Michele G. Sullivan

CHICAGO — A combination of specialized brain imaging and cerebrospinal amyloid β₄₂ measurements powerfully predicts the presence—and absence—of Alzheimer's-type dementia.

For several years researchers have focused on Aβ₄₂ in cerebrospinal fluid (CSF) as a possible biomarker of Alzheimer's disease (AD): Higher levels indicate the protein is still soluble, whereas lower levels suggest that it might be building up in the brain as neuropathologic plaque. But an unpredictable overlap of CSF Aβ₄₂ among controls, Alzheimer's patients, and those with mild cognitive impairment has confounded any definitive conclusions, Anne Fagan, Ph.D., said at the International Conference on Alzheimer's Disease.

“Over the years, many people have looked at the level of this protein in CSF in nondemented and Alzheimer's subjects,” said Dr. Fagan of Washington University, St. Louis. “Although the mean levels are different, there has always been a question over why there is this tremendous amount of overlap, with many controls showing Aβ₄₂ levels as low as those we see among Alzheimer's patients, and some Alzheimer's patients showing levels as high as those of normal controls.”

The advent of Pittsburgh imaging compound B (PIB), an imaging agent that lights up amyloid plaques during positron emission tomography scanning, has allowed Dr. Fagan to more fully explore the associations of Aβ₄₂ in the brain and the CSF. She presented the results of a prospective study of 132 subjects, all of whom underwent PIB scanning and a lumbar puncture for CSF Aβ₄₂ levels within a 2-year period. These volunteers had a mean age of 66 years; 113 were cognitively normal, 14 had very mild Alzheimer's dementia, and 5 had mild Alzheimer's dementia.

Dr. Fagan and her colleagues found what she called “a striking inverse relationship between the levels of amyloid in the brain and levels of Aβ₄₂ in the CSF.”

Of the 37 subjects whose PIB-PET scans showed high levels of brain amyloid, 36 (97%) had low CSF Aβ₄₂. Conversely, 80 of the 95 with low levels of brain amyloid (84%) had high CSF Aβ₄₂. These relationships were strong regardless of cognitive status at the time of testing. “Low CSF Aβ₄₂ appears to be an excellent marker for the presence of brain amyloid, regardless of whether people have dementia or not. The presence of low CSF Aβ₄₂ combined with PIB-positivity in the brain may be antecedent biomarkers of Alzheimer's disease, predicting who will develop future dementia.”

Indeed, some independent clinical follow-up data on the cohort seem to confirm this, Dr. Fagan said. Three subjects who were cognitively normal at the time of testing, but were PIB-positive and had low CSF Aβ₄₂, have since developed a diagnosis of very mild Alzheimer's dementia.

Four who had a diagnosis of very mild Alzheimer's at the time of testing, but who were PIB-negative and had high CSF Aβ₄₂ have had their diagnoses changed to either “no dementia” or “non-Alzheimer's dementia.” “This seems to say that high CSF Aβ₄₂ and cortical PIB-negativity may be useful for a differential diagnosis, identifying possible Alzheimer's misdiagnoses in the very early stages.”

Finally, Dr. Fagan noted, four subjects who were cognitively normal at the time of testing and were PIB-negative but had low CSF Aβ₄₂ have since undergone additional PIB scans. “One subject is now PIB-positive, indicating the presence of cortical amyloid, and two others may have PIB-positivity in some select brain regions. Levels of CSF Aβ₄₂ may decrease prior to cortical amyloid becoming detectable by PIB, and thus may be a very sensitive biomarker for the earliest, preclinical stages of Alzheimer's.”

The potential clinical impact of such an early diagnostic tool could be profound. “Our goal is to push the disease diagnosis back to a much earlier time, hopefully into this preclinical stage,” Dr. Fagan said at the meeting sponsored by the Alzheimer's Association.

'Our goal is to push the disease diagnosis back to a much earlier time, hopefully into this preclinical stage.' DR. FAGAN

CHICAGO — A combination of specialized brain imaging and cerebrospinal amyloid β₄₂ measurements powerfully predicts the presence—and absence—of Alzheimer's-type dementia.

For several years researchers have focused on Aβ₄₂ in cerebrospinal fluid (CSF) as a possible biomarker of Alzheimer's disease (AD): Higher levels indicate the protein is still soluble, whereas lower levels suggest that it might be building up in the brain as neuropathologic plaque. But an unpredictable overlap of CSF Aβ₄₂ among controls, Alzheimer's patients, and those with mild cognitive impairment has confounded any definitive conclusions, Anne Fagan, Ph.D., said at the International Conference on Alzheimer's Disease.

“Over the years, many people have looked at the level of this protein in CSF in nondemented and Alzheimer's subjects,” said Dr. Fagan of Washington University, St. Louis. “Although the mean levels are different, there has always been a question over why there is this tremendous amount of overlap, with many controls showing Aβ₄₂ levels as low as those we see among Alzheimer's patients, and some Alzheimer's patients showing levels as high as those of normal controls.”

The advent of Pittsburgh imaging compound B (PIB), an imaging agent that lights up amyloid plaques during positron emission tomography scanning, has allowed Dr. Fagan to more fully explore the associations of Aβ₄₂ in the brain and the CSF. She presented the results of a prospective study of 132 subjects, all of whom underwent PIB scanning and a lumbar puncture for CSF Aβ₄₂ levels within a 2-year period. These volunteers had a mean age of 66 years; 113 were cognitively normal, 14 had very mild Alzheimer's dementia, and 5 had mild Alzheimer's dementia.

Dr. Fagan and her colleagues found what she called “a striking inverse relationship between the levels of amyloid in the brain and levels of Aβ₄₂ in the CSF.”

Of the 37 subjects whose PIB-PET scans showed high levels of brain amyloid, 36 (97%) had low CSF Aβ₄₂. Conversely, 80 of the 95 with low levels of brain amyloid (84%) had high CSF Aβ₄₂. These relationships were strong regardless of cognitive status at the time of testing. “Low CSF Aβ₄₂ appears to be an excellent marker for the presence of brain amyloid, regardless of whether people have dementia or not. The presence of low CSF Aβ₄₂ combined with PIB-positivity in the brain may be antecedent biomarkers of Alzheimer's disease, predicting who will develop future dementia.”

Indeed, some independent clinical follow-up data on the cohort seem to confirm this, Dr. Fagan said. Three subjects who were cognitively normal at the time of testing, but were PIB-positive and had low CSF Aβ₄₂, have since developed a diagnosis of very mild Alzheimer's dementia.

Four who had a diagnosis of very mild Alzheimer's at the time of testing, but who were PIB-negative and had high CSF Aβ₄₂ have had their diagnoses changed to either “no dementia” or “non-Alzheimer's dementia.” “This seems to say that high CSF Aβ₄₂ and cortical PIB-negativity may be useful for a differential diagnosis, identifying possible Alzheimer's misdiagnoses in the very early stages.”

Finally, Dr. Fagan noted, four subjects who were cognitively normal at the time of testing and were PIB-negative but had low CSF Aβ₄₂ have since undergone additional PIB scans. “One subject is now PIB-positive, indicating the presence of cortical amyloid, and two others may have PIB-positivity in some select brain regions. Levels of CSF Aβ₄₂ may decrease prior to cortical amyloid becoming detectable by PIB, and thus may be a very sensitive biomarker for the earliest, preclinical stages of Alzheimer's.”

The potential clinical impact of such an early diagnostic tool could be profound. “Our goal is to push the disease diagnosis back to a much earlier time, hopefully into this preclinical stage,” Dr. Fagan said at the meeting sponsored by the Alzheimer's Association.

'Our goal is to push the disease diagnosis back to a much earlier time, hopefully into this preclinical stage.' DR. FAGAN

CHICAGO — A combination of specialized brain imaging and cerebrospinal amyloid β₄₂ measurements powerfully predicts the presence—and absence—of Alzheimer's-type dementia.

For several years researchers have focused on Aβ₄₂ in cerebrospinal fluid (CSF) as a possible biomarker of Alzheimer's disease (AD): Higher levels indicate the protein is still soluble, whereas lower levels suggest that it might be building up in the brain as neuropathologic plaque. But an unpredictable overlap of CSF Aβ₄₂ among controls, Alzheimer's patients, and those with mild cognitive impairment has confounded any definitive conclusions, Anne Fagan, Ph.D., said at the International Conference on Alzheimer's Disease.

“Over the years, many people have looked at the level of this protein in CSF in nondemented and Alzheimer's subjects,” said Dr. Fagan of Washington University, St. Louis. “Although the mean levels are different, there has always been a question over why there is this tremendous amount of overlap, with many controls showing Aβ₄₂ levels as low as those we see among Alzheimer's patients, and some Alzheimer's patients showing levels as high as those of normal controls.”

The advent of Pittsburgh imaging compound B (PIB), an imaging agent that lights up amyloid plaques during positron emission tomography scanning, has allowed Dr. Fagan to more fully explore the associations of Aβ₄₂ in the brain and the CSF. She presented the results of a prospective study of 132 subjects, all of whom underwent PIB scanning and a lumbar puncture for CSF Aβ₄₂ levels within a 2-year period. These volunteers had a mean age of 66 years; 113 were cognitively normal, 14 had very mild Alzheimer's dementia, and 5 had mild Alzheimer's dementia.

Dr. Fagan and her colleagues found what she called “a striking inverse relationship between the levels of amyloid in the brain and levels of Aβ₄₂ in the CSF.”

Of the 37 subjects whose PIB-PET scans showed high levels of brain amyloid, 36 (97%) had low CSF Aβ₄₂. Conversely, 80 of the 95 with low levels of brain amyloid (84%) had high CSF Aβ₄₂. These relationships were strong regardless of cognitive status at the time of testing. “Low CSF Aβ₄₂ appears to be an excellent marker for the presence of brain amyloid, regardless of whether people have dementia or not. The presence of low CSF Aβ₄₂ combined with PIB-positivity in the brain may be antecedent biomarkers of Alzheimer's disease, predicting who will develop future dementia.”

Indeed, some independent clinical follow-up data on the cohort seem to confirm this, Dr. Fagan said. Three subjects who were cognitively normal at the time of testing, but were PIB-positive and had low CSF Aβ₄₂, have since developed a diagnosis of very mild Alzheimer's dementia.

