Michele G. Sullivan

SAN FRANCISCO – Teens who filled out a personal digital assistant health screen before their physician visit reported better communication with their doctor and higher overall satisfaction with their visit, Cecelia Gaffney said at the annual meeting of the Society of Behavioral Medicine.

The PDA screener is a good tool for organizing the adolescent visit, said Ms. Gaffney, a researcher at Dartmouth-Hitchcock Medical Center in Lebanon, N.H. “Teens have a lot of things they want to discuss with their doctors, but most of them never get addressed during a typical 15-minute visit. We wanted to use technology to optimize the time physicians would have to discuss behavioral issues.”

The project, funded by the Robert Wood Johnson Foundation as part of the national “Prescription for Health” program,” incorporated a 90-question adolescent health screen loaded onto PDAs. The screen–based on the American Medical Association's Guidelines for Adolescent Preventive Services–also included questions about sports and cardiovascular risk, questions designed to assess readiness-to-change factors, a statement of confidentiality, and entertaining “health factoids” that popped up between questions.

“Ninety questions is a lot, but most kids didn't have to answer all of them,” Ms. Gaffney said. The questions were branching, so if a teen answered “no” to a particular health risk, none of the related questions appeared.

The 8-month study included 1,024 adolescents, aged 11–19 years. In addition to completing the PDA screen, subjects also completed a survey before and after their physician visit. The survey assessed factors such as how well teens felt their physician listened to them, how often they got to address all their topics of concern, and how confidential they felt their conversations were. Physicians reviewed the results before seeing each patient.

About half of each group had one or two health risk factors. Three to five risk factors were present in 28% of 11- to 14-year-olds and in 35% of 15- to 19-year-olds. Only 21% of the younger group and 12% of the older group screened negative for any risk factors.

About one-third of the subjects screened positive for at least one symptom of depression. The screen for the older group included a drug/alcohol risk assessment; 50% said they had used alcohol or drugs within the past month, and 15% screened positive for a potential drug or alcohol problem.

The screen showed that most subjects were getting adequate milk intake, but more than half didn't eat adequate amounts of fruits and vegetables. Time spent watching television was higher in the younger group, whereas the older teens reported spending more time on the computer and playing video games.

The readiness-to-change assessment showed that most subjects were highly confident of their abilities to change health behaviors, even if they had never attempted any changes.

Exit surveys showed that the screener significantly increased the subjects' perceptions of communication and trust in their physician. Before the visit, 63% said their physician listened well to them; after the visit, that number increased to 68%. The percentage who felt their doctor-patient conversation was confidential rose from 61% to 84%. Before the visit, 89% said they usually get to address all their concerns with their physician; after the visit, 98% said they discussed everything they wanted to. The PDA also increased the number of adolescents who thought the physician was the right person to go to as a resource, Ms. Gaffney said.

Physicians involved in the study liked the PDA screener, she added. Physicians “were able to give reinforcement for the positive behaviors the kids reported and focus more on the risk factors,” she said. The conversation started at the beginning of the visit, so the physicians spent more time counseling without making the visit longer.

SAN FRANCISCO – Teens who filled out a personal digital assistant health screen before their physician visit reported better communication with their doctor and higher overall satisfaction with their visit, Cecelia Gaffney said at the annual meeting of the Society of Behavioral Medicine.

The PDA screener is a good tool for organizing the adolescent visit, said Ms. Gaffney, a researcher at Dartmouth-Hitchcock Medical Center in Lebanon, N.H. “Teens have a lot of things they want to discuss with their doctors, but most of them never get addressed during a typical 15-minute visit. We wanted to use technology to optimize the time physicians would have to discuss behavioral issues.”

The project, funded by the Robert Wood Johnson Foundation as part of the national “Prescription for Health” program,” incorporated a 90-question adolescent health screen loaded onto PDAs. The screen–based on the American Medical Association's Guidelines for Adolescent Preventive Services–also included questions about sports and cardiovascular risk, questions designed to assess readiness-to-change factors, a statement of confidentiality, and entertaining “health factoids” that popped up between questions.

“Ninety questions is a lot, but most kids didn't have to answer all of them,” Ms. Gaffney said. The questions were branching, so if a teen answered “no” to a particular health risk, none of the related questions appeared.

The 8-month study included 1,024 adolescents, aged 11–19 years. In addition to completing the PDA screen, subjects also completed a survey before and after their physician visit. The survey assessed factors such as how well teens felt their physician listened to them, how often they got to address all their topics of concern, and how confidential they felt their conversations were. Physicians reviewed the results before seeing each patient.

About half of each group had one or two health risk factors. Three to five risk factors were present in 28% of 11- to 14-year-olds and in 35% of 15- to 19-year-olds. Only 21% of the younger group and 12% of the older group screened negative for any risk factors.

About one-third of the subjects screened positive for at least one symptom of depression. The screen for the older group included a drug/alcohol risk assessment; 50% said they had used alcohol or drugs within the past month, and 15% screened positive for a potential drug or alcohol problem.

The screen showed that most subjects were getting adequate milk intake, but more than half didn't eat adequate amounts of fruits and vegetables. Time spent watching television was higher in the younger group, whereas the older teens reported spending more time on the computer and playing video games.

The readiness-to-change assessment showed that most subjects were highly confident of their abilities to change health behaviors, even if they had never attempted any changes.

Exit surveys showed that the screener significantly increased the subjects' perceptions of communication and trust in their physician. Before the visit, 63% said their physician listened well to them; after the visit, that number increased to 68%. The percentage who felt their doctor-patient conversation was confidential rose from 61% to 84%. Before the visit, 89% said they usually get to address all their concerns with their physician; after the visit, 98% said they discussed everything they wanted to. The PDA also increased the number of adolescents who thought the physician was the right person to go to as a resource, Ms. Gaffney said.

Physicians involved in the study liked the PDA screener, she added. Physicians “were able to give reinforcement for the positive behaviors the kids reported and focus more on the risk factors,” she said. The conversation started at the beginning of the visit, so the physicians spent more time counseling without making the visit longer.

SAN FRANCISCO – Teens who filled out a personal digital assistant health screen before their physician visit reported better communication with their doctor and higher overall satisfaction with their visit, Cecelia Gaffney said at the annual meeting of the Society of Behavioral Medicine.

The PDA screener is a good tool for organizing the adolescent visit, said Ms. Gaffney, a researcher at Dartmouth-Hitchcock Medical Center in Lebanon, N.H. “Teens have a lot of things they want to discuss with their doctors, but most of them never get addressed during a typical 15-minute visit. We wanted to use technology to optimize the time physicians would have to discuss behavioral issues.”

The project, funded by the Robert Wood Johnson Foundation as part of the national “Prescription for Health” program,” incorporated a 90-question adolescent health screen loaded onto PDAs. The screen–based on the American Medical Association's Guidelines for Adolescent Preventive Services–also included questions about sports and cardiovascular risk, questions designed to assess readiness-to-change factors, a statement of confidentiality, and entertaining “health factoids” that popped up between questions.

“Ninety questions is a lot, but most kids didn't have to answer all of them,” Ms. Gaffney said. The questions were branching, so if a teen answered “no” to a particular health risk, none of the related questions appeared.

The 8-month study included 1,024 adolescents, aged 11–19 years. In addition to completing the PDA screen, subjects also completed a survey before and after their physician visit. The survey assessed factors such as how well teens felt their physician listened to them, how often they got to address all their topics of concern, and how confidential they felt their conversations were. Physicians reviewed the results before seeing each patient.

About half of each group had one or two health risk factors. Three to five risk factors were present in 28% of 11- to 14-year-olds and in 35% of 15- to 19-year-olds. Only 21% of the younger group and 12% of the older group screened negative for any risk factors.

About one-third of the subjects screened positive for at least one symptom of depression. The screen for the older group included a drug/alcohol risk assessment; 50% said they had used alcohol or drugs within the past month, and 15% screened positive for a potential drug or alcohol problem.

The screen showed that most subjects were getting adequate milk intake, but more than half didn't eat adequate amounts of fruits and vegetables. Time spent watching television was higher in the younger group, whereas the older teens reported spending more time on the computer and playing video games.

The readiness-to-change assessment showed that most subjects were highly confident of their abilities to change health behaviors, even if they had never attempted any changes.

Exit surveys showed that the screener significantly increased the subjects' perceptions of communication and trust in their physician. Before the visit, 63% said their physician listened well to them; after the visit, that number increased to 68%. The percentage who felt their doctor-patient conversation was confidential rose from 61% to 84%. Before the visit, 89% said they usually get to address all their concerns with their physician; after the visit, 98% said they discussed everything they wanted to. The PDA also increased the number of adolescents who thought the physician was the right person to go to as a resource, Ms. Gaffney said.

Physicians involved in the study liked the PDA screener, she added. Physicians “were able to give reinforcement for the positive behaviors the kids reported and focus more on the risk factors,” she said. The conversation started at the beginning of the visit, so the physicians spent more time counseling without making the visit longer.

HALIFAX, N.S. — A protocol of early antibiotics and hemodynamic stabilization decreases mortality in patients with severe sepsis or septic shock, Dr. Robert Stenstrom said at the 11th International Conference on Emergency Medicine.

Initiating the program in the emergency department requires an increase in nursing and physician bedside time, but the 23% decrease in mortality makes the investment worthwhile, said Dr. Stenstrom, director of research at St. Paul's Hospital, Vancouver.

His review examined mortality and time-dependent treatment before and after emergency department implementation of a sepsis protocol. The protocol, based on that described by Dr. Emanuel Rivers in 2001 (N. Engl. J. Med. 2001;345:1368–77), calls for early IV fluids and antibiotics, followed by initiation of early goal-directed therapy aimed at hemodynamic stabilization, said Dr. Stenstrom, who is also an emergency physician at the hospital.

