Mary Ann Moon

A new tetravalent meningococcal vaccine proved to be immunogenic and well tolerated in infants in a phase II study, investigators reported in JAMA.

The tetravalent meningococcal vaccine that is currently licensed in the United States is recommended for all 11- to 18-year-olds, but was found to be poorly immunogenic in infants so is not licensed for use in children under age 2 years.

Because infants are the age group at highest risk for meningococcal disease, a new vaccine was developed and tested in an open-label, randomized controlled trial involving 421 infants in England and Canada.

The new vaccine–MenACWY–covers serogroups A, C, W-135, and Y. It was developed by Novartis Vaccines and Diagnostics, which funded this phase II study.

Two different primary three-dose schedules were evaluated: a single dose at 2, 3, and 4 months of age, and a single dose at 2, 4, and 6 months of age.

A two-dose schedule (a single dose at 2 and 4 months) also was assessed.

This was to examine the new vaccine's safety and efficacy when given according to the different routine immunization schedules in different countries, said Dr. Matthew D. Snape of the Oxford Vaccine Group, University of Oxford (England), and his associates.

A subset of infants also received a booster dose at 12 months of age, since some waning in antibody titers was expected, as has been observed after immunization against serogroup C alone. Another subset of subjects received a reduced dose of the vaccine at 12 months as a probe for immunologic memory.

One month after the immunization series was complete, 92% of the infants who had received the 2-, 3-, and 4-month schedule showed human complement serum bactericidal antibody (hSBA) titers of 1:4 or better against all four serogroups, which is considered protective.

Similar results were obtained with the 2-, 4-, and 6-month schedule, except that the proportion of infants with protective hSBA titers against serogroup A was lower, at 81%, Dr. Snape and his associates said (JAMA 2008;299:173-84).

The infants who received MenACWY only at 2 and 4 months had less of a response. About 80% showed hSBA titers of 1:4 or better for serogroups C, W-135, and Y, and the response for serogroup A was 60%.

All serogroups, particularly serogroup A, showed a waning in antibody titers by 12 months of age. The subjects who received a booster at this time showed a “reassuring” increase in titers, suggesting that a booster dose of MenACWY may be required to provide sustained protection, the investigators said.

Results in the subjects who received an immune challenge at 12 months suggested that the new vaccine did induce immunologic memory, they added.

The new vaccine did not appear to affect the immunogenicity of other routine vaccines given concomitantly, including vaccines against hepatitis B, diphtheria, tetanus, and Haemophilus influenzae type b.

There were 66 adverse events reported during the study period, but only 2 were thought to be potentially related to the study vaccine. Both resolved spontaneously.

The first was a brief episode of idiopathic thrombocytopenic purpura after the booster dose, which occurred in a child who had had a viral-like illness with oral ulcers and rash 2 weeks previously.

The second was an episode of supraventricular tachycardia, and it was found that this child had a history of the arrhythmias and had been enrolled in violation of the study's exclusion criteria.

The most important limitation in this study was that the number of subjects was “too small to draw firm conclusions regarding the safety of this vaccine, and therefore further studies will be required,” Dr. Snape and his associates noted.

Nevertheless, in an editorial comment accompanying this report, Dr. Lee H. Harrison of the infectious diseases epidemiology research unit of the University of Pittsburgh, said the study “represents a substantial advance in the vaccine prevention of meningococcal disease.”

It is not yet known whether the new vaccine prevents pharyngeal carriage of meningococcal organisms, “a major public health benefit” that has been noted in other conjugate vaccines such as those against pneumococcal disease and Haemophilus influenzae type b, Dr. Harrison said (JAMA 2008;299:217-9).

Given that the MenACWY vaccine “behaves immunologically like a conjugate vaccine,” it would be expected to prevent pharyngeal carriage, which would in turn prevent transmission among the unimmunized population and thus promote herd immunity.

A new tetravalent meningococcal vaccine proved to be immunogenic and well tolerated in infants in a phase II study, investigators reported in JAMA.

The tetravalent meningococcal vaccine that is currently licensed in the United States is recommended for all 11- to 18-year-olds, but was found to be poorly immunogenic in infants so is not licensed for use in children under age 2 years.

Because infants are the age group at highest risk for meningococcal disease, a new vaccine was developed and tested in an open-label, randomized controlled trial involving 421 infants in England and Canada.

The new vaccine–MenACWY–covers serogroups A, C, W-135, and Y. It was developed by Novartis Vaccines and Diagnostics, which funded this phase II study.

Two different primary three-dose schedules were evaluated: a single dose at 2, 3, and 4 months of age, and a single dose at 2, 4, and 6 months of age.

A two-dose schedule (a single dose at 2 and 4 months) also was assessed.

This was to examine the new vaccine's safety and efficacy when given according to the different routine immunization schedules in different countries, said Dr. Matthew D. Snape of the Oxford Vaccine Group, University of Oxford (England), and his associates.

A subset of infants also received a booster dose at 12 months of age, since some waning in antibody titers was expected, as has been observed after immunization against serogroup C alone. Another subset of subjects received a reduced dose of the vaccine at 12 months as a probe for immunologic memory.

One month after the immunization series was complete, 92% of the infants who had received the 2-, 3-, and 4-month schedule showed human complement serum bactericidal antibody (hSBA) titers of 1:4 or better against all four serogroups, which is considered protective.

Similar results were obtained with the 2-, 4-, and 6-month schedule, except that the proportion of infants with protective hSBA titers against serogroup A was lower, at 81%, Dr. Snape and his associates said (JAMA 2008;299:173-84).

The infants who received MenACWY only at 2 and 4 months had less of a response. About 80% showed hSBA titers of 1:4 or better for serogroups C, W-135, and Y, and the response for serogroup A was 60%.

All serogroups, particularly serogroup A, showed a waning in antibody titers by 12 months of age. The subjects who received a booster at this time showed a “reassuring” increase in titers, suggesting that a booster dose of MenACWY may be required to provide sustained protection, the investigators said.

Results in the subjects who received an immune challenge at 12 months suggested that the new vaccine did induce immunologic memory, they added.

The new vaccine did not appear to affect the immunogenicity of other routine vaccines given concomitantly, including vaccines against hepatitis B, diphtheria, tetanus, and Haemophilus influenzae type b.

There were 66 adverse events reported during the study period, but only 2 were thought to be potentially related to the study vaccine. Both resolved spontaneously.

The first was a brief episode of idiopathic thrombocytopenic purpura after the booster dose, which occurred in a child who had had a viral-like illness with oral ulcers and rash 2 weeks previously.

The second was an episode of supraventricular tachycardia, and it was found that this child had a history of the arrhythmias and had been enrolled in violation of the study's exclusion criteria.

The most important limitation in this study was that the number of subjects was “too small to draw firm conclusions regarding the safety of this vaccine, and therefore further studies will be required,” Dr. Snape and his associates noted.

Nevertheless, in an editorial comment accompanying this report, Dr. Lee H. Harrison of the infectious diseases epidemiology research unit of the University of Pittsburgh, said the study “represents a substantial advance in the vaccine prevention of meningococcal disease.”

It is not yet known whether the new vaccine prevents pharyngeal carriage of meningococcal organisms, “a major public health benefit” that has been noted in other conjugate vaccines such as those against pneumococcal disease and Haemophilus influenzae type b, Dr. Harrison said (JAMA 2008;299:217-9).

Given that the MenACWY vaccine “behaves immunologically like a conjugate vaccine,” it would be expected to prevent pharyngeal carriage, which would in turn prevent transmission among the unimmunized population and thus promote herd immunity.

A new tetravalent meningococcal vaccine proved to be immunogenic and well tolerated in infants in a phase II study, investigators reported in JAMA.

The tetravalent meningococcal vaccine that is currently licensed in the United States is recommended for all 11- to 18-year-olds, but was found to be poorly immunogenic in infants so is not licensed for use in children under age 2 years.

Because infants are the age group at highest risk for meningococcal disease, a new vaccine was developed and tested in an open-label, randomized controlled trial involving 421 infants in England and Canada.

The new vaccine–MenACWY–covers serogroups A, C, W-135, and Y. It was developed by Novartis Vaccines and Diagnostics, which funded this phase II study.

Two different primary three-dose schedules were evaluated: a single dose at 2, 3, and 4 months of age, and a single dose at 2, 4, and 6 months of age.

A two-dose schedule (a single dose at 2 and 4 months) also was assessed.

This was to examine the new vaccine's safety and efficacy when given according to the different routine immunization schedules in different countries, said Dr. Matthew D. Snape of the Oxford Vaccine Group, University of Oxford (England), and his associates.

A subset of infants also received a booster dose at 12 months of age, since some waning in antibody titers was expected, as has been observed after immunization against serogroup C alone. Another subset of subjects received a reduced dose of the vaccine at 12 months as a probe for immunologic memory.

One month after the immunization series was complete, 92% of the infants who had received the 2-, 3-, and 4-month schedule showed human complement serum bactericidal antibody (hSBA) titers of 1:4 or better against all four serogroups, which is considered protective.

Similar results were obtained with the 2-, 4-, and 6-month schedule, except that the proportion of infants with protective hSBA titers against serogroup A was lower, at 81%, Dr. Snape and his associates said (JAMA 2008;299:173-84).

The infants who received MenACWY only at 2 and 4 months had less of a response. About 80% showed hSBA titers of 1:4 or better for serogroups C, W-135, and Y, and the response for serogroup A was 60%.

All serogroups, particularly serogroup A, showed a waning in antibody titers by 12 months of age. The subjects who received a booster at this time showed a “reassuring” increase in titers, suggesting that a booster dose of MenACWY may be required to provide sustained protection, the investigators said.

Results in the subjects who received an immune challenge at 12 months suggested that the new vaccine did induce immunologic memory, they added.

The new vaccine did not appear to affect the immunogenicity of other routine vaccines given concomitantly, including vaccines against hepatitis B, diphtheria, tetanus, and Haemophilus influenzae type b.

There were 66 adverse events reported during the study period, but only 2 were thought to be potentially related to the study vaccine. Both resolved spontaneously.

The first was a brief episode of idiopathic thrombocytopenic purpura after the booster dose, which occurred in a child who had had a viral-like illness with oral ulcers and rash 2 weeks previously.

The second was an episode of supraventricular tachycardia, and it was found that this child had a history of the arrhythmias and had been enrolled in violation of the study's exclusion criteria.

The most important limitation in this study was that the number of subjects was “too small to draw firm conclusions regarding the safety of this vaccine, and therefore further studies will be required,” Dr. Snape and his associates noted.

Nevertheless, in an editorial comment accompanying this report, Dr. Lee H. Harrison of the infectious diseases epidemiology research unit of the University of Pittsburgh, said the study “represents a substantial advance in the vaccine prevention of meningococcal disease.”

It is not yet known whether the new vaccine prevents pharyngeal carriage of meningococcal organisms, “a major public health benefit” that has been noted in other conjugate vaccines such as those against pneumococcal disease and Haemophilus influenzae type b, Dr. Harrison said (JAMA 2008;299:217-9).