Four who had a diagnosis of very mild Alzheimer's at the time of testing, but who were PIB-negative and had high CSF Aβ₄₂ have had their diagnoses changed to either “no dementia” or “non-Alzheimer's dementia.” “This seems to say that high CSF Aβ₄₂ and cortical PIB-negativity may be useful for a differential diagnosis, identifying possible Alzheimer's misdiagnoses in the very early stages.”

Finally, Dr. Fagan noted, four subjects who were cognitively normal at the time of testing and were PIB-negative but had low CSF Aβ₄₂ have since undergone additional PIB scans. “One subject is now PIB-positive, indicating the presence of cortical amyloid, and two others may have PIB-positivity in some select brain regions. Levels of CSF Aβ₄₂ may decrease prior to cortical amyloid becoming detectable by PIB, and thus may be a very sensitive biomarker for the earliest, preclinical stages of Alzheimer's.”

The potential clinical impact of such an early diagnostic tool could be profound. “Our goal is to push the disease diagnosis back to a much earlier time, hopefully into this preclinical stage,” Dr. Fagan said at the meeting sponsored by the Alzheimer's Association.

'Our goal is to push the disease diagnosis back to a much earlier time, hopefully into this preclinical stage.' DR. FAGAN

MADRID — Every child admitted with trauma-related myelopathy should have magnetic resonance imaging of the spine, because x-rays may not show even serious spinal cord injuries.

The juvenile spinal cord is less resilient than the malleable youthful vertebrae and ligaments to withstand the forces of an injury, Dr. Michael Vassilyadi said at the annual congress of the European Federation of Neurological Societies.

The incidence of spinal cord injury without radiographic abnormality (SCIWORA) is low in children, but the consequences of missing such an injury can be devastating.

Dr. Vassilyadi conducted a retrospective review to determine the incidence of SCIWORA at the facility over a 15-year period. Because there is no universally accepted criteria for the SCIWORA, he defined it as traumatic myelopathy (objective sensorimotor or motor deficits) that is either transient (but of at least 24 hours' duration) or permanent without radiologic evidence of spinal injury (no vertebral fracture or ligament instability, with normal flexion and extension cervical spine x-rays).

From 1990 to 2005, 22 children presented at the hospital with trauma-related myelopathy.

Of these, eight had both a spinal cord and head injury; four had spine fracture and four did not. Of those with fractures, only two had abnormal x-rays.

Fourteen additional children had spinal cord injuries without head injury. Of these, 12 had spine fractures and 2 did not; both of these 2 had abnormal x-rays.

“That left us with just two patients who had SCIWORA,” said Dr. Vassilyadi, a neurosurgeon at the Children's Hospital of Eastern Ontario. The first patient had been tackled while playing football and sustained the hit on the left side of his head and neck. He presented with partial anterior cord syndrome, complaining of a left extremity parasthesis that lasted about 45 minutes and left extremity weakness that persisted for 2 or 3 days. Both his cervical-spine and thoracic-spine x-rays were normal, although he complained of pain to palpation in the area of the lower cervical spine.

An MRI showed a small central disc herniation between C5 and C6. This patient recovered with no neurologic deficits.

The second patient was a 12-year-old boy who was involved in a motor vehicle accident.

He was admitted with paraplegia and no sensation below T3, although all of his spine x-rays were negative.

An MRI showed increased signal intensity on T2-weighted images between T1 and T3.

Five years later, the boy was still paraplegic. An MRI at that time showed the cord in the upper thoracic area had developed multiple syrinxes that tracked the original injury.

Although this patient has not experienced significant improvement in his neurologic status, children do have remarkable recovery ability, and families should be counseled to keep an eye out for improvement, Dr. Vassilyadi commented.

“We give the kids at least 2 years [before determining an injury as permanent],” he said.

A normal spine x-ray (top) after a car accident: Serious damage became apparent only with an MRI (bottom). Images courtesy Dr. Michael Vassilyadi

MADRID — Every child admitted with trauma-related myelopathy should have magnetic resonance imaging of the spine, because x-rays may not show even serious spinal cord injuries.

The juvenile spinal cord is less resilient than the malleable youthful vertebrae and ligaments to withstand the forces of an injury, Dr. Michael Vassilyadi said at the annual congress of the European Federation of Neurological Societies.

The incidence of spinal cord injury without radiographic abnormality (SCIWORA) is low in children, but the consequences of missing such an injury can be devastating.

Dr. Vassilyadi conducted a retrospective review to determine the incidence of SCIWORA at the facility over a 15-year period. Because there is no universally accepted criteria for the SCIWORA, he defined it as traumatic myelopathy (objective sensorimotor or motor deficits) that is either transient (but of at least 24 hours' duration) or permanent without radiologic evidence of spinal injury (no vertebral fracture or ligament instability, with normal flexion and extension cervical spine x-rays).

From 1990 to 2005, 22 children presented at the hospital with trauma-related myelopathy.

Of these, eight had both a spinal cord and head injury; four had spine fracture and four did not. Of those with fractures, only two had abnormal x-rays.

Fourteen additional children had spinal cord injuries without head injury. Of these, 12 had spine fractures and 2 did not; both of these 2 had abnormal x-rays.

“That left us with just two patients who had SCIWORA,” said Dr. Vassilyadi, a neurosurgeon at the Children's Hospital of Eastern Ontario. The first patient had been tackled while playing football and sustained the hit on the left side of his head and neck. He presented with partial anterior cord syndrome, complaining of a left extremity parasthesis that lasted about 45 minutes and left extremity weakness that persisted for 2 or 3 days. Both his cervical-spine and thoracic-spine x-rays were normal, although he complained of pain to palpation in the area of the lower cervical spine.

An MRI showed a small central disc herniation between C5 and C6. This patient recovered with no neurologic deficits.

The second patient was a 12-year-old boy who was involved in a motor vehicle accident.

He was admitted with paraplegia and no sensation below T3, although all of his spine x-rays were negative.

An MRI showed increased signal intensity on T2-weighted images between T1 and T3.

Five years later, the boy was still paraplegic. An MRI at that time showed the cord in the upper thoracic area had developed multiple syrinxes that tracked the original injury.

Although this patient has not experienced significant improvement in his neurologic status, children do have remarkable recovery ability, and families should be counseled to keep an eye out for improvement, Dr. Vassilyadi commented.

“We give the kids at least 2 years [before determining an injury as permanent],” he said.

A normal spine x-ray (top) after a car accident: Serious damage became apparent only with an MRI (bottom). Images courtesy Dr. Michael Vassilyadi

MADRID — Every child admitted with trauma-related myelopathy should have magnetic resonance imaging of the spine, because x-rays may not show even serious spinal cord injuries.

The juvenile spinal cord is less resilient than the malleable youthful vertebrae and ligaments to withstand the forces of an injury, Dr. Michael Vassilyadi said at the annual congress of the European Federation of Neurological Societies.

The incidence of spinal cord injury without radiographic abnormality (SCIWORA) is low in children, but the consequences of missing such an injury can be devastating.

Dr. Vassilyadi conducted a retrospective review to determine the incidence of SCIWORA at the facility over a 15-year period. Because there is no universally accepted criteria for the SCIWORA, he defined it as traumatic myelopathy (objective sensorimotor or motor deficits) that is either transient (but of at least 24 hours' duration) or permanent without radiologic evidence of spinal injury (no vertebral fracture or ligament instability, with normal flexion and extension cervical spine x-rays).

From 1990 to 2005, 22 children presented at the hospital with trauma-related myelopathy.

Of these, eight had both a spinal cord and head injury; four had spine fracture and four did not. Of those with fractures, only two had abnormal x-rays.

Fourteen additional children had spinal cord injuries without head injury. Of these, 12 had spine fractures and 2 did not; both of these 2 had abnormal x-rays.

“That left us with just two patients who had SCIWORA,” said Dr. Vassilyadi, a neurosurgeon at the Children's Hospital of Eastern Ontario. The first patient had been tackled while playing football and sustained the hit on the left side of his head and neck. He presented with partial anterior cord syndrome, complaining of a left extremity parasthesis that lasted about 45 minutes and left extremity weakness that persisted for 2 or 3 days. Both his cervical-spine and thoracic-spine x-rays were normal, although he complained of pain to palpation in the area of the lower cervical spine.

An MRI showed a small central disc herniation between C5 and C6. This patient recovered with no neurologic deficits.

The second patient was a 12-year-old boy who was involved in a motor vehicle accident.

He was admitted with paraplegia and no sensation below T3, although all of his spine x-rays were negative.

An MRI showed increased signal intensity on T2-weighted images between T1 and T3.

Five years later, the boy was still paraplegic. An MRI at that time showed the cord in the upper thoracic area had developed multiple syrinxes that tracked the original injury.

Although this patient has not experienced significant improvement in his neurologic status, children do have remarkable recovery ability, and families should be counseled to keep an eye out for improvement, Dr. Vassilyadi commented.

“We give the kids at least 2 years [before determining an injury as permanent],” he said.

A normal spine x-ray (top) after a car accident: Serious damage became apparent only with an MRI (bottom). Images courtesy Dr. Michael Vassilyadi

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

After taking the drug for 12 weeks, patients in the study 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.

The study enrolled 20 patients (mean age 70 years) at the Veterans Affairs Medical Center in Omaha. All had early Alzheimer's disease, with a mean Mini-Mental State Examination score of 23. Every patient had a score of greater than 30 on the Apathy Evaluation Scale; on this 72-point scale, anything above 30 is considered 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 ratings for frequency and severity. 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 because of loss of appetite and the other because of an increase in blood pressure. With this drug, as with many stimulants, an increase of 2–4 mm Hg in systolic blood pressure is not uncommon.

Dr. Padala said he 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 the results of a small prospective trial.

After taking the drug for 12 weeks, patients in the study 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.

The study enrolled 20 patients (mean age 70 years) at the Veterans Affairs Medical Center in Omaha. All had early Alzheimer's disease, with a mean Mini-Mental State Examination score of 23. Every patient had a score of greater than 30 on the Apathy Evaluation Scale; on this 72-point scale, anything above 30 is considered 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 ratings for frequency and severity. 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 because of loss of appetite and the other because of an increase in blood pressure. With this drug, as with many stimulants, an increase of 2–4 mm Hg in systolic blood pressure is not uncommon.

Dr. Padala said he 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 the results of a small prospective trial.

After taking the drug for 12 weeks, patients in the study 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.

