Mary Ann Moon

Heavy cannabis users show marked reduction in hippocampus volume on high-resolution 3-T MRI imaging, investigators have reported.

The volume reductions appear to correlate with the degree of exposure to the drug, according to Murat Yücel, Ph.D., of the University of Melbourne and associates.

These findings “challenge the widespread perception of cannabis as having limited or no neuroanatomical sequelae” and suggest that heavy use “may indeed be toxic to human brain tissue,” the investigators noted (Arch. Gen. Psychiatry 2008;65:694–701).

Few brain imaging studies have been conducted in cannabis users, and the results have been inconsistent. “Indeed, despite strong evidence of neurotoxicity in the animal literature, to our knowledge no neuroimaging study has examined the neurobiologic sequelae of long-term heavy cannabis use while controlling for the important confounds of polydrug abuse and co-occurring psychiatric disorders,” Dr. Yücel and his associates said.

They used high-resolution 3-T MRI to assess volume in the hippocampus and the amygdala, two brain regions rich in cannabinoid receptors, in 15 men (mean age 40 years) who were regular heavy cannabis users and in 16 healthy nonusers matched for age, premorbid intelligence, years of education, and anxiety symptoms. None of the subjects had any medical, neurologic, or psychiatric conditions, and none abused alcohol or other drugs. The mean duration of regular use was 19.7 years.

The cannabis users showed a significant, 12% reduction in hippocampus volume and a smaller but still significant 7% reduction in amygdala volume, compared with the control subjects, said Dr. Yücel and his associates, who had no financial conflicts to disclose.

The cannabis users also reported significantly greater symptoms on an assessment of subthreshold psychotic symptoms than did the controls, and they showed significantly poorer performance on a test of verbal learning ability.

There also was a significant inverse association between cumulative cannabis exposure in the preceding 10 years and hippocampus volume in the left, but not the right, hemisphere.

“Previous functional imaging studies have found reduced left hippocampal activation during cognitive performance in cannabis users, and there is evidence to suggest that hippocampal abnormalities in psychiatric disorders such as schizophrenia are more prominent in the left hemisphere,” they pointed out.

All of which suggests “that the left hippocampus may be particularly vulnerable to the effects of cannabis exposure and may be more closely related to the emergence of psychotic symptoms,” Dr. Yücel and his associates said.

Heavy cannabis users show marked reduction in hippocampus volume on high-resolution 3-T MRI imaging, investigators have reported.

The volume reductions appear to correlate with the degree of exposure to the drug, according to Murat Yücel, Ph.D., of the University of Melbourne and associates.

These findings “challenge the widespread perception of cannabis as having limited or no neuroanatomical sequelae” and suggest that heavy use “may indeed be toxic to human brain tissue,” the investigators noted (Arch. Gen. Psychiatry 2008;65:694–701).

Few brain imaging studies have been conducted in cannabis users, and the results have been inconsistent. “Indeed, despite strong evidence of neurotoxicity in the animal literature, to our knowledge no neuroimaging study has examined the neurobiologic sequelae of long-term heavy cannabis use while controlling for the important confounds of polydrug abuse and co-occurring psychiatric disorders,” Dr. Yücel and his associates said.

They used high-resolution 3-T MRI to assess volume in the hippocampus and the amygdala, two brain regions rich in cannabinoid receptors, in 15 men (mean age 40 years) who were regular heavy cannabis users and in 16 healthy nonusers matched for age, premorbid intelligence, years of education, and anxiety symptoms. None of the subjects had any medical, neurologic, or psychiatric conditions, and none abused alcohol or other drugs. The mean duration of regular use was 19.7 years.

The cannabis users showed a significant, 12% reduction in hippocampus volume and a smaller but still significant 7% reduction in amygdala volume, compared with the control subjects, said Dr. Yücel and his associates, who had no financial conflicts to disclose.

The cannabis users also reported significantly greater symptoms on an assessment of subthreshold psychotic symptoms than did the controls, and they showed significantly poorer performance on a test of verbal learning ability.

There also was a significant inverse association between cumulative cannabis exposure in the preceding 10 years and hippocampus volume in the left, but not the right, hemisphere.

“Previous functional imaging studies have found reduced left hippocampal activation during cognitive performance in cannabis users, and there is evidence to suggest that hippocampal abnormalities in psychiatric disorders such as schizophrenia are more prominent in the left hemisphere,” they pointed out.

All of which suggests “that the left hippocampus may be particularly vulnerable to the effects of cannabis exposure and may be more closely related to the emergence of psychotic symptoms,” Dr. Yücel and his associates said.

Heavy cannabis users show marked reduction in hippocampus volume on high-resolution 3-T MRI imaging, investigators have reported.

The volume reductions appear to correlate with the degree of exposure to the drug, according to Murat Yücel, Ph.D., of the University of Melbourne and associates.

These findings “challenge the widespread perception of cannabis as having limited or no neuroanatomical sequelae” and suggest that heavy use “may indeed be toxic to human brain tissue,” the investigators noted (Arch. Gen. Psychiatry 2008;65:694–701).

Few brain imaging studies have been conducted in cannabis users, and the results have been inconsistent. “Indeed, despite strong evidence of neurotoxicity in the animal literature, to our knowledge no neuroimaging study has examined the neurobiologic sequelae of long-term heavy cannabis use while controlling for the important confounds of polydrug abuse and co-occurring psychiatric disorders,” Dr. Yücel and his associates said.

They used high-resolution 3-T MRI to assess volume in the hippocampus and the amygdala, two brain regions rich in cannabinoid receptors, in 15 men (mean age 40 years) who were regular heavy cannabis users and in 16 healthy nonusers matched for age, premorbid intelligence, years of education, and anxiety symptoms. None of the subjects had any medical, neurologic, or psychiatric conditions, and none abused alcohol or other drugs. The mean duration of regular use was 19.7 years.

The cannabis users showed a significant, 12% reduction in hippocampus volume and a smaller but still significant 7% reduction in amygdala volume, compared with the control subjects, said Dr. Yücel and his associates, who had no financial conflicts to disclose.

The cannabis users also reported significantly greater symptoms on an assessment of subthreshold psychotic symptoms than did the controls, and they showed significantly poorer performance on a test of verbal learning ability.

There also was a significant inverse association between cumulative cannabis exposure in the preceding 10 years and hippocampus volume in the left, but not the right, hemisphere.

“Previous functional imaging studies have found reduced left hippocampal activation during cognitive performance in cannabis users, and there is evidence to suggest that hippocampal abnormalities in psychiatric disorders such as schizophrenia are more prominent in the left hemisphere,” they pointed out.

All of which suggests “that the left hippocampus may be particularly vulnerable to the effects of cannabis exposure and may be more closely related to the emergence of psychotic symptoms,” Dr. Yücel and his associates said.

An 8-week course of St. John's wort did not improve attention-deficit/hyperactivity disorder symptoms in what researchers described as the first-ever randomized clinical trial of the herbal remedy in children and adolescents, according to a report in JAMA.

Compared with placebo, St. John's wort–one of the three most common herbal treatments for ADHD in the pediatric population–did not improve hyperactivity, impulsivity, or inattentiveness, reported Wendy Weber, Ph.D., of Bastyr University's School of Naturopathic Medicine, Kenmore, Wash., and her associates.

As many as 30% of children with ADHD fail to respond to, or cannot tolerate, pharmaceutical medicine for the disorder, so many parents turn to complementary or alternative medicines. St. John's wort (Hypericum perforatum) has been found to inhibit the reuptake of norepinephrine, so in theory it might be beneficial in ADHD.

Dr. Weber and her associates studied 54 healthy subjects aged 6–17 years who met DSM-IV criteria for ADHD based on structured diagnostic interviews. Half the subjects were randomly assigned to take a 300-mg capsule of St. John's wort, and the other half were to take placebo capsules, three times daily (before school, after school, and before bed), for 8 weeks. ADHD symptoms were assessed at office visits at baseline and every 2 weeks thereafter using the ADHD Rating Scale-IV, an 18-item standardized instrument for weekly assessment of treatment response. The Clinical Global Impression Improvement Scale also was used at weeks 4 and 8 to evaluate whether global impairment worsened, remained steady, or improved.

The treatment's potential effect on other behavioral problems was assessed using the Child Behavior Checklist and Youth Self Report Form. Parents also reported their assessments of ADHD symptoms by completing the Conners' Parent Rating Scale at baseline and at the conclusion of the study.

Finally, changes in quality of life were evaluated using the PedsQL form.

Possible adverse effects were tracked using a measure of 76 potential adverse effects. There were no significant differences between the two groups in ADHD symptoms on any assessment, either in the intention-to-treat analysis or the per-protocol analysis, Dr. Weber and her associates said (JAMA 2008;299:2633–41).