Given that the MenACWY vaccine “behaves immunologically like a conjugate vaccine,” it would be expected to prevent pharyngeal carriage, which would in turn prevent transmission among the unimmunized population and thus promote herd immunity.

The Health Insurance Portability and Accountability Act's privacy rule has stymied clinical research by making it more expensive and time consuming, according to data from a national survey of more than 1,500 epidemiologists.

The Institute of Medicine commissioned this first-ever, large-scale survey to assess the effect of the privacy rule, which was implemented in 2003 to protect research subjects' privacy while still preserving the legitimate use and disclosure of their health information. The findings confirm those of case reports and smaller or single-institution studies: The privacy rule's overall effect on research has been more negative than positive, said Dr. Roberta B. Ness of the University of Pittsburgh and her associates.

The rule requires researchers to obtain written authorization to access medical records or to obtain a waiver from an institutional review board (IRB). In practice, compliance entails following and documenting complex bureaucratic procedures—particularly patient consent—that complicate the research process.

A total of 1,527 epidemiologists from academia, industry, government, and nongovernment organizations completed the anonymous Web-based survey, which elicited both positive and negative feedback on the privacy rule.

Three major themes emerged from the responses.

First, a solid majority “expressed frustration and concern that the implementation of the privacy rule had added patient burden without substantially enhancing privacy protection.” In the words of one respondent, an “already cumbersome patient consent form now has an additional [page and a half] explaining HIPAA restrictions. This detracts from the informed consent process pertaining to the more critical issue: the actual medical risks and benefits of participating.”

Nearly 70% of respondents said that complying with the rule made their work much more difficult; an additional 16% said it made their work more difficult. In all, 40% said the rule greatly increased costs, and another 21% said it raised costs moderately. And half said it added considerably to the time needed to complete studies, while an additional 20% said it required extra time. Only 10% said that the rule strengthened public trust, and only 25% said it enhanced patient confidentiality.

Second, research institutions varied widely in their interpretation of privacy rule regulations. This impeded multicenter projects, and left many researchers confused about what research their IRB might or might not sanction. As many as one in nine epidemiologists (11%) had conceived of a study but did not submit it to an IRB because they thought it would not obtain approval under the HIPAA privacy rule, Dr. Ness and her associates said (JAMA 2007;298:2164–70).

Third, compliance with the privacy rule slowed research to such a degree that half of the respondents felt it is “seriously affecting” public health surveillance, which may threaten the ability to combat epidemics and other dangers. As one respondent noted, “I and my staff spend more and more time doing compliance-related things and less and less time doing actual research.”

The Health Insurance Portability and Accountability Act's privacy rule has stymied clinical research by making it more expensive and time consuming, according to data from a national survey of more than 1,500 epidemiologists.

The Institute of Medicine commissioned this first-ever, large-scale survey to assess the effect of the privacy rule, which was implemented in 2003 to protect research subjects' privacy while still preserving the legitimate use and disclosure of their health information. The findings confirm those of case reports and smaller or single-institution studies: The privacy rule's overall effect on research has been more negative than positive, said Dr. Roberta B. Ness of the University of Pittsburgh and her associates.

The rule requires researchers to obtain written authorization to access medical records or to obtain a waiver from an institutional review board (IRB). In practice, compliance entails following and documenting complex bureaucratic procedures—particularly patient consent—that complicate the research process.

A total of 1,527 epidemiologists from academia, industry, government, and nongovernment organizations completed the anonymous Web-based survey, which elicited both positive and negative feedback on the privacy rule.

Three major themes emerged from the responses.

First, a solid majority “expressed frustration and concern that the implementation of the privacy rule had added patient burden without substantially enhancing privacy protection.” In the words of one respondent, an “already cumbersome patient consent form now has an additional [page and a half] explaining HIPAA restrictions. This detracts from the informed consent process pertaining to the more critical issue: the actual medical risks and benefits of participating.”

Nearly 70% of respondents said that complying with the rule made their work much more difficult; an additional 16% said it made their work more difficult. In all, 40% said the rule greatly increased costs, and another 21% said it raised costs moderately. And half said it added considerably to the time needed to complete studies, while an additional 20% said it required extra time. Only 10% said that the rule strengthened public trust, and only 25% said it enhanced patient confidentiality.

Second, research institutions varied widely in their interpretation of privacy rule regulations. This impeded multicenter projects, and left many researchers confused about what research their IRB might or might not sanction. As many as one in nine epidemiologists (11%) had conceived of a study but did not submit it to an IRB because they thought it would not obtain approval under the HIPAA privacy rule, Dr. Ness and her associates said (JAMA 2007;298:2164–70).

Third, compliance with the privacy rule slowed research to such a degree that half of the respondents felt it is “seriously affecting” public health surveillance, which may threaten the ability to combat epidemics and other dangers. As one respondent noted, “I and my staff spend more and more time doing compliance-related things and less and less time doing actual research.”

The Health Insurance Portability and Accountability Act's privacy rule has stymied clinical research by making it more expensive and time consuming, according to data from a national survey of more than 1,500 epidemiologists.

The Institute of Medicine commissioned this first-ever, large-scale survey to assess the effect of the privacy rule, which was implemented in 2003 to protect research subjects' privacy while still preserving the legitimate use and disclosure of their health information. The findings confirm those of case reports and smaller or single-institution studies: The privacy rule's overall effect on research has been more negative than positive, said Dr. Roberta B. Ness of the University of Pittsburgh and her associates.

The rule requires researchers to obtain written authorization to access medical records or to obtain a waiver from an institutional review board (IRB). In practice, compliance entails following and documenting complex bureaucratic procedures—particularly patient consent—that complicate the research process.

A total of 1,527 epidemiologists from academia, industry, government, and nongovernment organizations completed the anonymous Web-based survey, which elicited both positive and negative feedback on the privacy rule.

Three major themes emerged from the responses.

First, a solid majority “expressed frustration and concern that the implementation of the privacy rule had added patient burden without substantially enhancing privacy protection.” In the words of one respondent, an “already cumbersome patient consent form now has an additional [page and a half] explaining HIPAA restrictions. This detracts from the informed consent process pertaining to the more critical issue: the actual medical risks and benefits of participating.”

Nearly 70% of respondents said that complying with the rule made their work much more difficult; an additional 16% said it made their work more difficult. In all, 40% said the rule greatly increased costs, and another 21% said it raised costs moderately. And half said it added considerably to the time needed to complete studies, while an additional 20% said it required extra time. Only 10% said that the rule strengthened public trust, and only 25% said it enhanced patient confidentiality.

Second, research institutions varied widely in their interpretation of privacy rule regulations. This impeded multicenter projects, and left many researchers confused about what research their IRB might or might not sanction. As many as one in nine epidemiologists (11%) had conceived of a study but did not submit it to an IRB because they thought it would not obtain approval under the HIPAA privacy rule, Dr. Ness and her associates said (JAMA 2007;298:2164–70).

Third, compliance with the privacy rule slowed research to such a degree that half of the respondents felt it is “seriously affecting” public health surveillance, which may threaten the ability to combat epidemics and other dangers. As one respondent noted, “I and my staff spend more and more time doing compliance-related things and less and less time doing actual research.”

Metformin and lifestyle changes, either alone or in combination, counteracted the weight gain caused by atypical antipsychotic medications after an initial episode of schizophrenia, according to the findings of a prospective study.

These approaches also decrease waist circumference, body mass index, fasting glucose levels, insulin levels, and insulin resistance index in schizophrenia patients taking the drugs, compared with placebo, Dr. Ren-Rong Wu and associates at Central South University, Changsha, China, reported.

In what they described as the first double-blind placebo-controlled study to directly compare metformin and lifestyle interventions in a population of first-episode schizophrenia patients, the investigators randomly assigned 32 patients each to receive either 750 mg metformin alone daily, a placebo tablet alone, lifestyle interventions plus metformin, or lifestyle interventions plus placebo tablet, for 12 weeks.

All of the study subjects had developed their first episode of schizophrenia during the preceding year and had gained more than 10% of their predrug body weight during therapy with clozapine (Clozaril), olanzapine (Zyprexa), risperidone (Risperdal), or sulpiride. Most had been of normal weight before beginning treatment, and most were young adults.

All the subjects were living in the care of their parents or caregivers, who assisted with adherence to the interventions.

The lifestyle interventions included counseling; prescription of what the American Heart Association formerly called the step 2 diet—now known as the Therapeutic Lifestyle Changes diet—which allowed less than 30% of total calories from fat but did not decrease total daily caloric intake; and exercise such as walking, jogging, bicycling, sports, and vigorous activity such as chopping wood.

The subjects' weight decreased by 7.3% with metformin plus lifestyle interventions, by 4.9% with metformin alone, and by 2% with lifestyle interventions plus placebo. In contrast, weight continued to rise by 4.8% with placebo alone.

Similarly, all three treatment approaches significantly reduced mean fasting glucose, insulin levels, and insulin resistance index, while these measures significantly increased with placebo.

No major adverse events were attributed to the interventions. Ten of the subjects failed to complete the study, five of whom required hospitalization for exacerbation of psychosis.

For patients with schizophrenia who are taking atypical antipsychotic medications, “we recommend that lifestyle intervention[s] plus metformin be considered first for those with weight gain. If patients cannot tolerate or adhere poorly to lifestyle intervention[s], they should consider metformin alone,” Dr. Wu and associates said (JAMA 2008;299:185–93).

The authors noted that their study results may not be generalizable to Western populations, to people with schizophrenia who live independently, or to patients who have long-standing schizophrenia or who are older or more obese than these study subjects were when they began treatment.

ELSEVIER GLOBAL MEDICAL NEWS

Metformin and lifestyle changes, either alone or in combination, counteracted the weight gain caused by atypical antipsychotic medications after an initial episode of schizophrenia, according to the findings of a prospective study.

These approaches also decrease waist circumference, body mass index, fasting glucose levels, insulin levels, and insulin resistance index in schizophrenia patients taking the drugs, compared with placebo, Dr. Ren-Rong Wu and associates at Central South University, Changsha, China, reported.

In what they described as the first double-blind placebo-controlled study to directly compare metformin and lifestyle interventions in a population of first-episode schizophrenia patients, the investigators randomly assigned 32 patients each to receive either 750 mg metformin alone daily, a placebo tablet alone, lifestyle interventions plus metformin, or lifestyle interventions plus placebo tablet, for 12 weeks.

All of the study subjects had developed their first episode of schizophrenia during the preceding year and had gained more than 10% of their predrug body weight during therapy with clozapine (Clozaril), olanzapine (Zyprexa), risperidone (Risperdal), or sulpiride. Most had been of normal weight before beginning treatment, and most were young adults.

All the subjects were living in the care of their parents or caregivers, who assisted with adherence to the interventions.

The lifestyle interventions included counseling; prescription of what the American Heart Association formerly called the step 2 diet—now known as the Therapeutic Lifestyle Changes diet—which allowed less than 30% of total calories from fat but did not decrease total daily caloric intake; and exercise such as walking, jogging, bicycling, sports, and vigorous activity such as chopping wood.

