Jeff Evans

WASHINGTON — Proper early management of ingrown toenails may help to decrease the risk of recurrence whether or not surgery is necessary, Dr. C. Ralph Daniel III said at the annual meeting of the American Academy of Dermatology.

“An ingrown nail is primarily acting as a foreign-body reaction. That rigid spicule penetrates soft surrounding tissue” and produces swelling, granulation tissue, and sometimes a secondary infection, said Dr. Daniel of the departments of dermatology at the University of Mississippi, Jackson, and the University of Alabama, Birmingham.

For the early management of stage I ingrown toenails in which some granulation tissue but no infection is present, Dr. Daniel said he has trained a nurse to push wisps of cotton gently under the ingrowing nail by using a 2-mm nail elevator or a 1- to 2-mm curette. This procedure can be repeated as often as is needed.

He also uses a technique for early-stage ingrown toenails in which dental floss is inserted under the ingrown nail corner without anesthesia and is kept there to separate the nail edge from adjacent soft tissue (J. Am. Acad. Dermatol. 2004;50:939–40).

Dr. Daniel advises patients to combat the inflammation present in early stages (without infection) by soaking the toe for 10 minutes in 1–2 teaspoons of salt or Epsom salt in a liter of cold water. After drying off the toe, patients apply a mid- to high-potency topical steroid to the nail fold. These steps are repeated three times a day for 7–10 days.

When the cotton, dental floss, and/or toe soak methods are used, he advises patients to apply 30%–40% urea twice daily to soften the nail plate and decrease rigidity and the “splinterlike” effect.

In one procedure, reported as being successful for avoiding surgery, a plastic gutter tube is set under the ingrown part of the nail and acrylic is sculpted and allowed to polymerize around the ingrown part of the nail and hold the gutter tube in place. The tubes are removed after the inflammation has subsided and the nail has grown (Int. J. Dermatol. 2004;43:759–65).

Dr. Daniel said surgery should not be performed on a patient with an ingrown toenail in a more advanced stage until the level of inflammation has been reduced with salt soaks in warm water (not cold, because of the possibility of infection) and topical application of steroids three times a day for about a week. He added that urea is not often used in these cases because it doesn't seem to work as well as it does for early-stage ingrown toenails. In cases of suspected secondary infection, he usually prescribes 500 mg cephalexin (Keflex) four times per day; this prescription may change if the bacterial culture and sensitivity report indicates a different antibiotic may be better.

Before surgery, one should allow for time for anesthesia using a digital block or a distal approach to take effect. Premedication with NSAIDs, codeine, or dextropropoxyphene also may be appropriate, he said.

To cut away the offending section of nail, an English anvil nail splitter is inserted under the nail plate and the cut is made all the way to the proximal nail fold. The hypertrophic, granulated tissue should be cut away as well. Many ingrown toenails are recurrent, so Dr. Daniel performs a chemical matricectomy in nearly all patients after making sure that the surgical field is dry and bloodless.

The proximal nail fold can be flared back to expose more of the proximal matrix if necessary. Dr. Daniel inserts a Calgiswab coated with 88% phenol or 10% sodium hydroxide and applies the chemical for 30 seconds to the portion of the nail matrix that needs to be destroyed. This procedure is repeated three times, each time with a new Calgiswab. The chemical then is rinsed out with saline or alcohol.

An Ellman electrode can be used to electrodesiccate the matrix, followed by curettage. The CO2 laser also has been used to perform a partial matricectomy after removal of the nail spicule and staining of the nail matrix with methylene blue (Dermatol. Surg. 2005;31:302–5).

After surgery, Dr. Daniel applies bacitracin/polymyxin ointment, followed by a Telfa pad, 2-by-2-inch or 4-by-4-inch dressings, tube gauze, and then paper tape, making sure that the dressing is not too tight.

The foot should be elevated as much as possible during the first 24 hours and kept in an orthopedic shoe or old tennis shoe with the toe cut out. After 48 hours, the toe can be soaked in a warm salt bath for 20 minutes. Each soak should be followed with bacitracin/polymyxin ointment and a large adhesive bandage or bulky dressing. These steps are repeated three to four times a day for 1–2 weeks. Some physicians routinely add an oral antibiotic.

Dr. Daniel formerly was on the board of directors for Doak Dermatologics, a subsidiary of Bradley Pharmaceuticals Inc., which manufactures urea-based products for nail care. He holds stock options and has served as a speaker, consultant, and investigator for the company.

Surgery should not be performed on a patient with an ingrown toenail until the inflammation as been curbed. ©Jeff Horn/Fotolia

WASHINGTON — Proper early management of ingrown toenails may help to decrease the risk of recurrence whether or not surgery is necessary, Dr. C. Ralph Daniel III said at the annual meeting of the American Academy of Dermatology.

“An ingrown nail is primarily acting as a foreign-body reaction. That rigid spicule penetrates soft surrounding tissue” and produces swelling, granulation tissue, and sometimes a secondary infection, said Dr. Daniel of the departments of dermatology at the University of Mississippi, Jackson, and the University of Alabama, Birmingham.

For the early management of stage I ingrown toenails in which some granulation tissue but no infection is present, Dr. Daniel said he has trained a nurse to push wisps of cotton gently under the ingrowing nail by using a 2-mm nail elevator or a 1- to 2-mm curette. This procedure can be repeated as often as is needed.

He also uses a technique for early-stage ingrown toenails in which dental floss is inserted under the ingrown nail corner without anesthesia and is kept there to separate the nail edge from adjacent soft tissue (J. Am. Acad. Dermatol. 2004;50:939–40).

Dr. Daniel advises patients to combat the inflammation present in early stages (without infection) by soaking the toe for 10 minutes in 1–2 teaspoons of salt or Epsom salt in a liter of cold water. After drying off the toe, patients apply a mid- to high-potency topical steroid to the nail fold. These steps are repeated three times a day for 7–10 days.

When the cotton, dental floss, and/or toe soak methods are used, he advises patients to apply 30%–40% urea twice daily to soften the nail plate and decrease rigidity and the “splinterlike” effect.

In one procedure, reported as being successful for avoiding surgery, a plastic gutter tube is set under the ingrown part of the nail and acrylic is sculpted and allowed to polymerize around the ingrown part of the nail and hold the gutter tube in place. The tubes are removed after the inflammation has subsided and the nail has grown (Int. J. Dermatol. 2004;43:759–65).

Dr. Daniel said surgery should not be performed on a patient with an ingrown toenail in a more advanced stage until the level of inflammation has been reduced with salt soaks in warm water (not cold, because of the possibility of infection) and topical application of steroids three times a day for about a week. He added that urea is not often used in these cases because it doesn't seem to work as well as it does for early-stage ingrown toenails. In cases of suspected secondary infection, he usually prescribes 500 mg cephalexin (Keflex) four times per day; this prescription may change if the bacterial culture and sensitivity report indicates a different antibiotic may be better.

Before surgery, one should allow for time for anesthesia using a digital block or a distal approach to take effect. Premedication with NSAIDs, codeine, or dextropropoxyphene also may be appropriate, he said.

To cut away the offending section of nail, an English anvil nail splitter is inserted under the nail plate and the cut is made all the way to the proximal nail fold. The hypertrophic, granulated tissue should be cut away as well. Many ingrown toenails are recurrent, so Dr. Daniel performs a chemical matricectomy in nearly all patients after making sure that the surgical field is dry and bloodless.

The proximal nail fold can be flared back to expose more of the proximal matrix if necessary. Dr. Daniel inserts a Calgiswab coated with 88% phenol or 10% sodium hydroxide and applies the chemical for 30 seconds to the portion of the nail matrix that needs to be destroyed. This procedure is repeated three times, each time with a new Calgiswab. The chemical then is rinsed out with saline or alcohol.

An Ellman electrode can be used to electrodesiccate the matrix, followed by curettage. The CO2 laser also has been used to perform a partial matricectomy after removal of the nail spicule and staining of the nail matrix with methylene blue (Dermatol. Surg. 2005;31:302–5).

