day, for 12 months. They underwent monthly urine cultures for the first 6 months, and then every other month during the study period. At the end of the study, they all underwent a 99-mTc dimercaptosuccinic acid scan to determine the extent of any renal scarring.

Recurrent febrile UTIs occurred in 12 (9%) of the control group patients and in 15 (7%) of the prophylaxis group patients—not a significant difference. The difference remained nonsignificant even when the two groups were stratified by degree of vesicoureteral reflux (VUR). Recurrence rates among those with VUR grade I were 9% in the control group vs. 5% in the prophylaxis group. The rates in those with VUR II were 9% in the control group and 8% in the prophylaxis group. Among those with VUR III, the rate of recurrence was 43% in the prophylaxis group and 23% in the control group, although the difference was not significant.

In a bivariate analysis, younger age and VUR grade were associated with recurrence. The mean age among patients with recurrence was 7 months, compared with 15 months among those without recurrence. The rate of recurrence increased with VUR grade, from 4% among patients without VUR to 7% in those with VUR I, 9% of those with VUR II, and 30% of those with VUR III.

Most of the children (87%) underwent the renal scan at the end of the follow-up period. A new renal scar occurred in only four patients—just over 1%. Two scars were found in each treatment group.

During the study, 2,422 urinalyses were performed. Most of the 27 recurrences were from Escherichia coli infections (70%). Other infective agents included Proteus mirabilis and Enterobacter (7% each), and Pseudomonas aeruginosa, Klebsiella pneumoniae, and Citrobacter (4% each).

Antibiotic-resistant bacteria caused nine infections; eight of those occurred in the prophylaxis group, and the ninth in a child who was switched from the control to the prophylaxis group after developing two recurrences.

Ten percent more repeat positive urine cultures occurred in the control arm, but that finding doesn't necessarily indicate the need for antibiotics, the authors said. “This has been the driving force behind the use of prophylactic antibiotics; however, we believe that repeat positive urine cultures in the absence of fever or other symptoms of parenchymal localization of the infection are not clinically relevant and do not produce renal scars.”

Adverse events—mostly gastrointestinal—occurred in 25 children, all of whom were taking prophylactic therapy.

Dr. Andrew Kirsch, a professor of urology at Emory University, Atlanta, said the study was well designed but did not go far enough in identifying VUR status and its possible impact on recurrent infection. “Voiding cystourethrograms were not cyclic, and they probably underestimated the incidence of VUR,” he said in an interview. “Even in cases with VUR resolution, up to 20% may show VUR on a subsequent cystourethrogram, which was not done here. A second cycle may identify VUR in those not identified in the first cycle.”

Prophylactic antibiotics don't appear to protect children with a first febrile urinary tract infection from a recurrence, whether or not they have primary, nonsevere vesicoureteral reflux.

“Our study shows that prophylaxis does not reduce the rate of febrile urinary tract infection recurrence during the 12 months after the first episode,” wrote Dr. Giovanni Montini of Padua (Italy) University, and his colleagues (Pediatrics 2008;122:1064-71).

The randomized controlled trial was conducted at 22 centers and included 338 patients (mean age 15 months); 69% were girls. All the children received antibiotic treatment for their initial urinary tract infection (UTI), and were placed on prophylactic treatment until a voiding cystourethrogram was conducted.

After the test, children were randomized to either no prophylaxis or to prophylaxis with either co-trimoxazole 15 mg/kg a day or co-amoxiclav 15 mg/kg a day, for 12 months. They underwent monthly urine cultures for the first 6 months, and then every other month during the study period. At the end of the study, they all underwent a 99-mTc dimercaptosuccinic acid scan to determine the extent of any renal scarring.

Recurrent febrile UTIs occurred in 12 (9%) of the control group patients and in 15 (7%) of the prophylaxis group patients—not a significant difference. The difference remained nonsignificant even when the two groups were stratified by degree of vesicoureteral reflux (VUR). Recurrence rates among those with VUR grade I were 9% in the control group vs. 5% in the prophylaxis group. The rates in those with VUR II were 9% in the control group and 8% in the prophylaxis group. Among those with VUR III, the rate of recurrence was 43% in the prophylaxis group and 23% in the control group, although the difference was not significant.