The study enrolled 20 patients (mean age 70 years) at the Veterans Affairs Medical Center in Omaha. All had early Alzheimer's disease, with a mean Mini-Mental State Examination score of 23. Every patient had a score of greater than 30 on the Apathy Evaluation Scale; on this 72-point scale, anything above 30 is considered 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 ratings for frequency and severity. 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 because of loss of appetite and the other because of an increase in blood pressure. With this drug, as with many stimulants, an increase of 2–4 mm Hg in systolic blood pressure is not uncommon.

Dr. Padala said he had no financial disclosures with regard to the study drug.

SAN FRANCISCO — At 6 months after undergoing laparoscopic adjustable gastric banding, a small group of morbidly obese teenagers showed significant improvements in risk factors associated with the development of cardiovascular disease and diabetes, according to study findings.

Although the study included just 14 teens, it shows the potential of gastric banding in improving the metabolic profiles of young patients who are at risk for developing weight-related heart disorders, Dr. Ilene Fennoy reported in a poster presented at the annual meeting of the Endocrine Society.

The findings also may shed light on the causes of weight gain, said Dr. Fennoy, medical director of the comprehensive adolescent bariatric surgery program at New York-Presbyterian Hospital.

These initial data suggest that gastric banding “could be not only a weight-loss surgery, but a 'metabolic surgery.' We hope in the future to better understand changes in other markers, such as adipocytokines and gut peptides, that cause weight gain. Ultimately, we hope to use these data to design a preventive approach to obesity in the periadolescent population.”

The study included 14 patients (mean age, 16 years; 6 males, 8 females). The group included five white teens, one black, five Hispanics, and three of other racial/ethnic origins. They all were morbidly obese, with a mean initial weight of 152 kg, and a mean initial body mass index of 53 kg/m

All patients underwent laparoscopic adjustable gastric banding between April 2006 and April 2008; they were followed for 6 months. At 6 months, the mean weight loss was 20 pounds (9 kg), a significant difference. The mean BMI decreased from 53 to 47, which was also a significant reduction.

The patients also showed significant improvements in the following risk factors for cardiovascular disease and diabetes. The mean waist circumference decreased from 145 cm to 132 cm. Liver function tests improved, with alanine aminotransferase decreasing from 35 to 24 IU/L, and aspartate aminotransferase from 27 to 23 IU/L. Glycosylated hemoglobin (HbA_1c) decreased from a mean of 5.6% to a mean of 5.5%. C-reactive protein improved, dropping from 9 to 6 mg/L, as did triglycerides, falling from 129 to 95 mg/dL.

In some patients, insulin resistance as measured by the homeostasis model assessment (HOMA-IR) and the percentage of β-cell secretory capacity also improved, Dr. Fennoy noted. These changes were most pronounced in the teens who lost the most weight, and decreased as the weight loss became less.

SAN FRANCISCO — At 6 months after undergoing laparoscopic adjustable gastric banding, a small group of morbidly obese teenagers showed significant improvements in risk factors associated with the development of cardiovascular disease and diabetes, according to study findings.

Although the study included just 14 teens, it shows the potential of gastric banding in improving the metabolic profiles of young patients who are at risk for developing weight-related heart disorders, Dr. Ilene Fennoy reported in a poster presented at the annual meeting of the Endocrine Society.

The findings also may shed light on the causes of weight gain, said Dr. Fennoy, medical director of the comprehensive adolescent bariatric surgery program at New York-Presbyterian Hospital.

These initial data suggest that gastric banding “could be not only a weight-loss surgery, but a 'metabolic surgery.' We hope in the future to better understand changes in other markers, such as adipocytokines and gut peptides, that cause weight gain. Ultimately, we hope to use these data to design a preventive approach to obesity in the periadolescent population.”

The study included 14 patients (mean age, 16 years; 6 males, 8 females). The group included five white teens, one black, five Hispanics, and three of other racial/ethnic origins. They all were morbidly obese, with a mean initial weight of 152 kg, and a mean initial body mass index of 53 kg/m

All patients underwent laparoscopic adjustable gastric banding between April 2006 and April 2008; they were followed for 6 months. At 6 months, the mean weight loss was 20 pounds (9 kg), a significant difference. The mean BMI decreased from 53 to 47, which was also a significant reduction.

The patients also showed significant improvements in the following risk factors for cardiovascular disease and diabetes. The mean waist circumference decreased from 145 cm to 132 cm. Liver function tests improved, with alanine aminotransferase decreasing from 35 to 24 IU/L, and aspartate aminotransferase from 27 to 23 IU/L. Glycosylated hemoglobin (HbA_1c) decreased from a mean of 5.6% to a mean of 5.5%. C-reactive protein improved, dropping from 9 to 6 mg/L, as did triglycerides, falling from 129 to 95 mg/dL.

In some patients, insulin resistance as measured by the homeostasis model assessment (HOMA-IR) and the percentage of β-cell secretory capacity also improved, Dr. Fennoy noted. These changes were most pronounced in the teens who lost the most weight, and decreased as the weight loss became less.

SAN FRANCISCO — At 6 months after undergoing laparoscopic adjustable gastric banding, a small group of morbidly obese teenagers showed significant improvements in risk factors associated with the development of cardiovascular disease and diabetes, according to study findings.

Although the study included just 14 teens, it shows the potential of gastric banding in improving the metabolic profiles of young patients who are at risk for developing weight-related heart disorders, Dr. Ilene Fennoy reported in a poster presented at the annual meeting of the Endocrine Society.

The findings also may shed light on the causes of weight gain, said Dr. Fennoy, medical director of the comprehensive adolescent bariatric surgery program at New York-Presbyterian Hospital.

These initial data suggest that gastric banding “could be not only a weight-loss surgery, but a 'metabolic surgery.' We hope in the future to better understand changes in other markers, such as adipocytokines and gut peptides, that cause weight gain. Ultimately, we hope to use these data to design a preventive approach to obesity in the periadolescent population.”

The study included 14 patients (mean age, 16 years; 6 males, 8 females). The group included five white teens, one black, five Hispanics, and three of other racial/ethnic origins. They all were morbidly obese, with a mean initial weight of 152 kg, and a mean initial body mass index of 53 kg/m

All patients underwent laparoscopic adjustable gastric banding between April 2006 and April 2008; they were followed for 6 months. At 6 months, the mean weight loss was 20 pounds (9 kg), a significant difference. The mean BMI decreased from 53 to 47, which was also a significant reduction.

The patients also showed significant improvements in the following risk factors for cardiovascular disease and diabetes. The mean waist circumference decreased from 145 cm to 132 cm. Liver function tests improved, with alanine aminotransferase decreasing from 35 to 24 IU/L, and aspartate aminotransferase from 27 to 23 IU/L. Glycosylated hemoglobin (HbA_1c) decreased from a mean of 5.6% to a mean of 5.5%. C-reactive protein improved, dropping from 9 to 6 mg/L, as did triglycerides, falling from 129 to 95 mg/dL.

In some patients, insulin resistance as measured by the homeostasis model assessment (HOMA-IR) and the percentage of β-cell secretory capacity also improved, Dr. Fennoy noted. These changes were most pronounced in the teens who lost the most weight, and decreased as the weight loss became less.

Topiramate is associated with a significantly increased risk of major congenital malformations, whether given as monotherapy or as part of a polytherapy antiepileptic regimen, Dr. Stephen Hunt and his colleagues have reported.

Although the associations were strong—an 11-fold increase in the risk of oral clefts and a 14-fold increase in the risk of hypospadias, compared with background rates in the United Kingdom—the confidence intervals surrounding them were wide, noted Dr. Hunt of the Royal Group of Hospitals, Belfast, Ireland. Therefore, the data “should be interpreted with caution,” he and his colleagues wrote (Neurology 2008;71:272-6).

The U.K. registry is one of three national registries that track pregnancy outcomes in women taking antiepileptic drugs. Neither of the others—a North American and an Australian registry—has reported an association between topiramate and birth defects, said Dr. Kimford Meador, the Melvin Greer Professor of Neurology at the University of Florida, Gainesville.

“The U.K. data are the first data on topiramate risks during pregnancy,” Dr. Meador said in an interview. “The data suggest an association of increased malformations with topiramate exposure during pregnancy. However, the sample is small and the confidence intervals are large, so no definitive conclusion can be drawn.”

Because the results are preliminary, clinicians and their patients should be cautious about medication changes, said Dr. Martha Morrell, director of the Columbia Comprehensive Epilepsy Center, New York.

The analysis was drawn from the U.K. Epilepsy and Pregnancy Register. The present study included outcomes for 203 pregnancies with exposure to topiramate during the first trimester. Most of the women (133) were taking the drug as part of a polytherapy regimen (mean topiramate dose, 299 mg/day); the rest were on topiramate monotherapy (mean dose 245 mg/day).

Of all these pregnancies, 178 (88%) resulted in a live birth; there were a total of 31 congenital anomalies among these infants (16 major and 15 minor).

Among women on monotherapy, there were eight infants born with anomalies, three of which were considered major. Two infants had a cleft lip/palate, and one had hypospadias. The average daily dose of topiramate for the mothers of these infants was 400 mg/day, compared with the average 238 mg dose among women on monotherapy who had normal pregnancy outcomes.

The five minor anomalies in the monotherapy group were sacral dimple, “clicky” hips, plagiocephaly, webbed toes, and immature hip joints.

The combination of valproate with topiramate was associated with the highest rate of major congenital malformations (36%; 12 cases), followed by a regimen of three or more antiepileptic drugs (24%; 23 cases). Conversely, only 8% of polytherapy regimens that did not include valproate resulted in a major anomaly.

Janssen-Cilag, U.K. manufacturer of topiramate (Topamax), and other pharmaceutical firms provided unrestricted educational grants to help support to study. Several of the study authors have received honoraria from Janssen-Cilag and other pharmaceutical firms.

Topiramate is associated with a significantly increased risk of major congenital malformations, whether given as monotherapy or as part of a polytherapy antiepileptic regimen, Dr. Stephen Hunt and his colleagues have reported.

Although the associations were strong—an 11-fold increase in the risk of oral clefts and a 14-fold increase in the risk of hypospadias, compared with background rates in the United Kingdom—the confidence intervals surrounding them were wide, noted Dr. Hunt of the Royal Group of Hospitals, Belfast, Ireland. Therefore, the data “should be interpreted with caution,” he and his colleagues wrote (Neurology 2008;71:272-6).