The subset of children who had never taken pharmaceutical medication for ADHD before this study also showed no improvement beyond that achieved with placebo, the investigators added.

The study was supported by grants from the National Center for Complementary and Alternative Medicine, an agency of the National Institutes of Health. Dr. Weber reported no conflicts of interest.

St. John's wort (flower shown above) inhibits the reuptake of norepinephrine. ©Fradoray/Fotolia.com

An 8-week course of St. John's wort did not improve attention-deficit/hyperactivity disorder symptoms in what researchers described as the first-ever randomized clinical trial of the herbal remedy in children and adolescents, according to a report in JAMA.

Compared with placebo, St. John's wort–one of the three most common herbal treatments for ADHD in the pediatric population–did not improve hyperactivity, impulsivity, or inattentiveness, reported Wendy Weber, Ph.D., of Bastyr University's School of Naturopathic Medicine, Kenmore, Wash., and her associates.

As many as 30% of children with ADHD fail to respond to, or cannot tolerate, pharmaceutical medicine for the disorder, so many parents turn to complementary or alternative medicines. St. John's wort (Hypericum perforatum) has been found to inhibit the reuptake of norepinephrine, so in theory it might be beneficial in ADHD.

Dr. Weber and her associates studied 54 healthy subjects aged 6–17 years who met DSM-IV criteria for ADHD based on structured diagnostic interviews. Half the subjects were randomly assigned to take a 300-mg capsule of St. John's wort, and the other half were to take placebo capsules, three times daily (before school, after school, and before bed), for 8 weeks. ADHD symptoms were assessed at office visits at baseline and every 2 weeks thereafter using the ADHD Rating Scale-IV, an 18-item standardized instrument for weekly assessment of treatment response. The Clinical Global Impression Improvement Scale also was used at weeks 4 and 8 to evaluate whether global impairment worsened, remained steady, or improved.

The treatment's potential effect on other behavioral problems was assessed using the Child Behavior Checklist and Youth Self Report Form. Parents also reported their assessments of ADHD symptoms by completing the Conners' Parent Rating Scale at baseline and at the conclusion of the study.

Finally, changes in quality of life were evaluated using the PedsQL form.

Possible adverse effects were tracked using a measure of 76 potential adverse effects. There were no significant differences between the two groups in ADHD symptoms on any assessment, either in the intention-to-treat analysis or the per-protocol analysis, Dr. Weber and her associates said (JAMA 2008;299:2633–41).

The subset of children who had never taken pharmaceutical medication for ADHD before this study also showed no improvement beyond that achieved with placebo, the investigators added.

The study was supported by grants from the National Center for Complementary and Alternative Medicine, an agency of the National Institutes of Health. Dr. Weber reported no conflicts of interest.

St. John's wort (flower shown above) inhibits the reuptake of norepinephrine. ©Fradoray/Fotolia.com

An 8-week course of St. John's wort did not improve attention-deficit/hyperactivity disorder symptoms in what researchers described as the first-ever randomized clinical trial of the herbal remedy in children and adolescents, according to a report in JAMA.

Compared with placebo, St. John's wort–one of the three most common herbal treatments for ADHD in the pediatric population–did not improve hyperactivity, impulsivity, or inattentiveness, reported Wendy Weber, Ph.D., of Bastyr University's School of Naturopathic Medicine, Kenmore, Wash., and her associates.

As many as 30% of children with ADHD fail to respond to, or cannot tolerate, pharmaceutical medicine for the disorder, so many parents turn to complementary or alternative medicines. St. John's wort (Hypericum perforatum) has been found to inhibit the reuptake of norepinephrine, so in theory it might be beneficial in ADHD.

Dr. Weber and her associates studied 54 healthy subjects aged 6–17 years who met DSM-IV criteria for ADHD based on structured diagnostic interviews. Half the subjects were randomly assigned to take a 300-mg capsule of St. John's wort, and the other half were to take placebo capsules, three times daily (before school, after school, and before bed), for 8 weeks. ADHD symptoms were assessed at office visits at baseline and every 2 weeks thereafter using the ADHD Rating Scale-IV, an 18-item standardized instrument for weekly assessment of treatment response. The Clinical Global Impression Improvement Scale also was used at weeks 4 and 8 to evaluate whether global impairment worsened, remained steady, or improved.

The treatment's potential effect on other behavioral problems was assessed using the Child Behavior Checklist and Youth Self Report Form. Parents also reported their assessments of ADHD symptoms by completing the Conners' Parent Rating Scale at baseline and at the conclusion of the study.

Finally, changes in quality of life were evaluated using the PedsQL form.

Possible adverse effects were tracked using a measure of 76 potential adverse effects. There were no significant differences between the two groups in ADHD symptoms on any assessment, either in the intention-to-treat analysis or the per-protocol analysis, Dr. Weber and her associates said (JAMA 2008;299:2633–41).

The subset of children who had never taken pharmaceutical medication for ADHD before this study also showed no improvement beyond that achieved with placebo, the investigators added.

The study was supported by grants from the National Center for Complementary and Alternative Medicine, an agency of the National Institutes of Health. Dr. Weber reported no conflicts of interest.

St. John's wort (flower shown above) inhibits the reuptake of norepinephrine. ©Fradoray/Fotolia.com

Tight glucose control does not benefit critically ill patients and may even be harmful because it markedly raises the risk of hypoglycemia, according to a meta-analysis.

Given these findings, “it seems appropriate that the guidelines recommending tight glucose control in all critically ill patients should be reevaluated until the results of larger, more definitive clinical trials are available,” said Dr. Renda Soylemez Wiener of the Veterans Affairs Medical Center, White River Junction, Vt., and her associates.

In 2001, a single clinical trial showed that tight glucose control reduced in-hospital mortality by a third among critically ill surgical patients. “The results of this trial were enthusiastically received and rapidly incorporated into guidelines,” and tight glucose control is now recommended for all critically ill adults and endorsed by numerous professional societies worldwide.

However, “subsequent large randomized controlled trials of tight glucose control in medical and mixed medical-surgical ICU settings … have failed to replicate this mortality benefit,” and many have reported rates of hypoglycemia as high as 40%. “Hypoglycemia is not benign in critically ill patients; it has been linked to serious neurologic events ranging from seizures to coma,” the investigators noted.

They conducted a meta-analysis of 29 controlled trials involving 8,432 adult ICU patients with a wide range of disorders who were randomly assigned to either usual care or tight glucose control—a glucose goal of less than 150 mg/dL using an insulin infusion during part or all of the ICU stay.

In-hospital mortality was not significantly different for patients kept on tight glucose control (21.6%) than for those given usual care (23.3%). There also was no difference between the two groups in the need for dialysis, Dr. Soylemez Wiener and her associates said (JAMA 2008;300:933-44).

In subgroup analyses, tight glucose control did not benefit surgical patients vs. medical patients, nor did “very tight” glucose control prove more beneficial than “moderately tight” glucose control. Sensitivity analyses of the data based on several variables that might be clinically relevant, such as disease severity, did not alter these results.

Tight glucose control did reduce the incidence of septicemia, but only among surgical ICU patients.

“On the other hand, we found clear evidence of the main harm of tight glucose control: Hypoglycemia increased roughly fivefold regardless of the ICU setting and was more common with patients receiving very tight [rather] than moderately tight glucose control,” the researchers added.

“Our meta-analysis shows that subsequent trials have not borne out the impressive results of tight glucose control promised by the initial trial” in 2001. In fact, the subjects in that initial trial received early glucose infusions and parenteral nutrition, both of which might artificially induce hyperglycemia and both of which are atypical in clinical practice. This “may have contributed to the outlying results seen in [that] trial,” the researchers noted.

In an accompanying editorial comment, Dr. Simon Finfer and Dr. Anthony Delaney of the Royal North Shore Hospital, Sydney, said that the results of this “well-conducted” and “timely” meta-analysis “may surprise many clinicians” (JAMA 2008;300:963-5).

Not only does the meta-analysis call the benefit of tight glucose control into question, it also highlights that there is no agreed standard for glycemic control, that blood glucose levels are extremely variable during the course of an ICU stay, and that bedside measurement of blood glucose can be very inaccurate, Dr. Finfer and Dr. Delaney said.

Tight glucose control does not benefit critically ill patients and may even be harmful because it markedly raises the risk of hypoglycemia, according to a meta-analysis.

Given these findings, “it seems appropriate that the guidelines recommending tight glucose control in all critically ill patients should be reevaluated until the results of larger, more definitive clinical trials are available,” said Dr. Renda Soylemez Wiener of the Veterans Affairs Medical Center, White River Junction, Vt., and her associates.