After surgery, Dr. Daniel applies bacitracin/polymyxin ointment, followed by a Telfa pad, 2-by-2-inch or 4-by-4-inch dressings, tube gauze, and then paper tape, making sure that the dressing is not too tight.

The foot should be elevated as much as possible during the first 24 hours and kept in an orthopedic shoe or old tennis shoe with the toe cut out. After 48 hours, the toe can be soaked in a warm salt bath for 20 minutes. Each soak should be followed with bacitracin/polymyxin ointment and a large adhesive bandage or bulky dressing. These steps are repeated three to four times a day for 1–2 weeks. Some physicians routinely add an oral antibiotic.

Dr. Daniel formerly was on the board of directors for Doak Dermatologics, a subsidiary of Bradley Pharmaceuticals Inc., which manufactures urea-based products for nail care. He holds stock options and has served as a speaker, consultant, and investigator for the company.

Surgery should not be performed on a patient with an ingrown toenail until the inflammation as been curbed. ©Jeff Horn/Fotolia

WASHINGTON — Proper early management of ingrown toenails may help to decrease the risk of recurrence whether or not surgery is necessary, Dr. C. Ralph Daniel III said at the annual meeting of the American Academy of Dermatology.

“An ingrown nail is primarily acting as a foreign-body reaction. That rigid spicule penetrates soft surrounding tissue” and produces swelling, granulation tissue, and sometimes a secondary infection, said Dr. Daniel of the departments of dermatology at the University of Mississippi, Jackson, and the University of Alabama, Birmingham.

For the early management of stage I ingrown toenails in which some granulation tissue but no infection is present, Dr. Daniel said he has trained a nurse to push wisps of cotton gently under the ingrowing nail by using a 2-mm nail elevator or a 1- to 2-mm curette. This procedure can be repeated as often as is needed.

He also uses a technique for early-stage ingrown toenails in which dental floss is inserted under the ingrown nail corner without anesthesia and is kept there to separate the nail edge from adjacent soft tissue (J. Am. Acad. Dermatol. 2004;50:939–40).

Dr. Daniel advises patients to combat the inflammation present in early stages (without infection) by soaking the toe for 10 minutes in 1–2 teaspoons of salt or Epsom salt in a liter of cold water. After drying off the toe, patients apply a mid- to high-potency topical steroid to the nail fold. These steps are repeated three times a day for 7–10 days.

When the cotton, dental floss, and/or toe soak methods are used, he advises patients to apply 30%–40% urea twice daily to soften the nail plate and decrease rigidity and the “splinterlike” effect.

In one procedure, reported as being successful for avoiding surgery, a plastic gutter tube is set under the ingrown part of the nail and acrylic is sculpted and allowed to polymerize around the ingrown part of the nail and hold the gutter tube in place. The tubes are removed after the inflammation has subsided and the nail has grown (Int. J. Dermatol. 2004;43:759–65).

Dr. Daniel said surgery should not be performed on a patient with an ingrown toenail in a more advanced stage until the level of inflammation has been reduced with salt soaks in warm water (not cold, because of the possibility of infection) and topical application of steroids three times a day for about a week. He added that urea is not often used in these cases because it doesn't seem to work as well as it does for early-stage ingrown toenails. In cases of suspected secondary infection, he usually prescribes 500 mg cephalexin (Keflex) four times per day; this prescription may change if the bacterial culture and sensitivity report indicates a different antibiotic may be better.

Before surgery, one should allow for time for anesthesia using a digital block or a distal approach to take effect. Premedication with NSAIDs, codeine, or dextropropoxyphene also may be appropriate, he said.

To cut away the offending section of nail, an English anvil nail splitter is inserted under the nail plate and the cut is made all the way to the proximal nail fold. The hypertrophic, granulated tissue should be cut away as well. Many ingrown toenails are recurrent, so Dr. Daniel performs a chemical matricectomy in nearly all patients after making sure that the surgical field is dry and bloodless.

The proximal nail fold can be flared back to expose more of the proximal matrix if necessary. Dr. Daniel inserts a Calgiswab coated with 88% phenol or 10% sodium hydroxide and applies the chemical for 30 seconds to the portion of the nail matrix that needs to be destroyed. This procedure is repeated three times, each time with a new Calgiswab. The chemical then is rinsed out with saline or alcohol.

An Ellman electrode can be used to electrodesiccate the matrix, followed by curettage. The CO2 laser also has been used to perform a partial matricectomy after removal of the nail spicule and staining of the nail matrix with methylene blue (Dermatol. Surg. 2005;31:302–5).

After surgery, Dr. Daniel applies bacitracin/polymyxin ointment, followed by a Telfa pad, 2-by-2-inch or 4-by-4-inch dressings, tube gauze, and then paper tape, making sure that the dressing is not too tight.

The foot should be elevated as much as possible during the first 24 hours and kept in an orthopedic shoe or old tennis shoe with the toe cut out. After 48 hours, the toe can be soaked in a warm salt bath for 20 minutes. Each soak should be followed with bacitracin/polymyxin ointment and a large adhesive bandage or bulky dressing. These steps are repeated three to four times a day for 1–2 weeks. Some physicians routinely add an oral antibiotic.

Dr. Daniel formerly was on the board of directors for Doak Dermatologics, a subsidiary of Bradley Pharmaceuticals Inc., which manufactures urea-based products for nail care. He holds stock options and has served as a speaker, consultant, and investigator for the company.

Surgery should not be performed on a patient with an ingrown toenail until the inflammation as been curbed. ©Jeff Horn/Fotolia

WASHINGTON — Caffeine intake appears to exaggerate postmeal insulin resistance in prediabetic adults who regularly drink several cups of coffee each day, according to preliminary results of a randomized, double-blind, crossover study of 50 individuals.

The results “suggest that caffeine consumption promotes the development of type 2 diabetes in those people who are at greatest risk for this disease,” James D. Lane, Ph.D., said at the annual meeting of the Society of Behavioral Medicine.

This is the first time that caffeine's effects on insulin resistance have been measured in habitual coffee drinkers with prediabetes, said Dr. Lane of the department of psychiatry and behavioral medicine at Duke University, Durham, N.C. More than 12 other studies have shown that caffeine administration acutely raises insulin resistance both in healthy, nondiabetic volunteers and in patients with type 2 diabetes.

Other studies have shown that coffee drinking is associated with a significantly reduced risk of type 2 diabetes, but these conclusions have been “based on correlational observations, not controlled, experimental studies,” he noted.

In the current study, all participants had prediabetes (average impaired fasting blood glucose level of 111 mg/dL) and drank at least 2 cups of coffee per day, which was confirmed by a 7-day food diary. Each person fasted overnight and did not consume any caffeine, which preserved any tolerance that they had developed from their continued exposure to caffeine.

On the first day of testing, the participants received either 250 mg caffeine or placebo pills and had their fasting blood glucose levels measured. On the second day, they received the opposite of what they had taken on day 1. After 60 minutes, they had their blood glucose levels measured again, and they received a booster dose of 125 mg caffeine or placebo. They also drank a BoostPlus liquid meal replacement shake (75 g carbohydrates, plus fat and protein), which is similar to an oral glucose tolerance test except that it is more like a real meal, Dr. Lane said. Blood samples were drawn during each of the next 3 hours.

The total 375-mg dose of caffeine was equivalent to about 3 cups of brewed coffee, similar to what subjects consumed on average each day (409 mg).

For the first 41 participants with full results available, caffeine increased the 3-hour area under the curve (AUC) for plasma glucose by 15% more than placebo, though the result was not statistically significant. But the 3-hour AUC for plasma insulin was 18% greater with caffeine than with placebo—a significant difference. AUC is the standard method for measuring responses to oral glucose tolerance tests, said Dr. Lane. “This pattern of results shows that caffeine did increase insulin resistance in these prediabetic subjects.”