The U.K. registry is one of three national registries that track pregnancy outcomes in women taking antiepileptic drugs. Neither of the others—a North American and an Australian registry—has reported an association between topiramate and birth defects, said Dr. Kimford Meador, the Melvin Greer Professor of Neurology at the University of Florida, Gainesville.

“The U.K. data are the first data on topiramate risks during pregnancy,” Dr. Meador said in an interview. “The data suggest an association of increased malformations with topiramate exposure during pregnancy. However, the sample is small and the confidence intervals are large, so no definitive conclusion can be drawn.”

Because the results are preliminary, clinicians and their patients should be cautious about medication changes, said Dr. Martha Morrell, director of the Columbia Comprehensive Epilepsy Center, New York.

The analysis was drawn from the U.K. Epilepsy and Pregnancy Register. The present study included outcomes for 203 pregnancies with exposure to topiramate during the first trimester. Most of the women (133) were taking the drug as part of a polytherapy regimen (mean topiramate dose, 299 mg/day); the rest were on topiramate monotherapy (mean dose 245 mg/day).

Of all these pregnancies, 178 (88%) resulted in a live birth; there were a total of 31 congenital anomalies among these infants (16 major and 15 minor).

Among women on monotherapy, there were eight infants born with anomalies, three of which were considered major. Two infants had a cleft lip/palate, and one had hypospadias. The average daily dose of topiramate for the mothers of these infants was 400 mg/day, compared with the average 238 mg dose among women on monotherapy who had normal pregnancy outcomes.

The five minor anomalies in the monotherapy group were sacral dimple, “clicky” hips, plagiocephaly, webbed toes, and immature hip joints.

The combination of valproate with topiramate was associated with the highest rate of major congenital malformations (36%; 12 cases), followed by a regimen of three or more antiepileptic drugs (24%; 23 cases). Conversely, only 8% of polytherapy regimens that did not include valproate resulted in a major anomaly.

Janssen-Cilag, U.K. manufacturer of topiramate (Topamax), and other pharmaceutical firms provided unrestricted educational grants to help support to study. Several of the study authors have received honoraria from Janssen-Cilag and other pharmaceutical firms.

Topiramate is associated with a significantly increased risk of major congenital malformations, whether given as monotherapy or as part of a polytherapy antiepileptic regimen, Dr. Stephen Hunt and his colleagues have reported.

Although the associations were strong—an 11-fold increase in the risk of oral clefts and a 14-fold increase in the risk of hypospadias, compared with background rates in the United Kingdom—the confidence intervals surrounding them were wide, noted Dr. Hunt of the Royal Group of Hospitals, Belfast, Ireland. Therefore, the data “should be interpreted with caution,” he and his colleagues wrote (Neurology 2008;71:272-6).

The U.K. registry is one of three national registries that track pregnancy outcomes in women taking antiepileptic drugs. Neither of the others—a North American and an Australian registry—has reported an association between topiramate and birth defects, said Dr. Kimford Meador, the Melvin Greer Professor of Neurology at the University of Florida, Gainesville.

“The U.K. data are the first data on topiramate risks during pregnancy,” Dr. Meador said in an interview. “The data suggest an association of increased malformations with topiramate exposure during pregnancy. However, the sample is small and the confidence intervals are large, so no definitive conclusion can be drawn.”

Because the results are preliminary, clinicians and their patients should be cautious about medication changes, said Dr. Martha Morrell, director of the Columbia Comprehensive Epilepsy Center, New York.

The analysis was drawn from the U.K. Epilepsy and Pregnancy Register. The present study included outcomes for 203 pregnancies with exposure to topiramate during the first trimester. Most of the women (133) were taking the drug as part of a polytherapy regimen (mean topiramate dose, 299 mg/day); the rest were on topiramate monotherapy (mean dose 245 mg/day).

Of all these pregnancies, 178 (88%) resulted in a live birth; there were a total of 31 congenital anomalies among these infants (16 major and 15 minor).

Among women on monotherapy, there were eight infants born with anomalies, three of which were considered major. Two infants had a cleft lip/palate, and one had hypospadias. The average daily dose of topiramate for the mothers of these infants was 400 mg/day, compared with the average 238 mg dose among women on monotherapy who had normal pregnancy outcomes.

The five minor anomalies in the monotherapy group were sacral dimple, “clicky” hips, plagiocephaly, webbed toes, and immature hip joints.

The combination of valproate with topiramate was associated with the highest rate of major congenital malformations (36%; 12 cases), followed by a regimen of three or more antiepileptic drugs (24%; 23 cases). Conversely, only 8% of polytherapy regimens that did not include valproate resulted in a major anomaly.

Janssen-Cilag, U.K. manufacturer of topiramate (Topamax), and other pharmaceutical firms provided unrestricted educational grants to help support to study. Several of the study authors have received honoraria from Janssen-Cilag and other pharmaceutical firms.

CHICAGO – Keeping fit may help reduce brain atrophy in patients with early Alzheimer's, researchers said at the International Conference on Alzheimer's Disease.

An exercise-tolerance study confirmed that the hippocampus, one of the first brain regions to be affected in Alzheimer's, was significantly larger among patients who had higher fitness levels, Dr. Jeffrey Burns said at the meeting, which was sponsored by the Alzheimer's Association.

The association was also found with whole-brain volume during a previous study in the same cohort, Dr. Burns said in an interview. “Our data suggest that those in the lower half of fitness level have four times more brain atrophy than those in the higher-fitness group, compared to normal aging,” said Dr. Burns, director of the Hoglund Brain Imaging Center at the University of Kansas, Kansas City.

“Although we're a long way from proving that exercise decreases brain atrophy in Alzheimer's, this study certainly suggests that maintaining fitness has some kind of disease-specific effect.”

Dr. Burns and his colleague, Robyn Honea, Ph.D., evaluated cardiorespiratory fitness in 119 subjects older than 60 years; 56 had no dementia, while 63 had early-stage Alzheimer's.

All of the subjects undertook a treadmill test, which measured peak oxygen consumption during the most strenuous part of the test. All subjects also underwent magnetic resonance imaging to determine brain volume, Dr. Burns said in an interview.

All of the Alzheimer's patients showed disease-related atrophy in the hippocampus, temporal cortex, and parietal cortices. But those patients who had higher fitness levels had significantly greater white matter volume in the hippocampus, inferior temporal gyrus, and precentral gyrus.

“We found that the level of fitness was strongly related to volume in the parietal area, and also in the hippocampus,” Dr. Burns said. “That was most interesting because this is an area that's affected early in Alzheimer's, and the brain undergoes a lot of atrophy in that region as the disease progresses.”

Because the measurement tool–voxel-based morphometry–only provides a linear correlation, it was not possible to characterize the percentage of volume preserved in subjects who were more fit. “But on the whole, people who were more fit had larger brains, suggesting that maintaining fitness may slow the brain atrophy process in Alzheimer's,” Dr. Burns said.

Some animal studies suggest that exercise directly influences the disease process through a variety of pathways. “It may do something to the amyloid, but we also see lots of other changes in the body related to exercise. There are hormonal changes, changes in growth factors within the brain, and increased cerebral blood flow during exercise, which may increase brain vascularization.”

As understanding of the relationship grows, exercise prescriptions could become part of an Alzheimer's treatment program, Dr. Burns suggested.

“We want to be able to prescribe exercise and tell people how much is effective, but we're not there yet. The best advice we can give right now is what's good for the heart is good for the brain.”

The study presented at the meeting was the second study on this cohort, he added. In July, Dr. Burns and Dr. Honea published results showing that fitness positively influenced whole-brain volume in these same patients with early Alzheimer's (Neurology 2008;71:210-6).

Neither of the researchers disclosed any potential conflicts of interest.

CHICAGO – Keeping fit may help reduce brain atrophy in patients with early Alzheimer's, researchers said at the International Conference on Alzheimer's Disease.

An exercise-tolerance study confirmed that the hippocampus, one of the first brain regions to be affected in Alzheimer's, was significantly larger among patients who had higher fitness levels, Dr. Jeffrey Burns said at the meeting, which was sponsored by the Alzheimer's Association.

The association was also found with whole-brain volume during a previous study in the same cohort, Dr. Burns said in an interview. “Our data suggest that those in the lower half of fitness level have four times more brain atrophy than those in the higher-fitness group, compared to normal aging,” said Dr. Burns, director of the Hoglund Brain Imaging Center at the University of Kansas, Kansas City.

“Although we're a long way from proving that exercise decreases brain atrophy in Alzheimer's, this study certainly suggests that maintaining fitness has some kind of disease-specific effect.”

Dr. Burns and his colleague, Robyn Honea, Ph.D., evaluated cardiorespiratory fitness in 119 subjects older than 60 years; 56 had no dementia, while 63 had early-stage Alzheimer's.

All of the subjects undertook a treadmill test, which measured peak oxygen consumption during the most strenuous part of the test. All subjects also underwent magnetic resonance imaging to determine brain volume, Dr. Burns said in an interview.

All of the Alzheimer's patients showed disease-related atrophy in the hippocampus, temporal cortex, and parietal cortices. But those patients who had higher fitness levels had significantly greater white matter volume in the hippocampus, inferior temporal gyrus, and precentral gyrus.

“We found that the level of fitness was strongly related to volume in the parietal area, and also in the hippocampus,” Dr. Burns said. “That was most interesting because this is an area that's affected early in Alzheimer's, and the brain undergoes a lot of atrophy in that region as the disease progresses.”

Because the measurement tool–voxel-based morphometry–only provides a linear correlation, it was not possible to characterize the percentage of volume preserved in subjects who were more fit. “But on the whole, people who were more fit had larger brains, suggesting that maintaining fitness may slow the brain atrophy process in Alzheimer's,” Dr. Burns said.

Some animal studies suggest that exercise directly influences the disease process through a variety of pathways. “It may do something to the amyloid, but we also see lots of other changes in the body related to exercise. There are hormonal changes, changes in growth factors within the brain, and increased cerebral blood flow during exercise, which may increase brain vascularization.”

As understanding of the relationship grows, exercise prescriptions could become part of an Alzheimer's treatment program, Dr. Burns suggested.

“We want to be able to prescribe exercise and tell people how much is effective, but we're not there yet. The best advice we can give right now is what's good for the heart is good for the brain.”