Included in the study were 50 patients admitted to the ICU directly from the emergency department with severe sepsis (one or more organs failing or a lactate level of 4.0 mmol/L or greater) or septic shock (systolic blood pressure less than 90 mm Hg despite fluid bolus of 25 mL/kg). There were 20 patients in the preprotocol group and 30 in the protocol group. Their mean age was 50 years; the mean Acute Physiology and Chronic Health Evaluation score was 24.

In the preprotocol group, 7 of the 20 patients received first antibiotics in less than 1 hour, and the rest received the drugs in 1–10 hours. In the protocol group, 20 of 30 patients got antibiotics in less than 1 hour and 6 got them in 1–2 hours. Three more got the drugs by 4 hours, but one patient didn't receive them until almost 8 hours had passed. Time to completion of initial fluid bolus (usually 2 L of normal saline) decreased significantly, from about 2.5 hours in the preprotocol group to just over 1 hour in the protocol group.

In the preprotocol group, 14 patients were on early goal-directed therapy by 10 hours, but it took 12–60 hours in the other 6. In the protocol group, all were on early goal-directed therapy before 10 hours.

There was no significant difference in time to ICU transfer, Dr. Stenstrom said.

At 28 days, mortality was 46% in the preprotocol group and 23% in the protocol group—a decrease of 23%.

ELSEVIER GLOBAL MEDICAL NEWS

HALIFAX, N.S. — A protocol of early antibiotics and hemodynamic stabilization decreases mortality in patients with severe sepsis or septic shock, Dr. Robert Stenstrom said at the 11th International Conference on Emergency Medicine.

Initiating the program in the emergency department requires an increase in nursing and physician bedside time, but the 23% decrease in mortality makes the investment worthwhile, said Dr. Stenstrom, director of research at St. Paul's Hospital, Vancouver.

His review examined mortality and time-dependent treatment before and after emergency department implementation of a sepsis protocol. The protocol, based on that described by Dr. Emanuel Rivers in 2001 (N. Engl. J. Med. 2001;345:1368–77), calls for early IV fluids and antibiotics, followed by initiation of early goal-directed therapy aimed at hemodynamic stabilization, said Dr. Stenstrom, who is also an emergency physician at the hospital.

Included in the study were 50 patients admitted to the ICU directly from the emergency department with severe sepsis (one or more organs failing or a lactate level of 4.0 mmol/L or greater) or septic shock (systolic blood pressure less than 90 mm Hg despite fluid bolus of 25 mL/kg). There were 20 patients in the preprotocol group and 30 in the protocol group. Their mean age was 50 years; the mean Acute Physiology and Chronic Health Evaluation score was 24.

In the preprotocol group, 7 of the 20 patients received first antibiotics in less than 1 hour, and the rest received the drugs in 1–10 hours. In the protocol group, 20 of 30 patients got antibiotics in less than 1 hour and 6 got them in 1–2 hours. Three more got the drugs by 4 hours, but one patient didn't receive them until almost 8 hours had passed. Time to completion of initial fluid bolus (usually 2 L of normal saline) decreased significantly, from about 2.5 hours in the preprotocol group to just over 1 hour in the protocol group.

In the preprotocol group, 14 patients were on early goal-directed therapy by 10 hours, but it took 12–60 hours in the other 6. In the protocol group, all were on early goal-directed therapy before 10 hours.

There was no significant difference in time to ICU transfer, Dr. Stenstrom said.

At 28 days, mortality was 46% in the preprotocol group and 23% in the protocol group—a decrease of 23%.

ELSEVIER GLOBAL MEDICAL NEWS

HALIFAX, N.S. — A protocol of early antibiotics and hemodynamic stabilization decreases mortality in patients with severe sepsis or septic shock, Dr. Robert Stenstrom said at the 11th International Conference on Emergency Medicine.

Initiating the program in the emergency department requires an increase in nursing and physician bedside time, but the 23% decrease in mortality makes the investment worthwhile, said Dr. Stenstrom, director of research at St. Paul's Hospital, Vancouver.

His review examined mortality and time-dependent treatment before and after emergency department implementation of a sepsis protocol. The protocol, based on that described by Dr. Emanuel Rivers in 2001 (N. Engl. J. Med. 2001;345:1368–77), calls for early IV fluids and antibiotics, followed by initiation of early goal-directed therapy aimed at hemodynamic stabilization, said Dr. Stenstrom, who is also an emergency physician at the hospital.

Included in the study were 50 patients admitted to the ICU directly from the emergency department with severe sepsis (one or more organs failing or a lactate level of 4.0 mmol/L or greater) or septic shock (systolic blood pressure less than 90 mm Hg despite fluid bolus of 25 mL/kg). There were 20 patients in the preprotocol group and 30 in the protocol group. Their mean age was 50 years; the mean Acute Physiology and Chronic Health Evaluation score was 24.

In the preprotocol group, 7 of the 20 patients received first antibiotics in less than 1 hour, and the rest received the drugs in 1–10 hours. In the protocol group, 20 of 30 patients got antibiotics in less than 1 hour and 6 got them in 1–2 hours. Three more got the drugs by 4 hours, but one patient didn't receive them until almost 8 hours had passed. Time to completion of initial fluid bolus (usually 2 L of normal saline) decreased significantly, from about 2.5 hours in the preprotocol group to just over 1 hour in the protocol group.

In the preprotocol group, 14 patients were on early goal-directed therapy by 10 hours, but it took 12–60 hours in the other 6. In the protocol group, all were on early goal-directed therapy before 10 hours.

There was no significant difference in time to ICU transfer, Dr. Stenstrom said.

At 28 days, mortality was 46% in the preprotocol group and 23% in the protocol group—a decrease of 23%.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — The daughters of women with polycystic ovary syndrome have elevated levels of antimüllerian hormone from infancy to the perimenarchal period, suggesting that the underpinnings of PCOS may be present long before clinical symptoms develop.

Folliculogenesis may be altered in these girls, said Dr. Nicolas Crisosto of the University of Chile, Santiago, at the annual meeting of the Androgen Excess Society.

He compared anthropometric, hormonal, and metabolic parameters in 58 daughters of women with PCOS and in 65 daughters of control women at three time points: early infancy (2–3 months), childhood (4–7 years), and the perimenarchal period (8–15 years).

At each of the three time points, the girls received a physical exam that included assessment of weight, height, waist-to-hip ratio, and sexual development. A panel of tests was performed for serum hormone levels (gonadotropins, sex steroids, sex hormone-binding globulin, and antimüllerian hormone).

The girls in the perimenarchal group also underwent a transabdominal ultrasound exam of their ovaries.

There were no significant anthropometric differences between the daughters of women with PCOS and the daughters of controls at any of the exams, Dr. Crisosto said.

Antimüllerian hormone levels were significantly increased in the daughters of women with PCOS at all three stages. Free androgen level was elevated in the daughters of the PCOS group at the perimenarchal exam.

Other values were similar for the two groups.

The mean antimüllerian hormone levels in infants were 20.4 pmol/L in the girls born to women with PCOS vs. 9.2 pmol/L in girls born to women without PCOS.

In childhood, the values for the two groups were 14.8 pmol/L and 7.7 pmol/L.

In the perimenarchal period, the respective values were 25.2 pmol/L vs. 15.0 pmol/L.

The results of the transabdominal ultrasound showed a slightly higher ovarian volume (8.8 cm

The findings, recently published in the Journal of Clinical Endocrinology and Metabolism (DOI:10.1210/jc.2005–2693), led Dr. Crisosto and his colleagues to conclude that serum antimüllerian hormone levels seem to be correlated with the development of preantral and small antral follicles, from puberty to the end of reproductive life.

Elevated serum antimüllerian hormone concentrations in daughters of women with PCOS during childhood, at a time when the gonadal axis is relatively quiescent and other hormonal markers of ovarian function are very low, suggests that antimüllerian hormone may potentially be used as an early marker of ovarian follicular development.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — The daughters of women with polycystic ovary syndrome have elevated levels of antimüllerian hormone from infancy to the perimenarchal period, suggesting that the underpinnings of PCOS may be present long before clinical symptoms develop.

Folliculogenesis may be altered in these girls, said Dr. Nicolas Crisosto of the University of Chile, Santiago, at the annual meeting of the Androgen Excess Society.

He compared anthropometric, hormonal, and metabolic parameters in 58 daughters of women with PCOS and in 65 daughters of control women at three time points: early infancy (2–3 months), childhood (4–7 years), and the perimenarchal period (8–15 years).

At each of the three time points, the girls received a physical exam that included assessment of weight, height, waist-to-hip ratio, and sexual development. A panel of tests was performed for serum hormone levels (gonadotropins, sex steroids, sex hormone-binding globulin, and antimüllerian hormone).

The girls in the perimenarchal group also underwent a transabdominal ultrasound exam of their ovaries.

There were no significant anthropometric differences between the daughters of women with PCOS and the daughters of controls at any of the exams, Dr. Crisosto said.

Antimüllerian hormone levels were significantly increased in the daughters of women with PCOS at all three stages. Free androgen level was elevated in the daughters of the PCOS group at the perimenarchal exam.

Other values were similar for the two groups.

The mean antimüllerian hormone levels in infants were 20.4 pmol/L in the girls born to women with PCOS vs. 9.2 pmol/L in girls born to women without PCOS.

In childhood, the values for the two groups were 14.8 pmol/L and 7.7 pmol/L.

In the perimenarchal period, the respective values were 25.2 pmol/L vs. 15.0 pmol/L.

The results of the transabdominal ultrasound showed a slightly higher ovarian volume (8.8 cm

The findings, recently published in the Journal of Clinical Endocrinology and Metabolism (DOI:10.1210/jc.2005–2693), led Dr. Crisosto and his colleagues to conclude that serum antimüllerian hormone levels seem to be correlated with the development of preantral and small antral follicles, from puberty to the end of reproductive life.

Elevated serum antimüllerian hormone concentrations in daughters of women with PCOS during childhood, at a time when the gonadal axis is relatively quiescent and other hormonal markers of ovarian function are very low, suggests that antimüllerian hormone may potentially be used as an early marker of ovarian follicular development.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — The daughters of women with polycystic ovary syndrome have elevated levels of antimüllerian hormone from infancy to the perimenarchal period, suggesting that the underpinnings of PCOS may be present long before clinical symptoms develop.