A normal response to the extra insulin produced with caffeine would have been to reduce the peak glucose level to a point lower than what was seen with placebo. But “the glucose response was, if anything, a little larger in the caffeine condition,” he said. “Given the conditions of our study, we think that this insulin resistance effect occurs every day as these prediabetic individuals and others like them consume caffeinated beverages in the real world.”

If the results can be replicated in a larger, long-term prospective study, it would suggest that people who have prediabetes should curtail caffeine consumption to reduce their risk, Dr. Lane said.

WASHINGTON — Caffeine intake appears to exaggerate postmeal insulin resistance in prediabetic adults who regularly drink several cups of coffee each day, according to preliminary results of a randomized, double-blind, crossover study of 50 individuals.

The results “suggest that caffeine consumption promotes the development of type 2 diabetes in those people who are at greatest risk for this disease,” James D. Lane, Ph.D., said at the annual meeting of the Society of Behavioral Medicine.

This is the first time that caffeine's effects on insulin resistance have been measured in habitual coffee drinkers with prediabetes, said Dr. Lane of the department of psychiatry and behavioral medicine at Duke University, Durham, N.C. More than 12 other studies have shown that caffeine administration acutely raises insulin resistance both in healthy, nondiabetic volunteers and in patients with type 2 diabetes.

Other studies have shown that coffee drinking is associated with a significantly reduced risk of type 2 diabetes, but these conclusions have been “based on correlational observations, not controlled, experimental studies,” he noted.

In the current study, all participants had prediabetes (average impaired fasting blood glucose level of 111 mg/dL) and drank at least 2 cups of coffee per day, which was confirmed by a 7-day food diary. Each person fasted overnight and did not consume any caffeine, which preserved any tolerance that they had developed from their continued exposure to caffeine.

On the first day of testing, the participants received either 250 mg caffeine or placebo pills and had their fasting blood glucose levels measured. On the second day, they received the opposite of what they had taken on day 1. After 60 minutes, they had their blood glucose levels measured again, and they received a booster dose of 125 mg caffeine or placebo. They also drank a BoostPlus liquid meal replacement shake (75 g carbohydrates, plus fat and protein), which is similar to an oral glucose tolerance test except that it is more like a real meal, Dr. Lane said. Blood samples were drawn during each of the next 3 hours.

The total 375-mg dose of caffeine was equivalent to about 3 cups of brewed coffee, similar to what subjects consumed on average each day (409 mg).

For the first 41 participants with full results available, caffeine increased the 3-hour area under the curve (AUC) for plasma glucose by 15% more than placebo, though the result was not statistically significant. But the 3-hour AUC for plasma insulin was 18% greater with caffeine than with placebo—a significant difference. AUC is the standard method for measuring responses to oral glucose tolerance tests, said Dr. Lane. “This pattern of results shows that caffeine did increase insulin resistance in these prediabetic subjects.”

A normal response to the extra insulin produced with caffeine would have been to reduce the peak glucose level to a point lower than what was seen with placebo. But “the glucose response was, if anything, a little larger in the caffeine condition,” he said. “Given the conditions of our study, we think that this insulin resistance effect occurs every day as these prediabetic individuals and others like them consume caffeinated beverages in the real world.”

If the results can be replicated in a larger, long-term prospective study, it would suggest that people who have prediabetes should curtail caffeine consumption to reduce their risk, Dr. Lane said.

WASHINGTON — Caffeine intake appears to exaggerate postmeal insulin resistance in prediabetic adults who regularly drink several cups of coffee each day, according to preliminary results of a randomized, double-blind, crossover study of 50 individuals.

The results “suggest that caffeine consumption promotes the development of type 2 diabetes in those people who are at greatest risk for this disease,” James D. Lane, Ph.D., said at the annual meeting of the Society of Behavioral Medicine.

This is the first time that caffeine's effects on insulin resistance have been measured in habitual coffee drinkers with prediabetes, said Dr. Lane of the department of psychiatry and behavioral medicine at Duke University, Durham, N.C. More than 12 other studies have shown that caffeine administration acutely raises insulin resistance both in healthy, nondiabetic volunteers and in patients with type 2 diabetes.

Other studies have shown that coffee drinking is associated with a significantly reduced risk of type 2 diabetes, but these conclusions have been “based on correlational observations, not controlled, experimental studies,” he noted.

In the current study, all participants had prediabetes (average impaired fasting blood glucose level of 111 mg/dL) and drank at least 2 cups of coffee per day, which was confirmed by a 7-day food diary. Each person fasted overnight and did not consume any caffeine, which preserved any tolerance that they had developed from their continued exposure to caffeine.

On the first day of testing, the participants received either 250 mg caffeine or placebo pills and had their fasting blood glucose levels measured. On the second day, they received the opposite of what they had taken on day 1. After 60 minutes, they had their blood glucose levels measured again, and they received a booster dose of 125 mg caffeine or placebo. They also drank a BoostPlus liquid meal replacement shake (75 g carbohydrates, plus fat and protein), which is similar to an oral glucose tolerance test except that it is more like a real meal, Dr. Lane said. Blood samples were drawn during each of the next 3 hours.

The total 375-mg dose of caffeine was equivalent to about 3 cups of brewed coffee, similar to what subjects consumed on average each day (409 mg).

For the first 41 participants with full results available, caffeine increased the 3-hour area under the curve (AUC) for plasma glucose by 15% more than placebo, though the result was not statistically significant. But the 3-hour AUC for plasma insulin was 18% greater with caffeine than with placebo—a significant difference. AUC is the standard method for measuring responses to oral glucose tolerance tests, said Dr. Lane. “This pattern of results shows that caffeine did increase insulin resistance in these prediabetic subjects.”

A normal response to the extra insulin produced with caffeine would have been to reduce the peak glucose level to a point lower than what was seen with placebo. But “the glucose response was, if anything, a little larger in the caffeine condition,” he said. “Given the conditions of our study, we think that this insulin resistance effect occurs every day as these prediabetic individuals and others like them consume caffeinated beverages in the real world.”

If the results can be replicated in a larger, long-term prospective study, it would suggest that people who have prediabetes should curtail caffeine consumption to reduce their risk, Dr. Lane said.

Genetic variants of a protein involved in determining the fate of amyloid precursor protein are associated with an increased risk of developing Alzheimer's disease, reported Dr. Ekaterina Rogaeva of the University of Toronto and her associates.

The increased risk for the disease appears to be caused by certain haplotypes of the SORL1 gene that decrease the expression of the gene. As a result, more amyloid precursor protein follows a pathway in which excess amyloid-β peptide is produced in the brain–one of the central events in the pathogenesis of Alzheimer's disease (AD), according to the investigators.

Dr. Samuel E. Gandy, director of the Farber Institute for Neurosciences at Thomas Jefferson University, Philadelphia, said the study's results “fit well into the amyloid model for Alzheimer's, and that's certainly the one that's getting the most attention and most assessment clinically.”

Dr. Rogaeva and her colleagues found that several overlapping haplotypes in two different regions of the SORL1 gene increased the likelihood of developing late-onset familial Alzheimer's disease (FAD), based on results obtained from two cohorts of families with late-onset FAD and later replicated in a cohort of cases and controls in other studies.

“Taken together, our results suggest that genetic and possibly environmentally specified changes in SORL1 [protein] expression or function are causally linked to the pathogenesis [of Alzheimer's disease] and have a modest effect on risk for this disease,” the researchers said (Nat. Genet. 2007 Jan. 14 [Epub doi:10.1038/ng1943]).

The initial “discovery cohort” comprised 124 northern European FAD families and 228 Caribbean Hispanic FAD families. The “replication cohort” consisted of northern European individuals from a case-control study (178 cases with sporadic AD and 242 controls with self-identified white European ancestry), 276 white sibships from the Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE) study, 238 African American sibships from the MIRAGE study, and Israeli Arab individuals (111 with AD and 114 normal controls from the Wadi Ara population study).