In 2001, a single clinical trial showed that tight glucose control reduced in-hospital mortality by a third among critically ill surgical patients. “The results of this trial were enthusiastically received and rapidly incorporated into guidelines,” and tight glucose control is now recommended for all critically ill adults and endorsed by numerous professional societies worldwide.

However, “subsequent large randomized controlled trials of tight glucose control in medical and mixed medical-surgical ICU settings … have failed to replicate this mortality benefit,” and many have reported rates of hypoglycemia as high as 40%. “Hypoglycemia is not benign in critically ill patients; it has been linked to serious neurologic events ranging from seizures to coma,” the investigators noted.

They conducted a meta-analysis of 29 controlled trials involving 8,432 adult ICU patients with a wide range of disorders who were randomly assigned to either usual care or tight glucose control—a glucose goal of less than 150 mg/dL using an insulin infusion during part or all of the ICU stay.

In-hospital mortality was not significantly different for patients kept on tight glucose control (21.6%) than for those given usual care (23.3%). There also was no difference between the two groups in the need for dialysis, Dr. Soylemez Wiener and her associates said (JAMA 2008;300:933-44).

In subgroup analyses, tight glucose control did not benefit surgical patients vs. medical patients, nor did “very tight” glucose control prove more beneficial than “moderately tight” glucose control. Sensitivity analyses of the data based on several variables that might be clinically relevant, such as disease severity, did not alter these results.

Tight glucose control did reduce the incidence of septicemia, but only among surgical ICU patients.

“On the other hand, we found clear evidence of the main harm of tight glucose control: Hypoglycemia increased roughly fivefold regardless of the ICU setting and was more common with patients receiving very tight [rather] than moderately tight glucose control,” the researchers added.

“Our meta-analysis shows that subsequent trials have not borne out the impressive results of tight glucose control promised by the initial trial” in 2001. In fact, the subjects in that initial trial received early glucose infusions and parenteral nutrition, both of which might artificially induce hyperglycemia and both of which are atypical in clinical practice. This “may have contributed to the outlying results seen in [that] trial,” the researchers noted.

In an accompanying editorial comment, Dr. Simon Finfer and Dr. Anthony Delaney of the Royal North Shore Hospital, Sydney, said that the results of this “well-conducted” and “timely” meta-analysis “may surprise many clinicians” (JAMA 2008;300:963-5).

Not only does the meta-analysis call the benefit of tight glucose control into question, it also highlights that there is no agreed standard for glycemic control, that blood glucose levels are extremely variable during the course of an ICU stay, and that bedside measurement of blood glucose can be very inaccurate, Dr. Finfer and Dr. Delaney said.

Tight glucose control does not benefit critically ill patients and may even be harmful because it markedly raises the risk of hypoglycemia, according to a meta-analysis.

Given these findings, “it seems appropriate that the guidelines recommending tight glucose control in all critically ill patients should be reevaluated until the results of larger, more definitive clinical trials are available,” said Dr. Renda Soylemez Wiener of the Veterans Affairs Medical Center, White River Junction, Vt., and her associates.

In 2001, a single clinical trial showed that tight glucose control reduced in-hospital mortality by a third among critically ill surgical patients. “The results of this trial were enthusiastically received and rapidly incorporated into guidelines,” and tight glucose control is now recommended for all critically ill adults and endorsed by numerous professional societies worldwide.

However, “subsequent large randomized controlled trials of tight glucose control in medical and mixed medical-surgical ICU settings … have failed to replicate this mortality benefit,” and many have reported rates of hypoglycemia as high as 40%. “Hypoglycemia is not benign in critically ill patients; it has been linked to serious neurologic events ranging from seizures to coma,” the investigators noted.

They conducted a meta-analysis of 29 controlled trials involving 8,432 adult ICU patients with a wide range of disorders who were randomly assigned to either usual care or tight glucose control—a glucose goal of less than 150 mg/dL using an insulin infusion during part or all of the ICU stay.

In-hospital mortality was not significantly different for patients kept on tight glucose control (21.6%) than for those given usual care (23.3%). There also was no difference between the two groups in the need for dialysis, Dr. Soylemez Wiener and her associates said (JAMA 2008;300:933-44).

In subgroup analyses, tight glucose control did not benefit surgical patients vs. medical patients, nor did “very tight” glucose control prove more beneficial than “moderately tight” glucose control. Sensitivity analyses of the data based on several variables that might be clinically relevant, such as disease severity, did not alter these results.

Tight glucose control did reduce the incidence of septicemia, but only among surgical ICU patients.

“On the other hand, we found clear evidence of the main harm of tight glucose control: Hypoglycemia increased roughly fivefold regardless of the ICU setting and was more common with patients receiving very tight [rather] than moderately tight glucose control,” the researchers added.

“Our meta-analysis shows that subsequent trials have not borne out the impressive results of tight glucose control promised by the initial trial” in 2001. In fact, the subjects in that initial trial received early glucose infusions and parenteral nutrition, both of which might artificially induce hyperglycemia and both of which are atypical in clinical practice. This “may have contributed to the outlying results seen in [that] trial,” the researchers noted.

In an accompanying editorial comment, Dr. Simon Finfer and Dr. Anthony Delaney of the Royal North Shore Hospital, Sydney, said that the results of this “well-conducted” and “timely” meta-analysis “may surprise many clinicians” (JAMA 2008;300:963-5).

Not only does the meta-analysis call the benefit of tight glucose control into question, it also highlights that there is no agreed standard for glycemic control, that blood glucose levels are extremely variable during the course of an ICU stay, and that bedside measurement of blood glucose can be very inaccurate, Dr. Finfer and Dr. Delaney said.

Polyalkylimide dermal fillers can produce delayed adverse immune effects, including chronic inflammatory and granulomatous reactions, investigators reported in the Archives of Dermatology.

This is the first report of histologic granulomas related to polyalkylimide implants (PAIs) described in the literature, according to Dr. Jaume Alijotas-Reig of Vall d'Hebron University Hospital, Barcelona, and associates.

"Considering the increased use of polyalkylimide fillers in European countries and the United States, physicians should be aware that … delayed effects can occur with polyalkylimide implants just as they can with collagen, polyacrylamide, polylactic acid, or methacrylate," the researchers wrote.

PAIs are used for a variety of facial defects, including anatomic or traumatic deformities as well as aesthetic defects. They also are being used increasingly in lipodystrophy related to antiretroviral therapy in patients with HIV.

According to manufacturers PAIs do not change over time, do not move or migrate, and will not be reabsorbed, unlike other dermal implant materials. However, recent reports refute these statements, according to the investigators.

A voluntary registry of patients with delayed adverse effects related to implants was designed jointly by the Spanish Society of Cosmetic Medicine and Surgery and Dr. Alijotas-Reig and associates at the hospital's clinical immunology unit.

The researchers reported on 25 patients in the registry who had delayed adverse effects related to PAIs. Of the three study patients who were HIV-positive, two were not undergoing treatment with antiretrovirals.

"Multiple inflammatory tender nodules of different sizes, facial edema and/or angioedema, and swelling and/or skin induration were the most frequent local and/or regional complaints. … In six cases, distant or systemic manifestations appeared," including Sjögren's syndrome, they reported (Arch. Dermatol. 2008;144:637-42).

Pseudoabscesses were also common. "Recovered material looks like pus, but bacterial cultures are usually negative for organisms," Dr. Alijotas-Reig and associates wrote.

The mean interval between implantation and symptom onset was 13 months (range, 1-60 months).

Other factors—such as smoking status, personal or family history of autoimmune disease, and "triggering" events such as infection or trauma—did not contribute to granulomatous reactions in these patients.

Of the 17 patients who had laboratory assessments, 12 had at least one abnormal result. These included elevated levels of C-reactive protein and fibrinogen in 11 of the 12, "so underlying inflammatory processes in different stages had to be present."

Five patients also showed elevated lactate dehydrogenase levels, which probably indicated lymphocyte or macrophage activation. Six patients had elevated levels of angiotensin-converting enzyme, which also might be secondary to macrophage and granulomatous immune responses.

Biopsy of facial and distant nodules was performed in three patients, and all showed nonspecific foreign-body granulomas.

All patients were treated with NSAIDs, and some also received hydroxychloroquine or low-dose prednisone. At least 15 had previously received antibiotics, which were ineffective.

After an average of 21 months of follow-up, 11 patients had achieved remission, 10 had recurrent or residual nodules, induration, or edema, and 4 were lost to follow-up.

"Although infrequent, delayed, moderate to severe immune-mediated adverse effects may be caused by PAIs, occasionally with systemic manifestations," the investigators concluded.

Polyalkylimide dermal fillers can produce delayed adverse immune effects, including chronic inflammatory and granulomatous reactions, investigators reported in the Archives of Dermatology.