The subjects' weight decreased by 7.3% with metformin plus lifestyle interventions, by 4.9% with metformin alone, and by 2% with lifestyle interventions plus placebo. In contrast, weight continued to rise by 4.8% with placebo alone.

Similarly, all three treatment approaches significantly reduced mean fasting glucose, insulin levels, and insulin resistance index, while these measures significantly increased with placebo.

No major adverse events were attributed to the interventions. Ten of the subjects failed to complete the study, five of whom required hospitalization for exacerbation of psychosis.

For patients with schizophrenia who are taking atypical antipsychotic medications, “we recommend that lifestyle intervention[s] plus metformin be considered first for those with weight gain. If patients cannot tolerate or adhere poorly to lifestyle intervention[s], they should consider metformin alone,” Dr. Wu and associates said (JAMA 2008;299:185–93).

The authors noted that their study results may not be generalizable to Western populations, to people with schizophrenia who live independently, or to patients who have long-standing schizophrenia or who are older or more obese than these study subjects were when they began treatment.

ELSEVIER GLOBAL MEDICAL NEWS

Metformin and lifestyle changes, either alone or in combination, counteracted the weight gain caused by atypical antipsychotic medications after an initial episode of schizophrenia, according to the findings of a prospective study.

These approaches also decrease waist circumference, body mass index, fasting glucose levels, insulin levels, and insulin resistance index in schizophrenia patients taking the drugs, compared with placebo, Dr. Ren-Rong Wu and associates at Central South University, Changsha, China, reported.

In what they described as the first double-blind placebo-controlled study to directly compare metformin and lifestyle interventions in a population of first-episode schizophrenia patients, the investigators randomly assigned 32 patients each to receive either 750 mg metformin alone daily, a placebo tablet alone, lifestyle interventions plus metformin, or lifestyle interventions plus placebo tablet, for 12 weeks.

All of the study subjects had developed their first episode of schizophrenia during the preceding year and had gained more than 10% of their predrug body weight during therapy with clozapine (Clozaril), olanzapine (Zyprexa), risperidone (Risperdal), or sulpiride. Most had been of normal weight before beginning treatment, and most were young adults.

All the subjects were living in the care of their parents or caregivers, who assisted with adherence to the interventions.

The lifestyle interventions included counseling; prescription of what the American Heart Association formerly called the step 2 diet—now known as the Therapeutic Lifestyle Changes diet—which allowed less than 30% of total calories from fat but did not decrease total daily caloric intake; and exercise such as walking, jogging, bicycling, sports, and vigorous activity such as chopping wood.

The subjects' weight decreased by 7.3% with metformin plus lifestyle interventions, by 4.9% with metformin alone, and by 2% with lifestyle interventions plus placebo. In contrast, weight continued to rise by 4.8% with placebo alone.

Similarly, all three treatment approaches significantly reduced mean fasting glucose, insulin levels, and insulin resistance index, while these measures significantly increased with placebo.

No major adverse events were attributed to the interventions. Ten of the subjects failed to complete the study, five of whom required hospitalization for exacerbation of psychosis.

For patients with schizophrenia who are taking atypical antipsychotic medications, “we recommend that lifestyle intervention[s] plus metformin be considered first for those with weight gain. If patients cannot tolerate or adhere poorly to lifestyle intervention[s], they should consider metformin alone,” Dr. Wu and associates said (JAMA 2008;299:185–93).

The authors noted that their study results may not be generalizable to Western populations, to people with schizophrenia who live independently, or to patients who have long-standing schizophrenia or who are older or more obese than these study subjects were when they began treatment.

ELSEVIER GLOBAL MEDICAL NEWS

True acupuncture and sham acupuncture both were much more effective against chronic low-back pain than was conventional treatment in a large clinical trial comparing the three approaches.

Almost half the subjects who received either real or sham acupuncture for 6 months showed clinically relevant improvement in pain intensity or back-specific disability, compared with only one-fourth of the subjects who received a variety of conventional therapies, investigators in the German Acupuncture (GERAC) Trials reported. (See box.)

“To our knowledge, [this] study is the largest and most rigorous trial to investigate the efficacy of verum acupuncture for chronic low-back pain compared with sham acupuncture and guideline-based conventional therapy. The study yielded several surprising results,” said Dr. Michael Haake of the University of Regensburg, Bad Abbach, Germany, and his associates.

The subjects were 1,162 adults with chronic low-back pain who were randomized to conventional treatment or real or sham acupuncture administered by physicians at 340 outpatient practices. The study physicians belonged to various medical specialties, had acquired at least 140 hours of acupuncture training, and had practiced acupuncture for a median of 8 years.

Both types of acupuncture involved at least 10 30-minute sessions, usually twice per week, plus additional sessions if the subjects experienced a 10%–50% reduction in pain intensity. The two treatments were identical, except that the sham procedure avoided all known acupuncture points or meridians and involved only superficial insertion of the needles, without any manual stimulation. Subjects were unable to distinguish any difference.

Conventional therapies included at least ten 30-minute sessions with a physician or physiotherapist. Treating physicians were free to administer any combination of techniques they deemed useful, including physiotherapy, massage, heat therapy, electrotherapy, injections, analgesics, anti-inflammatory agents, yoga, hydrojet treatment, exercise, and patient education about managing back pain.

True acupuncture and sham acupuncture were equally effective, as well as more effective than conventional therapies, in relieving pain, improving function, and improving quality of life. All the improvements were significant and persisted long after treatment was completed.

“While all randomized trials and meta-analyses to date have failed to show a clear advantage of acupuncture over conventional therapy for chronic low-back pain, our findings demonstrate significant superiority,” the investigators said (Arch. Intern. Med. 2007;167:1892-8).

Largely on the basis of these results, the German Federal Joint Committee of Physicians and Health Insurance Plans–an agency similar to the National Institutes of Health–made acupuncture for low-back pain an insured benefit in that country.

The investigators' finding on sham acupuncture “forces us to question the underlying action mechanism of acupuncture and to ask whether the emphasis placed on learning the traditional Chinese acupuncture points may be superfluous,” Dr. Haake and his associates added.

“The superiority of both forms of acupuncture suggests a common underlying mechanism that may act on pain generation, transmission of pain signals, or processing of pain signals by the central nervous system and that is stronger than the action mechanism of conventional therapy,” they said.

ELSEVIER GLOBAL MEDICAL NEWS

True acupuncture and sham acupuncture both were much more effective against chronic low-back pain than was conventional treatment in a large clinical trial comparing the three approaches.

Almost half the subjects who received either real or sham acupuncture for 6 months showed clinically relevant improvement in pain intensity or back-specific disability, compared with only one-fourth of the subjects who received a variety of conventional therapies, investigators in the German Acupuncture (GERAC) Trials reported. (See box.)

“To our knowledge, [this] study is the largest and most rigorous trial to investigate the efficacy of verum acupuncture for chronic low-back pain compared with sham acupuncture and guideline-based conventional therapy. The study yielded several surprising results,” said Dr. Michael Haake of the University of Regensburg, Bad Abbach, Germany, and his associates.

The subjects were 1,162 adults with chronic low-back pain who were randomized to conventional treatment or real or sham acupuncture administered by physicians at 340 outpatient practices. The study physicians belonged to various medical specialties, had acquired at least 140 hours of acupuncture training, and had practiced acupuncture for a median of 8 years.

Both types of acupuncture involved at least 10 30-minute sessions, usually twice per week, plus additional sessions if the subjects experienced a 10%–50% reduction in pain intensity. The two treatments were identical, except that the sham procedure avoided all known acupuncture points or meridians and involved only superficial insertion of the needles, without any manual stimulation. Subjects were unable to distinguish any difference.

Conventional therapies included at least ten 30-minute sessions with a physician or physiotherapist. Treating physicians were free to administer any combination of techniques they deemed useful, including physiotherapy, massage, heat therapy, electrotherapy, injections, analgesics, anti-inflammatory agents, yoga, hydrojet treatment, exercise, and patient education about managing back pain.

True acupuncture and sham acupuncture were equally effective, as well as more effective than conventional therapies, in relieving pain, improving function, and improving quality of life. All the improvements were significant and persisted long after treatment was completed.

“While all randomized trials and meta-analyses to date have failed to show a clear advantage of acupuncture over conventional therapy for chronic low-back pain, our findings demonstrate significant superiority,” the investigators said (Arch. Intern. Med. 2007;167:1892-8).

Largely on the basis of these results, the German Federal Joint Committee of Physicians and Health Insurance Plans–an agency similar to the National Institutes of Health–made acupuncture for low-back pain an insured benefit in that country.

The investigators' finding on sham acupuncture “forces us to question the underlying action mechanism of acupuncture and to ask whether the emphasis placed on learning the traditional Chinese acupuncture points may be superfluous,” Dr. Haake and his associates added.

“The superiority of both forms of acupuncture suggests a common underlying mechanism that may act on pain generation, transmission of pain signals, or processing of pain signals by the central nervous system and that is stronger than the action mechanism of conventional therapy,” they said.

ELSEVIER GLOBAL MEDICAL NEWS

True acupuncture and sham acupuncture both were much more effective against chronic low-back pain than was conventional treatment in a large clinical trial comparing the three approaches.

Almost half the subjects who received either real or sham acupuncture for 6 months showed clinically relevant improvement in pain intensity or back-specific disability, compared with only one-fourth of the subjects who received a variety of conventional therapies, investigators in the German Acupuncture (GERAC) Trials reported. (See box.)

“To our knowledge, [this] study is the largest and most rigorous trial to investigate the efficacy of verum acupuncture for chronic low-back pain compared with sham acupuncture and guideline-based conventional therapy. The study yielded several surprising results,” said Dr. Michael Haake of the University of Regensburg, Bad Abbach, Germany, and his associates.

The subjects were 1,162 adults with chronic low-back pain who were randomized to conventional treatment or real or sham acupuncture administered by physicians at 340 outpatient practices. The study physicians belonged to various medical specialties, had acquired at least 140 hours of acupuncture training, and had practiced acupuncture for a median of 8 years.

Both types of acupuncture involved at least 10 30-minute sessions, usually twice per week, plus additional sessions if the subjects experienced a 10%–50% reduction in pain intensity. The two treatments were identical, except that the sham procedure avoided all known acupuncture points or meridians and involved only superficial insertion of the needles, without any manual stimulation. Subjects were unable to distinguish any difference.

Conventional therapies included at least ten 30-minute sessions with a physician or physiotherapist. Treating physicians were free to administer any combination of techniques they deemed useful, including physiotherapy, massage, heat therapy, electrotherapy, injections, analgesics, anti-inflammatory agents, yoga, hydrojet treatment, exercise, and patient education about managing back pain.

True acupuncture and sham acupuncture were equally effective, as well as more effective than conventional therapies, in relieving pain, improving function, and improving quality of life. All the improvements were significant and persisted long after treatment was completed.