The researchers confirmed the association between AD and the SORL1 gene by genotyping the single-nucleotide polymorphisms that were contained in the haplotypes and then analyzing them at an independent facility in three series of cases and controls of European ancestry from different Mayo Clinic centers (totaling 1,405 late-onset AD cases and 2,124 controls).

In genetic studies, particularly those involving Alzheimer's disease, there has “been an issue of one group making a report and then a number of other groups being unable to replicate [the results] across different ethnic groups,” Dr. Gandy said in an interview. “The good thing about this paper is that they've already tested several totally independent ethnic groups, so you can feel a bit more confident that this is true.”

SORL1 protein directly binds amyloid precursor protein and differentially regulates whether it sorts into a recycling pathway or into a pathway that generates amyloid-β. Experiments that suppressed SORL1 protein expression–mimicking what is speculated to be the effects of AD-associated variants in the SORL1 gene–led to an overproduction of amyloid-β.

The actual disease-causing variants of the SORL1 gene are unlikely to be the single-nucleotide polymorphisms and haplotypes that were identified in the SORL1 gene's exons, the researchers noted. Instead, the pathogenic variants are likely located in sequences in the introns of the SORL1 gene and may “modulate the cell type-specific transcription or translation of the SORL1 gene in carriers of the Alzheimer's disease-associated haplotypes,” the investigators said.

One of the disease-associated haplotypes of the SORL1 gene was expressed in AD haplotype carriers at less than half the levels of carriers of nondisease haplotypes. But univariate regression analyses showed that the disease variants of the SORL1 gene accounted for about only 14% of the variance in the SORL1 protein expression that was seen in those individuals.

“This latter result implies that other genetic and nongenetic factors can also modulate SORL1 [protein] expression and, perhaps, therefore, risk for Alzheimer's disease,” the researchers said.

Although variants of the SORL1 gene may not raise the risk of AD as much as the apo E ϵ4 allele, Dr. Gandy noted that the results point out a new target for drug therapy that can raise SORL1 protein levels.

“We never know when we're going to encounter side effects, so it's good to have multiple possible targets,” he said.

Genetic variants of a protein involved in determining the fate of amyloid precursor protein are associated with an increased risk of developing Alzheimer's disease, reported Dr. Ekaterina Rogaeva of the University of Toronto and her associates.

The increased risk for the disease appears to be caused by certain haplotypes of the SORL1 gene that decrease the expression of the gene. As a result, more amyloid precursor protein follows a pathway in which excess amyloid-β peptide is produced in the brain–one of the central events in the pathogenesis of Alzheimer's disease (AD), according to the investigators.

Dr. Samuel E. Gandy, director of the Farber Institute for Neurosciences at Thomas Jefferson University, Philadelphia, said the study's results “fit well into the amyloid model for Alzheimer's, and that's certainly the one that's getting the most attention and most assessment clinically.”

Dr. Rogaeva and her colleagues found that several overlapping haplotypes in two different regions of the SORL1 gene increased the likelihood of developing late-onset familial Alzheimer's disease (FAD), based on results obtained from two cohorts of families with late-onset FAD and later replicated in a cohort of cases and controls in other studies.

“Taken together, our results suggest that genetic and possibly environmentally specified changes in SORL1 [protein] expression or function are causally linked to the pathogenesis [of Alzheimer's disease] and have a modest effect on risk for this disease,” the researchers said (Nat. Genet. 2007 Jan. 14 [Epub doi:10.1038/ng1943]).

The initial “discovery cohort” comprised 124 northern European FAD families and 228 Caribbean Hispanic FAD families. The “replication cohort” consisted of northern European individuals from a case-control study (178 cases with sporadic AD and 242 controls with self-identified white European ancestry), 276 white sibships from the Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE) study, 238 African American sibships from the MIRAGE study, and Israeli Arab individuals (111 with AD and 114 normal controls from the Wadi Ara population study).

The researchers confirmed the association between AD and the SORL1 gene by genotyping the single-nucleotide polymorphisms that were contained in the haplotypes and then analyzing them at an independent facility in three series of cases and controls of European ancestry from different Mayo Clinic centers (totaling 1,405 late-onset AD cases and 2,124 controls).

In genetic studies, particularly those involving Alzheimer's disease, there has “been an issue of one group making a report and then a number of other groups being unable to replicate [the results] across different ethnic groups,” Dr. Gandy said in an interview. “The good thing about this paper is that they've already tested several totally independent ethnic groups, so you can feel a bit more confident that this is true.”

SORL1 protein directly binds amyloid precursor protein and differentially regulates whether it sorts into a recycling pathway or into a pathway that generates amyloid-β. Experiments that suppressed SORL1 protein expression–mimicking what is speculated to be the effects of AD-associated variants in the SORL1 gene–led to an overproduction of amyloid-β.

The actual disease-causing variants of the SORL1 gene are unlikely to be the single-nucleotide polymorphisms and haplotypes that were identified in the SORL1 gene's exons, the researchers noted. Instead, the pathogenic variants are likely located in sequences in the introns of the SORL1 gene and may “modulate the cell type-specific transcription or translation of the SORL1 gene in carriers of the Alzheimer's disease-associated haplotypes,” the investigators said.

One of the disease-associated haplotypes of the SORL1 gene was expressed in AD haplotype carriers at less than half the levels of carriers of nondisease haplotypes. But univariate regression analyses showed that the disease variants of the SORL1 gene accounted for about only 14% of the variance in the SORL1 protein expression that was seen in those individuals.

“This latter result implies that other genetic and nongenetic factors can also modulate SORL1 [protein] expression and, perhaps, therefore, risk for Alzheimer's disease,” the researchers said.

Although variants of the SORL1 gene may not raise the risk of AD as much as the apo E ϵ4 allele, Dr. Gandy noted that the results point out a new target for drug therapy that can raise SORL1 protein levels.

“We never know when we're going to encounter side effects, so it's good to have multiple possible targets,” he said.

Genetic variants of a protein involved in determining the fate of amyloid precursor protein are associated with an increased risk of developing Alzheimer's disease, reported Dr. Ekaterina Rogaeva of the University of Toronto and her associates.

The increased risk for the disease appears to be caused by certain haplotypes of the SORL1 gene that decrease the expression of the gene. As a result, more amyloid precursor protein follows a pathway in which excess amyloid-β peptide is produced in the brain–one of the central events in the pathogenesis of Alzheimer's disease (AD), according to the investigators.

Dr. Samuel E. Gandy, director of the Farber Institute for Neurosciences at Thomas Jefferson University, Philadelphia, said the study's results “fit well into the amyloid model for Alzheimer's, and that's certainly the one that's getting the most attention and most assessment clinically.”

Dr. Rogaeva and her colleagues found that several overlapping haplotypes in two different regions of the SORL1 gene increased the likelihood of developing late-onset familial Alzheimer's disease (FAD), based on results obtained from two cohorts of families with late-onset FAD and later replicated in a cohort of cases and controls in other studies.

“Taken together, our results suggest that genetic and possibly environmentally specified changes in SORL1 [protein] expression or function are causally linked to the pathogenesis [of Alzheimer's disease] and have a modest effect on risk for this disease,” the researchers said (Nat. Genet. 2007 Jan. 14 [Epub doi:10.1038/ng1943]).

The initial “discovery cohort” comprised 124 northern European FAD families and 228 Caribbean Hispanic FAD families. The “replication cohort” consisted of northern European individuals from a case-control study (178 cases with sporadic AD and 242 controls with self-identified white European ancestry), 276 white sibships from the Multi-Institutional Research in Alzheimer's Genetic Epidemiology (MIRAGE) study, 238 African American sibships from the MIRAGE study, and Israeli Arab individuals (111 with AD and 114 normal controls from the Wadi Ara population study).

The researchers confirmed the association between AD and the SORL1 gene by genotyping the single-nucleotide polymorphisms that were contained in the haplotypes and then analyzing them at an independent facility in three series of cases and controls of European ancestry from different Mayo Clinic centers (totaling 1,405 late-onset AD cases and 2,124 controls).