Folliculogenesis may be altered in these girls, said Dr. Nicolas Crisosto of the University of Chile, Santiago, at the annual meeting of the Androgen Excess Society.

He compared anthropometric, hormonal, and metabolic parameters in 58 daughters of women with PCOS and in 65 daughters of control women at three time points: early infancy (2–3 months), childhood (4–7 years), and the perimenarchal period (8–15 years).

At each of the three time points, the girls received a physical exam that included assessment of weight, height, waist-to-hip ratio, and sexual development. A panel of tests was performed for serum hormone levels (gonadotropins, sex steroids, sex hormone-binding globulin, and antimüllerian hormone).

The girls in the perimenarchal group also underwent a transabdominal ultrasound exam of their ovaries.

There were no significant anthropometric differences between the daughters of women with PCOS and the daughters of controls at any of the exams, Dr. Crisosto said.

Antimüllerian hormone levels were significantly increased in the daughters of women with PCOS at all three stages. Free androgen level was elevated in the daughters of the PCOS group at the perimenarchal exam.

Other values were similar for the two groups.

The mean antimüllerian hormone levels in infants were 20.4 pmol/L in the girls born to women with PCOS vs. 9.2 pmol/L in girls born to women without PCOS.

In childhood, the values for the two groups were 14.8 pmol/L and 7.7 pmol/L.

In the perimenarchal period, the respective values were 25.2 pmol/L vs. 15.0 pmol/L.

The results of the transabdominal ultrasound showed a slightly higher ovarian volume (8.8 cm

The findings, recently published in the Journal of Clinical Endocrinology and Metabolism (DOI:10.1210/jc.2005–2693), led Dr. Crisosto and his colleagues to conclude that serum antimüllerian hormone levels seem to be correlated with the development of preantral and small antral follicles, from puberty to the end of reproductive life.

Elevated serum antimüllerian hormone concentrations in daughters of women with PCOS during childhood, at a time when the gonadal axis is relatively quiescent and other hormonal markers of ovarian function are very low, suggests that antimüllerian hormone may potentially be used as an early marker of ovarian follicular development.

ELSEVIER GLOBAL MEDICAL NEWS

MADRID — Tight control of blood glucose levels may decrease the incidence of dementia and Alzheimer's disease among patients with diabetes, and even among those with borderline diabetes, researchers reported at the 10th International Conference on Alzheimer's Disease and Related Disorders.

The findings speak volumes about the need for early implementation of significant lifestyle changes among those at risk for diabetes, especially in light of the ongoing obesity epidemic, said Dr. Ronald Petersen, who moderated a press conference on the studies. “The number of people with Alzheimer's, and the number who will soon get it, is rising dramatically as the baby boomers turn 50,” said Dr. Petersen, vice chair of the Alzheimer's Association's Medical and Scientific Advisory Council. ¨Will this growth be redoubled by the rising tide of obesity and diabetes?”

Glycemic control is a crucial factor in protecting diabetic patients from dementia, said Rachel Whitmer, Ph.D., of Kaiser Permanente, Oakland, Calif. Her population-based study included 22,852 members of Kaiser's Northern California Diabetes Registry, who were surveyed from 1994 to 1996. The patients' mean age at baseline was 66 years; 66% were white, 10% black, and the rest were Hispanic, Asian, or Native American.

The patients were followed until 2005. By then, 11% had developed new-onset dementias. Hemoglobin A_1c (HbA_1c) was significantly associated with the incidence of dementia. Patients with the highest HbA_1c (15% and higher) were the most likely to develop dementia, with an elevated risk of 78% compared with those whose levels were below 10%. Diabetic patients are advised to keep their HbA_1c below 7%.

Those with HbA_1c levels of 12%–15% were 22% more likely to develop dementia, while those whose levels were between 10% and 11.9% had a 16% increased risk. The increased risks remained significant even after adjusting for age, race, gender, weight, and diabetes treatment.

“This shows us that tight glycemic control continues to be as important as patients' age,” Dr. Whitmer said at the meeting, presented by the Alzheimer's Association. “And it will become more and more important as we experience the epidemic of obesity.”

Even patients with borderline diabetes should be aware of controlling their glucose levels, said Dr. Laura Fratiglioni, who presented research completed by her colleague, Dr. Weili Xu of the Karolinska Institute, Stockholm.

Their 9-year study tracked the incidence of dementia in 1,173 subjects older than 75 years who were free of both dementia and diabetes at baseline.

The subjects were examined three times during the study period; each exam included a blood glucose test and testing for dementia and Alzheimer's disease.

The mean follow-up was 5 years per person. By that time, borderline diabetes had been identified in 47 subjects and 397 had been diagnosed with dementia (307 with Alzheimer's).

After controlling for vascular risk factors, borderline diabetes was associated with a 67% increased risk for developing a dementia and a 77% increased risk for developing Alzheimer's, Dr. Fratiglioni said. Additional analysis found that the risk was increased yet again in those with borderline diabetes who also had a systolic blood pressure of 180 mm Hg or higher.

MADRID — Tight control of blood glucose levels may decrease the incidence of dementia and Alzheimer's disease among patients with diabetes, and even among those with borderline diabetes, researchers reported at the 10th International Conference on Alzheimer's Disease and Related Disorders.

The findings speak volumes about the need for early implementation of significant lifestyle changes among those at risk for diabetes, especially in light of the ongoing obesity epidemic, said Dr. Ronald Petersen, who moderated a press conference on the studies. “The number of people with Alzheimer's, and the number who will soon get it, is rising dramatically as the baby boomers turn 50,” said Dr. Petersen, vice chair of the Alzheimer's Association's Medical and Scientific Advisory Council. ¨Will this growth be redoubled by the rising tide of obesity and diabetes?”

Glycemic control is a crucial factor in protecting diabetic patients from dementia, said Rachel Whitmer, Ph.D., of Kaiser Permanente, Oakland, Calif. Her population-based study included 22,852 members of Kaiser's Northern California Diabetes Registry, who were surveyed from 1994 to 1996. The patients' mean age at baseline was 66 years; 66% were white, 10% black, and the rest were Hispanic, Asian, or Native American.

The patients were followed until 2005. By then, 11% had developed new-onset dementias. Hemoglobin A_1c (HbA_1c) was significantly associated with the incidence of dementia. Patients with the highest HbA_1c (15% and higher) were the most likely to develop dementia, with an elevated risk of 78% compared with those whose levels were below 10%. Diabetic patients are advised to keep their HbA_1c below 7%.

Those with HbA_1c levels of 12%–15% were 22% more likely to develop dementia, while those whose levels were between 10% and 11.9% had a 16% increased risk. The increased risks remained significant even after adjusting for age, race, gender, weight, and diabetes treatment.

“This shows us that tight glycemic control continues to be as important as patients' age,” Dr. Whitmer said at the meeting, presented by the Alzheimer's Association. “And it will become more and more important as we experience the epidemic of obesity.”

Even patients with borderline diabetes should be aware of controlling their glucose levels, said Dr. Laura Fratiglioni, who presented research completed by her colleague, Dr. Weili Xu of the Karolinska Institute, Stockholm.

Their 9-year study tracked the incidence of dementia in 1,173 subjects older than 75 years who were free of both dementia and diabetes at baseline.

The subjects were examined three times during the study period; each exam included a blood glucose test and testing for dementia and Alzheimer's disease.

The mean follow-up was 5 years per person. By that time, borderline diabetes had been identified in 47 subjects and 397 had been diagnosed with dementia (307 with Alzheimer's).

After controlling for vascular risk factors, borderline diabetes was associated with a 67% increased risk for developing a dementia and a 77% increased risk for developing Alzheimer's, Dr. Fratiglioni said. Additional analysis found that the risk was increased yet again in those with borderline diabetes who also had a systolic blood pressure of 180 mm Hg or higher.

MADRID — Tight control of blood glucose levels may decrease the incidence of dementia and Alzheimer's disease among patients with diabetes, and even among those with borderline diabetes, researchers reported at the 10th International Conference on Alzheimer's Disease and Related Disorders.

The findings speak volumes about the need for early implementation of significant lifestyle changes among those at risk for diabetes, especially in light of the ongoing obesity epidemic, said Dr. Ronald Petersen, who moderated a press conference on the studies. “The number of people with Alzheimer's, and the number who will soon get it, is rising dramatically as the baby boomers turn 50,” said Dr. Petersen, vice chair of the Alzheimer's Association's Medical and Scientific Advisory Council. ¨Will this growth be redoubled by the rising tide of obesity and diabetes?”

Glycemic control is a crucial factor in protecting diabetic patients from dementia, said Rachel Whitmer, Ph.D., of Kaiser Permanente, Oakland, Calif. Her population-based study included 22,852 members of Kaiser's Northern California Diabetes Registry, who were surveyed from 1994 to 1996. The patients' mean age at baseline was 66 years; 66% were white, 10% black, and the rest were Hispanic, Asian, or Native American.

The patients were followed until 2005. By then, 11% had developed new-onset dementias. Hemoglobin A_1c (HbA_1c) was significantly associated with the incidence of dementia. Patients with the highest HbA_1c (15% and higher) were the most likely to develop dementia, with an elevated risk of 78% compared with those whose levels were below 10%. Diabetic patients are advised to keep their HbA_1c below 7%.

Those with HbA_1c levels of 12%–15% were 22% more likely to develop dementia, while those whose levels were between 10% and 11.9% had a 16% increased risk. The increased risks remained significant even after adjusting for age, race, gender, weight, and diabetes treatment.

“This shows us that tight glycemic control continues to be as important as patients' age,” Dr. Whitmer said at the meeting, presented by the Alzheimer's Association. “And it will become more and more important as we experience the epidemic of obesity.”

Even patients with borderline diabetes should be aware of controlling their glucose levels, said Dr. Laura Fratiglioni, who presented research completed by her colleague, Dr. Weili Xu of the Karolinska Institute, Stockholm.