“While all randomized trials and meta-analyses to date have failed to show a clear advantage of acupuncture over conventional therapy for chronic low-back pain, our findings demonstrate significant superiority,” the investigators said (Arch. Intern. Med. 2007;167:1892-8).

Largely on the basis of these results, the German Federal Joint Committee of Physicians and Health Insurance Plans–an agency similar to the National Institutes of Health–made acupuncture for low-back pain an insured benefit in that country.

The investigators' finding on sham acupuncture “forces us to question the underlying action mechanism of acupuncture and to ask whether the emphasis placed on learning the traditional Chinese acupuncture points may be superfluous,” Dr. Haake and his associates added.

“The superiority of both forms of acupuncture suggests a common underlying mechanism that may act on pain generation, transmission of pain signals, or processing of pain signals by the central nervous system and that is stronger than the action mechanism of conventional therapy,” they said.

ELSEVIER GLOBAL MEDICAL NEWS

Hypertension increases the risk for nonamnestic mild cognitive impairment in the elderly, researchers at Columbia University, New York, have reported.

This finding suggests that preventing and treating hypertension “may have an important impact in lowering the risk of cognitive impairment,” the researchers said in the December 2007 issue of the Archives of Neurology. Previously, data linking hypertension to cognitive impairment and dementia had been inconclusive.

Dr. Christiane Reitz of the university's Gertrude H. Sergievsky Center and her associates assessed the development of mild cognitive impairment (MCI) in a longitudinal cohort study of 918 Medicare recipients 65 years or older living in northern Manhattan in New York.

The subjects underwent general medical examinations, neurologic assessments, and detailed neuropsychological evaluations at 18-month intervals, beginning in 1992-1994. The mean age was 76 years, and the cohort included large numbers of white, African American, and Hispanic subjects.

About 63% of the study subjects had hypertension at baseline. After a mean of 5 years of follow-up, 334 cases of incident MCI developed. A total of 160 were classified as amnestic and 174 as nonamnestic.

Hypertension was associated with an increased risk of all-cause MCI, which was found to be attributable almost entirely to nonamnestic MCI. No association was found between hypertension and amnestic MCI, nor between hypertension and a decline over time in memory or language abilities, the investigators said (Arch. Neurol. 2007;64:1734-40).

The link between hypertension and nonamnestic MCI remained robust after the data were adjusted to account for subject age, sex, years of education, ethnicity, and vascular risk factors such as diabetes, cholesterol level, smoking status, and the presence of heart disease.

The association also remained unchanged after the data were adjusted for use of antihypertensive medication and apolipoprotein-E genotype, Dr. Reitz and her associates said.

Their findings suggest that hypertension affects executive function rather than memory, though the mechanism of action remains unclear. Hypertension may cause cognitive impairment by inducing cerebrovascular disease, or it may contribute to a blood-brain barrier dysfunction.

Given these findings, “preventing and treating hypertension may have an important impact in lowering the risk of cognitive impairment,” they said.

Hypertension increases the risk for nonamnestic mild cognitive impairment in the elderly, researchers at Columbia University, New York, have reported.

This finding suggests that preventing and treating hypertension “may have an important impact in lowering the risk of cognitive impairment,” the researchers said in the December 2007 issue of the Archives of Neurology. Previously, data linking hypertension to cognitive impairment and dementia had been inconclusive.

Dr. Christiane Reitz of the university's Gertrude H. Sergievsky Center and her associates assessed the development of mild cognitive impairment (MCI) in a longitudinal cohort study of 918 Medicare recipients 65 years or older living in northern Manhattan in New York.

The subjects underwent general medical examinations, neurologic assessments, and detailed neuropsychological evaluations at 18-month intervals, beginning in 1992-1994. The mean age was 76 years, and the cohort included large numbers of white, African American, and Hispanic subjects.

About 63% of the study subjects had hypertension at baseline. After a mean of 5 years of follow-up, 334 cases of incident MCI developed. A total of 160 were classified as amnestic and 174 as nonamnestic.

Hypertension was associated with an increased risk of all-cause MCI, which was found to be attributable almost entirely to nonamnestic MCI. No association was found between hypertension and amnestic MCI, nor between hypertension and a decline over time in memory or language abilities, the investigators said (Arch. Neurol. 2007;64:1734-40).

The link between hypertension and nonamnestic MCI remained robust after the data were adjusted to account for subject age, sex, years of education, ethnicity, and vascular risk factors such as diabetes, cholesterol level, smoking status, and the presence of heart disease.

The association also remained unchanged after the data were adjusted for use of antihypertensive medication and apolipoprotein-E genotype, Dr. Reitz and her associates said.

Their findings suggest that hypertension affects executive function rather than memory, though the mechanism of action remains unclear. Hypertension may cause cognitive impairment by inducing cerebrovascular disease, or it may contribute to a blood-brain barrier dysfunction.

Given these findings, “preventing and treating hypertension may have an important impact in lowering the risk of cognitive impairment,” they said.

Hypertension increases the risk for nonamnestic mild cognitive impairment in the elderly, researchers at Columbia University, New York, have reported.

This finding suggests that preventing and treating hypertension “may have an important impact in lowering the risk of cognitive impairment,” the researchers said in the December 2007 issue of the Archives of Neurology. Previously, data linking hypertension to cognitive impairment and dementia had been inconclusive.

Dr. Christiane Reitz of the university's Gertrude H. Sergievsky Center and her associates assessed the development of mild cognitive impairment (MCI) in a longitudinal cohort study of 918 Medicare recipients 65 years or older living in northern Manhattan in New York.

The subjects underwent general medical examinations, neurologic assessments, and detailed neuropsychological evaluations at 18-month intervals, beginning in 1992-1994. The mean age was 76 years, and the cohort included large numbers of white, African American, and Hispanic subjects.

About 63% of the study subjects had hypertension at baseline. After a mean of 5 years of follow-up, 334 cases of incident MCI developed. A total of 160 were classified as amnestic and 174 as nonamnestic.

Hypertension was associated with an increased risk of all-cause MCI, which was found to be attributable almost entirely to nonamnestic MCI. No association was found between hypertension and amnestic MCI, nor between hypertension and a decline over time in memory or language abilities, the investigators said (Arch. Neurol. 2007;64:1734-40).

The link between hypertension and nonamnestic MCI remained robust after the data were adjusted to account for subject age, sex, years of education, ethnicity, and vascular risk factors such as diabetes, cholesterol level, smoking status, and the presence of heart disease.

The association also remained unchanged after the data were adjusted for use of antihypertensive medication and apolipoprotein-E genotype, Dr. Reitz and her associates said.

Their findings suggest that hypertension affects executive function rather than memory, though the mechanism of action remains unclear. Hypertension may cause cognitive impairment by inducing cerebrovascular disease, or it may contribute to a blood-brain barrier dysfunction.

Given these findings, “preventing and treating hypertension may have an important impact in lowering the risk of cognitive impairment,” they said.

Three independent studies implicate the CNTNAP2 gene on chromosome 7 as an autism-susceptibility gene, researchers reported.

The three studies used different strategies to examine the possible genetic basis for autism, and all independently arrived at the same conclusion: Variations–some common and some rare–in the CNTNAP2 gene predispose carriers to autism.

“It will be important to begin to characterize the genotype-phenotype correlations across this gene so that we may begin to use CNTNAP2 as a diagnostic and prognostic tool,” Dr. Dietrich A. Stephan said in an editorial comment accompanying the three reports (Am. J. Hum. Genet. 2008;82:7-9).

“These preliminary findings lead one to speculate whether early detection of CNTNAP2 mutation carriers, coupled with early intervention, could coax children through a critical period in development (12-24 months of age) and allow them to emerge undamaged and continue to develop normally thereafter,” said Dr. Stephan of the Translational Genomics Research Institute, Phoenix.

In the first study, Maricela Alarcón, Ph.D., of the University of California, Los Angeles, Center for Autism Research and Treatment and her associates built on their previous finding linking a region of chromosome 7q35 that contains approximately 200 known genes with language deficits and autism spectrum disorders. They first genotyped the region in 172 parent-child trios from the Autism Genetics Research Exchange database on 2,758 single nucleotide polymorphisms. This narrowed the search to four likely candidate genes, including CNTNAP2.

This gene was already suspected of being involved in autism since it is a member of the neurexin superfamily; in case studies, mutations in these genes have been linked to severe autism, temporal lobe seizures, language regression, and repetitive behaviors.

The researchers then tested a different set of 304 parent-child trios and confirmed that only the CNTNAP2 gene significantly correlated with a delay in language acquisition–specifically, the age at which carriers used their first word. The investigators then identified a rare microdeletion within CNTNAP2 that was present in an autistic child and his father but not in 1,000 control chromosomes.

Dr. Alarcón and her associates also examined regional gene expression in human fetal brains, and found that CNTNAP2 was highly restricted to areas “known to contribute to complex human behaviors including speech and language, reward, frontal executive function, as well as joint attention, a core deficit in autism spectrum disorders.”

“Our demonstration of the developmental expression of CNTNAP2 being confined to brain circuitry known to be disrupted in autism spectrum disorders provides, to our knowledge for the first time, a link between genetic risk for language dysfunction in autism and specific brain regions known to underlie core processes impaired in this disorder,” the investigators noted (Am. J. Hum. Genet. 2008;82:150-9).

In the second study, Dan E. Arking, Ph.D., of Johns Hopkins University, Baltimore, and his associates genotyped 72 families with multiple affected children in the National Institute of Mental Health Autism Genetics Initiative database.

They confined their analysis to the most strict phenotypic inclusion criteria ever used in a sample of that size, “which allowed [the] subtle association to be detected without genomewide background noise,” Dr. Stephan said.

Dr. Arking and his associates identified one common single nucleotide polymorphism, rs7794745, in the CNTNAP2 gene that was significantly associated with autism. They then confirmed the finding by genotyping a separate sample of 1,295 parent-child trios from the database. The researchers also found that transmission frequency was significantly greater from mothers than from fathers.

“It is likely that additional genetic variants in this gene that contribute to autism susceptibility remain to be discovered,” Dr. Arking and his associates said (Am. J. Hum. Genet. 2008;82:160-4).

In the third study, Dr. Betul Bakkaloglu of Yale University, New Haven, Conn., and associates mapped balanced rearrangements in children who had social and cognitive delays “as a means of identifying candidate genes that may harbor rare disease alleles.” They found an inversion of chromosome 7 in a mentally retarded child with autistic features, and further analysis showed disruption in the CNTNAP2 gene at 7q35.

Dr. Bakkaloglu and associates then resequenced all 24 exons of CNTNAP2 in a sample of 635 subjects with autism spectrum disorders and 942 controls. They found eight rare variants predicted to have an adverse effect on the gene's function. These variants occurred twice as often in affected subjects as in controls.

One particular deleterious variant, I869T, was found in four autistic children from three different families, but was not present in more than 4,000 chromosomes assessed in controls, Dr. Bakkaloglu and associates said (Am. J. Hum. Genet. 2008;82:165-73).