In genetic studies, particularly those involving Alzheimer's disease, there has “been an issue of one group making a report and then a number of other groups being unable to replicate [the results] across different ethnic groups,” Dr. Gandy said in an interview. “The good thing about this paper is that they've already tested several totally independent ethnic groups, so you can feel a bit more confident that this is true.”

SORL1 protein directly binds amyloid precursor protein and differentially regulates whether it sorts into a recycling pathway or into a pathway that generates amyloid-β. Experiments that suppressed SORL1 protein expression–mimicking what is speculated to be the effects of AD-associated variants in the SORL1 gene–led to an overproduction of amyloid-β.

The actual disease-causing variants of the SORL1 gene are unlikely to be the single-nucleotide polymorphisms and haplotypes that were identified in the SORL1 gene's exons, the researchers noted. Instead, the pathogenic variants are likely located in sequences in the introns of the SORL1 gene and may “modulate the cell type-specific transcription or translation of the SORL1 gene in carriers of the Alzheimer's disease-associated haplotypes,” the investigators said.

One of the disease-associated haplotypes of the SORL1 gene was expressed in AD haplotype carriers at less than half the levels of carriers of nondisease haplotypes. But univariate regression analyses showed that the disease variants of the SORL1 gene accounted for about only 14% of the variance in the SORL1 protein expression that was seen in those individuals.

“This latter result implies that other genetic and nongenetic factors can also modulate SORL1 [protein] expression and, perhaps, therefore, risk for Alzheimer's disease,” the researchers said.

Although variants of the SORL1 gene may not raise the risk of AD as much as the apo E ϵ4 allele, Dr. Gandy noted that the results point out a new target for drug therapy that can raise SORL1 protein levels.

“We never know when we're going to encounter side effects, so it's good to have multiple possible targets,” he said.

ARLINGTON, VA. — People who take sufficiently high supplement doses of vitamin D or those who already have adequate levels of vitamin D were found to have a small but significantly reduced risk of specific fractures, falls, and low bone mineral density, according to an Agency for Healthcare Research and Quality report on the effect of vitamin D supplements on bone health outcomes.

Dr. Ann B. Cranney and her associates at the University of Ottawa Evidence-Based Practice Center extensively reviewed the literature regarding the effects of 25-hydroxyvitamin D (25[OH]D) concentration or vitamin D supplementation. She presented the results of meta-analyses based on studies that met eligibility criteria at a conference sponsored by the American Society for Bone and Mineral Research.

It was not possible to quantitatively summarize the results of 10 randomized controlled clinical trials or 31 observational studies that examined the effect of 25(OH)D levels on bone health outcomes in postmenopausal women and older men, so Dr. Cranney and her colleagues categorized the evidence supporting the effect of the vitamin D metabolite as good, fair, or inconsistent. For serum 25(OH)D levels of at least 50–80 nmol/L, there was good evidence of an association with increased bone mineral density in the hip, fair evidence of an inverse association with the risk of hip fracture, and inconsistent evidence of an association with a reduction in falls and functional measures such as grip strength and body sway.

In 74 randomized controlled trials of supplementation with either vitamin D₃ or vitamin D₂, the investigators found that 25(OH)D levels increased more with supplementation with vitamin D₃ than with vitamin D₂. Data collected from 16 randomized controlled trials provided enough information on 25(OH)D levels in both the control group and treatment group at baseline as well as at the end of the study to enable the investigators to determine that supplementation with 700 IU/day or more of vitamin D₃ was associated with a drop in serum parathyroid hormone levels. The investigators also calculated from the clinical trial results that 1 IU vitamin D₃ raises the serum 25(OH)D concentration by 0.016 nmol/L.

Clinical trials that used supplements with either vitamin D₃ or vitamin D₂ did not show a significant effect on reducing the risk of fractures overall or on the risk of hip fractures in particular. Also, supplementation with vitamin D plus calcium or vitamin D alone did not have a significant effect on the risk of nonvertebral fractures. But in eight clinical trials, vitamin D₃ supplements of 700 IU/day or more significantly reduced the risk of nonvertebral fractures by 15%.

This risk reduction was driven primarily by two clinical trials that involved individuals in an institutional setting, who had a 22% reduction in the risk of nonvertebral fractures. Supplements of 700 IU/day or more vitamin D₃ also significantly lowered the risk of hip fractures; clinical trials in an institutional setting, rather than in the community, factored strongly in the overall results, Dr. Cranney noted.

The investigators found that participants in trials of vitamin D₃ supplementation that recorded serum 25(OH)D concentrations of 74 nmol/L or higher had a significant 23% lower risk of nonvertebral fractures than did participants of trials that did not achieve a 25(OH)D level of 74 nmol/L.

Vitamin D supplements did not reduce the risk of falls overall in 12 clinical trials. But vitamin D supplements did significantly lower the risk of a fall by 11% in six clinical trials in which falls were defined or independently ascertained, Dr. Cranney said.

The Agency for Healthcare Research and Quality requested the report on behalf of the National Institutes of Health Office of Dietary Supplements.

ARLINGTON, VA. — People who take sufficiently high supplement doses of vitamin D or those who already have adequate levels of vitamin D were found to have a small but significantly reduced risk of specific fractures, falls, and low bone mineral density, according to an Agency for Healthcare Research and Quality report on the effect of vitamin D supplements on bone health outcomes.

Dr. Ann B. Cranney and her associates at the University of Ottawa Evidence-Based Practice Center extensively reviewed the literature regarding the effects of 25-hydroxyvitamin D (25[OH]D) concentration or vitamin D supplementation. She presented the results of meta-analyses based on studies that met eligibility criteria at a conference sponsored by the American Society for Bone and Mineral Research.

It was not possible to quantitatively summarize the results of 10 randomized controlled clinical trials or 31 observational studies that examined the effect of 25(OH)D levels on bone health outcomes in postmenopausal women and older men, so Dr. Cranney and her colleagues categorized the evidence supporting the effect of the vitamin D metabolite as good, fair, or inconsistent. For serum 25(OH)D levels of at least 50–80 nmol/L, there was good evidence of an association with increased bone mineral density in the hip, fair evidence of an inverse association with the risk of hip fracture, and inconsistent evidence of an association with a reduction in falls and functional measures such as grip strength and body sway.

In 74 randomized controlled trials of supplementation with either vitamin D₃ or vitamin D₂, the investigators found that 25(OH)D levels increased more with supplementation with vitamin D₃ than with vitamin D₂. Data collected from 16 randomized controlled trials provided enough information on 25(OH)D levels in both the control group and treatment group at baseline as well as at the end of the study to enable the investigators to determine that supplementation with 700 IU/day or more of vitamin D₃ was associated with a drop in serum parathyroid hormone levels. The investigators also calculated from the clinical trial results that 1 IU vitamin D₃ raises the serum 25(OH)D concentration by 0.016 nmol/L.

Clinical trials that used supplements with either vitamin D₃ or vitamin D₂ did not show a significant effect on reducing the risk of fractures overall or on the risk of hip fractures in particular. Also, supplementation with vitamin D plus calcium or vitamin D alone did not have a significant effect on the risk of nonvertebral fractures. But in eight clinical trials, vitamin D₃ supplements of 700 IU/day or more significantly reduced the risk of nonvertebral fractures by 15%.

This risk reduction was driven primarily by two clinical trials that involved individuals in an institutional setting, who had a 22% reduction in the risk of nonvertebral fractures. Supplements of 700 IU/day or more vitamin D₃ also significantly lowered the risk of hip fractures; clinical trials in an institutional setting, rather than in the community, factored strongly in the overall results, Dr. Cranney noted.

The investigators found that participants in trials of vitamin D₃ supplementation that recorded serum 25(OH)D concentrations of 74 nmol/L or higher had a significant 23% lower risk of nonvertebral fractures than did participants of trials that did not achieve a 25(OH)D level of 74 nmol/L.