In a bivariate analysis, younger age and VUR grade were associated with recurrence. The mean age among patients with recurrence was 7 months, compared with 15 months among those without recurrence. The rate of recurrence increased with VUR grade, from 4% among patients without VUR to 7% in those with VUR I, 9% of those with VUR II, and 30% of those with VUR III.

Most of the children (87%) underwent the renal scan at the end of the follow-up period. A new renal scar occurred in only four patients—just over 1%. Two scars were found in each treatment group.

During the study, 2,422 urinalyses were performed. Most of the 27 recurrences were from Escherichia coli infections (70%). Other infective agents included Proteus mirabilis and Enterobacter (7% each), and Pseudomonas aeruginosa, Klebsiella pneumoniae, and Citrobacter (4% each).

Antibiotic-resistant bacteria caused nine infections; eight of those occurred in the prophylaxis group, and the ninth in a child who was switched from the control to the prophylaxis group after developing two recurrences.

Ten percent more repeat positive urine cultures occurred in the control arm, but that finding doesn't necessarily indicate the need for antibiotics, the authors said. “This has been the driving force behind the use of prophylactic antibiotics; however, we believe that repeat positive urine cultures in the absence of fever or other symptoms of parenchymal localization of the infection are not clinically relevant and do not produce renal scars.”

Adverse events—mostly gastrointestinal—occurred in 25 children, all of whom were taking prophylactic therapy.

Dr. Andrew Kirsch, a professor of urology at Emory University, Atlanta, said the study was well designed but did not go far enough in identifying VUR status and its possible impact on recurrent infection. “Voiding cystourethrograms were not cyclic, and they probably underestimated the incidence of VUR,” he said in an interview. “Even in cases with VUR resolution, up to 20% may show VUR on a subsequent cystourethrogram, which was not done here. A second cycle may identify VUR in those not identified in the first cycle.”

MADRID — Glatiramer acetate significantly reduced relapse and disease progression in patients with multiple sclerosis who received the drug after a course of methotrexate, according to the results of a small Italian study.

“In our experience, six multiple sclerosis patients treated with methotrexate followed by glatiramer acetate showed a significant reduction of inflammatory activity parameters during the follow-up,” Dr. Yasmin Handouk wrote in a poster that was presented at the annual congress of the European Federation of Neurological Societies.

“This was associated with a lack of disease progression,” Dr. Handouk added.

Glatiramer acetate received Food and Drug Administration approval in 2001 for use in reduction of the frequency of relapses in relapsing-remitting multiple sclerosis.

The randomized trial included 12 patients with refractory MS (6 with relapsing-remitting disease and 6 with progressive-relapsing disease).

All of the patients had undergone a course of methotrexate after failing to respond to interferon therapy, wrote Dr. Handouk of the Università Politecnica delle Marche, Ancona, Italy.

After methotrexate, patients had magnetic resonance imaging of the brain. Within 3 months of ending methotrexate, six started maintenance therapy with glatiramer acetate 20 mg/day for a mean of 8 months; the rest received no further treatment.

Follow-up assessments were done at 6-month intervals for 2 years.

At the 2-year follow-up, only one patient in the active group had relapsed. Disability, as measured by the Expanded Disability Status Scale, had significantly improved, with patients dropping an average of 1 point on the scale.

There were no new or enhanced lesions.

In the nontreated group, two patients had relapsed. The disability score was not improved from baseline. Two patients showed new gadolinium-enhancing lesions.

“[Dr. Jason Ramtahal] previously proved the usefulness of 6-month glatiramer acetate beginning 2 months before ending methotrexate, although a case of acute promyelocytic leukemia was registered [J. Neuro. 2006;253:1160–4],” Dr. Handouk noted.

“Our patients started glatiramer acetate therapy at least 3 months after methotrexate without serious adverse event.”

Dr. Handouk made no financial declarations with regard to the study.