“Now that we have definitive evidence from several perspectives that integrity of the neuroligin-neurexin axis is critical for normal development, we must launch into a candidate gene-resequencing effort to fully describe mutations in the other members of these gene families in autism spectrum disorders,” Dr. Stephan noted.

Three independent studies implicate the CNTNAP2 gene on chromosome 7 as an autism-susceptibility gene, researchers reported.

The three studies used different strategies to examine the possible genetic basis for autism, and all independently arrived at the same conclusion: Variations–some common and some rare–in the CNTNAP2 gene predispose carriers to autism.

“It will be important to begin to characterize the genotype-phenotype correlations across this gene so that we may begin to use CNTNAP2 as a diagnostic and prognostic tool,” Dr. Dietrich A. Stephan said in an editorial comment accompanying the three reports (Am. J. Hum. Genet. 2008;82:7-9).

“These preliminary findings lead one to speculate whether early detection of CNTNAP2 mutation carriers, coupled with early intervention, could coax children through a critical period in development (12-24 months of age) and allow them to emerge undamaged and continue to develop normally thereafter,” said Dr. Stephan of the Translational Genomics Research Institute, Phoenix.

In the first study, Maricela Alarcón, Ph.D., of the University of California, Los Angeles, Center for Autism Research and Treatment and her associates built on their previous finding linking a region of chromosome 7q35 that contains approximately 200 known genes with language deficits and autism spectrum disorders. They first genotyped the region in 172 parent-child trios from the Autism Genetics Research Exchange database on 2,758 single nucleotide polymorphisms. This narrowed the search to four likely candidate genes, including CNTNAP2.

This gene was already suspected of being involved in autism since it is a member of the neurexin superfamily; in case studies, mutations in these genes have been linked to severe autism, temporal lobe seizures, language regression, and repetitive behaviors.

The researchers then tested a different set of 304 parent-child trios and confirmed that only the CNTNAP2 gene significantly correlated with a delay in language acquisition–specifically, the age at which carriers used their first word. The investigators then identified a rare microdeletion within CNTNAP2 that was present in an autistic child and his father but not in 1,000 control chromosomes.

Dr. Alarcón and her associates also examined regional gene expression in human fetal brains, and found that CNTNAP2 was highly restricted to areas “known to contribute to complex human behaviors including speech and language, reward, frontal executive function, as well as joint attention, a core deficit in autism spectrum disorders.”

“Our demonstration of the developmental expression of CNTNAP2 being confined to brain circuitry known to be disrupted in autism spectrum disorders provides, to our knowledge for the first time, a link between genetic risk for language dysfunction in autism and specific brain regions known to underlie core processes impaired in this disorder,” the investigators noted (Am. J. Hum. Genet. 2008;82:150-9).

In the second study, Dan E. Arking, Ph.D., of Johns Hopkins University, Baltimore, and his associates genotyped 72 families with multiple affected children in the National Institute of Mental Health Autism Genetics Initiative database.

They confined their analysis to the most strict phenotypic inclusion criteria ever used in a sample of that size, “which allowed [the] subtle association to be detected without genomewide background noise,” Dr. Stephan said.

Dr. Arking and his associates identified one common single nucleotide polymorphism, rs7794745, in the CNTNAP2 gene that was significantly associated with autism. They then confirmed the finding by genotyping a separate sample of 1,295 parent-child trios from the database. The researchers also found that transmission frequency was significantly greater from mothers than from fathers.

“It is likely that additional genetic variants in this gene that contribute to autism susceptibility remain to be discovered,” Dr. Arking and his associates said (Am. J. Hum. Genet. 2008;82:160-4).

In the third study, Dr. Betul Bakkaloglu of Yale University, New Haven, Conn., and associates mapped balanced rearrangements in children who had social and cognitive delays “as a means of identifying candidate genes that may harbor rare disease alleles.” They found an inversion of chromosome 7 in a mentally retarded child with autistic features, and further analysis showed disruption in the CNTNAP2 gene at 7q35.

Dr. Bakkaloglu and associates then resequenced all 24 exons of CNTNAP2 in a sample of 635 subjects with autism spectrum disorders and 942 controls. They found eight rare variants predicted to have an adverse effect on the gene's function. These variants occurred twice as often in affected subjects as in controls.

One particular deleterious variant, I869T, was found in four autistic children from three different families, but was not present in more than 4,000 chromosomes assessed in controls, Dr. Bakkaloglu and associates said (Am. J. Hum. Genet. 2008;82:165-73).

“Now that we have definitive evidence from several perspectives that integrity of the neuroligin-neurexin axis is critical for normal development, we must launch into a candidate gene-resequencing effort to fully describe mutations in the other members of these gene families in autism spectrum disorders,” Dr. Stephan noted.

Three independent studies implicate the CNTNAP2 gene on chromosome 7 as an autism-susceptibility gene, researchers reported.

The three studies used different strategies to examine the possible genetic basis for autism, and all independently arrived at the same conclusion: Variations–some common and some rare–in the CNTNAP2 gene predispose carriers to autism.

“It will be important to begin to characterize the genotype-phenotype correlations across this gene so that we may begin to use CNTNAP2 as a diagnostic and prognostic tool,” Dr. Dietrich A. Stephan said in an editorial comment accompanying the three reports (Am. J. Hum. Genet. 2008;82:7-9).

“These preliminary findings lead one to speculate whether early detection of CNTNAP2 mutation carriers, coupled with early intervention, could coax children through a critical period in development (12-24 months of age) and allow them to emerge undamaged and continue to develop normally thereafter,” said Dr. Stephan of the Translational Genomics Research Institute, Phoenix.

In the first study, Maricela Alarcón, Ph.D., of the University of California, Los Angeles, Center for Autism Research and Treatment and her associates built on their previous finding linking a region of chromosome 7q35 that contains approximately 200 known genes with language deficits and autism spectrum disorders. They first genotyped the region in 172 parent-child trios from the Autism Genetics Research Exchange database on 2,758 single nucleotide polymorphisms. This narrowed the search to four likely candidate genes, including CNTNAP2.

This gene was already suspected of being involved in autism since it is a member of the neurexin superfamily; in case studies, mutations in these genes have been linked to severe autism, temporal lobe seizures, language regression, and repetitive behaviors.

The researchers then tested a different set of 304 parent-child trios and confirmed that only the CNTNAP2 gene significantly correlated with a delay in language acquisition–specifically, the age at which carriers used their first word. The investigators then identified a rare microdeletion within CNTNAP2 that was present in an autistic child and his father but not in 1,000 control chromosomes.

Dr. Alarcón and her associates also examined regional gene expression in human fetal brains, and found that CNTNAP2 was highly restricted to areas “known to contribute to complex human behaviors including speech and language, reward, frontal executive function, as well as joint attention, a core deficit in autism spectrum disorders.”

“Our demonstration of the developmental expression of CNTNAP2 being confined to brain circuitry known to be disrupted in autism spectrum disorders provides, to our knowledge for the first time, a link between genetic risk for language dysfunction in autism and specific brain regions known to underlie core processes impaired in this disorder,” the investigators noted (Am. J. Hum. Genet. 2008;82:150-9).

In the second study, Dan E. Arking, Ph.D., of Johns Hopkins University, Baltimore, and his associates genotyped 72 families with multiple affected children in the National Institute of Mental Health Autism Genetics Initiative database.

They confined their analysis to the most strict phenotypic inclusion criteria ever used in a sample of that size, “which allowed [the] subtle association to be detected without genomewide background noise,” Dr. Stephan said.

Dr. Arking and his associates identified one common single nucleotide polymorphism, rs7794745, in the CNTNAP2 gene that was significantly associated with autism. They then confirmed the finding by genotyping a separate sample of 1,295 parent-child trios from the database. The researchers also found that transmission frequency was significantly greater from mothers than from fathers.

“It is likely that additional genetic variants in this gene that contribute to autism susceptibility remain to be discovered,” Dr. Arking and his associates said (Am. J. Hum. Genet. 2008;82:160-4).

In the third study, Dr. Betul Bakkaloglu of Yale University, New Haven, Conn., and associates mapped balanced rearrangements in children who had social and cognitive delays “as a means of identifying candidate genes that may harbor rare disease alleles.” They found an inversion of chromosome 7 in a mentally retarded child with autistic features, and further analysis showed disruption in the CNTNAP2 gene at 7q35.

Dr. Bakkaloglu and associates then resequenced all 24 exons of CNTNAP2 in a sample of 635 subjects with autism spectrum disorders and 942 controls. They found eight rare variants predicted to have an adverse effect on the gene's function. These variants occurred twice as often in affected subjects as in controls.

One particular deleterious variant, I869T, was found in four autistic children from three different families, but was not present in more than 4,000 chromosomes assessed in controls, Dr. Bakkaloglu and associates said (Am. J. Hum. Genet. 2008;82:165-73).

“Now that we have definitive evidence from several perspectives that integrity of the neuroligin-neurexin axis is critical for normal development, we must launch into a candidate gene-resequencing effort to fully describe mutations in the other members of these gene families in autism spectrum disorders,” Dr. Stephan noted.

A novel, recurrent microdeletion, as well as a reciprocal microduplication, on a specific region of chromosome 16 appears to confer substantial susceptibility to autism, researchers have reported in the New England Journal of Medicine.

The two mutations might account for approximately 1% of cases of autism, a frequency that is the same as that for the most common known cause of autism (duplication of the Prader-Willi/Angelman region), according to Lauren A. Weiss, Ph.D., of Massachusetts General Hospital's Center for Human Genetic Research, Boston, and her associates.

The investigators conducted a genomewide analysis of a sample of families in the Autism Genetic Resource Exchange to identify any recurrent deletions or duplications that conferred risk of autism in multiple families. One region on chromosome 16p11.2 carried deletions in four independent families with five autistic children. The same region showed duplication rather than deletion in another three independent families with seven autistic children.

The researchers then attempted to confirm their findings by searching for the same microdeletion in a genetic database of 512 children with autism, developmental delay, or mental retardation from Children's Hospital Boston. They found identical deletions with exactly the same boundaries in five autistic boys.

In contrast, they found no such deletions in a sample of 434 Children's Hospital patients who had undergone genetic testing because of dysmorphic features, multiple congenital anomalies, congenital heart disease, seizures, or other disorders unrelated to autism. Similarly, there were identical duplications at 16p11.2 in four children in the sample with autism, developmental delay, or mental retardation, but none in the sample of children with disorders unrelated to autism.

Dr. Weiss and her associates then tried to replicate their findings in a genetic database of more than 19,000 members of the general population in Iceland. They found three cases of the 16p11.2 deletion in the subgroup of 299 subjects who had autism or developmental disorders, “a finding that was consistent with the 1% frequency observed” in the Children's Hospital cohort with autism or developmental disorders.

In contrast, only two cases of the deletion were found in the 18,834 Icelandic control subjects, a rate that was 1/100th of that in the autistic Icelanders.

The microduplication mutation was not seen in any Icelandic subjects who had autism but was found in two people with bipolar disorder and in five unscreened control subjects.