Their 9-year study tracked the incidence of dementia in 1,173 subjects older than 75 years who were free of both dementia and diabetes at baseline.

The subjects were examined three times during the study period; each exam included a blood glucose test and testing for dementia and Alzheimer's disease.

The mean follow-up was 5 years per person. By that time, borderline diabetes had been identified in 47 subjects and 397 had been diagnosed with dementia (307 with Alzheimer's).

After controlling for vascular risk factors, borderline diabetes was associated with a 67% increased risk for developing a dementia and a 77% increased risk for developing Alzheimer's, Dr. Fratiglioni said. Additional analysis found that the risk was increased yet again in those with borderline diabetes who also had a systolic blood pressure of 180 mm Hg or higher.

BOSTON — The daughters of women with polycystic ovary syndrome have elevated levels of antimüllerian hormone from infancy to the perimenarche, suggesting the underpinnings of PCOS may be present long before clinical symptoms develop.

Folliculogenesis may be altered in these girls, said Dr. Nicolas Crisosto of the University of Chile, Santiago, at the annual meeting of the Androgen Excess Society. He compared anthropometric, hormonal, and metabolic parameters in 58 daughters of women with PCOS and in 65 daughters of control women at three time points: early infancy (2–3 months), childhood (4–7 years), and the perimenarchal period (8–15 years).

At each of the time points, the girls received a physical exam that included assessment of weight, height, waist-to-hip ratio, and sexual development. A panel of tests was performed for serum hormone levels (gonadotropins, sex steroids, sex hormone-binding globulin, and antimüllerian hormone). The girls in perimenarche also had a transabdominal ultrasound of their ovaries.

There were no significant anthropometric differences between the two groups at any of the exams, Dr. Crisosto said. Antimüllerian hormone levels were significantly increased in the PCOS group at all three stages. Free androgen level was elevated in the PCOS group at the perimenarchal exam.

The mean antimüllerian hormone levels in infants were 20.4 pmol/L in the girls born to women with PCOS vs. 9.2 pmol/L in girls born to women without PCOS. In childhood, the values for the two groups were 14.8 pmol/L and 7.7 pmol/L. In the perimenarchal period, the respective values were 25.2 pmol/L vs. 15.0 pmol/L. The results of the transabdominal ultrasound showed slightly higher ovarian volume (8.8 cm

The findings, recently published in the Journal of Clinical Endocrinology and Metabolism (DOI:10.1210/jc.2005–2693), led the investigators to conclude that serum antimüllerian hormone levels seem to be correlated with the development of preantral and small antral follicles, from puberty to the end of reproductive life. Elevated serum antimüllerian hormone concentrations in daughters of PCOS women during childhood, at a time when the gonadal axis is relatively quiescent and other hormonal markers of ovarian function are very low, suggests that antimüllerian hormone may be used as an early marker of ovarian follicular development.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — The daughters of women with polycystic ovary syndrome have elevated levels of antimüllerian hormone from infancy to the perimenarche, suggesting the underpinnings of PCOS may be present long before clinical symptoms develop.

Folliculogenesis may be altered in these girls, said Dr. Nicolas Crisosto of the University of Chile, Santiago, at the annual meeting of the Androgen Excess Society. He compared anthropometric, hormonal, and metabolic parameters in 58 daughters of women with PCOS and in 65 daughters of control women at three time points: early infancy (2–3 months), childhood (4–7 years), and the perimenarchal period (8–15 years).

At each of the time points, the girls received a physical exam that included assessment of weight, height, waist-to-hip ratio, and sexual development. A panel of tests was performed for serum hormone levels (gonadotropins, sex steroids, sex hormone-binding globulin, and antimüllerian hormone). The girls in perimenarche also had a transabdominal ultrasound of their ovaries.

There were no significant anthropometric differences between the two groups at any of the exams, Dr. Crisosto said. Antimüllerian hormone levels were significantly increased in the PCOS group at all three stages. Free androgen level was elevated in the PCOS group at the perimenarchal exam.

The mean antimüllerian hormone levels in infants were 20.4 pmol/L in the girls born to women with PCOS vs. 9.2 pmol/L in girls born to women without PCOS. In childhood, the values for the two groups were 14.8 pmol/L and 7.7 pmol/L. In the perimenarchal period, the respective values were 25.2 pmol/L vs. 15.0 pmol/L. The results of the transabdominal ultrasound showed slightly higher ovarian volume (8.8 cm

The findings, recently published in the Journal of Clinical Endocrinology and Metabolism (DOI:10.1210/jc.2005–2693), led the investigators to conclude that serum antimüllerian hormone levels seem to be correlated with the development of preantral and small antral follicles, from puberty to the end of reproductive life. Elevated serum antimüllerian hormone concentrations in daughters of PCOS women during childhood, at a time when the gonadal axis is relatively quiescent and other hormonal markers of ovarian function are very low, suggests that antimüllerian hormone may be used as an early marker of ovarian follicular development.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — The daughters of women with polycystic ovary syndrome have elevated levels of antimüllerian hormone from infancy to the perimenarche, suggesting the underpinnings of PCOS may be present long before clinical symptoms develop.

Folliculogenesis may be altered in these girls, said Dr. Nicolas Crisosto of the University of Chile, Santiago, at the annual meeting of the Androgen Excess Society. He compared anthropometric, hormonal, and metabolic parameters in 58 daughters of women with PCOS and in 65 daughters of control women at three time points: early infancy (2–3 months), childhood (4–7 years), and the perimenarchal period (8–15 years).

At each of the time points, the girls received a physical exam that included assessment of weight, height, waist-to-hip ratio, and sexual development. A panel of tests was performed for serum hormone levels (gonadotropins, sex steroids, sex hormone-binding globulin, and antimüllerian hormone). The girls in perimenarche also had a transabdominal ultrasound of their ovaries.

There were no significant anthropometric differences between the two groups at any of the exams, Dr. Crisosto said. Antimüllerian hormone levels were significantly increased in the PCOS group at all three stages. Free androgen level was elevated in the PCOS group at the perimenarchal exam.

The mean antimüllerian hormone levels in infants were 20.4 pmol/L in the girls born to women with PCOS vs. 9.2 pmol/L in girls born to women without PCOS. In childhood, the values for the two groups were 14.8 pmol/L and 7.7 pmol/L. In the perimenarchal period, the respective values were 25.2 pmol/L vs. 15.0 pmol/L. The results of the transabdominal ultrasound showed slightly higher ovarian volume (8.8 cm

The findings, recently published in the Journal of Clinical Endocrinology and Metabolism (DOI:10.1210/jc.2005–2693), led the investigators to conclude that serum antimüllerian hormone levels seem to be correlated with the development of preantral and small antral follicles, from puberty to the end of reproductive life. Elevated serum antimüllerian hormone concentrations in daughters of PCOS women during childhood, at a time when the gonadal axis is relatively quiescent and other hormonal markers of ovarian function are very low, suggests that antimüllerian hormone may be used as an early marker of ovarian follicular development.

ELSEVIER GLOBAL MEDICAL NEWS

BOSTON — Bariatric surgery may resolve symptoms of polycystic ovary syndrome in obese women with the condition, Dr. Héctor Escobar-Morreale reported at the annual meeting of the Androgen Excess Society.

“In some women, the syndrome is so driven by insulin resistance that it may resolve completely with weight loss,” said the endocrinologist, of the Hospital Ramón y Cajal in Madrid.

Among women seeking weight-loss advice at his endocrinology practice, Dr. Escobar-Morreale found a PCOS prevalence of 28%, more than five times the prevalence among lean women in Madrid. This discovery prompted him to examine the prevalence of the disorder among 36 obese women referred for bariatric surgery, and to also track the effect of surgically induced weight loss on their symptoms.

In this group of women, 17 (47%) were diagnosed with PCOS according to the 1990 National Institutes of Health criteria. Follow-up data at 1 year were available on 12 of them.

By 12 months, the women had lost an average of 41 kg and their hirsutism had resolved. Significant decreases were noted in their sex steroid levels: Total testosterone dropped from a mean of 69 ng/dL to 19 ng/dL. Insulin sensitivity returned to normal and regular menstruation was restored. Among 10 women who were tested, all had hormonal evidence of ovulation.

Of course, Dr. Escobar-Morreale said, bariatric surgery is a serious proposal and is indicated only for morbidly obese patients who have repeatedly failed to lose weight. “Lifestyle modification should be attempted first,” he said.

BOSTON — Bariatric surgery may resolve symptoms of polycystic ovary syndrome in obese women with the condition, Dr. Héctor Escobar-Morreale reported at the annual meeting of the Androgen Excess Society.

“In some women, the syndrome is so driven by insulin resistance that it may resolve completely with weight loss,” said the endocrinologist, of the Hospital Ramón y Cajal in Madrid.

Among women seeking weight-loss advice at his endocrinology practice, Dr. Escobar-Morreale found a PCOS prevalence of 28%, more than five times the prevalence among lean women in Madrid. This discovery prompted him to examine the prevalence of the disorder among 36 obese women referred for bariatric surgery, and to also track the effect of surgically induced weight loss on their symptoms.

In this group of women, 17 (47%) were diagnosed with PCOS according to the 1990 National Institutes of Health criteria. Follow-up data at 1 year were available on 12 of them.

By 12 months, the women had lost an average of 41 kg and their hirsutism had resolved. Significant decreases were noted in their sex steroid levels: Total testosterone dropped from a mean of 69 ng/dL to 19 ng/dL. Insulin sensitivity returned to normal and regular menstruation was restored. Among 10 women who were tested, all had hormonal evidence of ovulation.

Of course, Dr. Escobar-Morreale said, bariatric surgery is a serious proposal and is indicated only for morbidly obese patients who have repeatedly failed to lose weight. “Lifestyle modification should be attempted first,” he said.

BOSTON — Bariatric surgery may resolve symptoms of polycystic ovary syndrome in obese women with the condition, Dr. Héctor Escobar-Morreale reported at the annual meeting of the Androgen Excess Society.