Vitamin D supplements did not reduce the risk of falls overall in 12 clinical trials. But vitamin D supplements did significantly lower the risk of a fall by 11% in six clinical trials in which falls were defined or independently ascertained, Dr. Cranney said.

The Agency for Healthcare Research and Quality requested the report on behalf of the National Institutes of Health Office of Dietary Supplements.

ARLINGTON, VA. — People who take sufficiently high supplement doses of vitamin D or those who already have adequate levels of vitamin D were found to have a small but significantly reduced risk of specific fractures, falls, and low bone mineral density, according to an Agency for Healthcare Research and Quality report on the effect of vitamin D supplements on bone health outcomes.

Dr. Ann B. Cranney and her associates at the University of Ottawa Evidence-Based Practice Center extensively reviewed the literature regarding the effects of 25-hydroxyvitamin D (25[OH]D) concentration or vitamin D supplementation. She presented the results of meta-analyses based on studies that met eligibility criteria at a conference sponsored by the American Society for Bone and Mineral Research.

It was not possible to quantitatively summarize the results of 10 randomized controlled clinical trials or 31 observational studies that examined the effect of 25(OH)D levels on bone health outcomes in postmenopausal women and older men, so Dr. Cranney and her colleagues categorized the evidence supporting the effect of the vitamin D metabolite as good, fair, or inconsistent. For serum 25(OH)D levels of at least 50–80 nmol/L, there was good evidence of an association with increased bone mineral density in the hip, fair evidence of an inverse association with the risk of hip fracture, and inconsistent evidence of an association with a reduction in falls and functional measures such as grip strength and body sway.

In 74 randomized controlled trials of supplementation with either vitamin D₃ or vitamin D₂, the investigators found that 25(OH)D levels increased more with supplementation with vitamin D₃ than with vitamin D₂. Data collected from 16 randomized controlled trials provided enough information on 25(OH)D levels in both the control group and treatment group at baseline as well as at the end of the study to enable the investigators to determine that supplementation with 700 IU/day or more of vitamin D₃ was associated with a drop in serum parathyroid hormone levels. The investigators also calculated from the clinical trial results that 1 IU vitamin D₃ raises the serum 25(OH)D concentration by 0.016 nmol/L.

Clinical trials that used supplements with either vitamin D₃ or vitamin D₂ did not show a significant effect on reducing the risk of fractures overall or on the risk of hip fractures in particular. Also, supplementation with vitamin D plus calcium or vitamin D alone did not have a significant effect on the risk of nonvertebral fractures. But in eight clinical trials, vitamin D₃ supplements of 700 IU/day or more significantly reduced the risk of nonvertebral fractures by 15%.

This risk reduction was driven primarily by two clinical trials that involved individuals in an institutional setting, who had a 22% reduction in the risk of nonvertebral fractures. Supplements of 700 IU/day or more vitamin D₃ also significantly lowered the risk of hip fractures; clinical trials in an institutional setting, rather than in the community, factored strongly in the overall results, Dr. Cranney noted.

The investigators found that participants in trials of vitamin D₃ supplementation that recorded serum 25(OH)D concentrations of 74 nmol/L or higher had a significant 23% lower risk of nonvertebral fractures than did participants of trials that did not achieve a 25(OH)D level of 74 nmol/L.

Vitamin D supplements did not reduce the risk of falls overall in 12 clinical trials. But vitamin D supplements did significantly lower the risk of a fall by 11% in six clinical trials in which falls were defined or independently ascertained, Dr. Cranney said.

The Agency for Healthcare Research and Quality requested the report on behalf of the National Institutes of Health Office of Dietary Supplements.

WASHINGTON — Bleeding during or after superficial cutaneous surgery may provoke more worry from both patients and their clinicians, but thrombotic events actually have greater consequences and are harder to detect, Dr. Clark C. Otley said at the annual meeting of the American Academy of Dermatology.

Bleeding "almost never causes a permanent disability," but a thrombotic complication that occurs after stopping a patient's blood thinner perioperatively "is much more serious and underappreciated because they're going to go to an ER for their stroke and you may never know about it," said Dr. Otley, who is a professor of dermatology at the Mayo Clinic, Rochester, Minn.

Based on the results of a survey of dermatologic surgeons, Dr. Otley found that 72% of them believed that they could tell if a patient was taking a blood thinner based on how the patient "oozed" intraoperatively.

In another study, however, with 110 patients undergoing cutaneous excisional surgery, Dr. Otley and his colleagues found that blinded dermatologic surgeon observers were able to determine if patients were taking a blood-thinning agent with a sensitivity of only 14% and a false-positive rate of 16% (Plast. Reconstr. Surg. 2002;110:98–103).

In another blinded study of 100 patients undergoing coronary artery bypass graft who were taking a placebo or aspirin, cardiac surgeons were correct about the patients' blood thinner status only 51% of the time.

"I would argue that, objectively, you really can't tell whether somebody [is] on a blood thinner," he said.

Of 11 studies that have evaluated patient risk of hemorrhage while on blood thinners, 10 have found no increased risk of severe hemorrhagic complications.

In the one conflicting study of 21 patients, warfarin complications such as persistent bleeding, hematoma, infection, and graft loss occurred (Aesthetic Plast. Surg. 2002;26:483–5).

In a member survey of the American College of Mohs Micrographic Surgery and Cutaneous Oncology, 168 surgeons reported 46 patients who had thrombotic events within a 3-day period before or after stopping a blood thinner, including three deaths.

This yielded a rate of 1 thrombotic event per 12,816 operations, or 1 of every 6,219 operations in which warfarin was discontinued and 1 of every 21,448 when aspirin was not used (J. Am. Acad. Dermatol. 2003;48:233–7).

Another more recent study reported thrombotic complications in 126 patients, including 15 deaths.

"Medically necessary blood thinners should, in general, be continued if there aren't countermanding variables that indicate a need to stop them," Dr. Otley commented.

WASHINGTON — Bleeding during or after superficial cutaneous surgery may provoke more worry from both patients and their clinicians, but thrombotic events actually have greater consequences and are harder to detect, Dr. Clark C. Otley said at the annual meeting of the American Academy of Dermatology.

Bleeding "almost never causes a permanent disability," but a thrombotic complication that occurs after stopping a patient's blood thinner perioperatively "is much more serious and underappreciated because they're going to go to an ER for their stroke and you may never know about it," said Dr. Otley, who is a professor of dermatology at the Mayo Clinic, Rochester, Minn.

Based on the results of a survey of dermatologic surgeons, Dr. Otley found that 72% of them believed that they could tell if a patient was taking a blood thinner based on how the patient "oozed" intraoperatively.

In another study, however, with 110 patients undergoing cutaneous excisional surgery, Dr. Otley and his colleagues found that blinded dermatologic surgeon observers were able to determine if patients were taking a blood-thinning agent with a sensitivity of only 14% and a false-positive rate of 16% (Plast. Reconstr. Surg. 2002;110:98–103).

In another blinded study of 100 patients undergoing coronary artery bypass graft who were taking a placebo or aspirin, cardiac surgeons were correct about the patients' blood thinner status only 51% of the time.

"I would argue that, objectively, you really can't tell whether somebody [is] on a blood thinner," he said.

Of 11 studies that have evaluated patient risk of hemorrhage while on blood thinners, 10 have found no increased risk of severe hemorrhagic complications.

In the one conflicting study of 21 patients, warfarin complications such as persistent bleeding, hematoma, infection, and graft loss occurred (Aesthetic Plast. Surg. 2002;26:483–5).

In a member survey of the American College of Mohs Micrographic Surgery and Cutaneous Oncology, 168 surgeons reported 46 patients who had thrombotic events within a 3-day period before or after stopping a blood thinner, including three deaths.

This yielded a rate of 1 thrombotic event per 12,816 operations, or 1 of every 6,219 operations in which warfarin was discontinued and 1 of every 21,448 when aspirin was not used (J. Am. Acad. Dermatol. 2003;48:233–7).