The study presented at the meeting was the second study on this cohort, he added. In July, Dr. Burns and Dr. Honea published results showing that fitness positively influenced whole-brain volume in these same patients with early Alzheimer's (Neurology 2008;71:210-6).

Neither of the researchers disclosed any potential conflicts of interest.

CHICAGO – Keeping fit may help reduce brain atrophy in patients with early Alzheimer's, researchers said at the International Conference on Alzheimer's Disease.

An exercise-tolerance study confirmed that the hippocampus, one of the first brain regions to be affected in Alzheimer's, was significantly larger among patients who had higher fitness levels, Dr. Jeffrey Burns said at the meeting, which was sponsored by the Alzheimer's Association.

The association was also found with whole-brain volume during a previous study in the same cohort, Dr. Burns said in an interview. “Our data suggest that those in the lower half of fitness level have four times more brain atrophy than those in the higher-fitness group, compared to normal aging,” said Dr. Burns, director of the Hoglund Brain Imaging Center at the University of Kansas, Kansas City.

“Although we're a long way from proving that exercise decreases brain atrophy in Alzheimer's, this study certainly suggests that maintaining fitness has some kind of disease-specific effect.”

Dr. Burns and his colleague, Robyn Honea, Ph.D., evaluated cardiorespiratory fitness in 119 subjects older than 60 years; 56 had no dementia, while 63 had early-stage Alzheimer's.

All of the subjects undertook a treadmill test, which measured peak oxygen consumption during the most strenuous part of the test. All subjects also underwent magnetic resonance imaging to determine brain volume, Dr. Burns said in an interview.

All of the Alzheimer's patients showed disease-related atrophy in the hippocampus, temporal cortex, and parietal cortices. But those patients who had higher fitness levels had significantly greater white matter volume in the hippocampus, inferior temporal gyrus, and precentral gyrus.

“We found that the level of fitness was strongly related to volume in the parietal area, and also in the hippocampus,” Dr. Burns said. “That was most interesting because this is an area that's affected early in Alzheimer's, and the brain undergoes a lot of atrophy in that region as the disease progresses.”

Because the measurement tool–voxel-based morphometry–only provides a linear correlation, it was not possible to characterize the percentage of volume preserved in subjects who were more fit. “But on the whole, people who were more fit had larger brains, suggesting that maintaining fitness may slow the brain atrophy process in Alzheimer's,” Dr. Burns said.

Some animal studies suggest that exercise directly influences the disease process through a variety of pathways. “It may do something to the amyloid, but we also see lots of other changes in the body related to exercise. There are hormonal changes, changes in growth factors within the brain, and increased cerebral blood flow during exercise, which may increase brain vascularization.”

As understanding of the relationship grows, exercise prescriptions could become part of an Alzheimer's treatment program, Dr. Burns suggested.

“We want to be able to prescribe exercise and tell people how much is effective, but we're not there yet. The best advice we can give right now is what's good for the heart is good for the brain.”

The study presented at the meeting was the second study on this cohort, he added. In July, Dr. Burns and Dr. Honea published results showing that fitness positively influenced whole-brain volume in these same patients with early Alzheimer's (Neurology 2008;71:210-6).

Neither of the researchers disclosed any potential conflicts of interest.

Perioperative β-blockers may reduce the risk of myocardial infarction after noncardiac surgery, but they confer a doubling in the risk of disabling strokes, especially among lower-risk patients, according to a meta-analysis of 33 randomized controlled trials.

In light of these findings, the guideline committee of the American College of Cardiology, which recommends the drugs for patients undergoing noncardiac surgery, “should soften their stance on perioperative β-blockade until definitive evidence shows clear benefit,” Dr. Sripal Bangalore wrote in an article published online in The Lancet (doi:10.1016/S0140-6736(08)61560-3). “β-Blockers should not be routinely used for perioperative treatment … unless patients are already taking them for clinically indicated reasons.”

The risks associated with β-blockers were most apparent in trials that included low- to intermediate-risk patients, particularly the recent Perioperative Ischemic Evaluation (POISE) trial, which is considered a landmark study (Lancet 2008;371:1839–47). POISE, which included more than 8,300 patients randomized to extended-release metoprolol succinate or placebo before surgery, found a doubling in the risk of stroke among those in the active group.

The drugs also were associated with significant increases in other cardiac problems, wrote Dr. Bangalore of Brigham and Women's Hospital, Boston, and his colleagues. “For the overall cohort, we estimate that treatment of 1,000 patients with β-blockers results in 16 fewer nonfatal myocardial infarctions in survivors, but at the expense of three disabling strokes, 45 patients with clinically significant perioperative bradycardia, 59 with hypotension, and potentially increased mortality.”

The 33 trials included in the meta-analysis comprised 12,300 patients: 6,300 randomly assigned to β-blockers and 6,000 given placebo. The trials varied with regard to the drug used, the dosage, and the timing and duration of administration.

Overall, β-blockers did not result in any significant decrease in the risk of all-cause mortality, cardiovascular mortality, or heart failure. There was a 35% decreased risk of nonfatal heart attack (number needed to treat [NNT]: 63), and a 64% decreased risk of myocardial ischemia (NNT: 16). But the investigators also found a 116% increased risk of nonfatal stroke (number needed to harm [NNH]: 275), based on trials with low- or intermediate-risk patients.

β-Blockade also resulted in a tripling of the risk of perioperative bradycardia (NNH: 8), as well as a 70% increased risk of perioperative hypotension (NNH: 17).

When the researchers examined outcomes according to the risk level of patients in each trial, trials including high-risk patients drove the beneficial effects of β-blockers, while trials with low- or intermediate-risk patients drove the risks.

In high-risk trials, the investigators found no increased risk of all-cause mortality, an 81% decreased risk of nonfatal MI (NNT: 15), and a 69% decreased risk of MI (NNT: 9), although there were no significant benefits for cardiovascular mortality or heart failure.

Trials conducted using low- or intermediate-risk patients found a 28% increased risk of all-cause mortality (NNH: 164), and a 116% increased risk of nonfatal stroke (NNH: 275), with a 28% decreased risk of nonfatal MI (NNT: 80), a 59% decreased risk of myocardial ischemia (NNT: 23), and no reduction in rates of cardiovascular mortality or heart failure.

The POISE trial carried the most statistical weight among lower-risk trials, while a 1999 study drove the findings among high-risk trials. That study randomized 59 high-risk patients to perioperative bisoprolol or standard care. Nine patients in the standard-care group and two in the bisoprolol group died of cardiac causes during the perioperative period (N. Eng. J. Med. 1999;341:1789–94).

This study had no sponsors, noted the authors, none of whom declared any financial conflicts of interest.

Perioperative β-blockers may reduce the risk of myocardial infarction after noncardiac surgery, but they confer a doubling in the risk of disabling strokes, especially among lower-risk patients, according to a meta-analysis of 33 randomized controlled trials.

In light of these findings, the guideline committee of the American College of Cardiology, which recommends the drugs for patients undergoing noncardiac surgery, “should soften their stance on perioperative β-blockade until definitive evidence shows clear benefit,” Dr. Sripal Bangalore wrote in an article published online in The Lancet (doi:10.1016/S0140-6736(08)61560-3). “β-Blockers should not be routinely used for perioperative treatment … unless patients are already taking them for clinically indicated reasons.”

The risks associated with β-blockers were most apparent in trials that included low- to intermediate-risk patients, particularly the recent Perioperative Ischemic Evaluation (POISE) trial, which is considered a landmark study (Lancet 2008;371:1839–47). POISE, which included more than 8,300 patients randomized to extended-release metoprolol succinate or placebo before surgery, found a doubling in the risk of stroke among those in the active group.

The drugs also were associated with significant increases in other cardiac problems, wrote Dr. Bangalore of Brigham and Women's Hospital, Boston, and his colleagues. “For the overall cohort, we estimate that treatment of 1,000 patients with β-blockers results in 16 fewer nonfatal myocardial infarctions in survivors, but at the expense of three disabling strokes, 45 patients with clinically significant perioperative bradycardia, 59 with hypotension, and potentially increased mortality.”

The 33 trials included in the meta-analysis comprised 12,300 patients: 6,300 randomly assigned to β-blockers and 6,000 given placebo. The trials varied with regard to the drug used, the dosage, and the timing and duration of administration.

Overall, β-blockers did not result in any significant decrease in the risk of all-cause mortality, cardiovascular mortality, or heart failure. There was a 35% decreased risk of nonfatal heart attack (number needed to treat [NNT]: 63), and a 64% decreased risk of myocardial ischemia (NNT: 16). But the investigators also found a 116% increased risk of nonfatal stroke (number needed to harm [NNH]: 275), based on trials with low- or intermediate-risk patients.

β-Blockade also resulted in a tripling of the risk of perioperative bradycardia (NNH: 8), as well as a 70% increased risk of perioperative hypotension (NNH: 17).

When the researchers examined outcomes according to the risk level of patients in each trial, trials including high-risk patients drove the beneficial effects of β-blockers, while trials with low- or intermediate-risk patients drove the risks.

In high-risk trials, the investigators found no increased risk of all-cause mortality, an 81% decreased risk of nonfatal MI (NNT: 15), and a 69% decreased risk of MI (NNT: 9), although there were no significant benefits for cardiovascular mortality or heart failure.

Trials conducted using low- or intermediate-risk patients found a 28% increased risk of all-cause mortality (NNH: 164), and a 116% increased risk of nonfatal stroke (NNH: 275), with a 28% decreased risk of nonfatal MI (NNT: 80), a 59% decreased risk of myocardial ischemia (NNT: 23), and no reduction in rates of cardiovascular mortality or heart failure.

The POISE trial carried the most statistical weight among lower-risk trials, while a 1999 study drove the findings among high-risk trials. That study randomized 59 high-risk patients to perioperative bisoprolol or standard care. Nine patients in the standard-care group and two in the bisoprolol group died of cardiac causes during the perioperative period (N. Eng. J. Med. 1999;341:1789–94).

This study had no sponsors, noted the authors, none of whom declared any financial conflicts of interest.

Perioperative β-blockers may reduce the risk of myocardial infarction after noncardiac surgery, but they confer a doubling in the risk of disabling strokes, especially among lower-risk patients, according to a meta-analysis of 33 randomized controlled trials.