“In some women, the syndrome is so driven by insulin resistance that it may resolve completely with weight loss,” said the endocrinologist, of the Hospital Ramón y Cajal in Madrid.

Among women seeking weight-loss advice at his endocrinology practice, Dr. Escobar-Morreale found a PCOS prevalence of 28%, more than five times the prevalence among lean women in Madrid. This discovery prompted him to examine the prevalence of the disorder among 36 obese women referred for bariatric surgery, and to also track the effect of surgically induced weight loss on their symptoms.

In this group of women, 17 (47%) were diagnosed with PCOS according to the 1990 National Institutes of Health criteria. Follow-up data at 1 year were available on 12 of them.

By 12 months, the women had lost an average of 41 kg and their hirsutism had resolved. Significant decreases were noted in their sex steroid levels: Total testosterone dropped from a mean of 69 ng/dL to 19 ng/dL. Insulin sensitivity returned to normal and regular menstruation was restored. Among 10 women who were tested, all had hormonal evidence of ovulation.

Of course, Dr. Escobar-Morreale said, bariatric surgery is a serious proposal and is indicated only for morbidly obese patients who have repeatedly failed to lose weight. “Lifestyle modification should be attempted first,” he said.

MADRID — Thiazolidinediones may reduce the incidence of Alzheimer's disease or forestall its progression in both diabetic and nondiabetic patients, researchers reported at the 10th International Conference on Alzheimer's Disease and Related Disorders.

Diabetes is thought to increase the incidence of Alzheimer's disease through several pathways, including decreased cortical utilization of glucose, and increased oxidative stress, inflammation, and deposition of amyloid-β. Besides regulating insulin and improving glucose usage, the drugs have been shown in animal models to suppress microglial-mediated inflammation and reduce amyloid plaque formation, Donald Miller, Sc.D., and Dr. David Geldmacher said at a press conference during the meeting, which was sponsored by the Alzheimer's Association.

Dr. Miller examined the incidence of new Alzheimer's cases among a cohort of 142,328 veterans (mean age 66 years) with diabetes, who were followed for 6 years. The group included patients who received a new prescription for either a thiazolidinedione (74,525) or insulin (67,803).

After 6 years' follow-up, there were 3,191 new cases of Alzheimer's, a rate of 0.24% per year.

Patients who got a thiazolidinedione were 19% less likely to develop the disorder than were those treated with insulin, said Dr. Miller of the department of health services at Boston University School of Public Health. The results remained significant even after controlling for potential confounders including demographics, body mass index, and other medications.

Dr. Miller obtained similarly significant results favoring thiazolidinediones when he compared the drugs with metformin.

More research is necessary before any firm conclusions can be drawn, however. “It would be premature to say that these drugs prevent Alzheimer's in diabetes patients,” he said. “These are preliminary results, although they are encouraging.”

Dr. Geldmacher, director of the memory disorder program at the University of Virginia, Charlottesville, examined the effect of pioglitazone compared with placebo in nondiabetic patients with probable Alzheimer's disease. The randomized, controlled trial included 30 subjects (mean age 70 years) whose mean Mini-Mental State Examination score was 21.

All patients maintained their existing antidementia drugs during the trial; 15 also received pioglitazone (45 mg/day), while the remaining 15 received the placebo.

After 18 months, there was a nonsignificant trend toward better cognitive performance in the treated patients, Dr. Geldmacher said. “None of the measures reached statistical significance, but the effect size we saw was similar to that seen with existing antidementia drugs.”

In fact, he said, pioglitazone appeared to have a synergistic effect with existing drug therapy, doubling its cognitive impact.

Just as importantly, the drug was safe and well tolerated, he added. “We were somewhat concerned that it could cause hypoglycemia in these patients, none of whom had diabetes, but that was not the case.” The only significant adverse event observed was lower extremity edema, a side effect also seen in diabetic patients who take the drug.

MADRID — Thiazolidinediones may reduce the incidence of Alzheimer's disease or forestall its progression in both diabetic and nondiabetic patients, researchers reported at the 10th International Conference on Alzheimer's Disease and Related Disorders.

Diabetes is thought to increase the incidence of Alzheimer's disease through several pathways, including decreased cortical utilization of glucose, and increased oxidative stress, inflammation, and deposition of amyloid-β. Besides regulating insulin and improving glucose usage, the drugs have been shown in animal models to suppress microglial-mediated inflammation and reduce amyloid plaque formation, Donald Miller, Sc.D., and Dr. David Geldmacher said at a press conference during the meeting, which was sponsored by the Alzheimer's Association.

Dr. Miller examined the incidence of new Alzheimer's cases among a cohort of 142,328 veterans (mean age 66 years) with diabetes, who were followed for 6 years. The group included patients who received a new prescription for either a thiazolidinedione (74,525) or insulin (67,803).

After 6 years' follow-up, there were 3,191 new cases of Alzheimer's, a rate of 0.24% per year.

Patients who got a thiazolidinedione were 19% less likely to develop the disorder than were those treated with insulin, said Dr. Miller of the department of health services at Boston University School of Public Health. The results remained significant even after controlling for potential confounders including demographics, body mass index, and other medications.

Dr. Miller obtained similarly significant results favoring thiazolidinediones when he compared the drugs with metformin.

More research is necessary before any firm conclusions can be drawn, however. “It would be premature to say that these drugs prevent Alzheimer's in diabetes patients,” he said. “These are preliminary results, although they are encouraging.”

Dr. Geldmacher, director of the memory disorder program at the University of Virginia, Charlottesville, examined the effect of pioglitazone compared with placebo in nondiabetic patients with probable Alzheimer's disease. The randomized, controlled trial included 30 subjects (mean age 70 years) whose mean Mini-Mental State Examination score was 21.

All patients maintained their existing antidementia drugs during the trial; 15 also received pioglitazone (45 mg/day), while the remaining 15 received the placebo.

After 18 months, there was a nonsignificant trend toward better cognitive performance in the treated patients, Dr. Geldmacher said. “None of the measures reached statistical significance, but the effect size we saw was similar to that seen with existing antidementia drugs.”

In fact, he said, pioglitazone appeared to have a synergistic effect with existing drug therapy, doubling its cognitive impact.

Just as importantly, the drug was safe and well tolerated, he added. “We were somewhat concerned that it could cause hypoglycemia in these patients, none of whom had diabetes, but that was not the case.” The only significant adverse event observed was lower extremity edema, a side effect also seen in diabetic patients who take the drug.

MADRID — Thiazolidinediones may reduce the incidence of Alzheimer's disease or forestall its progression in both diabetic and nondiabetic patients, researchers reported at the 10th International Conference on Alzheimer's Disease and Related Disorders.

Diabetes is thought to increase the incidence of Alzheimer's disease through several pathways, including decreased cortical utilization of glucose, and increased oxidative stress, inflammation, and deposition of amyloid-β. Besides regulating insulin and improving glucose usage, the drugs have been shown in animal models to suppress microglial-mediated inflammation and reduce amyloid plaque formation, Donald Miller, Sc.D., and Dr. David Geldmacher said at a press conference during the meeting, which was sponsored by the Alzheimer's Association.

Dr. Miller examined the incidence of new Alzheimer's cases among a cohort of 142,328 veterans (mean age 66 years) with diabetes, who were followed for 6 years. The group included patients who received a new prescription for either a thiazolidinedione (74,525) or insulin (67,803).

After 6 years' follow-up, there were 3,191 new cases of Alzheimer's, a rate of 0.24% per year.

Patients who got a thiazolidinedione were 19% less likely to develop the disorder than were those treated with insulin, said Dr. Miller of the department of health services at Boston University School of Public Health. The results remained significant even after controlling for potential confounders including demographics, body mass index, and other medications.

Dr. Miller obtained similarly significant results favoring thiazolidinediones when he compared the drugs with metformin.

More research is necessary before any firm conclusions can be drawn, however. “It would be premature to say that these drugs prevent Alzheimer's in diabetes patients,” he said. “These are preliminary results, although they are encouraging.”

Dr. Geldmacher, director of the memory disorder program at the University of Virginia, Charlottesville, examined the effect of pioglitazone compared with placebo in nondiabetic patients with probable Alzheimer's disease. The randomized, controlled trial included 30 subjects (mean age 70 years) whose mean Mini-Mental State Examination score was 21.

All patients maintained their existing antidementia drugs during the trial; 15 also received pioglitazone (45 mg/day), while the remaining 15 received the placebo.

After 18 months, there was a nonsignificant trend toward better cognitive performance in the treated patients, Dr. Geldmacher said. “None of the measures reached statistical significance, but the effect size we saw was similar to that seen with existing antidementia drugs.”

In fact, he said, pioglitazone appeared to have a synergistic effect with existing drug therapy, doubling its cognitive impact.

Just as importantly, the drug was safe and well tolerated, he added. “We were somewhat concerned that it could cause hypoglycemia in these patients, none of whom had diabetes, but that was not the case.” The only significant adverse event observed was lower extremity edema, a side effect also seen in diabetic patients who take the drug.

BOSTON — Bariatric surgery may resolve symptoms of polycystic ovary syndrome in obese women with the condition, Dr. Héctor Escobar-Morreale reported at the annual meeting of the Androgen Excess Society.

“In some women, the syndrome is so driven by insulin resistance that it may resolve completely with weight loss,” said the endocrinologist, of the Hospital Ramón y Cajal in Madrid.

Among women seeking weight-loss advice at his endocrinology practice, Dr. Escobar-Morreale found a PCOS prevalence of 28%, more than five times the prevalence among lean women in Madrid. This discovery prompted him to examine the prevalence of the disorder among 36 obese women referred for bariatric surgery, and to also track the effect of surgically induced weight loss on their symptoms.

In this group of women, 17 (47%) were diagnosed with PCOS according to the 1990 National Institutes of Health criteria. Follow-up data at 1 year were available on 12 of them.