Interestingly, a separate study of the Icelandic cohort showed that the deletion occurred “at a markedly increased rate” in people who had various language or psychiatric disorders. It was found in one subject each with schizophrenia; bipolar disorder; attention-deficit hyperactivity disorder; panic disorder, anxiety, depression, or addiction; and dyslexia.

“In total, we have observed the identical deletion of nearly 600 kb [kilobase] in 13 subjects with autism or developmental or language delay (10 confirmed de novo mutations, 2 confirmed inherited mutations from parents with ADHD or mental retardation, and 1 mutation of unknown inheritance), with the reciprocal duplication of the same region documented in 11 additional subjects,” said Dr. Weiss, also with the Autism Consortium, and her associates (N. Engl. J. Med. 2008 Jan. 9 [doi:10.1056/NEJMoa075974

“The fact that [the deletion mutation] is seen extremely rarely in the general population not only establishes a significant difference between rates in autism and control populations, but also unambiguously establishes that strong natural selection is acting against transmission of this deletion (as might be expected from an allele that increases the risk of autism by as much as a factor of 100), given how often it arises de novo in a single generation,” added the researchers, whose study was funded by several organizations, including the Autism Consortium. The researchers reported no conflicts of interest.

In an accompanying editorial, Evan E. Eichler, Ph.D., and Dr. Andrew W. Zimmerman said that after larger case-control groups have undergone genotyping, it is possible that some of the 50 other large de novo events observed by Dr. Weiss and her colleagues and other events described in recent studies might be specifically associated with autism. Dr. Eichler is affiliated with the University of Washington, Seattle; Dr. Zimmerman is with the Kennedy Krieger Institute and Johns Hopkins University, Baltimore.

“The discovery of significant associations for the rarer loci may require the screening of tens of thousands of DNA samples from patients rather than a few thousand,” they wrote [doi:10.1056/NEJMe0708756

“Deeper sample collection and new cost-effective genomic techniques may be needed to peel away the remaining layers of the onion,” they added.

A novel, recurrent microdeletion, as well as a reciprocal microduplication, on a specific region of chromosome 16 appears to confer substantial susceptibility to autism, researchers have reported in the New England Journal of Medicine.

The two mutations might account for approximately 1% of cases of autism, a frequency that is the same as that for the most common known cause of autism (duplication of the Prader-Willi/Angelman region), according to Lauren A. Weiss, Ph.D., of Massachusetts General Hospital's Center for Human Genetic Research, Boston, and her associates.

The investigators conducted a genomewide analysis of a sample of families in the Autism Genetic Resource Exchange to identify any recurrent deletions or duplications that conferred risk of autism in multiple families. One region on chromosome 16p11.2 carried deletions in four independent families with five autistic children. The same region showed duplication rather than deletion in another three independent families with seven autistic children.

The researchers then attempted to confirm their findings by searching for the same microdeletion in a genetic database of 512 children with autism, developmental delay, or mental retardation from Children's Hospital Boston. They found identical deletions with exactly the same boundaries in five autistic boys.

In contrast, they found no such deletions in a sample of 434 Children's Hospital patients who had undergone genetic testing because of dysmorphic features, multiple congenital anomalies, congenital heart disease, seizures, or other disorders unrelated to autism. Similarly, there were identical duplications at 16p11.2 in four children in the sample with autism, developmental delay, or mental retardation, but none in the sample of children with disorders unrelated to autism.

Dr. Weiss and her associates then tried to replicate their findings in a genetic database of more than 19,000 members of the general population in Iceland. They found three cases of the 16p11.2 deletion in the subgroup of 299 subjects who had autism or developmental disorders, “a finding that was consistent with the 1% frequency observed” in the Children's Hospital cohort with autism or developmental disorders.

In contrast, only two cases of the deletion were found in the 18,834 Icelandic control subjects, a rate that was 1/100th of that in the autistic Icelanders.

The microduplication mutation was not seen in any Icelandic subjects who had autism but was found in two people with bipolar disorder and in five unscreened control subjects.

Interestingly, a separate study of the Icelandic cohort showed that the deletion occurred “at a markedly increased rate” in people who had various language or psychiatric disorders. It was found in one subject each with schizophrenia; bipolar disorder; attention-deficit hyperactivity disorder; panic disorder, anxiety, depression, or addiction; and dyslexia.

“In total, we have observed the identical deletion of nearly 600 kb [kilobase] in 13 subjects with autism or developmental or language delay (10 confirmed de novo mutations, 2 confirmed inherited mutations from parents with ADHD or mental retardation, and 1 mutation of unknown inheritance), with the reciprocal duplication of the same region documented in 11 additional subjects,” said Dr. Weiss, also with the Autism Consortium, and her associates (N. Engl. J. Med. 2008 Jan. 9 [doi:10.1056/NEJMoa075974

“The fact that [the deletion mutation] is seen extremely rarely in the general population not only establishes a significant difference between rates in autism and control populations, but also unambiguously establishes that strong natural selection is acting against transmission of this deletion (as might be expected from an allele that increases the risk of autism by as much as a factor of 100), given how often it arises de novo in a single generation,” added the researchers, whose study was funded by several organizations, including the Autism Consortium. The researchers reported no conflicts of interest.

In an accompanying editorial, Evan E. Eichler, Ph.D., and Dr. Andrew W. Zimmerman said that after larger case-control groups have undergone genotyping, it is possible that some of the 50 other large de novo events observed by Dr. Weiss and her colleagues and other events described in recent studies might be specifically associated with autism. Dr. Eichler is affiliated with the University of Washington, Seattle; Dr. Zimmerman is with the Kennedy Krieger Institute and Johns Hopkins University, Baltimore.

“The discovery of significant associations for the rarer loci may require the screening of tens of thousands of DNA samples from patients rather than a few thousand,” they wrote [doi:10.1056/NEJMe0708756

“Deeper sample collection and new cost-effective genomic techniques may be needed to peel away the remaining layers of the onion,” they added.

A novel, recurrent microdeletion, as well as a reciprocal microduplication, on a specific region of chromosome 16 appears to confer substantial susceptibility to autism, researchers have reported in the New England Journal of Medicine.

The two mutations might account for approximately 1% of cases of autism, a frequency that is the same as that for the most common known cause of autism (duplication of the Prader-Willi/Angelman region), according to Lauren A. Weiss, Ph.D., of Massachusetts General Hospital's Center for Human Genetic Research, Boston, and her associates.

The investigators conducted a genomewide analysis of a sample of families in the Autism Genetic Resource Exchange to identify any recurrent deletions or duplications that conferred risk of autism in multiple families. One region on chromosome 16p11.2 carried deletions in four independent families with five autistic children. The same region showed duplication rather than deletion in another three independent families with seven autistic children.

The researchers then attempted to confirm their findings by searching for the same microdeletion in a genetic database of 512 children with autism, developmental delay, or mental retardation from Children's Hospital Boston. They found identical deletions with exactly the same boundaries in five autistic boys.

In contrast, they found no such deletions in a sample of 434 Children's Hospital patients who had undergone genetic testing because of dysmorphic features, multiple congenital anomalies, congenital heart disease, seizures, or other disorders unrelated to autism. Similarly, there were identical duplications at 16p11.2 in four children in the sample with autism, developmental delay, or mental retardation, but none in the sample of children with disorders unrelated to autism.

Dr. Weiss and her associates then tried to replicate their findings in a genetic database of more than 19,000 members of the general population in Iceland. They found three cases of the 16p11.2 deletion in the subgroup of 299 subjects who had autism or developmental disorders, “a finding that was consistent with the 1% frequency observed” in the Children's Hospital cohort with autism or developmental disorders.

In contrast, only two cases of the deletion were found in the 18,834 Icelandic control subjects, a rate that was 1/100th of that in the autistic Icelanders.

The microduplication mutation was not seen in any Icelandic subjects who had autism but was found in two people with bipolar disorder and in five unscreened control subjects.

Interestingly, a separate study of the Icelandic cohort showed that the deletion occurred “at a markedly increased rate” in people who had various language or psychiatric disorders. It was found in one subject each with schizophrenia; bipolar disorder; attention-deficit hyperactivity disorder; panic disorder, anxiety, depression, or addiction; and dyslexia.

“In total, we have observed the identical deletion of nearly 600 kb [kilobase] in 13 subjects with autism or developmental or language delay (10 confirmed de novo mutations, 2 confirmed inherited mutations from parents with ADHD or mental retardation, and 1 mutation of unknown inheritance), with the reciprocal duplication of the same region documented in 11 additional subjects,” said Dr. Weiss, also with the Autism Consortium, and her associates (N. Engl. J. Med. 2008 Jan. 9 [doi:10.1056/NEJMoa075974

“The fact that [the deletion mutation] is seen extremely rarely in the general population not only establishes a significant difference between rates in autism and control populations, but also unambiguously establishes that strong natural selection is acting against transmission of this deletion (as might be expected from an allele that increases the risk of autism by as much as a factor of 100), given how often it arises de novo in a single generation,” added the researchers, whose study was funded by several organizations, including the Autism Consortium. The researchers reported no conflicts of interest.

In an accompanying editorial, Evan E. Eichler, Ph.D., and Dr. Andrew W. Zimmerman said that after larger case-control groups have undergone genotyping, it is possible that some of the 50 other large de novo events observed by Dr. Weiss and her colleagues and other events described in recent studies might be specifically associated with autism. Dr. Eichler is affiliated with the University of Washington, Seattle; Dr. Zimmerman is with the Kennedy Krieger Institute and Johns Hopkins University, Baltimore.

“The discovery of significant associations for the rarer loci may require the screening of tens of thousands of DNA samples from patients rather than a few thousand,” they wrote [doi:10.1056/NEJMe0708756

“Deeper sample collection and new cost-effective genomic techniques may be needed to peel away the remaining layers of the onion,” they added.

Cigarette smoking was significantly associated with androgenetic alopecia after investigators controlled for age and family history in a community-based survey conducted in Taiwan.

Androgenetic alopecia, the most common type of hair loss in men, is known to be a hereditary disorder, but environmental factors are presumed to play a role in pathogenesis as well. Three earlier studies addressed a possible link with cigarette smoking, but their results were inconsistent, the Taiwanese investigators wrote (Arch. Dermatol. 2007;143:1401–6).

Dr. Lin-Hui Su of Far Eastern Memorial Hospital and Tony Hsiu-Hsi Chen, Ph.D., D.D.S., of National Taiwan University, both in Taipei, surveyed 740 men from the general population aged 40–91 years who were found to have cosmetically significant male-pattern baldness.

After controlling for the effects of age and family history, they found that current and former smokers were significantly more likely to have moderate or severe androgenetic alopecia than were men who had never smoked (odds ratio 1.8). Men who currently smoked at least 20 cigarettes per day had more than double the risk of those who had never smoked (odds ratio 2.3).

Smoking intensity—defined as duration of smoking in years multiplied by the number of cigarettes smoked per day—was positively correlated with the degree of baldness.