In light of these findings, the guideline committee of the American College of Cardiology, which recommends the drugs for patients undergoing noncardiac surgery, “should soften their stance on perioperative β-blockade until definitive evidence shows clear benefit,” Dr. Sripal Bangalore wrote in an article published online in The Lancet (doi:10.1016/S0140-6736(08)61560-3). “β-Blockers should not be routinely used for perioperative treatment … unless patients are already taking them for clinically indicated reasons.”

The risks associated with β-blockers were most apparent in trials that included low- to intermediate-risk patients, particularly the recent Perioperative Ischemic Evaluation (POISE) trial, which is considered a landmark study (Lancet 2008;371:1839–47). POISE, which included more than 8,300 patients randomized to extended-release metoprolol succinate or placebo before surgery, found a doubling in the risk of stroke among those in the active group.

The drugs also were associated with significant increases in other cardiac problems, wrote Dr. Bangalore of Brigham and Women's Hospital, Boston, and his colleagues. “For the overall cohort, we estimate that treatment of 1,000 patients with β-blockers results in 16 fewer nonfatal myocardial infarctions in survivors, but at the expense of three disabling strokes, 45 patients with clinically significant perioperative bradycardia, 59 with hypotension, and potentially increased mortality.”

The 33 trials included in the meta-analysis comprised 12,300 patients: 6,300 randomly assigned to β-blockers and 6,000 given placebo. The trials varied with regard to the drug used, the dosage, and the timing and duration of administration.

Overall, β-blockers did not result in any significant decrease in the risk of all-cause mortality, cardiovascular mortality, or heart failure. There was a 35% decreased risk of nonfatal heart attack (number needed to treat [NNT]: 63), and a 64% decreased risk of myocardial ischemia (NNT: 16). But the investigators also found a 116% increased risk of nonfatal stroke (number needed to harm [NNH]: 275), based on trials with low- or intermediate-risk patients.

β-Blockade also resulted in a tripling of the risk of perioperative bradycardia (NNH: 8), as well as a 70% increased risk of perioperative hypotension (NNH: 17).

When the researchers examined outcomes according to the risk level of patients in each trial, trials including high-risk patients drove the beneficial effects of β-blockers, while trials with low- or intermediate-risk patients drove the risks.

In high-risk trials, the investigators found no increased risk of all-cause mortality, an 81% decreased risk of nonfatal MI (NNT: 15), and a 69% decreased risk of MI (NNT: 9), although there were no significant benefits for cardiovascular mortality or heart failure.

Trials conducted using low- or intermediate-risk patients found a 28% increased risk of all-cause mortality (NNH: 164), and a 116% increased risk of nonfatal stroke (NNH: 275), with a 28% decreased risk of nonfatal MI (NNT: 80), a 59% decreased risk of myocardial ischemia (NNT: 23), and no reduction in rates of cardiovascular mortality or heart failure.

The POISE trial carried the most statistical weight among lower-risk trials, while a 1999 study drove the findings among high-risk trials. That study randomized 59 high-risk patients to perioperative bisoprolol or standard care. Nine patients in the standard-care group and two in the bisoprolol group died of cardiac causes during the perioperative period (N. Eng. J. Med. 1999;341:1789–94).

This study had no sponsors, noted the authors, none of whom declared any financial conflicts of interest.

SAN FRANCISCO — Community-associated methicillin-resistant Staphylococcus aureus—almost unheard of 10 years ago—has become the single biggest cause of skin infections in the United States, Dr. Greg Moran said at the 12th International Conference on Emergency Medicine.

“We really don't know what's begun this sudden explosion of resistant staph in the community all over the United States, as well as in Canada and Europe,” said Dr. Moran, an emergency physician at the Olive View-UCLA Medical Center, Sylmar, Calif. “One thing we do know is that this is not a phenomenon of the hospital strains moving into the community. These are genetically distinct strains.”

The hospital strains are usually USA100 and 200, while the overwhelming majority of the community strains are USA300. In his 2006 study, virtually all skin infections cultured from hospitals in 11 cities across the country were caused by community-associated strains; 78% of those were a single clone of USA300. “There is something about this strain that has given it a very, very strong survival advantage in the community,” Dr. Moran said. “Almost all of [the skin infections] (98%) carried the Panton-Valentine leukocidin toxin gene and the SCCmec type IV gene.”

The SCCmec gene confers methicillin resistance, while the Panton-Valentine leukocidin toxin gene is associated with spontaneous skin and soft-tissue infections, as well as necrotizing pneumonia. The mutations make the community-associated MRSA strains much more likely to cause infections than those MRSA strains found in hospitals, he said.

In addition to authoring a seminal paper on the topic (N. Engl. J. Med. 2006;355:666-74), Dr. Moran has kept track of the MRSA skin infections occurring in his own hospital since 1997. There were 25 cases documented that year. “That number rose to almost 450 per year in 2006 and 2007,” he said. “In 2001, 29% of our skin infections were MRSA. That more than doubled by 2003–2004, to 64%. In a very short time, we went from something we virtually never saw in the community, to it being the single largest cause of skin infections.”

A few clinical features are associated with an increased risk of the community-associated MRSA infections, Dr. Moran said, including recent antibiotic use, abscess, a history of “spider bite” (insect bite of unknown origin), prior MRSA infection, and close contact with a MRSA-infected individual. But none of those was a strong predictor.

“The reality is you can't use any of these risk factors to decide who you're going to treat for MRSA,” he said. Despite their prevalence, most of these infections are not serious and don't grow the “killer flesh-eating super bugs” touted in grocery store tabloids, Dr. Moran said. “We still have a number of antibiotic options. More than 90% of the isolates in our study were susceptible to at least one agent.”

Dr. Moran made these comments about the available antibiotic choices:

▸ Vancomycin. “Even though this is the gold standard, we are now recognizing its limitations. We are seeing more resistance to this than we used to.”

▸ Clindamycin. “Ninety-five percent of the isolates were susceptible to this in our study, although that appears to be decreasing. In our hospital, susceptibility is now down to about 85%.”

▸ Linezolid. “It's very effective, but also very, very expensive. Post hoc data suggest that it may be clinically superior for hospital-acquired MRSA pneumonia, but there are no prospective data on this. It's a good drug, but I think it's prohibitively expensive.”

▸ Daptomycin. “Very good for skin infections, but we don't use it for MRSA pneumonia—it binds to the pulmonary surfactant and is inactivated.”

▸ Tigecycline. “This is a good choice when you want both gram-negative and gram-positive activity.”

▸ Trimethoprim sulfa. “This is close to 100% effective in vitro, but there isn't much clinical data for its use in skin infections.”

▸ Tetracycline. “It's a cheap generic with reasonable effectiveness.”

Current studies conclude that there's no real benefit to adding antibiotics to the treatment regimen, he said. However, there are many limitations to those studies: Many had small treatment numbers and were done before the MRSA phenomenon, he added. Therefore, more aggressive treatment may be warranted now. “The truth is, we don't know the answer.”

For most uncomplicated skin infections, he performs an incision and drainage, and doesn't give antibiotics. However, “I do give antibiotics if there is a fever, significant associated cellulitis, immune or vascular compromise, if the lesion is in a high-risk area like the hands or face, or if the patient has already failed an incision and drainage,” he explained.

SAN FRANCISCO — Community-associated methicillin-resistant Staphylococcus aureus—almost unheard of 10 years ago—has become the single biggest cause of skin infections in the United States, Dr. Greg Moran said at the 12th International Conference on Emergency Medicine.

“We really don't know what's begun this sudden explosion of resistant staph in the community all over the United States, as well as in Canada and Europe,” said Dr. Moran, an emergency physician at the Olive View-UCLA Medical Center, Sylmar, Calif. “One thing we do know is that this is not a phenomenon of the hospital strains moving into the community. These are genetically distinct strains.”

The hospital strains are usually USA100 and 200, while the overwhelming majority of the community strains are USA300. In his 2006 study, virtually all skin infections cultured from hospitals in 11 cities across the country were caused by community-associated strains; 78% of those were a single clone of USA300. “There is something about this strain that has given it a very, very strong survival advantage in the community,” Dr. Moran said. “Almost all of [the skin infections] (98%) carried the Panton-Valentine leukocidin toxin gene and the SCCmec type IV gene.”

The SCCmec gene confers methicillin resistance, while the Panton-Valentine leukocidin toxin gene is associated with spontaneous skin and soft-tissue infections, as well as necrotizing pneumonia. The mutations make the community-associated MRSA strains much more likely to cause infections than those MRSA strains found in hospitals, he said.

In addition to authoring a seminal paper on the topic (N. Engl. J. Med. 2006;355:666-74), Dr. Moran has kept track of the MRSA skin infections occurring in his own hospital since 1997. There were 25 cases documented that year. “That number rose to almost 450 per year in 2006 and 2007,” he said. “In 2001, 29% of our skin infections were MRSA. That more than doubled by 2003–2004, to 64%. In a very short time, we went from something we virtually never saw in the community, to it being the single largest cause of skin infections.”

A few clinical features are associated with an increased risk of the community-associated MRSA infections, Dr. Moran said, including recent antibiotic use, abscess, a history of “spider bite” (insect bite of unknown origin), prior MRSA infection, and close contact with a MRSA-infected individual. But none of those was a strong predictor.

“The reality is you can't use any of these risk factors to decide who you're going to treat for MRSA,” he said. Despite their prevalence, most of these infections are not serious and don't grow the “killer flesh-eating super bugs” touted in grocery store tabloids, Dr. Moran said. “We still have a number of antibiotic options. More than 90% of the isolates in our study were susceptible to at least one agent.”

Dr. Moran made these comments about the available antibiotic choices:

▸ Vancomycin. “Even though this is the gold standard, we are now recognizing its limitations. We are seeing more resistance to this than we used to.”

▸ Clindamycin. “Ninety-five percent of the isolates were susceptible to this in our study, although that appears to be decreasing. In our hospital, susceptibility is now down to about 85%.”

▸ Linezolid. “It's very effective, but also very, very expensive. Post hoc data suggest that it may be clinically superior for hospital-acquired MRSA pneumonia, but there are no prospective data on this. It's a good drug, but I think it's prohibitively expensive.”

▸ Daptomycin. “Very good for skin infections, but we don't use it for MRSA pneumonia—it binds to the pulmonary surfactant and is inactivated.”

▸ Tigecycline. “This is a good choice when you want both gram-negative and gram-positive activity.”

▸ Trimethoprim sulfa. “This is close to 100% effective in vitro, but there isn't much clinical data for its use in skin infections.”