Another more recent study reported thrombotic complications in 126 patients, including 15 deaths.

"Medically necessary blood thinners should, in general, be continued if there aren't countermanding variables that indicate a need to stop them," Dr. Otley commented.

WASHINGTON — Bleeding during or after superficial cutaneous surgery may provoke more worry from both patients and their clinicians, but thrombotic events actually have greater consequences and are harder to detect, Dr. Clark C. Otley said at the annual meeting of the American Academy of Dermatology.

Bleeding "almost never causes a permanent disability," but a thrombotic complication that occurs after stopping a patient's blood thinner perioperatively "is much more serious and underappreciated because they're going to go to an ER for their stroke and you may never know about it," said Dr. Otley, who is a professor of dermatology at the Mayo Clinic, Rochester, Minn.

Based on the results of a survey of dermatologic surgeons, Dr. Otley found that 72% of them believed that they could tell if a patient was taking a blood thinner based on how the patient "oozed" intraoperatively.

In another study, however, with 110 patients undergoing cutaneous excisional surgery, Dr. Otley and his colleagues found that blinded dermatologic surgeon observers were able to determine if patients were taking a blood-thinning agent with a sensitivity of only 14% and a false-positive rate of 16% (Plast. Reconstr. Surg. 2002;110:98–103).

In another blinded study of 100 patients undergoing coronary artery bypass graft who were taking a placebo or aspirin, cardiac surgeons were correct about the patients' blood thinner status only 51% of the time.

"I would argue that, objectively, you really can't tell whether somebody [is] on a blood thinner," he said.

Of 11 studies that have evaluated patient risk of hemorrhage while on blood thinners, 10 have found no increased risk of severe hemorrhagic complications.

In the one conflicting study of 21 patients, warfarin complications such as persistent bleeding, hematoma, infection, and graft loss occurred (Aesthetic Plast. Surg. 2002;26:483–5).

In a member survey of the American College of Mohs Micrographic Surgery and Cutaneous Oncology, 168 surgeons reported 46 patients who had thrombotic events within a 3-day period before or after stopping a blood thinner, including three deaths.

This yielded a rate of 1 thrombotic event per 12,816 operations, or 1 of every 6,219 operations in which warfarin was discontinued and 1 of every 21,448 when aspirin was not used (J. Am. Acad. Dermatol. 2003;48:233–7).

Another more recent study reported thrombotic complications in 126 patients, including 15 deaths.

"Medically necessary blood thinners should, in general, be continued if there aren't countermanding variables that indicate a need to stop them," Dr. Otley commented.

VAIL, COLO. — An animal-derived extracellular matrix implant could be a longer-lasting alternative to the short-lived fillers used to augment nasolabial folds, lips, and glabella, Dr. Edmund A. Pribitkin said at a symposium sponsored by the American Academy of Facial Plastic and Reconstructive Surgery.

Dr. Pribitkin has used the Food and Drug Administration-approved Surgisis soft tissue graft, which is made from the small intestinal submucosa of pigs, to augment those locations on patients in his practice.

In his experience with using Surgisis to augment nasolabial folds, "the longest person is a year out, so we can't really say anything beyond that. We do seem to get improvement more in people who are thin, who don't have a lot of extra jowling or extra cheek fat that you're really going to have difficulty filling in," said Dr. Pribitkin, professor in the department of otolaryngology-head and neck surgery at Jefferson Medical College, Philadelphia.

Dr. Pribitkin placed the implant at no charge in the nasolabial folds of 15 consecutive women whom he had seen previously for other procedures. Currently, eight patients have 10–12 months of follow-up, five have 7 months, and two have 6 months. Eleven of the women were satisfied early with the implant and said that they would pay to have it done. Two patients wanted more augmentation, and another two thought that it didn't help at all.

At 6 months, 8 of 15 women were satisfied with the results of the implant, but after almost a year, 3 are asking, "'Did I have something done?'" he said.

In eight patients who have undergone lip augmentation, the implant has "been relatively effective" in treating seven upper lips and eight lower lips, he noted.

"Generally speaking, the problem with the lips is—at least in most cases—it's never enough. They want more and more augmentation of the lips," Dr. Pribitkin said at the symposium, which also was sponsored by the American Society for Dermatologic Surgery and the American Society of Ophthalmic Plastic and Reconstructive Surgery.

Before the procedure, patients use a pHisoHex (hexachlorophene) scrub in the morning and do not apply any makeup, and the treatment area is swabbed with alcohol prior to incision. The implant, with a trocar attached, is soaked for about 5 minutes.

With the patient under local anesthesia with 1% lidocaine and epinephrine, the round-shaped trocar is inserted into a stab incision of the lower portion of nasolabial fold. A second stab incision is made in the upper portion of the fold. The implant is run through the incision at a point just underneath the dermis—not deep in the subcutaneous tissue but at the dermal-subcutaneous interface—while the surgeon tries not to touch the implant with gloves.

The implant rolls up on itself as it is pulled through. It is cut at both ends and pulled tight, and one fast-absorbing gut suture is sewn at each point of incision. The patient is then given a dose of antibiotics.

He disclosed that he is a consultant to Cook Biotech Inc., which manufactures Surgisis. The company did not sponsor the use of the implant in facial augmentation, but did provide materials free of charge for evaluation in this trial.

This patient is shown at baseline (top) and 3 months after receiving the Surgisis implant in her nasolabial folds. Photos courtesy Dr. Edmund A. Pribitkin

VAIL, COLO. — An animal-derived extracellular matrix implant could be a longer-lasting alternative to the short-lived fillers used to augment nasolabial folds, lips, and glabella, Dr. Edmund A. Pribitkin said at a symposium sponsored by the American Academy of Facial Plastic and Reconstructive Surgery.

Dr. Pribitkin has used the Food and Drug Administration-approved Surgisis soft tissue graft, which is made from the small intestinal submucosa of pigs, to augment those locations on patients in his practice.

In his experience with using Surgisis to augment nasolabial folds, "the longest person is a year out, so we can't really say anything beyond that. We do seem to get improvement more in people who are thin, who don't have a lot of extra jowling or extra cheek fat that you're really going to have difficulty filling in," said Dr. Pribitkin, professor in the department of otolaryngology-head and neck surgery at Jefferson Medical College, Philadelphia.

Dr. Pribitkin placed the implant at no charge in the nasolabial folds of 15 consecutive women whom he had seen previously for other procedures. Currently, eight patients have 10–12 months of follow-up, five have 7 months, and two have 6 months. Eleven of the women were satisfied early with the implant and said that they would pay to have it done. Two patients wanted more augmentation, and another two thought that it didn't help at all.

At 6 months, 8 of 15 women were satisfied with the results of the implant, but after almost a year, 3 are asking, "'Did I have something done?'" he said.

In eight patients who have undergone lip augmentation, the implant has "been relatively effective" in treating seven upper lips and eight lower lips, he noted.

"Generally speaking, the problem with the lips is—at least in most cases—it's never enough. They want more and more augmentation of the lips," Dr. Pribitkin said at the symposium, which also was sponsored by the American Society for Dermatologic Surgery and the American Society of Ophthalmic Plastic and Reconstructive Surgery.

Before the procedure, patients use a pHisoHex (hexachlorophene) scrub in the morning and do not apply any makeup, and the treatment area is swabbed with alcohol prior to incision. The implant, with a trocar attached, is soaked for about 5 minutes.

With the patient under local anesthesia with 1% lidocaine and epinephrine, the round-shaped trocar is inserted into a stab incision of the lower portion of nasolabial fold. A second stab incision is made in the upper portion of the fold. The implant is run through the incision at a point just underneath the dermis—not deep in the subcutaneous tissue but at the dermal-subcutaneous interface—while the surgeon tries not to touch the implant with gloves.

The implant rolls up on itself as it is pulled through. It is cut at both ends and pulled tight, and one fast-absorbing gut suture is sewn at each point of incision. The patient is then given a dose of antibiotics.