This is the first report of histologic granulomas related to polyalkylimide implants (PAIs) described in the literature, according to Dr. Jaume Alijotas-Reig of Vall d'Hebron University Hospital, Barcelona, and associates.

"Considering the increased use of polyalkylimide fillers in European countries and the United States, physicians should be aware that … delayed effects can occur with polyalkylimide implants just as they can with collagen, polyacrylamide, polylactic acid, or methacrylate," the researchers wrote.

PAIs are used for a variety of facial defects, including anatomic or traumatic deformities as well as aesthetic defects. They also are being used increasingly in lipodystrophy related to antiretroviral therapy in patients with HIV.

According to manufacturers PAIs do not change over time, do not move or migrate, and will not be reabsorbed, unlike other dermal implant materials. However, recent reports refute these statements, according to the investigators.

A voluntary registry of patients with delayed adverse effects related to implants was designed jointly by the Spanish Society of Cosmetic Medicine and Surgery and Dr. Alijotas-Reig and associates at the hospital's clinical immunology unit.

The researchers reported on 25 patients in the registry who had delayed adverse effects related to PAIs. Of the three study patients who were HIV-positive, two were not undergoing treatment with antiretrovirals.

"Multiple inflammatory tender nodules of different sizes, facial edema and/or angioedema, and swelling and/or skin induration were the most frequent local and/or regional complaints. … In six cases, distant or systemic manifestations appeared," including Sjögren's syndrome, they reported (Arch. Dermatol. 2008;144:637-42).

Pseudoabscesses were also common. "Recovered material looks like pus, but bacterial cultures are usually negative for organisms," Dr. Alijotas-Reig and associates wrote.

The mean interval between implantation and symptom onset was 13 months (range, 1-60 months).

Other factors—such as smoking status, personal or family history of autoimmune disease, and "triggering" events such as infection or trauma—did not contribute to granulomatous reactions in these patients.

Of the 17 patients who had laboratory assessments, 12 had at least one abnormal result. These included elevated levels of C-reactive protein and fibrinogen in 11 of the 12, "so underlying inflammatory processes in different stages had to be present."

Five patients also showed elevated lactate dehydrogenase levels, which probably indicated lymphocyte or macrophage activation. Six patients had elevated levels of angiotensin-converting enzyme, which also might be secondary to macrophage and granulomatous immune responses.

Biopsy of facial and distant nodules was performed in three patients, and all showed nonspecific foreign-body granulomas.

All patients were treated with NSAIDs, and some also received hydroxychloroquine or low-dose prednisone. At least 15 had previously received antibiotics, which were ineffective.

After an average of 21 months of follow-up, 11 patients had achieved remission, 10 had recurrent or residual nodules, induration, or edema, and 4 were lost to follow-up.

"Although infrequent, delayed, moderate to severe immune-mediated adverse effects may be caused by PAIs, occasionally with systemic manifestations," the investigators concluded.

Polyalkylimide dermal fillers can produce delayed adverse immune effects, including chronic inflammatory and granulomatous reactions, investigators reported in the Archives of Dermatology.

This is the first report of histologic granulomas related to polyalkylimide implants (PAIs) described in the literature, according to Dr. Jaume Alijotas-Reig of Vall d'Hebron University Hospital, Barcelona, and associates.

"Considering the increased use of polyalkylimide fillers in European countries and the United States, physicians should be aware that … delayed effects can occur with polyalkylimide implants just as they can with collagen, polyacrylamide, polylactic acid, or methacrylate," the researchers wrote.

PAIs are used for a variety of facial defects, including anatomic or traumatic deformities as well as aesthetic defects. They also are being used increasingly in lipodystrophy related to antiretroviral therapy in patients with HIV.

According to manufacturers PAIs do not change over time, do not move or migrate, and will not be reabsorbed, unlike other dermal implant materials. However, recent reports refute these statements, according to the investigators.

A voluntary registry of patients with delayed adverse effects related to implants was designed jointly by the Spanish Society of Cosmetic Medicine and Surgery and Dr. Alijotas-Reig and associates at the hospital's clinical immunology unit.

The researchers reported on 25 patients in the registry who had delayed adverse effects related to PAIs. Of the three study patients who were HIV-positive, two were not undergoing treatment with antiretrovirals.

"Multiple inflammatory tender nodules of different sizes, facial edema and/or angioedema, and swelling and/or skin induration were the most frequent local and/or regional complaints. … In six cases, distant or systemic manifestations appeared," including Sjögren's syndrome, they reported (Arch. Dermatol. 2008;144:637-42).

Pseudoabscesses were also common. "Recovered material looks like pus, but bacterial cultures are usually negative for organisms," Dr. Alijotas-Reig and associates wrote.

The mean interval between implantation and symptom onset was 13 months (range, 1-60 months).

Other factors—such as smoking status, personal or family history of autoimmune disease, and "triggering" events such as infection or trauma—did not contribute to granulomatous reactions in these patients.

Of the 17 patients who had laboratory assessments, 12 had at least one abnormal result. These included elevated levels of C-reactive protein and fibrinogen in 11 of the 12, "so underlying inflammatory processes in different stages had to be present."

Five patients also showed elevated lactate dehydrogenase levels, which probably indicated lymphocyte or macrophage activation. Six patients had elevated levels of angiotensin-converting enzyme, which also might be secondary to macrophage and granulomatous immune responses.

Biopsy of facial and distant nodules was performed in three patients, and all showed nonspecific foreign-body granulomas.

All patients were treated with NSAIDs, and some also received hydroxychloroquine or low-dose prednisone. At least 15 had previously received antibiotics, which were ineffective.

After an average of 21 months of follow-up, 11 patients had achieved remission, 10 had recurrent or residual nodules, induration, or edema, and 4 were lost to follow-up.

"Although infrequent, delayed, moderate to severe immune-mediated adverse effects may be caused by PAIs, occasionally with systemic manifestations," the investigators concluded.

The risk of developing herpes zoster appears to be strongly associated with a family history of the disorder, researchers said in a study published in the Archives of Dermatology.

If further studies confirm this link, people whose family histories put them at risk can be targeted for vaccination, according to Lindsey D. Hicks, a medical student at the University of Texas at Houston, and her associates.

Noting that a recent literature review suggested that a family history of herpes zoster might be predictive but that the issue has not been adequately studied, the investigators conducted a case-control analysis involving 504 patients treated between 1992 and 2005 and 523 well-matched control subjects who never had herpes zoster.

Nearly equal proportions of cases and controls (76%) recalled having had primary infection with varicella-zoster virus.

Case patients were about four times more likely than control subjects were to report having a first-degree relative with a history of herpes zoster, and they were only slightly less likely to report having a more distant blood relative with a history of the disorder.

Moreover, the risk of developing herpes zoster rose in a dose-dependent fashion as the number of affected relatives increased.

"An odds ratio of 4.5 was calculated for [patients] reporting single [affected] relatives, and an odds ratio of 13.7 was calculated for those reporting multiple [affected] relatives," Ms. Hicks and her associates wrote (Arch. Dermatol. 2008;144:603-8).

"Our study indicates the possibility of inherited susceptibility to herpes zoster and indicates that further studies into this area may be necessary in order to recognize and vaccinate susceptible individuals," the researchers said.

Vaccinating these at-risk individuals "may decrease both their chance of future herpes zoster infection and health care expenditures toward herpes zoster morbidity," they added.

At press time, the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) had recommended that all individuals aged 60 years and older should receive the herpes zoster vaccine to prevent the development of shingles.

The new herpes zoster vaccine recommendation, which was published in an early-release electronic edition of Morbidity and Mortality Weekly Report, replaced a provisional recommendation that ACIP had made after licensure of the vaccine in 2006 by the Food and Drug Administration.

Although most adults are seropositive for primary varicella zoster infection, the lifetime risk of developing herpes zoster—reactivation of latent varicella-zoster virus residing in dorsal root ganglia after primary infection—is 10%-30%, the investigators noted.

Risk rises dramatically with age, so that the risk for people aged 85 years and older approaches 50%, said Ms. Hicks and her associates, who reported that they had no financial conflicts regarding this study.

ELSEVIER GLOBAL MEDICAL NEWS

The risk of developing herpes zoster appears to be strongly associated with a family history of the disorder, researchers said in a study published in the Archives of Dermatology.

If further studies confirm this link, people whose family histories put them at risk can be targeted for vaccination, according to Lindsey D. Hicks, a medical student at the University of Texas at Houston, and her associates.

Noting that a recent literature review suggested that a family history of herpes zoster might be predictive but that the issue has not been adequately studied, the investigators conducted a case-control analysis involving 504 patients treated between 1992 and 2005 and 523 well-matched control subjects who never had herpes zoster.

Nearly equal proportions of cases and controls (76%) recalled having had primary infection with varicella-zoster virus.