▸ Tetracycline. “It's a cheap generic with reasonable effectiveness.”

Current studies conclude that there's no real benefit to adding antibiotics to the treatment regimen, he said. However, there are many limitations to those studies: Many had small treatment numbers and were done before the MRSA phenomenon, he added. Therefore, more aggressive treatment may be warranted now. “The truth is, we don't know the answer.”

For most uncomplicated skin infections, he performs an incision and drainage, and doesn't give antibiotics. However, “I do give antibiotics if there is a fever, significant associated cellulitis, immune or vascular compromise, if the lesion is in a high-risk area like the hands or face, or if the patient has already failed an incision and drainage,” he explained.

SAN FRANCISCO — Community-associated methicillin-resistant Staphylococcus aureus—almost unheard of 10 years ago—has become the single biggest cause of skin infections in the United States, Dr. Greg Moran said at the 12th International Conference on Emergency Medicine.

“We really don't know what's begun this sudden explosion of resistant staph in the community all over the United States, as well as in Canada and Europe,” said Dr. Moran, an emergency physician at the Olive View-UCLA Medical Center, Sylmar, Calif. “One thing we do know is that this is not a phenomenon of the hospital strains moving into the community. These are genetically distinct strains.”

The hospital strains are usually USA100 and 200, while the overwhelming majority of the community strains are USA300. In his 2006 study, virtually all skin infections cultured from hospitals in 11 cities across the country were caused by community-associated strains; 78% of those were a single clone of USA300. “There is something about this strain that has given it a very, very strong survival advantage in the community,” Dr. Moran said. “Almost all of [the skin infections] (98%) carried the Panton-Valentine leukocidin toxin gene and the SCCmec type IV gene.”

The SCCmec gene confers methicillin resistance, while the Panton-Valentine leukocidin toxin gene is associated with spontaneous skin and soft-tissue infections, as well as necrotizing pneumonia. The mutations make the community-associated MRSA strains much more likely to cause infections than those MRSA strains found in hospitals, he said.

In addition to authoring a seminal paper on the topic (N. Engl. J. Med. 2006;355:666-74), Dr. Moran has kept track of the MRSA skin infections occurring in his own hospital since 1997. There were 25 cases documented that year. “That number rose to almost 450 per year in 2006 and 2007,” he said. “In 2001, 29% of our skin infections were MRSA. That more than doubled by 2003–2004, to 64%. In a very short time, we went from something we virtually never saw in the community, to it being the single largest cause of skin infections.”

A few clinical features are associated with an increased risk of the community-associated MRSA infections, Dr. Moran said, including recent antibiotic use, abscess, a history of “spider bite” (insect bite of unknown origin), prior MRSA infection, and close contact with a MRSA-infected individual. But none of those was a strong predictor.

“The reality is you can't use any of these risk factors to decide who you're going to treat for MRSA,” he said. Despite their prevalence, most of these infections are not serious and don't grow the “killer flesh-eating super bugs” touted in grocery store tabloids, Dr. Moran said. “We still have a number of antibiotic options. More than 90% of the isolates in our study were susceptible to at least one agent.”

Dr. Moran made these comments about the available antibiotic choices:

▸ Vancomycin. “Even though this is the gold standard, we are now recognizing its limitations. We are seeing more resistance to this than we used to.”

▸ Clindamycin. “Ninety-five percent of the isolates were susceptible to this in our study, although that appears to be decreasing. In our hospital, susceptibility is now down to about 85%.”

▸ Linezolid. “It's very effective, but also very, very expensive. Post hoc data suggest that it may be clinically superior for hospital-acquired MRSA pneumonia, but there are no prospective data on this. It's a good drug, but I think it's prohibitively expensive.”

▸ Daptomycin. “Very good for skin infections, but we don't use it for MRSA pneumonia—it binds to the pulmonary surfactant and is inactivated.”

▸ Tigecycline. “This is a good choice when you want both gram-negative and gram-positive activity.”

▸ Trimethoprim sulfa. “This is close to 100% effective in vitro, but there isn't much clinical data for its use in skin infections.”

▸ Tetracycline. “It's a cheap generic with reasonable effectiveness.”

Current studies conclude that there's no real benefit to adding antibiotics to the treatment regimen, he said. However, there are many limitations to those studies: Many had small treatment numbers and were done before the MRSA phenomenon, he added. Therefore, more aggressive treatment may be warranted now. “The truth is, we don't know the answer.”

For most uncomplicated skin infections, he performs an incision and drainage, and doesn't give antibiotics. However, “I do give antibiotics if there is a fever, significant associated cellulitis, immune or vascular compromise, if the lesion is in a high-risk area like the hands or face, or if the patient has already failed an incision and drainage,” he explained.

SAN FRANCISCO — A diagnosis of subclinical hyperthyroidism significantly increases the risk of death from any cause in the subsequent 10 years, especially among elderly patients, according to Dr. Patrick Haentjens.

The increased risk of death starts low and increases up until about age 80, with an overall increased risk of 41%, Dr. Haentjens said at the annual meeting of the Endocrine Society. After age 80, competing causes of death eliminate the association with thyroid dysfunction.

When translated to an absolute risk of death, excess mortality for a white U.S. woman diagnosed at age 70 was only 1.5% at 2 years, but increased to almost 9% by 10 years, said Dr. Haentjens of the Center for Outcomes Research, University of Ziekenhuis, Brussels. Men seemed to fare worse; for a white U.S. man diagnosed at age 70, the excess mortality risk was 2% at 2 years, 6% at 5 years, and almost 11% at 10 years after the diagnosis.

However, Dr. Haentjens' meta-analysis found no significantly increased mortality risk associated with subclinical hypothyroidism. The study was published online in the European Journal of Endocrinology (doi:10.1530/EJE-08-0110

The meta-analysis included nine papers, which reported data on seven cohorts with subclinical hyperthyroidism (290 patients) and nine cohorts with subclinical hypothyroidism (1,580 patients). The individual studies compared long-term outcomes among these patients and 13,000 euthyroid controls. Follow-up ranged from 2 to 20 years.

Among the seven cohorts with subclinical hyperthyroidism, the hazard ratio for all-cause mortality ranged from 0.84 to 2.22. Only one paper (Lancet 2001;358:861-5) found a significant increase. However, in the pooled analysis, the overall risk was significantly increased, with a hazard ratio of 1.41, compared with euthyroid controls. Among the nine cohorts that explored all-cause mortality in patients with subclinical hypothyroidism, the hazard ratio ranged from 0.49 to 2. Three studies found significant differences, but one of them reported a significantly decreased risk of all-cause mortality, while the other two reported a significantly increased risk. Overall, the pooled analysis did not show an increased all-cause mortality risk.

SAN FRANCISCO — A diagnosis of subclinical hyperthyroidism significantly increases the risk of death from any cause in the subsequent 10 years, especially among elderly patients, according to Dr. Patrick Haentjens.

The increased risk of death starts low and increases up until about age 80, with an overall increased risk of 41%, Dr. Haentjens said at the annual meeting of the Endocrine Society. After age 80, competing causes of death eliminate the association with thyroid dysfunction.

When translated to an absolute risk of death, excess mortality for a white U.S. woman diagnosed at age 70 was only 1.5% at 2 years, but increased to almost 9% by 10 years, said Dr. Haentjens of the Center for Outcomes Research, University of Ziekenhuis, Brussels. Men seemed to fare worse; for a white U.S. man diagnosed at age 70, the excess mortality risk was 2% at 2 years, 6% at 5 years, and almost 11% at 10 years after the diagnosis.

However, Dr. Haentjens' meta-analysis found no significantly increased mortality risk associated with subclinical hypothyroidism. The study was published online in the European Journal of Endocrinology (doi:10.1530/EJE-08-0110

The meta-analysis included nine papers, which reported data on seven cohorts with subclinical hyperthyroidism (290 patients) and nine cohorts with subclinical hypothyroidism (1,580 patients). The individual studies compared long-term outcomes among these patients and 13,000 euthyroid controls. Follow-up ranged from 2 to 20 years.

Among the seven cohorts with subclinical hyperthyroidism, the hazard ratio for all-cause mortality ranged from 0.84 to 2.22. Only one paper (Lancet 2001;358:861-5) found a significant increase. However, in the pooled analysis, the overall risk was significantly increased, with a hazard ratio of 1.41, compared with euthyroid controls. Among the nine cohorts that explored all-cause mortality in patients with subclinical hypothyroidism, the hazard ratio ranged from 0.49 to 2. Three studies found significant differences, but one of them reported a significantly decreased risk of all-cause mortality, while the other two reported a significantly increased risk. Overall, the pooled analysis did not show an increased all-cause mortality risk.

SAN FRANCISCO — A diagnosis of subclinical hyperthyroidism significantly increases the risk of death from any cause in the subsequent 10 years, especially among elderly patients, according to Dr. Patrick Haentjens.

The increased risk of death starts low and increases up until about age 80, with an overall increased risk of 41%, Dr. Haentjens said at the annual meeting of the Endocrine Society. After age 80, competing causes of death eliminate the association with thyroid dysfunction.

When translated to an absolute risk of death, excess mortality for a white U.S. woman diagnosed at age 70 was only 1.5% at 2 years, but increased to almost 9% by 10 years, said Dr. Haentjens of the Center for Outcomes Research, University of Ziekenhuis, Brussels. Men seemed to fare worse; for a white U.S. man diagnosed at age 70, the excess mortality risk was 2% at 2 years, 6% at 5 years, and almost 11% at 10 years after the diagnosis.

However, Dr. Haentjens' meta-analysis found no significantly increased mortality risk associated with subclinical hypothyroidism. The study was published online in the European Journal of Endocrinology (doi:10.1530/EJE-08-0110

The meta-analysis included nine papers, which reported data on seven cohorts with subclinical hyperthyroidism (290 patients) and nine cohorts with subclinical hypothyroidism (1,580 patients). The individual studies compared long-term outcomes among these patients and 13,000 euthyroid controls. Follow-up ranged from 2 to 20 years.

Among the seven cohorts with subclinical hyperthyroidism, the hazard ratio for all-cause mortality ranged from 0.84 to 2.22. Only one paper (Lancet 2001;358:861-5) found a significant increase. However, in the pooled analysis, the overall risk was significantly increased, with a hazard ratio of 1.41, compared with euthyroid controls. Among the nine cohorts that explored all-cause mortality in patients with subclinical hypothyroidism, the hazard ratio ranged from 0.49 to 2. Three studies found significant differences, but one of them reported a significantly decreased risk of all-cause mortality, while the other two reported a significantly increased risk. Overall, the pooled analysis did not show an increased all-cause mortality risk.