By 12 months, the women had lost an average of 41 kg and their hirsutism had resolved. Significant decreases were noted in their sex steroid levels: Total testosterone dropped from a mean of 69 ng/dL to 19 ng/dL, free testosterone from 1.6 to 0.3 ng/dL, androstenedione from 4.1 to 1.5 ng/dL, and dehydroepiandrosterone sulfate from 2,000 to 795 ng/dL.

Insulin sensitivity returned to normal and regular menstruation was restored. Among 10 women who were tested, all had hormonal evidence of ovulation.

Of course, Dr. Escobar-Morreale said, bariatric surgery is a serious proposal and is indicated only for morbidly obese patients who have repeatedly failed to lose weight through caloric restriction and lifestyle modification. In fact, he said, one of the PCOS patients died from postoperative surgical complications.

“Lifestyle modification should be attempted first,” he said. “But we already know that only about 20% of patients achieve success, which we define as at least a 10% weight loss that's maintained for at least 1 year. That's not very good.”

BOSTON — Bariatric surgery may resolve symptoms of polycystic ovary syndrome in obese women with the condition, Dr. Héctor Escobar-Morreale reported at the annual meeting of the Androgen Excess Society.

“In some women, the syndrome is so driven by insulin resistance that it may resolve completely with weight loss,” said the endocrinologist, of the Hospital Ramón y Cajal in Madrid.

Among women seeking weight-loss advice at his endocrinology practice, Dr. Escobar-Morreale found a PCOS prevalence of 28%, more than five times the prevalence among lean women in Madrid. This discovery prompted him to examine the prevalence of the disorder among 36 obese women referred for bariatric surgery, and to also track the effect of surgically induced weight loss on their symptoms.

In this group of women, 17 (47%) were diagnosed with PCOS according to the 1990 National Institutes of Health criteria. Follow-up data at 1 year were available on 12 of them.

By 12 months, the women had lost an average of 41 kg and their hirsutism had resolved. Significant decreases were noted in their sex steroid levels: Total testosterone dropped from a mean of 69 ng/dL to 19 ng/dL, free testosterone from 1.6 to 0.3 ng/dL, androstenedione from 4.1 to 1.5 ng/dL, and dehydroepiandrosterone sulfate from 2,000 to 795 ng/dL.

Insulin sensitivity returned to normal and regular menstruation was restored. Among 10 women who were tested, all had hormonal evidence of ovulation.

Of course, Dr. Escobar-Morreale said, bariatric surgery is a serious proposal and is indicated only for morbidly obese patients who have repeatedly failed to lose weight through caloric restriction and lifestyle modification. In fact, he said, one of the PCOS patients died from postoperative surgical complications.

“Lifestyle modification should be attempted first,” he said. “But we already know that only about 20% of patients achieve success, which we define as at least a 10% weight loss that's maintained for at least 1 year. That's not very good.”

BOSTON — Bariatric surgery may resolve symptoms of polycystic ovary syndrome in obese women with the condition, Dr. Héctor Escobar-Morreale reported at the annual meeting of the Androgen Excess Society.

“In some women, the syndrome is so driven by insulin resistance that it may resolve completely with weight loss,” said the endocrinologist, of the Hospital Ramón y Cajal in Madrid.

Among women seeking weight-loss advice at his endocrinology practice, Dr. Escobar-Morreale found a PCOS prevalence of 28%, more than five times the prevalence among lean women in Madrid. This discovery prompted him to examine the prevalence of the disorder among 36 obese women referred for bariatric surgery, and to also track the effect of surgically induced weight loss on their symptoms.

In this group of women, 17 (47%) were diagnosed with PCOS according to the 1990 National Institutes of Health criteria. Follow-up data at 1 year were available on 12 of them.

By 12 months, the women had lost an average of 41 kg and their hirsutism had resolved. Significant decreases were noted in their sex steroid levels: Total testosterone dropped from a mean of 69 ng/dL to 19 ng/dL, free testosterone from 1.6 to 0.3 ng/dL, androstenedione from 4.1 to 1.5 ng/dL, and dehydroepiandrosterone sulfate from 2,000 to 795 ng/dL.

Insulin sensitivity returned to normal and regular menstruation was restored. Among 10 women who were tested, all had hormonal evidence of ovulation.

Of course, Dr. Escobar-Morreale said, bariatric surgery is a serious proposal and is indicated only for morbidly obese patients who have repeatedly failed to lose weight through caloric restriction and lifestyle modification. In fact, he said, one of the PCOS patients died from postoperative surgical complications.

“Lifestyle modification should be attempted first,” he said. “But we already know that only about 20% of patients achieve success, which we define as at least a 10% weight loss that's maintained for at least 1 year. That's not very good.”

BOSTON — To maintain skeletal health and reach optimal bone development, patients with childhood-onset growth hormone deficiency should continue therapy as they approach young adulthood, according to new treatment guidelines issued by The Endocrine Society.

“The mind set in the past has been that you treat these children until they stop growing,” Dr. Mark Molitch said at the society's annual meeting. “But the bones don't mature until the mid-20s, so they may still need the hormone as they transition into adulthood.”

In addition, he said, skeletal maturity may occur more slowly in patients with delayed onset of puberty or decreased gonadotropin secretion, so continuation of treatment is even more important for this population. Bone mineral density testing may provide additional valuable information for the decisions about continuing therapy.

The new guidelines, presented for the first time at the meeting, recommend retesting all children with idiopathic growth hormone deficiency as soon as possible after discontinuing the medication. Although many will have normal values, therapy should be quickly reinstituted for those who remain deficient.

The guidelines are based on 166 published studies examining the prevalence and diagnosis of growth hormone deficiency in adults, as well as treatment strategies and their long-term risks and benefits, said Dr. Molitch, chairman of the guidelines committee and professor of endocrinology at Northwestern University, Chicago.

The recommendations are aimed only at adults with clinically proven deficiency.

In the past, the insulin tolerance test was the favored diagnostic tool. However, this test carries an increased risk in patients with seizure disorders and cardiovascular disease, and requires close monitoring of even healthy patients. Recently, Dr. Molitch said, stimulation testing with growth hormone releasing hormone-arginine (GRHR-arginine) has gained favor. The test is less affected by age or obesity.

In a recent study of five different tests, including stimulation with GHRH-arginine and insulin tolerance, the stimulation test had 95% sensitivity and 91% specificity at the growth hormone cutoff level of 4.1 mcg/L; insulin testing was 96% sensitive and 92% specific at the cutoff level of 5.1 mcg/L.

Testing is indicated for adults with pituitary disease; surgery, trauma, or radiation in the pituitary area; or other pituitary deficiencies. Although children with idiopathic growth hormone deficiency should be retested as they approach adulthood, testing may be unnecessary for those with low insulinlike growth factor-1 and known defects, lesions, surgery or radiation of the hypothalamic-pituitary region, or a proven genetic defect of their capacity to secrete growth hormone. “This [combination] generally suffices to document continuing growth hormone deficiency,” the guidelines state. The evidence strongly supports individualized growth hormone dosing regimens. Generally, treatment should start low and be titrated upward based on clinical response, side effects, and IGF-1 levels.

Younger patients are likely to need higher doses, as are women, especially those on oral contraceptives, Dr. Molitch said. Patients aged 30–60 years can usually start at 300 mcg/day; dosing should be increased by 100–200 mcg/day every 1–2 months, with a therapeutic target of an IGF-1 level in the upper half of the normal range.

Older patients should be started on 100–200 mcg/day, while those younger than 30 years may benefit from initially higher doses (400–500 mcg/day).

Although no studies have linked growth hormone therapy with malignancies, the guidelines recommend against using the hormone in anyone with an active cancer. There is no evidence that treatment affects the recurrence of pituitary tumors. Patients with diabetes may need adjustments to their diabetes medications when on growth hormone. The side effects of growth hormone therapy are usually dose-related and can be alleviated by adjusting the medication. The most common are related to fluid retention. These effects occur in up to 18% of patients and include paresthesias, joint stiffness, peripheral edema, arthralgia, and myalgia. Increased blood pressure is sometimes seen, but can be avoided with appropriate dosing.

Therapy offers significant benefits, including a decrease in fat mass and its attendant risk reductions of improved lipid levels and decreased insulin resistance. The modest increases in muscle mass improve exercise tolerance, which in turn has beneficial effects on blood pressure and cardiac function. Patients with childhood-onset growth hormone deficiency also may experience improvements in left ventricular muscle mass and end diastolic volume, as well as stroke volume. Therapy also benefits bone health with both anabolic and antiresorptive effects.

While no studies have confirmed a mortality benefit with growth hormone therapy, some do suggest that mortality is increased in those with hypopituitarism. It is not proved that growth hormone decreases it.

BOSTON — To maintain skeletal health and reach optimal bone development, patients with childhood-onset growth hormone deficiency should continue therapy as they approach young adulthood, according to new treatment guidelines issued by The Endocrine Society.

“The mind set in the past has been that you treat these children until they stop growing,” Dr. Mark Molitch said at the society's annual meeting. “But the bones don't mature until the mid-20s, so they may still need the hormone as they transition into adulthood.”

In addition, he said, skeletal maturity may occur more slowly in patients with delayed onset of puberty or decreased gonadotropin secretion, so continuation of treatment is even more important for this population. Bone mineral density testing may provide additional valuable information for the decisions about continuing therapy.

The new guidelines, presented for the first time at the meeting, recommend retesting all children with idiopathic growth hormone deficiency as soon as possible after discontinuing the medication. Although many will have normal values, therapy should be quickly reinstituted for those who remain deficient.

The guidelines are based on 166 published studies examining the prevalence and diagnosis of growth hormone deficiency in adults, as well as treatment strategies and their long-term risks and benefits, said Dr. Molitch, chairman of the guidelines committee and professor of endocrinology at Northwestern University, Chicago.

The recommendations are aimed only at adults with clinically proven deficiency.

In the past, the insulin tolerance test was the favored diagnostic tool. However, this test carries an increased risk in patients with seizure disorders and cardiovascular disease, and requires close monitoring of even healthy patients. Recently, Dr. Molitch said, stimulation testing with growth hormone releasing hormone-arginine (GRHR-arginine) has gained favor. The test is less affected by age or obesity.