Case patients were about four times more likely than control subjects were to report having a first-degree relative with a history of herpes zoster, and they were only slightly less likely to report having a more distant blood relative with a history of the disorder.

Moreover, the risk of developing herpes zoster rose in a dose-dependent fashion as the number of affected relatives increased.

"An odds ratio of 4.5 was calculated for [patients] reporting single [affected] relatives, and an odds ratio of 13.7 was calculated for those reporting multiple [affected] relatives," Ms. Hicks and her associates wrote (Arch. Dermatol. 2008;144:603-8).

"Our study indicates the possibility of inherited susceptibility to herpes zoster and indicates that further studies into this area may be necessary in order to recognize and vaccinate susceptible individuals," the researchers said.

Vaccinating these at-risk individuals "may decrease both their chance of future herpes zoster infection and health care expenditures toward herpes zoster morbidity," they added.

At press time, the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) had recommended that all individuals aged 60 years and older should receive the herpes zoster vaccine to prevent the development of shingles.

The new herpes zoster vaccine recommendation, which was published in an early-release electronic edition of Morbidity and Mortality Weekly Report, replaced a provisional recommendation that ACIP had made after licensure of the vaccine in 2006 by the Food and Drug Administration.

Although most adults are seropositive for primary varicella zoster infection, the lifetime risk of developing herpes zoster—reactivation of latent varicella-zoster virus residing in dorsal root ganglia after primary infection—is 10%-30%, the investigators noted.

Risk rises dramatically with age, so that the risk for people aged 85 years and older approaches 50%, said Ms. Hicks and her associates, who reported that they had no financial conflicts regarding this study.

ELSEVIER GLOBAL MEDICAL NEWS

The risk of developing herpes zoster appears to be strongly associated with a family history of the disorder, researchers said in a study published in the Archives of Dermatology.

If further studies confirm this link, people whose family histories put them at risk can be targeted for vaccination, according to Lindsey D. Hicks, a medical student at the University of Texas at Houston, and her associates.

Noting that a recent literature review suggested that a family history of herpes zoster might be predictive but that the issue has not been adequately studied, the investigators conducted a case-control analysis involving 504 patients treated between 1992 and 2005 and 523 well-matched control subjects who never had herpes zoster.

Nearly equal proportions of cases and controls (76%) recalled having had primary infection with varicella-zoster virus.

Case patients were about four times more likely than control subjects were to report having a first-degree relative with a history of herpes zoster, and they were only slightly less likely to report having a more distant blood relative with a history of the disorder.

Moreover, the risk of developing herpes zoster rose in a dose-dependent fashion as the number of affected relatives increased.

"An odds ratio of 4.5 was calculated for [patients] reporting single [affected] relatives, and an odds ratio of 13.7 was calculated for those reporting multiple [affected] relatives," Ms. Hicks and her associates wrote (Arch. Dermatol. 2008;144:603-8).

"Our study indicates the possibility of inherited susceptibility to herpes zoster and indicates that further studies into this area may be necessary in order to recognize and vaccinate susceptible individuals," the researchers said.

Vaccinating these at-risk individuals "may decrease both their chance of future herpes zoster infection and health care expenditures toward herpes zoster morbidity," they added.

At press time, the Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) had recommended that all individuals aged 60 years and older should receive the herpes zoster vaccine to prevent the development of shingles.

The new herpes zoster vaccine recommendation, which was published in an early-release electronic edition of Morbidity and Mortality Weekly Report, replaced a provisional recommendation that ACIP had made after licensure of the vaccine in 2006 by the Food and Drug Administration.

Although most adults are seropositive for primary varicella zoster infection, the lifetime risk of developing herpes zoster—reactivation of latent varicella-zoster virus residing in dorsal root ganglia after primary infection—is 10%-30%, the investigators noted.

Risk rises dramatically with age, so that the risk for people aged 85 years and older approaches 50%, said Ms. Hicks and her associates, who reported that they had no financial conflicts regarding this study.

ELSEVIER GLOBAL MEDICAL NEWS

The risk of developing herpes zoster appears to be associated with a family history of the disorder, according to case-control study findings.

If further studies confirm this link, people whose family histories put them at risk can be targeted for vaccination, according to Lindsey D. Hicks, a medical student at the University of Texas at Houston.

Ms. Hicks and her associates conducted a case-control analysis involving 504 patients treated between 1992 and 2005 and 523 well-matched control subjects who never had herpes zoster. Nearly equal proportions of cases and controls (76%) recalled having had primary infection with varicella-zoster virus.

Case patients were about four times more likely than control subjects were to report having a first-degree relative with a history of herpes zoster, and they were only slightly less likely to report having a more distant blood relative with a history of the disorder.

The risk of developing herpes zoster rose in a dose-dependent fashion as the number of affected relatives increased. “An odds ratio of 4.5 was calculated for [patients] reporting single [affected] relatives, and an odds ratio of 13.7 was calculated for those reporting multiple [affected] relatives,” Ms. Hicks and her associates wrote (Arch. Dermatol. 2008;144:603-8).

“Our study indicates the possibility of inherited susceptibility to herpes zoster and indicates that further studies into this area may be necessary in order to recognize and vaccinate susceptible individuals,” the researchers said.

The Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) recently advised that all individuals aged 60 years and older receive the herpes zoster vaccine to prevent the development of shingles.

The risk of developing herpes zoster appears to be associated with a family history of the disorder, according to case-control study findings.

If further studies confirm this link, people whose family histories put them at risk can be targeted for vaccination, according to Lindsey D. Hicks, a medical student at the University of Texas at Houston.

Ms. Hicks and her associates conducted a case-control analysis involving 504 patients treated between 1992 and 2005 and 523 well-matched control subjects who never had herpes zoster. Nearly equal proportions of cases and controls (76%) recalled having had primary infection with varicella-zoster virus.

Case patients were about four times more likely than control subjects were to report having a first-degree relative with a history of herpes zoster, and they were only slightly less likely to report having a more distant blood relative with a history of the disorder.

The risk of developing herpes zoster rose in a dose-dependent fashion as the number of affected relatives increased. “An odds ratio of 4.5 was calculated for [patients] reporting single [affected] relatives, and an odds ratio of 13.7 was calculated for those reporting multiple [affected] relatives,” Ms. Hicks and her associates wrote (Arch. Dermatol. 2008;144:603-8).

“Our study indicates the possibility of inherited susceptibility to herpes zoster and indicates that further studies into this area may be necessary in order to recognize and vaccinate susceptible individuals,” the researchers said.

The Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) recently advised that all individuals aged 60 years and older receive the herpes zoster vaccine to prevent the development of shingles.

The risk of developing herpes zoster appears to be associated with a family history of the disorder, according to case-control study findings.

If further studies confirm this link, people whose family histories put them at risk can be targeted for vaccination, according to Lindsey D. Hicks, a medical student at the University of Texas at Houston.

Ms. Hicks and her associates conducted a case-control analysis involving 504 patients treated between 1992 and 2005 and 523 well-matched control subjects who never had herpes zoster. Nearly equal proportions of cases and controls (76%) recalled having had primary infection with varicella-zoster virus.

Case patients were about four times more likely than control subjects were to report having a first-degree relative with a history of herpes zoster, and they were only slightly less likely to report having a more distant blood relative with a history of the disorder.

The risk of developing herpes zoster rose in a dose-dependent fashion as the number of affected relatives increased. “An odds ratio of 4.5 was calculated for [patients] reporting single [affected] relatives, and an odds ratio of 13.7 was calculated for those reporting multiple [affected] relatives,” Ms. Hicks and her associates wrote (Arch. Dermatol. 2008;144:603-8).

“Our study indicates the possibility of inherited susceptibility to herpes zoster and indicates that further studies into this area may be necessary in order to recognize and vaccinate susceptible individuals,” the researchers said.

The Centers for Disease Control and Prevention's Advisory Committee on Immunization Practices (ACIP) recently advised that all individuals aged 60 years and older receive the herpes zoster vaccine to prevent the development of shingles.

The risk of developing herpes zoster appears to be strongly associated with a family history of the disorder, researchers said.

If further studies confirm this link, people whose family histories put them at risk can be targeted for vaccination, according to Lindsey D. Hicks, a medical student at the University of Texas at Houston, and her associates.

Noting that a recent literature review suggested that a family history of herpes zoster might be predictive but that the issue has not been adequately studied, the investigators conducted a case-control analysis involving 504 patients treated between 1992 and 2005 and 523 well-matched control subjects who never had herpes zoster. Nearly equal proportions of cases and controls (76%) recalled having had primary infection with varicella-zoster virus.

Case patients were about four times more likely than were control subjects to report having a first-degree relative with a history of herpes zoster.