Although this study did not assess the mechanisms by which smoking may promote hair loss, the investigators proposed four possibilities.

"First, smoking might be deleterious to the microvasculature of the dermal hair papilla. Second, smoke genotoxicants may do damage to DNA of the hair follicle," they said.

Third, smoking may cause an imbalance in the follicular protease or antiprotease systems. "Smoking-induced oxidative stress may lead to the release of proinflammatory cytokines that, in turn, results in follicular microinflammation and fibrosis."

Fourth, smoking may induce a hypo-estrogenic state by increasing the hydroxylation of estradiol and the inhibition of aromatase.

Cigarette smoking was significantly associated with androgenetic alopecia after investigators controlled for age and family history in a community-based survey conducted in Taiwan.

Androgenetic alopecia, the most common type of hair loss in men, is known to be a hereditary disorder, but environmental factors are presumed to play a role in pathogenesis as well. Three earlier studies addressed a possible link with cigarette smoking, but their results were inconsistent, the Taiwanese investigators wrote (Arch. Dermatol. 2007;143:1401–6).

Dr. Lin-Hui Su of Far Eastern Memorial Hospital and Tony Hsiu-Hsi Chen, Ph.D., D.D.S., of National Taiwan University, both in Taipei, surveyed 740 men from the general population aged 40–91 years who were found to have cosmetically significant male-pattern baldness.

After controlling for the effects of age and family history, they found that current and former smokers were significantly more likely to have moderate or severe androgenetic alopecia than were men who had never smoked (odds ratio 1.8). Men who currently smoked at least 20 cigarettes per day had more than double the risk of those who had never smoked (odds ratio 2.3).

Smoking intensity—defined as duration of smoking in years multiplied by the number of cigarettes smoked per day—was positively correlated with the degree of baldness.

Although this study did not assess the mechanisms by which smoking may promote hair loss, the investigators proposed four possibilities.

"First, smoking might be deleterious to the microvasculature of the dermal hair papilla. Second, smoke genotoxicants may do damage to DNA of the hair follicle," they said.

Third, smoking may cause an imbalance in the follicular protease or antiprotease systems. "Smoking-induced oxidative stress may lead to the release of proinflammatory cytokines that, in turn, results in follicular microinflammation and fibrosis."

Fourth, smoking may induce a hypo-estrogenic state by increasing the hydroxylation of estradiol and the inhibition of aromatase.

Cigarette smoking was significantly associated with androgenetic alopecia after investigators controlled for age and family history in a community-based survey conducted in Taiwan.

Androgenetic alopecia, the most common type of hair loss in men, is known to be a hereditary disorder, but environmental factors are presumed to play a role in pathogenesis as well. Three earlier studies addressed a possible link with cigarette smoking, but their results were inconsistent, the Taiwanese investigators wrote (Arch. Dermatol. 2007;143:1401–6).

Dr. Lin-Hui Su of Far Eastern Memorial Hospital and Tony Hsiu-Hsi Chen, Ph.D., D.D.S., of National Taiwan University, both in Taipei, surveyed 740 men from the general population aged 40–91 years who were found to have cosmetically significant male-pattern baldness.

After controlling for the effects of age and family history, they found that current and former smokers were significantly more likely to have moderate or severe androgenetic alopecia than were men who had never smoked (odds ratio 1.8). Men who currently smoked at least 20 cigarettes per day had more than double the risk of those who had never smoked (odds ratio 2.3).

Smoking intensity—defined as duration of smoking in years multiplied by the number of cigarettes smoked per day—was positively correlated with the degree of baldness.

Although this study did not assess the mechanisms by which smoking may promote hair loss, the investigators proposed four possibilities.

"First, smoking might be deleterious to the microvasculature of the dermal hair papilla. Second, smoke genotoxicants may do damage to DNA of the hair follicle," they said.

Third, smoking may cause an imbalance in the follicular protease or antiprotease systems. "Smoking-induced oxidative stress may lead to the release of proinflammatory cytokines that, in turn, results in follicular microinflammation and fibrosis."

Fourth, smoking may induce a hypo-estrogenic state by increasing the hydroxylation of estradiol and the inhibition of aromatase.

Childhood and adolescent overweight are associated with an increased risk of coronary heart disease in young and middle-aged adults, researchers in two separate studies reported.

Given the current surge in pediatric weight gain worldwide, these findings indicate that there will be substantial rises in CHD-related morbidity and mortality in coming years among even young and middle-aged adults, both groups of investigators predicted.

In the first study, Jennifer L. Baker, Ph.D., of the Institute for Health and Society, Copenhagen, and her associates analyzed data from a cohort of people born between 1930 and 1976 who had initially been examined as schoolchildren. The study sample included “virtually every schoolchild in Copenhagen” during that interval.

The investigators calculated the subjects' body mass index from these records, then used national databases to track CHD diagnoses and deaths that occurred in 280,678 of the subjects in adulthood.

There were 10,235 CHD events in men and 4,318 in women during follow-up. The risk of an event rose significantly and in a linear fashion for every 1-U increase in BMI z score at every age from 7 to 13 years.

The CHD risk rose with increasing child age, so that the risk in adults who had had a high BMI at age 13 was twice as high as that for adults who had had a high BMI at age 7. “We speculate that … increases in BMI z scores at these later ages could reflect a greater accumulation of fat, in particular intraabdominal fat, which increases the risk of CHD,” the investigators said.

“In comparison with an average-size 13-year-old boy, a boy of the same age and height weighing 11.2 kg more had a 33% higher risk of having a CHD event” before age 60. Similar results were observed for girls, Dr. Baker and her associates said (N. Engl. J. Med. 2007;357:2329-37).

This pattern held true for both fatal and nonfatal CHD events, even after the data had been adjusted to account for the subjects' birth weight. Moreover, the pattern held true regardless of whether subjects were born before or during the current obesity epidemic.

“Currently, children are typically classified as being at risk only if their BMI values are above cutoff points such as the 85th or 95th percentile on growth charts. Our results do not support this approach. The linearity of the associations we identified between childhood BMI and adult CHD implies that even a surprisingly small amount of weight gain will increase the risk of CHD,” they noted.

In the second study, Kirsten Bibbins-Domingo, Ph.D., of the University of California, San Francisco, and her associates used computer simulation models to estimate the potential effect of adolescent overweight on future adult CHD. The models incorporated data from the U.S. Census, the National Center for Health Statistics, Medicare, the Framingham Heart Study, and the National Health and Nutrition Examination Surveys to project the proportion of obese 35-year-old men and women in successive cohorts from 2020 to 2035.

The prevalence of adolescent overweight in 2000 was 17% in boys and 15% in girls. “By the time these adolescents turn 35 years old in 2020, the proportion of obese 35-year-olds is projected to be 30%-37% in men (as compared with 25% now) and 34%-44% in women (as compared with 32% now),” the investigators said.

They projected a steep rise in total CHD events, “with 550 absolute excess events in 2020 (an excess of 10%) increasing to 33,000 excess events in 2035 (an excess of 14%).

“The annual excess in the incidence of CHD is projected to rise from 1,600 in 2000 to 40,000 in 2035, an excess of 15% over the incidence that would have been expected without the increase in future obesity.” Similarly, the number of excess CHD deaths is projected to rise from 59 in 2020 to 3,600 in 2035, Dr. Bibbins-Domingo and her associates said (N. Engl. J. Med. 2007;357:2371-9).

Although projections into the future “are notoriously unreliable,” analyses of current treatments and trends “suggest that barring a major advance in the treatment of either excessive weight gain itself or its associated alterations in blood pressure, lipid levels, and glucose metabolism, current adolescent overweight will have a substantial effect on public health far into the future,” they noted.

Childhood and adolescent overweight are associated with an increased risk of coronary heart disease in young and middle-aged adults, researchers in two separate studies reported.

Given the current surge in pediatric weight gain worldwide, these findings indicate that there will be substantial rises in CHD-related morbidity and mortality in coming years among even young and middle-aged adults, both groups of investigators predicted.

In the first study, Jennifer L. Baker, Ph.D., of the Institute for Health and Society, Copenhagen, and her associates analyzed data from a cohort of people born between 1930 and 1976 who had initially been examined as schoolchildren. The study sample included “virtually every schoolchild in Copenhagen” during that interval.

The investigators calculated the subjects' body mass index from these records, then used national databases to track CHD diagnoses and deaths that occurred in 280,678 of the subjects in adulthood.

There were 10,235 CHD events in men and 4,318 in women during follow-up. The risk of an event rose significantly and in a linear fashion for every 1-U increase in BMI z score at every age from 7 to 13 years.

The CHD risk rose with increasing child age, so that the risk in adults who had had a high BMI at age 13 was twice as high as that for adults who had had a high BMI at age 7. “We speculate that … increases in BMI z scores at these later ages could reflect a greater accumulation of fat, in particular intraabdominal fat, which increases the risk of CHD,” the investigators said.

“In comparison with an average-size 13-year-old boy, a boy of the same age and height weighing 11.2 kg more had a 33% higher risk of having a CHD event” before age 60. Similar results were observed for girls, Dr. Baker and her associates said (N. Engl. J. Med. 2007;357:2329-37).

This pattern held true for both fatal and nonfatal CHD events, even after the data had been adjusted to account for the subjects' birth weight. Moreover, the pattern held true regardless of whether subjects were born before or during the current obesity epidemic.

“Currently, children are typically classified as being at risk only if their BMI values are above cutoff points such as the 85th or 95th percentile on growth charts. Our results do not support this approach. The linearity of the associations we identified between childhood BMI and adult CHD implies that even a surprisingly small amount of weight gain will increase the risk of CHD,” they noted.

In the second study, Kirsten Bibbins-Domingo, Ph.D., of the University of California, San Francisco, and her associates used computer simulation models to estimate the potential effect of adolescent overweight on future adult CHD. The models incorporated data from the U.S. Census, the National Center for Health Statistics, Medicare, the Framingham Heart Study, and the National Health and Nutrition Examination Surveys to project the proportion of obese 35-year-old men and women in successive cohorts from 2020 to 2035.

The prevalence of adolescent overweight in 2000 was 17% in boys and 15% in girls. “By the time these adolescents turn 35 years old in 2020, the proportion of obese 35-year-olds is projected to be 30%-37% in men (as compared with 25% now) and 34%-44% in women (as compared with 32% now),” the investigators said.

They projected a steep rise in total CHD events, “with 550 absolute excess events in 2020 (an excess of 10%) increasing to 33,000 excess events in 2035 (an excess of 14%).

“The annual excess in the incidence of CHD is projected to rise from 1,600 in 2000 to 40,000 in 2035, an excess of 15% over the incidence that would have been expected without the increase in future obesity.” Similarly, the number of excess CHD deaths is projected to rise from 59 in 2020 to 3,600 in 2035, Dr. Bibbins-Domingo and her associates said (N. Engl. J. Med. 2007;357:2371-9).

Although projections into the future “are notoriously unreliable,” analyses of current treatments and trends “suggest that barring a major advance in the treatment of either excessive weight gain itself or its associated alterations in blood pressure, lipid levels, and glucose metabolism, current adolescent overweight will have a substantial effect on public health far into the future,” they noted.