MADRID — Glatiramer acetate significantly reduced relapse and disease progression in patients with multiple sclerosis who received the drug after a course of methotrexate, according to the results of a small Italian study.

“In our experience, six multiple sclerosis patients treated with methotrexate followed by glatiramer acetate showed a significant reduction of inflammatory activity parameters during the follow-up,” Dr. Yasmin Handouk wrote in a poster that was presented at the annual congress of the European Federation of Neurological Societies.

“This was associated with a lack of disease progression,” Dr. Handouk added.

Glatiramer acetate received Food and Drug Administration approval in 2001 for use in reduction of the frequency of relapses in relapsing-remitting multiple sclerosis.

The randomized trial included 12 patients with refractory MS (6 with relapsing-remitting disease and 6 with progressive-relapsing disease).

All of the patients had undergone a course of methotrexate after failing to respond to interferon therapy, wrote Dr. Handouk of the Università Politecnica delle Marche, Ancona, Italy.

After methotrexate, patients had magnetic resonance imaging of the brain. Within 3 months of ending methotrexate, six started maintenance therapy with glatiramer acetate 20 mg/day for a mean of 8 months; the rest received no further treatment.

Follow-up assessments were done at 6-month intervals for 2 years.

At the 2-year follow-up, only one patient in the active group had relapsed. Disability, as measured by the Expanded Disability Status Scale, had significantly improved, with patients dropping an average of 1 point on the scale.

There were no new or enhanced lesions.

In the nontreated group, two patients had relapsed. The disability score was not improved from baseline. Two patients showed new gadolinium-enhancing lesions.

“[Dr. Jason Ramtahal] previously proved the usefulness of 6-month glatiramer acetate beginning 2 months before ending methotrexate, although a case of acute promyelocytic leukemia was registered [J. Neuro. 2006;253:1160–4],” Dr. Handouk noted.

“Our patients started glatiramer acetate therapy at least 3 months after methotrexate without serious adverse event.”

Dr. Handouk made no financial declarations with regard to the study.

MADRID — Glatiramer acetate significantly reduced relapse and disease progression in patients with multiple sclerosis who received the drug after a course of methotrexate, according to the results of a small Italian study.

“In our experience, six multiple sclerosis patients treated with methotrexate followed by glatiramer acetate showed a significant reduction of inflammatory activity parameters during the follow-up,” Dr. Yasmin Handouk wrote in a poster that was presented at the annual congress of the European Federation of Neurological Societies.

“This was associated with a lack of disease progression,” Dr. Handouk added.

Glatiramer acetate received Food and Drug Administration approval in 2001 for use in reduction of the frequency of relapses in relapsing-remitting multiple sclerosis.

The randomized trial included 12 patients with refractory MS (6 with relapsing-remitting disease and 6 with progressive-relapsing disease).

All of the patients had undergone a course of methotrexate after failing to respond to interferon therapy, wrote Dr. Handouk of the Università Politecnica delle Marche, Ancona, Italy.

After methotrexate, patients had magnetic resonance imaging of the brain. Within 3 months of ending methotrexate, six started maintenance therapy with glatiramer acetate 20 mg/day for a mean of 8 months; the rest received no further treatment.

Follow-up assessments were done at 6-month intervals for 2 years.

At the 2-year follow-up, only one patient in the active group had relapsed. Disability, as measured by the Expanded Disability Status Scale, had significantly improved, with patients dropping an average of 1 point on the scale.

There were no new or enhanced lesions.

In the nontreated group, two patients had relapsed. The disability score was not improved from baseline. Two patients showed new gadolinium-enhancing lesions.

“[Dr. Jason Ramtahal] previously proved the usefulness of 6-month glatiramer acetate beginning 2 months before ending methotrexate, although a case of acute promyelocytic leukemia was registered [J. Neuro. 2006;253:1160–4],” Dr. Handouk noted.

“Our patients started glatiramer acetate therapy at least 3 months after methotrexate without serious adverse event.”

Dr. Handouk made no financial declarations with regard to the study.