Moreover, the risk of developing herpes zoster rose in a dose-dependent fashion as the number of affected relatives increased. “An odds ratio of 4.5 was calculated for [patients] reporting single [affected] relatives, and an odds ratio of 13.7 was calculated for those reporting multiple [affected] relatives,” Ms. Hicks and her associates wrote (Arch. Dermatol. 2008;144:603–8).

The risk of developing herpes zoster appears to be strongly associated with a family history of the disorder, researchers said.

If further studies confirm this link, people whose family histories put them at risk can be targeted for vaccination, according to Lindsey D. Hicks, a medical student at the University of Texas at Houston, and her associates.

Noting that a recent literature review suggested that a family history of herpes zoster might be predictive but that the issue has not been adequately studied, the investigators conducted a case-control analysis involving 504 patients treated between 1992 and 2005 and 523 well-matched control subjects who never had herpes zoster. Nearly equal proportions of cases and controls (76%) recalled having had primary infection with varicella-zoster virus.

Case patients were about four times more likely than were control subjects to report having a first-degree relative with a history of herpes zoster.

Moreover, the risk of developing herpes zoster rose in a dose-dependent fashion as the number of affected relatives increased. “An odds ratio of 4.5 was calculated for [patients] reporting single [affected] relatives, and an odds ratio of 13.7 was calculated for those reporting multiple [affected] relatives,” Ms. Hicks and her associates wrote (Arch. Dermatol. 2008;144:603–8).

The risk of developing herpes zoster appears to be strongly associated with a family history of the disorder, researchers said.

If further studies confirm this link, people whose family histories put them at risk can be targeted for vaccination, according to Lindsey D. Hicks, a medical student at the University of Texas at Houston, and her associates.

Noting that a recent literature review suggested that a family history of herpes zoster might be predictive but that the issue has not been adequately studied, the investigators conducted a case-control analysis involving 504 patients treated between 1992 and 2005 and 523 well-matched control subjects who never had herpes zoster. Nearly equal proportions of cases and controls (76%) recalled having had primary infection with varicella-zoster virus.

Case patients were about four times more likely than were control subjects to report having a first-degree relative with a history of herpes zoster.

Moreover, the risk of developing herpes zoster rose in a dose-dependent fashion as the number of affected relatives increased. “An odds ratio of 4.5 was calculated for [patients] reporting single [affected] relatives, and an odds ratio of 13.7 was calculated for those reporting multiple [affected] relatives,” Ms. Hicks and her associates wrote (Arch. Dermatol. 2008;144:603–8).

Maternal glucose levels that were high but below the diagnostic threshold for gestational diabetes were strongly associated with high fetal insulin levels and birth weights in a large international study, investigators reported in the New England Journal of Medicine.

There were also weaker—but still significant—associations between maternal hyperglycemia that fell short of overt gestational diabetes and a host of neonatal problems: hypoglycemia in the neonate, the need for cesarean delivery, premature delivery, shoulder dystocia or birth injury, the need for intensive neonatal care, hyperbilirubinemia, and preeclampsia.

These findings “indicate the need to reconsider current criteria for diagnosing and treating hyperglycemia during pregnancy,” said Dr. Boyd E. Metzger of Northwestern University, Chicago, and his associates in the Hyperglycemia and Adverse Pregnancy Outcome study.

The researchers assessed 23,316 pregnant women “to clarify the risk of adverse outcomes associated with degrees of maternal glucose intolerance less severe than overt diabetes mellitus.” The study subjects underwent standard oral glucose tolerance testing at 24–32 weeks' gestation at 15 medical centers in nine countries.

Cord blood specimens were obtained at delivery to assess serum C-peptide levels, an indicator of fetal ?-cell function.

High levels of fasting, 1-hour, and 2-hour plasma glucose were strongly correlated with birth weight above the 90th percentile and C-peptide levels above the 90th percentile, and the rates of these problems increased as plasma glucose levels increased.

There were weaker but significant correlations between maternal hyperglycemia and two other primary outcomes of this study (cesarean delivery and clinical neonatal hyperglycemia), as well as five secondary outcomes. A similar dose-response relationship was seen between increasing maternal glucose level and rising rates of these problems, Dr. Metzger and his associates said (N. Engl. J. Med. 2008;358:1991–2002).

In a separate study of gestational diabetes published in the same issue, Dr. Janet A. Rowan of Auckland City Hospital, New Zealand, and her associates in the Metformin in Gestational Diabetes trial found that metformin was “noninferior” to insulin in safety and efficacy, and was preferred by patients with overt disease. In that open-label study, Dr. Rowan and her associates compared oral metformin with insulin therapy in 733 women who had overt gestational diabetes and were followed at 10 New Zealand and Australian obstetric hospitals.

The composite outcome of numerous neonatal complications, including hypoglycemia in the infant, was no different between the metformin group and the insulin group, at 32% in both. There also were no differences between the two groups in neonatal anthropometric measures or in umbilical cord serum insulin concentrations.

The women preferred metformin to insulin. However, 46% of those who took metformin eventually required supplemental insulin as well, Dr. Rowan and her associates said (N. Engl. J. Med. 2008;358:2003–15).

Further follow-up data on the offspring are needed to determine the long-term safety of metformin use in pregnancy, they noted.

The findings suggest a need to reconsider criteria for diagnosing and treating hyperglycemia in pregnancy. DR. METZGER

Maternal glucose levels that were high but below the diagnostic threshold for gestational diabetes were strongly associated with high fetal insulin levels and birth weights in a large international study, investigators reported in the New England Journal of Medicine.

There were also weaker—but still significant—associations between maternal hyperglycemia that fell short of overt gestational diabetes and a host of neonatal problems: hypoglycemia in the neonate, the need for cesarean delivery, premature delivery, shoulder dystocia or birth injury, the need for intensive neonatal care, hyperbilirubinemia, and preeclampsia.

These findings “indicate the need to reconsider current criteria for diagnosing and treating hyperglycemia during pregnancy,” said Dr. Boyd E. Metzger of Northwestern University, Chicago, and his associates in the Hyperglycemia and Adverse Pregnancy Outcome study.

The researchers assessed 23,316 pregnant women “to clarify the risk of adverse outcomes associated with degrees of maternal glucose intolerance less severe than overt diabetes mellitus.” The study subjects underwent standard oral glucose tolerance testing at 24–32 weeks' gestation at 15 medical centers in nine countries.

Cord blood specimens were obtained at delivery to assess serum C-peptide levels, an indicator of fetal ?-cell function.

High levels of fasting, 1-hour, and 2-hour plasma glucose were strongly correlated with birth weight above the 90th percentile and C-peptide levels above the 90th percentile, and the rates of these problems increased as plasma glucose levels increased.

There were weaker but significant correlations between maternal hyperglycemia and two other primary outcomes of this study (cesarean delivery and clinical neonatal hyperglycemia), as well as five secondary outcomes. A similar dose-response relationship was seen between increasing maternal glucose level and rising rates of these problems, Dr. Metzger and his associates said (N. Engl. J. Med. 2008;358:1991–2002).

In a separate study of gestational diabetes published in the same issue, Dr. Janet A. Rowan of Auckland City Hospital, New Zealand, and her associates in the Metformin in Gestational Diabetes trial found that metformin was “noninferior” to insulin in safety and efficacy, and was preferred by patients with overt disease. In that open-label study, Dr. Rowan and her associates compared oral metformin with insulin therapy in 733 women who had overt gestational diabetes and were followed at 10 New Zealand and Australian obstetric hospitals.

The composite outcome of numerous neonatal complications, including hypoglycemia in the infant, was no different between the metformin group and the insulin group, at 32% in both. There also were no differences between the two groups in neonatal anthropometric measures or in umbilical cord serum insulin concentrations.

The women preferred metformin to insulin. However, 46% of those who took metformin eventually required supplemental insulin as well, Dr. Rowan and her associates said (N. Engl. J. Med. 2008;358:2003–15).

Further follow-up data on the offspring are needed to determine the long-term safety of metformin use in pregnancy, they noted.

The findings suggest a need to reconsider criteria for diagnosing and treating hyperglycemia in pregnancy. DR. METZGER

Maternal glucose levels that were high but below the diagnostic threshold for gestational diabetes were strongly associated with high fetal insulin levels and birth weights in a large international study, investigators reported in the New England Journal of Medicine.

There were also weaker—but still significant—associations between maternal hyperglycemia that fell short of overt gestational diabetes and a host of neonatal problems: hypoglycemia in the neonate, the need for cesarean delivery, premature delivery, shoulder dystocia or birth injury, the need for intensive neonatal care, hyperbilirubinemia, and preeclampsia.

These findings “indicate the need to reconsider current criteria for diagnosing and treating hyperglycemia during pregnancy,” said Dr. Boyd E. Metzger of Northwestern University, Chicago, and his associates in the Hyperglycemia and Adverse Pregnancy Outcome study.