In a recent study of five different tests, including stimulation with GHRH-arginine and insulin tolerance, the stimulation test had 95% sensitivity and 91% specificity at the growth hormone cutoff level of 4.1 mcg/L; insulin testing was 96% sensitive and 92% specific at the cutoff level of 5.1 mcg/L.

Testing is indicated for adults with pituitary disease; surgery, trauma, or radiation in the pituitary area; or other pituitary deficiencies. Although children with idiopathic growth hormone deficiency should be retested as they approach adulthood, testing may be unnecessary for those with low insulinlike growth factor-1 and known defects, lesions, surgery or radiation of the hypothalamic-pituitary region, or a proven genetic defect of their capacity to secrete growth hormone. “This [combination] generally suffices to document continuing growth hormone deficiency,” the guidelines state. The evidence strongly supports individualized growth hormone dosing regimens. Generally, treatment should start low and be titrated upward based on clinical response, side effects, and IGF-1 levels.

Younger patients are likely to need higher doses, as are women, especially those on oral contraceptives, Dr. Molitch said. Patients aged 30–60 years can usually start at 300 mcg/day; dosing should be increased by 100–200 mcg/day every 1–2 months, with a therapeutic target of an IGF-1 level in the upper half of the normal range.

Older patients should be started on 100–200 mcg/day, while those younger than 30 years may benefit from initially higher doses (400–500 mcg/day).

Although no studies have linked growth hormone therapy with malignancies, the guidelines recommend against using the hormone in anyone with an active cancer. There is no evidence that treatment affects the recurrence of pituitary tumors. Patients with diabetes may need adjustments to their diabetes medications when on growth hormone. The side effects of growth hormone therapy are usually dose-related and can be alleviated by adjusting the medication. The most common are related to fluid retention. These effects occur in up to 18% of patients and include paresthesias, joint stiffness, peripheral edema, arthralgia, and myalgia. Increased blood pressure is sometimes seen, but can be avoided with appropriate dosing.

Therapy offers significant benefits, including a decrease in fat mass and its attendant risk reductions of improved lipid levels and decreased insulin resistance. The modest increases in muscle mass improve exercise tolerance, which in turn has beneficial effects on blood pressure and cardiac function. Patients with childhood-onset growth hormone deficiency also may experience improvements in left ventricular muscle mass and end diastolic volume, as well as stroke volume. Therapy also benefits bone health with both anabolic and antiresorptive effects.

While no studies have confirmed a mortality benefit with growth hormone therapy, some do suggest that mortality is increased in those with hypopituitarism. It is not proved that growth hormone decreases it.

BOSTON — To maintain skeletal health and reach optimal bone development, patients with childhood-onset growth hormone deficiency should continue therapy as they approach young adulthood, according to new treatment guidelines issued by The Endocrine Society.

“The mind set in the past has been that you treat these children until they stop growing,” Dr. Mark Molitch said at the society's annual meeting. “But the bones don't mature until the mid-20s, so they may still need the hormone as they transition into adulthood.”

In addition, he said, skeletal maturity may occur more slowly in patients with delayed onset of puberty or decreased gonadotropin secretion, so continuation of treatment is even more important for this population. Bone mineral density testing may provide additional valuable information for the decisions about continuing therapy.

The new guidelines, presented for the first time at the meeting, recommend retesting all children with idiopathic growth hormone deficiency as soon as possible after discontinuing the medication. Although many will have normal values, therapy should be quickly reinstituted for those who remain deficient.

The guidelines are based on 166 published studies examining the prevalence and diagnosis of growth hormone deficiency in adults, as well as treatment strategies and their long-term risks and benefits, said Dr. Molitch, chairman of the guidelines committee and professor of endocrinology at Northwestern University, Chicago.

The recommendations are aimed only at adults with clinically proven deficiency.

In the past, the insulin tolerance test was the favored diagnostic tool. However, this test carries an increased risk in patients with seizure disorders and cardiovascular disease, and requires close monitoring of even healthy patients. Recently, Dr. Molitch said, stimulation testing with growth hormone releasing hormone-arginine (GRHR-arginine) has gained favor. The test is less affected by age or obesity.

In a recent study of five different tests, including stimulation with GHRH-arginine and insulin tolerance, the stimulation test had 95% sensitivity and 91% specificity at the growth hormone cutoff level of 4.1 mcg/L; insulin testing was 96% sensitive and 92% specific at the cutoff level of 5.1 mcg/L.

Testing is indicated for adults with pituitary disease; surgery, trauma, or radiation in the pituitary area; or other pituitary deficiencies. Although children with idiopathic growth hormone deficiency should be retested as they approach adulthood, testing may be unnecessary for those with low insulinlike growth factor-1 and known defects, lesions, surgery or radiation of the hypothalamic-pituitary region, or a proven genetic defect of their capacity to secrete growth hormone. “This [combination] generally suffices to document continuing growth hormone deficiency,” the guidelines state. The evidence strongly supports individualized growth hormone dosing regimens. Generally, treatment should start low and be titrated upward based on clinical response, side effects, and IGF-1 levels.

Younger patients are likely to need higher doses, as are women, especially those on oral contraceptives, Dr. Molitch said. Patients aged 30–60 years can usually start at 300 mcg/day; dosing should be increased by 100–200 mcg/day every 1–2 months, with a therapeutic target of an IGF-1 level in the upper half of the normal range.

Older patients should be started on 100–200 mcg/day, while those younger than 30 years may benefit from initially higher doses (400–500 mcg/day).

Although no studies have linked growth hormone therapy with malignancies, the guidelines recommend against using the hormone in anyone with an active cancer. There is no evidence that treatment affects the recurrence of pituitary tumors. Patients with diabetes may need adjustments to their diabetes medications when on growth hormone. The side effects of growth hormone therapy are usually dose-related and can be alleviated by adjusting the medication. The most common are related to fluid retention. These effects occur in up to 18% of patients and include paresthesias, joint stiffness, peripheral edema, arthralgia, and myalgia. Increased blood pressure is sometimes seen, but can be avoided with appropriate dosing.

Therapy offers significant benefits, including a decrease in fat mass and its attendant risk reductions of improved lipid levels and decreased insulin resistance. The modest increases in muscle mass improve exercise tolerance, which in turn has beneficial effects on blood pressure and cardiac function. Patients with childhood-onset growth hormone deficiency also may experience improvements in left ventricular muscle mass and end diastolic volume, as well as stroke volume. Therapy also benefits bone health with both anabolic and antiresorptive effects.

While no studies have confirmed a mortality benefit with growth hormone therapy, some do suggest that mortality is increased in those with hypopituitarism. It is not proved that growth hormone decreases it.

The discovery of a common polymorphism in the gene for β₁-adrenergic-receptor blocker that predicts response to the β-blocker bucindolol has resurrected interest in the discarded drug.

Bucindolol could be the first genetically targeted cardiovascular drug, said Dr. Michael Bristow, codirector of the Cardiovascular Institute at the University of Colorado. His company, ARCA Discovery Inc. of Denver, intends to file a new drug and diagnostic test application with the Food and Drug Administration. If approved, the drug would be marketed along with a genetic test to identify potential responders.

Subjects with heart failure who were homozygous for the arginine variant of the β₁ AR-389 gene (Arg-389 variant) and who took bucindolol had a 38% reduction in mortality, compared with such patients who were treated with placebo, Dr. Bristow and his colleagues have reported. They also had a 34% reduction in the combined end point of hospitalizations and mortality (PNAS 2006;doi/10.1073/pnas.0509937103).

“This is where the field of pharmacogenetic therapy needs to go in cardiovascular medicine,” Dr. Bristow said in an interview. “Developing therapies that are specifically effective on pharmacogenetic subsets, so patients unlikely to respond to therapy aren't exposed to the risks and costs of treatment.”

The drug could be especially important for blacks, who are twice as likely as whites to develop heart failure, but who also have a poorer response to drugs, he said. The DNA test would target blacks who could benefit from bucindolol. “We wouldn't have to rely on skin color to assign therapy. We could assign therapy based on much better criteria: biology as predicted by a genetic profile.”

The bucindolol study is an exciting one, said Dr. Sidney Goldstein, head, emeritus, of the division of cardiovascular medicine at Henry Ford Hospital in Detroit. “Previous studies trying to link genotypes to β-blocker efficacy have shown some association. This study, which is the largest randomized population that has been looked at, certainly lends further credibility to the thought.”

But it will take more than one DNA study to bring bucindolol to market, he predicted. “It's very intriguing, but in order to get approval we'd need a lot more clinical evidence in this particular population,” said Dr. Goldstein, medical editor of CARDIOLOGY NEWS.

Mainstream research abandoned bucindolol in 1999, when the Beta-Blocker Evaluation of Survival Time study (BEST) was halted for ethical reasons. After a median of 2 years, bucindolol offered no significant survival advantage over placebo, while other β-blockers had long been confirmed as beneficial.

But as the study was further analyzed, substudies using its database emerged, including one using DNA collected from 1,040 BEST subjects. In 1998, Dr. Steve Liggett, BEST's lead investigator, identified several genetic variants of the β₁-adrenergic receptor—the target of β-blocker therapy. In a DNA substudy submitted before BEST ended, Dr. Liggett and Dr. Bristow hypothesized that the Arg-389 variant would predict bucindolol response.

Dr. Bristow and his colleagues reexamined the BEST response data, stratifying survival of placebo and bucindolol-treated patients according to genetic type. Only homozygous Arg-389 variant patients treated with bucindolol showed a significant survival advantage: a hazard ratio of 0.62 for mortality, compared with Arg-389 variant placebo-treated patients.

The polymorphism occurred more frequently in whites than in blacks (51% vs. 35%), Dr. Bristow said—an intriguing finding that probably speaks to bucindolol's better performance among whites in the original BEST study (N. Engl. J. Med. 2001;344:1659–67). “We need more research on this point, but it may be possible that this genetic variant has a great deal to do with why black patients have more heart failure, and worse outcomes, than white patients.”