SAN FRANCISCO — A few hours' buffer between taking thyroxine and other medications can help ensure optimal absorption of the thyroid hormone, according to several researchers.

Many nutritional supplements and commonly prescribed medications interfere with thyroid absorption, the researchers said at the annual meeting of the Endocrine Society. When taken together, some medications bind the hormone so completely that virtually none enters the bloodstream.

“In most cases, it's believed that malabsorption of levothyroxine is due to binding of the hormone to other medications in the gut lumen, forming an insoluble or nonabsorbable complex,” Dr. Steven P. Weitzman said in a poster presented at the meeting. Even newer compounds, which were thought to result in less malabsorption, seem to be problematic.

Dr. Weitzman, an endocrinologist at Stony Brook University, New York, examined the interaction of levothyroxine with two relatively new drugs—colesevelam (Welchol), the newest bile acid sequestrant approved for hyperlipidemia and diabetes; and lanthanum carbonate (Fosrenol), a new phosphate binder used in end-stage renal disease. The study included six healthy, euthyroid subjects, who first took levothyroxine 1 mg alone, then levothyroxine with 3.8 g colesevelam, then levothyroxine with 500 mg lanthanum carbonate. A minimum of 3 weeks separated each dosing study.

Total serum T₄ and TSH were measured at regular intervals during the 6 hours after administration of the study medications. Results were reported as both the area under the curve response and serum T₄ concentration.

Within 1 hour of taking levothyroxine alone, subjects displayed a sharp increase in serum T₄ from a mean of 7 mcg/dL to 10 mcg/dL. Serum T₄ peaked at 4 hours, reaching a mean level of 13 mcg/dL. The area under the curve response was 1,692 g-min/mL.

T₄ concentrations were significantly lower after the subjects took the hormone with lanthanum carbonate. At 1 hour, the T₄ level had risen to a mean of 8.6 mcg/dL. At 6 hours, the peak level was 11 mcg/dL. The area under the curve response was 982 g-min/mL.

Colesevelam exerted the largest inhibitory response on serum T₄. By 1 hour after taking the hormone and the medication together, mean T₄ levels rose to 7.6 mcg/dL and peaked there after 2 hours. The area under the curve response was only 107 g-min/mL.

“Both colesevelam and lanthanum carbonate reduced the absorption of levothyroxine and blunted the rise in serum T₄ when given with levothyroxine,” Dr. Weitzman said. “Colesevelam appeared to be a particularly potent inhibitor of T₄ absorption and nearly abolished the increase in serum T₄.

In a second study, Dr. Bandar Alshehri, an endocrinology fellow at the University of Toronto, and colleagues performed a chart review of 549 hospitalized patients treated with levothyroxine during a mean 11-day hospital stay. Most of these patients (67%) were also receiving supplements or drugs known to inhibit the absorption of T₄. The offending compounds were proton pump inhibitors (42%), calcium supplements (28%), iron supplements (15%), multivitamins (13%), psyllium fiber (12%), and magnesium-containing antacids or laxatives (1%).

Most of the patients (97%) received their levothyroxine during the daytime; the majority (88%) also got their other medications during the same period.

Ninety percent of patients were getting the hormone within 1 hour of the potentially interfering medications. Fewer than 1% received the medications at least 4 hours apart. A simple change—routine administration of levothyroxine at bedtime—could reduce the offending coadministration rate to around 19%, because the interfering medications are not usually administered at bedtime, Dr. Alshehri said.

SAN FRANCISCO — A few hours' buffer between taking thyroxine and other medications can help ensure optimal absorption of the thyroid hormone, according to several researchers.

Many nutritional supplements and commonly prescribed medications interfere with thyroid absorption, the researchers said at the annual meeting of the Endocrine Society. When taken together, some medications bind the hormone so completely that virtually none enters the bloodstream.

“In most cases, it's believed that malabsorption of levothyroxine is due to binding of the hormone to other medications in the gut lumen, forming an insoluble or nonabsorbable complex,” Dr. Steven P. Weitzman said in a poster presented at the meeting. Even newer compounds, which were thought to result in less malabsorption, seem to be problematic.

Dr. Weitzman, an endocrinologist at Stony Brook University, New York, examined the interaction of levothyroxine with two relatively new drugs—colesevelam (Welchol), the newest bile acid sequestrant approved for hyperlipidemia and diabetes; and lanthanum carbonate (Fosrenol), a new phosphate binder used in end-stage renal disease. The study included six healthy, euthyroid subjects, who first took levothyroxine 1 mg alone, then levothyroxine with 3.8 g colesevelam, then levothyroxine with 500 mg lanthanum carbonate. A minimum of 3 weeks separated each dosing study.

Total serum T₄ and TSH were measured at regular intervals during the 6 hours after administration of the study medications. Results were reported as both the area under the curve response and serum T₄ concentration.

Within 1 hour of taking levothyroxine alone, subjects displayed a sharp increase in serum T₄ from a mean of 7 mcg/dL to 10 mcg/dL. Serum T₄ peaked at 4 hours, reaching a mean level of 13 mcg/dL. The area under the curve response was 1,692 g-min/mL.

T₄ concentrations were significantly lower after the subjects took the hormone with lanthanum carbonate. At 1 hour, the T₄ level had risen to a mean of 8.6 mcg/dL. At 6 hours, the peak level was 11 mcg/dL. The area under the curve response was 982 g-min/mL.

Colesevelam exerted the largest inhibitory response on serum T₄. By 1 hour after taking the hormone and the medication together, mean T₄ levels rose to 7.6 mcg/dL and peaked there after 2 hours. The area under the curve response was only 107 g-min/mL.

“Both colesevelam and lanthanum carbonate reduced the absorption of levothyroxine and blunted the rise in serum T₄ when given with levothyroxine,” Dr. Weitzman said. “Colesevelam appeared to be a particularly potent inhibitor of T₄ absorption and nearly abolished the increase in serum T₄.

In a second study, Dr. Bandar Alshehri, an endocrinology fellow at the University of Toronto, and colleagues performed a chart review of 549 hospitalized patients treated with levothyroxine during a mean 11-day hospital stay. Most of these patients (67%) were also receiving supplements or drugs known to inhibit the absorption of T₄. The offending compounds were proton pump inhibitors (42%), calcium supplements (28%), iron supplements (15%), multivitamins (13%), psyllium fiber (12%), and magnesium-containing antacids or laxatives (1%).

Most of the patients (97%) received their levothyroxine during the daytime; the majority (88%) also got their other medications during the same period.

Ninety percent of patients were getting the hormone within 1 hour of the potentially interfering medications. Fewer than 1% received the medications at least 4 hours apart. A simple change—routine administration of levothyroxine at bedtime—could reduce the offending coadministration rate to around 19%, because the interfering medications are not usually administered at bedtime, Dr. Alshehri said.

SAN FRANCISCO — A few hours' buffer between taking thyroxine and other medications can help ensure optimal absorption of the thyroid hormone, according to several researchers.

Many nutritional supplements and commonly prescribed medications interfere with thyroid absorption, the researchers said at the annual meeting of the Endocrine Society. When taken together, some medications bind the hormone so completely that virtually none enters the bloodstream.

“In most cases, it's believed that malabsorption of levothyroxine is due to binding of the hormone to other medications in the gut lumen, forming an insoluble or nonabsorbable complex,” Dr. Steven P. Weitzman said in a poster presented at the meeting. Even newer compounds, which were thought to result in less malabsorption, seem to be problematic.

Dr. Weitzman, an endocrinologist at Stony Brook University, New York, examined the interaction of levothyroxine with two relatively new drugs—colesevelam (Welchol), the newest bile acid sequestrant approved for hyperlipidemia and diabetes; and lanthanum carbonate (Fosrenol), a new phosphate binder used in end-stage renal disease. The study included six healthy, euthyroid subjects, who first took levothyroxine 1 mg alone, then levothyroxine with 3.8 g colesevelam, then levothyroxine with 500 mg lanthanum carbonate. A minimum of 3 weeks separated each dosing study.

Total serum T₄ and TSH were measured at regular intervals during the 6 hours after administration of the study medications. Results were reported as both the area under the curve response and serum T₄ concentration.

Within 1 hour of taking levothyroxine alone, subjects displayed a sharp increase in serum T₄ from a mean of 7 mcg/dL to 10 mcg/dL. Serum T₄ peaked at 4 hours, reaching a mean level of 13 mcg/dL. The area under the curve response was 1,692 g-min/mL.

T₄ concentrations were significantly lower after the subjects took the hormone with lanthanum carbonate. At 1 hour, the T₄ level had risen to a mean of 8.6 mcg/dL. At 6 hours, the peak level was 11 mcg/dL. The area under the curve response was 982 g-min/mL.

Colesevelam exerted the largest inhibitory response on serum T₄. By 1 hour after taking the hormone and the medication together, mean T₄ levels rose to 7.6 mcg/dL and peaked there after 2 hours. The area under the curve response was only 107 g-min/mL.

“Both colesevelam and lanthanum carbonate reduced the absorption of levothyroxine and blunted the rise in serum T₄ when given with levothyroxine,” Dr. Weitzman said. “Colesevelam appeared to be a particularly potent inhibitor of T₄ absorption and nearly abolished the increase in serum T₄.

In a second study, Dr. Bandar Alshehri, an endocrinology fellow at the University of Toronto, and colleagues performed a chart review of 549 hospitalized patients treated with levothyroxine during a mean 11-day hospital stay. Most of these patients (67%) were also receiving supplements or drugs known to inhibit the absorption of T₄. The offending compounds were proton pump inhibitors (42%), calcium supplements (28%), iron supplements (15%), multivitamins (13%), psyllium fiber (12%), and magnesium-containing antacids or laxatives (1%).

Most of the patients (97%) received their levothyroxine during the daytime; the majority (88%) also got their other medications during the same period.

Ninety percent of patients were getting the hormone within 1 hour of the potentially interfering medications. Fewer than 1% received the medications at least 4 hours apart. A simple change—routine administration of levothyroxine at bedtime—could reduce the offending coadministration rate to around 19%, because the interfering medications are not usually administered at bedtime, Dr. Alshehri said.