The researchers assessed 23,316 pregnant women “to clarify the risk of adverse outcomes associated with degrees of maternal glucose intolerance less severe than overt diabetes mellitus.” The study subjects underwent standard oral glucose tolerance testing at 24–32 weeks' gestation at 15 medical centers in nine countries.

Cord blood specimens were obtained at delivery to assess serum C-peptide levels, an indicator of fetal ?-cell function.

High levels of fasting, 1-hour, and 2-hour plasma glucose were strongly correlated with birth weight above the 90th percentile and C-peptide levels above the 90th percentile, and the rates of these problems increased as plasma glucose levels increased.

There were weaker but significant correlations between maternal hyperglycemia and two other primary outcomes of this study (cesarean delivery and clinical neonatal hyperglycemia), as well as five secondary outcomes. A similar dose-response relationship was seen between increasing maternal glucose level and rising rates of these problems, Dr. Metzger and his associates said (N. Engl. J. Med. 2008;358:1991–2002).

In a separate study of gestational diabetes published in the same issue, Dr. Janet A. Rowan of Auckland City Hospital, New Zealand, and her associates in the Metformin in Gestational Diabetes trial found that metformin was “noninferior” to insulin in safety and efficacy, and was preferred by patients with overt disease. In that open-label study, Dr. Rowan and her associates compared oral metformin with insulin therapy in 733 women who had overt gestational diabetes and were followed at 10 New Zealand and Australian obstetric hospitals.

The composite outcome of numerous neonatal complications, including hypoglycemia in the infant, was no different between the metformin group and the insulin group, at 32% in both. There also were no differences between the two groups in neonatal anthropometric measures or in umbilical cord serum insulin concentrations.

The women preferred metformin to insulin. However, 46% of those who took metformin eventually required supplemental insulin as well, Dr. Rowan and her associates said (N. Engl. J. Med. 2008;358:2003–15).

Further follow-up data on the offspring are needed to determine the long-term safety of metformin use in pregnancy, they noted.

The findings suggest a need to reconsider criteria for diagnosing and treating hyperglycemia in pregnancy. DR. METZGER

Maternal glucose levels that were high but below the diagnostic threshold for gestational diabetes were strongly associated with high fetal insulin levels and birth weights in an international study of 23,316 pregnant women.

There were also weaker—but still significant—associations between maternal hyperglycemia that fell short of overt gestational diabetes and a host of neonatal problems: hypoglycemia in the neonate, the need for cesarean delivery, premature delivery, shoulder dystocia or birth injury, the need for intensive neonatal care, hyperbilirubinemia, and preeclampsia, investigators reported in the New England Journal of Medicine.

These findings “indicate the need to reconsider current criteria for diagnosing and treating hyperglycemia during pregnancy,” reported Dr. Boyd E. Metzger of Northwestern University, Chicago, and his associates in the Hyperglycemia and Adverse Pregnancy Outcome study (N. Engl. J. Med. 2008;358:1991–2002).

The researchers assessed the 23,316 gravid women “to clarify the risk of adverse outcomes associated with degrees of maternal glucose intolerance less severe than overt diabetes mellitus.” The study subjects underwent standard oral glucose tolerance testing at 24–32 weeks' gestation at 15 medical centers in nine countries.

Cord blood specimens were obtained at delivery to assess serum C-peptide levels, an indicator of fetal β-cell function.

High levels of fasting, 1-hour, and 2-hour plasma glucose were strongly correlated with birth weight above the 90th percentile and C-peptide levels above the 90th percentile, and the rates of these problems increased as plasma glucose levels increased.

There were weaker but significant correlations between maternal hyperglycemia and two other primary outcomes of this study (cesarean delivery and clinical neonatal hyperglycemia), as well as five secondary outcomes. A similar dose-response relationship was seen between increasing maternal glucose level and rising rates of these problems, Dr. Metzger and his associates said.

In a separate study of gestational diabetes published in the same issue, Dr. Janet A. Rowan of Auckland City (New Zealand) Hospital and her associates in the Metformin in Gestational Diabetes trial found that metformin was “noninferior” to insulin in safety and efficacy, and was preferred by patients with overt disease.

In that open-label study, Dr. Rowan and her associates compared oral metformin with insulin therapy in 733 women who had overt gestational diabetes and were followed at 10 New Zealand and Australian obstetric hospitals.

The composite outcome of numerous neonatal complications, including hypoglycemia in the infant, was no different between the metformin group and the insulin group, at 32% in both. There also were no differences between the two groups in neonatal anthropometric measures or in umbilical cord serum insulin concentrations.

The women preferred metformin to insulin. However, 46% of those who took metformin eventually required supplemental insulin as well, Dr. Rowan and her associates said (N. Engl. J. Med. 2008;358:2003–15).

Further follow-up data on the offspring are needed to determine the long-term safety of metformin use in pregnancy, they noted.

Maternal glucose levels that were high but below the diagnostic threshold for gestational diabetes were strongly associated with high fetal insulin levels and birth weights in an international study of 23,316 pregnant women.

There were also weaker—but still significant—associations between maternal hyperglycemia that fell short of overt gestational diabetes and a host of neonatal problems: hypoglycemia in the neonate, the need for cesarean delivery, premature delivery, shoulder dystocia or birth injury, the need for intensive neonatal care, hyperbilirubinemia, and preeclampsia, investigators reported in the New England Journal of Medicine.

These findings “indicate the need to reconsider current criteria for diagnosing and treating hyperglycemia during pregnancy,” reported Dr. Boyd E. Metzger of Northwestern University, Chicago, and his associates in the Hyperglycemia and Adverse Pregnancy Outcome study (N. Engl. J. Med. 2008;358:1991–2002).

The researchers assessed the 23,316 gravid women “to clarify the risk of adverse outcomes associated with degrees of maternal glucose intolerance less severe than overt diabetes mellitus.” The study subjects underwent standard oral glucose tolerance testing at 24–32 weeks' gestation at 15 medical centers in nine countries.

Cord blood specimens were obtained at delivery to assess serum C-peptide levels, an indicator of fetal β-cell function.

High levels of fasting, 1-hour, and 2-hour plasma glucose were strongly correlated with birth weight above the 90th percentile and C-peptide levels above the 90th percentile, and the rates of these problems increased as plasma glucose levels increased.

There were weaker but significant correlations between maternal hyperglycemia and two other primary outcomes of this study (cesarean delivery and clinical neonatal hyperglycemia), as well as five secondary outcomes. A similar dose-response relationship was seen between increasing maternal glucose level and rising rates of these problems, Dr. Metzger and his associates said.

In a separate study of gestational diabetes published in the same issue, Dr. Janet A. Rowan of Auckland City (New Zealand) Hospital and her associates in the Metformin in Gestational Diabetes trial found that metformin was “noninferior” to insulin in safety and efficacy, and was preferred by patients with overt disease.

In that open-label study, Dr. Rowan and her associates compared oral metformin with insulin therapy in 733 women who had overt gestational diabetes and were followed at 10 New Zealand and Australian obstetric hospitals.

The composite outcome of numerous neonatal complications, including hypoglycemia in the infant, was no different between the metformin group and the insulin group, at 32% in both. There also were no differences between the two groups in neonatal anthropometric measures or in umbilical cord serum insulin concentrations.

The women preferred metformin to insulin. However, 46% of those who took metformin eventually required supplemental insulin as well, Dr. Rowan and her associates said (N. Engl. J. Med. 2008;358:2003–15).

Further follow-up data on the offspring are needed to determine the long-term safety of metformin use in pregnancy, they noted.

Maternal glucose levels that were high but below the diagnostic threshold for gestational diabetes were strongly associated with high fetal insulin levels and birth weights in an international study of 23,316 pregnant women.

There were also weaker—but still significant—associations between maternal hyperglycemia that fell short of overt gestational diabetes and a host of neonatal problems: hypoglycemia in the neonate, the need for cesarean delivery, premature delivery, shoulder dystocia or birth injury, the need for intensive neonatal care, hyperbilirubinemia, and preeclampsia, investigators reported in the New England Journal of Medicine.

These findings “indicate the need to reconsider current criteria for diagnosing and treating hyperglycemia during pregnancy,” reported Dr. Boyd E. Metzger of Northwestern University, Chicago, and his associates in the Hyperglycemia and Adverse Pregnancy Outcome study (N. Engl. J. Med. 2008;358:1991–2002).

The researchers assessed the 23,316 gravid women “to clarify the risk of adverse outcomes associated with degrees of maternal glucose intolerance less severe than overt diabetes mellitus.” The study subjects underwent standard oral glucose tolerance testing at 24–32 weeks' gestation at 15 medical centers in nine countries.