Childhood and adolescent overweight are associated with an increased risk of coronary heart disease in young and middle-aged adults, researchers in two separate studies reported.

Given the current surge in pediatric weight gain worldwide, these findings indicate that there will be substantial rises in CHD-related morbidity and mortality in coming years among even young and middle-aged adults, both groups of investigators predicted.

In the first study, Jennifer L. Baker, Ph.D., of the Institute for Health and Society, Copenhagen, and her associates analyzed data from a cohort of people born between 1930 and 1976 who had initially been examined as schoolchildren. The study sample included “virtually every schoolchild in Copenhagen” during that interval.

The investigators calculated the subjects' body mass index from these records, then used national databases to track CHD diagnoses and deaths that occurred in 280,678 of the subjects in adulthood.

There were 10,235 CHD events in men and 4,318 in women during follow-up. The risk of an event rose significantly and in a linear fashion for every 1-U increase in BMI z score at every age from 7 to 13 years.

The CHD risk rose with increasing child age, so that the risk in adults who had had a high BMI at age 13 was twice as high as that for adults who had had a high BMI at age 7. “We speculate that … increases in BMI z scores at these later ages could reflect a greater accumulation of fat, in particular intraabdominal fat, which increases the risk of CHD,” the investigators said.

“In comparison with an average-size 13-year-old boy, a boy of the same age and height weighing 11.2 kg more had a 33% higher risk of having a CHD event” before age 60. Similar results were observed for girls, Dr. Baker and her associates said (N. Engl. J. Med. 2007;357:2329-37).

This pattern held true for both fatal and nonfatal CHD events, even after the data had been adjusted to account for the subjects' birth weight. Moreover, the pattern held true regardless of whether subjects were born before or during the current obesity epidemic.

“Currently, children are typically classified as being at risk only if their BMI values are above cutoff points such as the 85th or 95th percentile on growth charts. Our results do not support this approach. The linearity of the associations we identified between childhood BMI and adult CHD implies that even a surprisingly small amount of weight gain will increase the risk of CHD,” they noted.

In the second study, Kirsten Bibbins-Domingo, Ph.D., of the University of California, San Francisco, and her associates used computer simulation models to estimate the potential effect of adolescent overweight on future adult CHD. The models incorporated data from the U.S. Census, the National Center for Health Statistics, Medicare, the Framingham Heart Study, and the National Health and Nutrition Examination Surveys to project the proportion of obese 35-year-old men and women in successive cohorts from 2020 to 2035.

The prevalence of adolescent overweight in 2000 was 17% in boys and 15% in girls. “By the time these adolescents turn 35 years old in 2020, the proportion of obese 35-year-olds is projected to be 30%-37% in men (as compared with 25% now) and 34%-44% in women (as compared with 32% now),” the investigators said.

They projected a steep rise in total CHD events, “with 550 absolute excess events in 2020 (an excess of 10%) increasing to 33,000 excess events in 2035 (an excess of 14%).

“The annual excess in the incidence of CHD is projected to rise from 1,600 in 2000 to 40,000 in 2035, an excess of 15% over the incidence that would have been expected without the increase in future obesity.” Similarly, the number of excess CHD deaths is projected to rise from 59 in 2020 to 3,600 in 2035, Dr. Bibbins-Domingo and her associates said (N. Engl. J. Med. 2007;357:2371-9).

Although projections into the future “are notoriously unreliable,” analyses of current treatments and trends “suggest that barring a major advance in the treatment of either excessive weight gain itself or its associated alterations in blood pressure, lipid levels, and glucose metabolism, current adolescent overweight will have a substantial effect on public health far into the future,” they noted.

Cigarette smoking is associated with an increased risk of developing type 2 diabetes, results of a meta-analysis suggest.

“Active smokers had an increased risk of developing type 2 diabetes, compared with nonsmokers, with a pooled relative risk of 1.44,” the study authors reported last month in JAMA.

The researchers conducted a meta-analysis of all 25 prospective cohort studies of the issue in the United States, Europe, Japan, and Israel that were published between 1992 and 2006. All of the studies examined a possible link between smoking and irregularities of glucose metabolism, and all but one found a positive association, Dr. Carole Willi of the University of Lausanne (Switzerland) and her associates wrote.

The number of study subjects ranged from 630 people to more than 700,000 people, for a total of 1.2 million subjects and 45,844 cases of incident diabetes in the meta-analysis. Overall, 35% of the people were current smokers. Follow-up ranged from 5 to 30 years.

The association between smoking and diabetes remained robust through numerous statistical analyses that explored study factors as well as clinical variables. The findings also suggested a dose-response relationship, because the association with diabetes was stronger among heavy smokers than among light smokers, and was stronger in active smokers than in former smokers.

“Given this consistency, we conclude that the relevant question should no longer be whether this association exists, but rather whether this established association is causal,” Dr. Willi and her associates said (JAMA 2007;298:2654–64).

The adverse effect of smoking on diabetes risk “has been generally underrecognized,” Dr. Eric L. Ding and Dr. Frank B. Hu of the Harvard School of Public Health, Boston, said in an editorial accompanying the report.

Dr. Ding and Dr. Hu estimated that 12% of all type 2 diabetes in the United States may be attributable to smoking, based on this study's estimates, statistics on smoking prevalence, and an accepted population-attributable risk formula (JAMA 2007;298:2675–6). In addition, “an estimated 2.3 million cases of diabetes in the United States and a corresponding $14.9 billion of the annual U.S. $132 billion diabetes cost burden may be attributable to smoking,” they said.

Although the exact mechanism by which smoking may contribute to the development of diabetes hasn't been identified, smoking is known to be related to central adiposity, to increase inflammation and oxidative stress, to directly damage beta-cell function, to impair endothelial function, and to impair insulin sensitivity and glucose tolerance, Dr. Ding and Dr. Hu said.

Given the findings of Dr. Willi and her associates, it is “important and prudent for clinicians to screen for and carefully monitor glucose levels among current and former smokers,” they added.

Smoking may account for $14.9 billion of the U.S. diabetes cost burden. PhotoDisc

Cigarette smoking is associated with an increased risk of developing type 2 diabetes, results of a meta-analysis suggest.

“Active smokers had an increased risk of developing type 2 diabetes, compared with nonsmokers, with a pooled relative risk of 1.44,” the study authors reported last month in JAMA.

The researchers conducted a meta-analysis of all 25 prospective cohort studies of the issue in the United States, Europe, Japan, and Israel that were published between 1992 and 2006. All of the studies examined a possible link between smoking and irregularities of glucose metabolism, and all but one found a positive association, Dr. Carole Willi of the University of Lausanne (Switzerland) and her associates wrote.

The number of study subjects ranged from 630 people to more than 700,000 people, for a total of 1.2 million subjects and 45,844 cases of incident diabetes in the meta-analysis. Overall, 35% of the people were current smokers. Follow-up ranged from 5 to 30 years.

The association between smoking and diabetes remained robust through numerous statistical analyses that explored study factors as well as clinical variables. The findings also suggested a dose-response relationship, because the association with diabetes was stronger among heavy smokers than among light smokers, and was stronger in active smokers than in former smokers.

“Given this consistency, we conclude that the relevant question should no longer be whether this association exists, but rather whether this established association is causal,” Dr. Willi and her associates said (JAMA 2007;298:2654–64).

The adverse effect of smoking on diabetes risk “has been generally underrecognized,” Dr. Eric L. Ding and Dr. Frank B. Hu of the Harvard School of Public Health, Boston, said in an editorial accompanying the report.

Dr. Ding and Dr. Hu estimated that 12% of all type 2 diabetes in the United States may be attributable to smoking, based on this study's estimates, statistics on smoking prevalence, and an accepted population-attributable risk formula (JAMA 2007;298:2675–6). In addition, “an estimated 2.3 million cases of diabetes in the United States and a corresponding $14.9 billion of the annual U.S. $132 billion diabetes cost burden may be attributable to smoking,” they said.

Although the exact mechanism by which smoking may contribute to the development of diabetes hasn't been identified, smoking is known to be related to central adiposity, to increase inflammation and oxidative stress, to directly damage beta-cell function, to impair endothelial function, and to impair insulin sensitivity and glucose tolerance, Dr. Ding and Dr. Hu said.

Given the findings of Dr. Willi and her associates, it is “important and prudent for clinicians to screen for and carefully monitor glucose levels among current and former smokers,” they added.

Smoking may account for $14.9 billion of the U.S. diabetes cost burden. PhotoDisc

Cigarette smoking is associated with an increased risk of developing type 2 diabetes, results of a meta-analysis suggest.

“Active smokers had an increased risk of developing type 2 diabetes, compared with nonsmokers, with a pooled relative risk of 1.44,” the study authors reported last month in JAMA.

The researchers conducted a meta-analysis of all 25 prospective cohort studies of the issue in the United States, Europe, Japan, and Israel that were published between 1992 and 2006. All of the studies examined a possible link between smoking and irregularities of glucose metabolism, and all but one found a positive association, Dr. Carole Willi of the University of Lausanne (Switzerland) and her associates wrote.

The number of study subjects ranged from 630 people to more than 700,000 people, for a total of 1.2 million subjects and 45,844 cases of incident diabetes in the meta-analysis. Overall, 35% of the people were current smokers. Follow-up ranged from 5 to 30 years.

The association between smoking and diabetes remained robust through numerous statistical analyses that explored study factors as well as clinical variables. The findings also suggested a dose-response relationship, because the association with diabetes was stronger among heavy smokers than among light smokers, and was stronger in active smokers than in former smokers.

“Given this consistency, we conclude that the relevant question should no longer be whether this association exists, but rather whether this established association is causal,” Dr. Willi and her associates said (JAMA 2007;298:2654–64).

The adverse effect of smoking on diabetes risk “has been generally underrecognized,” Dr. Eric L. Ding and Dr. Frank B. Hu of the Harvard School of Public Health, Boston, said in an editorial accompanying the report.

Dr. Ding and Dr. Hu estimated that 12% of all type 2 diabetes in the United States may be attributable to smoking, based on this study's estimates, statistics on smoking prevalence, and an accepted population-attributable risk formula (JAMA 2007;298:2675–6). In addition, “an estimated 2.3 million cases of diabetes in the United States and a corresponding $14.9 billion of the annual U.S. $132 billion diabetes cost burden may be attributable to smoking,” they said.

Although the exact mechanism by which smoking may contribute to the development of diabetes hasn't been identified, smoking is known to be related to central adiposity, to increase inflammation and oxidative stress, to directly damage beta-cell function, to impair endothelial function, and to impair insulin sensitivity and glucose tolerance, Dr. Ding and Dr. Hu said.

Given the findings of Dr. Willi and her associates, it is “important and prudent for clinicians to screen for and carefully monitor glucose levels among current and former smokers,” they added.

Smoking may account for $14.9 billion of the U.S. diabetes cost burden. PhotoDisc