Bucindolol has a unique pharmacologic profile among β-blockers, not only blocking adrenergic receptors but lowering norepinephrine as well. “It appears that those with the Arg/Arg polymorphism can tolerate the loss of norepinephrine signalling better than those who don't have it,” Dr. Bristow said. “In them, the combination of actions produces a supertherapeutic response.”

It's impossible to extrapolate bucindolol's positive effect on patients with the arginine variant to any other β-blocker, however. One study has already addressed this issue, finding no association between β₁-AR genetic subtype and survival in patients taking metoprolol (Eur. J. Heart Fail. 2003;5:463–78). There are no data available on carvedilol or bisoprolol.

If bucindolol and its accompanying genetic screen are eventually approved, physicians and patients will have to decide if the additional time and expense of genetic testing will be worth the drug's benefit, Dr. Goldstein said. “Metoprolol and carvedilol will probably both be coming out in generic forms pretty quickly. In all probability they will be substantially less expensive than bucindolol, and it's hard to believe bucindolol would be better than those drugs, although it does appear to be just as good for these particular patients.”

The discovery of a common polymorphism in the gene for β₁-adrenergic-receptor blocker that predicts response to the β-blocker bucindolol has resurrected interest in the discarded drug.

Bucindolol could be the first genetically targeted cardiovascular drug, said Dr. Michael Bristow, codirector of the Cardiovascular Institute at the University of Colorado. His company, ARCA Discovery Inc. of Denver, intends to file a new drug and diagnostic test application with the Food and Drug Administration. If approved, the drug would be marketed along with a genetic test to identify potential responders.

Subjects with heart failure who were homozygous for the arginine variant of the β₁ AR-389 gene (Arg-389 variant) and who took bucindolol had a 38% reduction in mortality, compared with such patients who were treated with placebo, Dr. Bristow and his colleagues have reported. They also had a 34% reduction in the combined end point of hospitalizations and mortality (PNAS 2006;doi/10.1073/pnas.0509937103).

“This is where the field of pharmacogenetic therapy needs to go in cardiovascular medicine,” Dr. Bristow said in an interview. “Developing therapies that are specifically effective on pharmacogenetic subsets, so patients unlikely to respond to therapy aren't exposed to the risks and costs of treatment.”

The drug could be especially important for blacks, who are twice as likely as whites to develop heart failure, but who also have a poorer response to drugs, he said. The DNA test would target blacks who could benefit from bucindolol. “We wouldn't have to rely on skin color to assign therapy. We could assign therapy based on much better criteria: biology as predicted by a genetic profile.”

The bucindolol study is an exciting one, said Dr. Sidney Goldstein, head, emeritus, of the division of cardiovascular medicine at Henry Ford Hospital in Detroit. “Previous studies trying to link genotypes to β-blocker efficacy have shown some association. This study, which is the largest randomized population that has been looked at, certainly lends further credibility to the thought.”

But it will take more than one DNA study to bring bucindolol to market, he predicted. “It's very intriguing, but in order to get approval we'd need a lot more clinical evidence in this particular population,” said Dr. Goldstein, medical editor of CARDIOLOGY NEWS.

Mainstream research abandoned bucindolol in 1999, when the Beta-Blocker Evaluation of Survival Time study (BEST) was halted for ethical reasons. After a median of 2 years, bucindolol offered no significant survival advantage over placebo, while other β-blockers had long been confirmed as beneficial.

But as the study was further analyzed, substudies using its database emerged, including one using DNA collected from 1,040 BEST subjects. In 1998, Dr. Steve Liggett, BEST's lead investigator, identified several genetic variants of the β₁-adrenergic receptor—the target of β-blocker therapy. In a DNA substudy submitted before BEST ended, Dr. Liggett and Dr. Bristow hypothesized that the Arg-389 variant would predict bucindolol response.

Dr. Bristow and his colleagues reexamined the BEST response data, stratifying survival of placebo and bucindolol-treated patients according to genetic type. Only homozygous Arg-389 variant patients treated with bucindolol showed a significant survival advantage: a hazard ratio of 0.62 for mortality, compared with Arg-389 variant placebo-treated patients.

The polymorphism occurred more frequently in whites than in blacks (51% vs. 35%), Dr. Bristow said—an intriguing finding that probably speaks to bucindolol's better performance among whites in the original BEST study (N. Engl. J. Med. 2001;344:1659–67). “We need more research on this point, but it may be possible that this genetic variant has a great deal to do with why black patients have more heart failure, and worse outcomes, than white patients.”

Bucindolol has a unique pharmacologic profile among β-blockers, not only blocking adrenergic receptors but lowering norepinephrine as well. “It appears that those with the Arg/Arg polymorphism can tolerate the loss of norepinephrine signalling better than those who don't have it,” Dr. Bristow said. “In them, the combination of actions produces a supertherapeutic response.”

It's impossible to extrapolate bucindolol's positive effect on patients with the arginine variant to any other β-blocker, however. One study has already addressed this issue, finding no association between β₁-AR genetic subtype and survival in patients taking metoprolol (Eur. J. Heart Fail. 2003;5:463–78). There are no data available on carvedilol or bisoprolol.

If bucindolol and its accompanying genetic screen are eventually approved, physicians and patients will have to decide if the additional time and expense of genetic testing will be worth the drug's benefit, Dr. Goldstein said. “Metoprolol and carvedilol will probably both be coming out in generic forms pretty quickly. In all probability they will be substantially less expensive than bucindolol, and it's hard to believe bucindolol would be better than those drugs, although it does appear to be just as good for these particular patients.”

The discovery of a common polymorphism in the gene for β₁-adrenergic-receptor blocker that predicts response to the β-blocker bucindolol has resurrected interest in the discarded drug.

Bucindolol could be the first genetically targeted cardiovascular drug, said Dr. Michael Bristow, codirector of the Cardiovascular Institute at the University of Colorado. His company, ARCA Discovery Inc. of Denver, intends to file a new drug and diagnostic test application with the Food and Drug Administration. If approved, the drug would be marketed along with a genetic test to identify potential responders.

Subjects with heart failure who were homozygous for the arginine variant of the β₁ AR-389 gene (Arg-389 variant) and who took bucindolol had a 38% reduction in mortality, compared with such patients who were treated with placebo, Dr. Bristow and his colleagues have reported. They also had a 34% reduction in the combined end point of hospitalizations and mortality (PNAS 2006;doi/10.1073/pnas.0509937103).

“This is where the field of pharmacogenetic therapy needs to go in cardiovascular medicine,” Dr. Bristow said in an interview. “Developing therapies that are specifically effective on pharmacogenetic subsets, so patients unlikely to respond to therapy aren't exposed to the risks and costs of treatment.”

The drug could be especially important for blacks, who are twice as likely as whites to develop heart failure, but who also have a poorer response to drugs, he said. The DNA test would target blacks who could benefit from bucindolol. “We wouldn't have to rely on skin color to assign therapy. We could assign therapy based on much better criteria: biology as predicted by a genetic profile.”

The bucindolol study is an exciting one, said Dr. Sidney Goldstein, head, emeritus, of the division of cardiovascular medicine at Henry Ford Hospital in Detroit. “Previous studies trying to link genotypes to β-blocker efficacy have shown some association. This study, which is the largest randomized population that has been looked at, certainly lends further credibility to the thought.”

But it will take more than one DNA study to bring bucindolol to market, he predicted. “It's very intriguing, but in order to get approval we'd need a lot more clinical evidence in this particular population,” said Dr. Goldstein, medical editor of CARDIOLOGY NEWS.

Mainstream research abandoned bucindolol in 1999, when the Beta-Blocker Evaluation of Survival Time study (BEST) was halted for ethical reasons. After a median of 2 years, bucindolol offered no significant survival advantage over placebo, while other β-blockers had long been confirmed as beneficial.

But as the study was further analyzed, substudies using its database emerged, including one using DNA collected from 1,040 BEST subjects. In 1998, Dr. Steve Liggett, BEST's lead investigator, identified several genetic variants of the β₁-adrenergic receptor—the target of β-blocker therapy. In a DNA substudy submitted before BEST ended, Dr. Liggett and Dr. Bristow hypothesized that the Arg-389 variant would predict bucindolol response.

Dr. Bristow and his colleagues reexamined the BEST response data, stratifying survival of placebo and bucindolol-treated patients according to genetic type. Only homozygous Arg-389 variant patients treated with bucindolol showed a significant survival advantage: a hazard ratio of 0.62 for mortality, compared with Arg-389 variant placebo-treated patients.

The polymorphism occurred more frequently in whites than in blacks (51% vs. 35%), Dr. Bristow said—an intriguing finding that probably speaks to bucindolol's better performance among whites in the original BEST study (N. Engl. J. Med. 2001;344:1659–67). “We need more research on this point, but it may be possible that this genetic variant has a great deal to do with why black patients have more heart failure, and worse outcomes, than white patients.”

Bucindolol has a unique pharmacologic profile among β-blockers, not only blocking adrenergic receptors but lowering norepinephrine as well. “It appears that those with the Arg/Arg polymorphism can tolerate the loss of norepinephrine signalling better than those who don't have it,” Dr. Bristow said. “In them, the combination of actions produces a supertherapeutic response.”

It's impossible to extrapolate bucindolol's positive effect on patients with the arginine variant to any other β-blocker, however. One study has already addressed this issue, finding no association between β₁-AR genetic subtype and survival in patients taking metoprolol (Eur. J. Heart Fail. 2003;5:463–78). There are no data available on carvedilol or bisoprolol.

If bucindolol and its accompanying genetic screen are eventually approved, physicians and patients will have to decide if the additional time and expense of genetic testing will be worth the drug's benefit, Dr. Goldstein said. “Metoprolol and carvedilol will probably both be coming out in generic forms pretty quickly. In all probability they will be substantially less expensive than bucindolol, and it's hard to believe bucindolol would be better than those drugs, although it does appear to be just as good for these particular patients.”