Cord blood specimens were obtained at delivery to assess serum C-peptide levels, an indicator of fetal β-cell function.

High levels of fasting, 1-hour, and 2-hour plasma glucose were strongly correlated with birth weight above the 90th percentile and C-peptide levels above the 90th percentile, and the rates of these problems increased as plasma glucose levels increased.

There were weaker but significant correlations between maternal hyperglycemia and two other primary outcomes of this study (cesarean delivery and clinical neonatal hyperglycemia), as well as five secondary outcomes. A similar dose-response relationship was seen between increasing maternal glucose level and rising rates of these problems, Dr. Metzger and his associates said.

In a separate study of gestational diabetes published in the same issue, Dr. Janet A. Rowan of Auckland City (New Zealand) Hospital and her associates in the Metformin in Gestational Diabetes trial found that metformin was “noninferior” to insulin in safety and efficacy, and was preferred by patients with overt disease.

In that open-label study, Dr. Rowan and her associates compared oral metformin with insulin therapy in 733 women who had overt gestational diabetes and were followed at 10 New Zealand and Australian obstetric hospitals.

The composite outcome of numerous neonatal complications, including hypoglycemia in the infant, was no different between the metformin group and the insulin group, at 32% in both. There also were no differences between the two groups in neonatal anthropometric measures or in umbilical cord serum insulin concentrations.

The women preferred metformin to insulin. However, 46% of those who took metformin eventually required supplemental insulin as well, Dr. Rowan and her associates said (N. Engl. J. Med. 2008;358:2003–15).

Further follow-up data on the offspring are needed to determine the long-term safety of metformin use in pregnancy, they noted.

The incidence of invasive group B streptococcal disease declined among infants aged 0–6 days after stricter measures for perinatal prevention were widely adopted across the country in 2002, federal scientists have reported.

However, there was a significant increase in the disease among black infants during this period, a finding that is “particularly concerning and requires investigation,” said Christina R. Phares, Ph.D., of the Centers for Disease Control and Prevention (CDC)and her associates.

The revised guidelines recommended antenatal culture-based screening as the optimal method for identifying candidates for intrapartum chemoprophylaxis.

The CDCinvestigators assessed epidemiologic trends among 14,573 cases of invasive group B streptococcal (GBS) disease identified by a national surveillance program between 1999 and 2005, the most recent year for which data are available.

In 2005, there were an estimated 21,500 cases of invasive GBS in the United States, including 1,700 fatalities (JAMA 2008;299:2056–65).

The overall incidence of invasive GBS disease among adults and children in 2005 was 12.8 per 100,000 population in blacks, 6.5 per 100,000 in whites, and 5.1 per 100,000 in all other races combined.

Mortality also was significantly higher for black neonates and black adults aged 45 years and older than for other racial groups.

Early-onset GBS (before 1 week of age) decreased by 27%, from 0.47 per 1,000 live births before the revised guidelines to 0.34 per 1,000 live births in 2003–2005. This is “very close” to the impact that the stricter guidelines were predicted to have, the researchers said. However, there were small increases in incidence in 2004 and 2005, almost all of which occurred among black infants.

The incidence of late-onset GBS (age 7–89 days) remained stable, averaging 0.34 cases per 1,000 live births throughout the 7-year study. Similarly, the incidence of childhood disease (90 days-14 years) remained stable at 0.56 per 100,000 population, with 61% of these cases occurring in children aged 3–12 months.

In contrast, the incidence increased significantly among adults—by 48% in people aged 15–64 years and by 20% in people aged 65 and older. This might be in part because of the increase in underlying medical conditions such as diabetes in this age group, Dr. Phares and her associates said.

Serotype data suggested that a pentavalent conjugate vaccine potentially could have prevented “up to 96% of neonatal disease and 88% of pediatric, adult, and pregnancy-associated disease, which translates to approximately 19,000 cases” of the 21,500 estimated to have occurred in 2005.

“Maternal GBS vaccination trials should be a public health priority, followed by expanded vaccine development to target disease among elderly and younger adults with chronic underlying conditions,” they concluded.

The incidence of invasive group B streptococcal disease declined among infants aged 0–6 days after stricter measures for perinatal prevention were widely adopted across the country in 2002, federal scientists have reported.

However, there was a significant increase in the disease among black infants during this period, a finding that is “particularly concerning and requires investigation,” said Christina R. Phares, Ph.D., of the Centers for Disease Control and Prevention (CDC)and her associates.

The revised guidelines recommended antenatal culture-based screening as the optimal method for identifying candidates for intrapartum chemoprophylaxis.

The CDCinvestigators assessed epidemiologic trends among 14,573 cases of invasive group B streptococcal (GBS) disease identified by a national surveillance program between 1999 and 2005, the most recent year for which data are available.

In 2005, there were an estimated 21,500 cases of invasive GBS in the United States, including 1,700 fatalities (JAMA 2008;299:2056–65).

The overall incidence of invasive GBS disease among adults and children in 2005 was 12.8 per 100,000 population in blacks, 6.5 per 100,000 in whites, and 5.1 per 100,000 in all other races combined.

Mortality also was significantly higher for black neonates and black adults aged 45 years and older than for other racial groups.

Early-onset GBS (before 1 week of age) decreased by 27%, from 0.47 per 1,000 live births before the revised guidelines to 0.34 per 1,000 live births in 2003–2005. This is “very close” to the impact that the stricter guidelines were predicted to have, the researchers said. However, there were small increases in incidence in 2004 and 2005, almost all of which occurred among black infants.

The incidence of late-onset GBS (age 7–89 days) remained stable, averaging 0.34 cases per 1,000 live births throughout the 7-year study. Similarly, the incidence of childhood disease (90 days-14 years) remained stable at 0.56 per 100,000 population, with 61% of these cases occurring in children aged 3–12 months.

In contrast, the incidence increased significantly among adults—by 48% in people aged 15–64 years and by 20% in people aged 65 and older. This might be in part because of the increase in underlying medical conditions such as diabetes in this age group, Dr. Phares and her associates said.

Serotype data suggested that a pentavalent conjugate vaccine potentially could have prevented “up to 96% of neonatal disease and 88% of pediatric, adult, and pregnancy-associated disease, which translates to approximately 19,000 cases” of the 21,500 estimated to have occurred in 2005.

“Maternal GBS vaccination trials should be a public health priority, followed by expanded vaccine development to target disease among elderly and younger adults with chronic underlying conditions,” they concluded.

The incidence of invasive group B streptococcal disease declined among infants aged 0–6 days after stricter measures for perinatal prevention were widely adopted across the country in 2002, federal scientists have reported.

However, there was a significant increase in the disease among black infants during this period, a finding that is “particularly concerning and requires investigation,” said Christina R. Phares, Ph.D., of the Centers for Disease Control and Prevention (CDC)and her associates.

The revised guidelines recommended antenatal culture-based screening as the optimal method for identifying candidates for intrapartum chemoprophylaxis.

The CDCinvestigators assessed epidemiologic trends among 14,573 cases of invasive group B streptococcal (GBS) disease identified by a national surveillance program between 1999 and 2005, the most recent year for which data are available.

In 2005, there were an estimated 21,500 cases of invasive GBS in the United States, including 1,700 fatalities (JAMA 2008;299:2056–65).

The overall incidence of invasive GBS disease among adults and children in 2005 was 12.8 per 100,000 population in blacks, 6.5 per 100,000 in whites, and 5.1 per 100,000 in all other races combined.

Mortality also was significantly higher for black neonates and black adults aged 45 years and older than for other racial groups.

Early-onset GBS (before 1 week of age) decreased by 27%, from 0.47 per 1,000 live births before the revised guidelines to 0.34 per 1,000 live births in 2003–2005. This is “very close” to the impact that the stricter guidelines were predicted to have, the researchers said. However, there were small increases in incidence in 2004 and 2005, almost all of which occurred among black infants.

The incidence of late-onset GBS (age 7–89 days) remained stable, averaging 0.34 cases per 1,000 live births throughout the 7-year study. Similarly, the incidence of childhood disease (90 days-14 years) remained stable at 0.56 per 100,000 population, with 61% of these cases occurring in children aged 3–12 months.

In contrast, the incidence increased significantly among adults—by 48% in people aged 15–64 years and by 20% in people aged 65 and older. This might be in part because of the increase in underlying medical conditions such as diabetes in this age group, Dr. Phares and her associates said.

Serotype data suggested that a pentavalent conjugate vaccine potentially could have prevented “up to 96% of neonatal disease and 88% of pediatric, adult, and pregnancy-associated disease, which translates to approximately 19,000 cases” of the 21,500 estimated to have occurred in 2005.

“Maternal GBS vaccination trials should be a public health priority, followed by expanded vaccine development to target disease among elderly and younger adults with chronic underlying conditions,” they concluded.