He disclosed that he is a consultant to Cook Biotech Inc., which manufactures Surgisis. The company did not sponsor the use of the implant in facial augmentation, but did provide materials free of charge for evaluation in this trial.

This patient is shown at baseline (top) and 3 months after receiving the Surgisis implant in her nasolabial folds. Photos courtesy Dr. Edmund A. Pribitkin

VAIL, COLO. — An animal-derived extracellular matrix implant could be a longer-lasting alternative to the short-lived fillers used to augment nasolabial folds, lips, and glabella, Dr. Edmund A. Pribitkin said at a symposium sponsored by the American Academy of Facial Plastic and Reconstructive Surgery.

Dr. Pribitkin has used the Food and Drug Administration-approved Surgisis soft tissue graft, which is made from the small intestinal submucosa of pigs, to augment those locations on patients in his practice.

In his experience with using Surgisis to augment nasolabial folds, "the longest person is a year out, so we can't really say anything beyond that. We do seem to get improvement more in people who are thin, who don't have a lot of extra jowling or extra cheek fat that you're really going to have difficulty filling in," said Dr. Pribitkin, professor in the department of otolaryngology-head and neck surgery at Jefferson Medical College, Philadelphia.

Dr. Pribitkin placed the implant at no charge in the nasolabial folds of 15 consecutive women whom he had seen previously for other procedures. Currently, eight patients have 10–12 months of follow-up, five have 7 months, and two have 6 months. Eleven of the women were satisfied early with the implant and said that they would pay to have it done. Two patients wanted more augmentation, and another two thought that it didn't help at all.

At 6 months, 8 of 15 women were satisfied with the results of the implant, but after almost a year, 3 are asking, "'Did I have something done?'" he said.

In eight patients who have undergone lip augmentation, the implant has "been relatively effective" in treating seven upper lips and eight lower lips, he noted.

"Generally speaking, the problem with the lips is—at least in most cases—it's never enough. They want more and more augmentation of the lips," Dr. Pribitkin said at the symposium, which also was sponsored by the American Society for Dermatologic Surgery and the American Society of Ophthalmic Plastic and Reconstructive Surgery.

Before the procedure, patients use a pHisoHex (hexachlorophene) scrub in the morning and do not apply any makeup, and the treatment area is swabbed with alcohol prior to incision. The implant, with a trocar attached, is soaked for about 5 minutes.

With the patient under local anesthesia with 1% lidocaine and epinephrine, the round-shaped trocar is inserted into a stab incision of the lower portion of nasolabial fold. A second stab incision is made in the upper portion of the fold. The implant is run through the incision at a point just underneath the dermis—not deep in the subcutaneous tissue but at the dermal-subcutaneous interface—while the surgeon tries not to touch the implant with gloves.

The implant rolls up on itself as it is pulled through. It is cut at both ends and pulled tight, and one fast-absorbing gut suture is sewn at each point of incision. The patient is then given a dose of antibiotics.

He disclosed that he is a consultant to Cook Biotech Inc., which manufactures Surgisis. The company did not sponsor the use of the implant in facial augmentation, but did provide materials free of charge for evaluation in this trial.

This patient is shown at baseline (top) and 3 months after receiving the Surgisis implant in her nasolabial folds. Photos courtesy Dr. Edmund A. Pribitkin

WASHINGTON — Proper early management of ingrown toenails may help to decrease the risk of recurrence whether or not surgery is necessary, Dr. C. Ralph Daniel III said at the annual meeting of the American Academy of Dermatology.

"An ingrown nail is primarily acting as a foreign-body reaction. That rigid spicule penetrates soft surrounding tissue" and produces swelling, granulation tissue, and sometimes a secondary infection, said Dr. Daniel of the departments of dermatology at the University of Mississippi, Jackson, and the University of Alabama, Birmingham.

For the early management of stage I ingrown toenails in which some granulation tissue but no infection is present, Dr. Daniel has trained his nurse to push wisps of cotton gently under the involved ingrowing nail by using a 2-mm nail elevator or a 1− to 2-mm curette.

He also uses a technique for early-stage ingrown toenails in which dental floss is inserted under the ingrown nail corner without anesthesia and is kept there to separate the nail edge from adjacent soft tissue (J. Am. Acad. Dermatol. 2004;50:939–40).

Dr. Daniel formerly was on the board of directors for Doak Dermatologics, a subsidiary of Bradley Pharmaceuticals Inc., which manufactures urea-based products for nail care. He holds stock options and has served as a speaker, consultant, and investigator for the company.

A procedure that uses an acrylic-affixed gutter splint has been reported to be successful for avoiding surgery, Dr. Daniel said. A plastic gutter tube is set under the ingrown part of the nail and acrylic is sculpted and allowed to polymerize around the ingrown part of the nail and hold the gutter tube in place. The tubes are removed once the inflammation has subsided and the nail has grown appropriately (Int. J. Dermatol. 2004;43:759–65).

Surgery should not be performed on a patient with an ingrown toenail in a more advanced stage—more granulation tissue, significant pain, possible infection—until the level of inflammation has been reduced with salt soaks in warm water (as opposed to cold, because of the possibility of infection) and topical application of steroids three times a day for about a week, Dr. Daniel said. He doesn't use urea very often in these cases because it does not seem to work as well as it does for early-stage ingrown toenails.

Before surgery, leave plenty of time for anesthesia using a digital block or a distal approach to take effect. Premedication with NSAIDs, codeine, or dextropropoxyphene also may be appropriate, he said. Dr. Daniel uses a timer and does not keep a tourniquet on for more than 15 minutes; most procedures do not take longer than that (some surgeons do not use tourniquets).

To cut away the offending section of nail, an English anvil nail splitter is inserted under the nail plate and the cut is made all the way to the proximal nail fold. The hypertrophic, granulated tissue should be cut away as well. Many ingrown toenails are recurrent, so Dr. Daniel performs a chemical matricectomy in nearly all patients after making sure that the surgical field is dry and bloodless.

The proximal nail fold can be flared back to expose more of the proximal matrix if necessary. He inserts a Calgiswab coated with 88% phenol or 10% sodium hydroxide and applies the chemical for 30 seconds to the portion of the nail matrix that needs to be destroyed.

An Ellman electrode can be used to electrodesiccate the matrix, followed by curettage. The CO2 laser also has been used to perform a partial matricectomy after removal of the nail spicule and staining of the nail matrix with methylene blue (Dermatol. Surg. 2005;31:302–5).

An ingrown toenail is shown. ©Jeff Horn/Fotolia

WASHINGTON — Proper early management of ingrown toenails may help to decrease the risk of recurrence whether or not surgery is necessary, Dr. C. Ralph Daniel III said at the annual meeting of the American Academy of Dermatology.

"An ingrown nail is primarily acting as a foreign-body reaction. That rigid spicule penetrates soft surrounding tissue" and produces swelling, granulation tissue, and sometimes a secondary infection, said Dr. Daniel of the departments of dermatology at the University of Mississippi, Jackson, and the University of Alabama, Birmingham.

For the early management of stage I ingrown toenails in which some granulation tissue but no infection is present, Dr. Daniel has trained his nurse to push wisps of cotton gently under the involved ingrowing nail by using a 2-mm nail elevator or a 1− to 2-mm curette.

He also uses a technique for early-stage ingrown toenails in which dental floss is inserted under the ingrown nail corner without anesthesia and is kept there to separate the nail edge from adjacent soft tissue (J. Am. Acad. Dermatol. 2004;50:939–40).

Dr. Daniel formerly was on the board of directors for Doak Dermatologics, a subsidiary of Bradley Pharmaceuticals Inc., which manufactures urea-based products for nail care. He holds stock options and has served as a speaker, consultant, and investigator for the company.

A procedure that uses an acrylic-affixed gutter splint has been reported to be successful for avoiding surgery, Dr. Daniel said. A plastic gutter tube is set under the ingrown part of the nail and acrylic is sculpted and allowed to polymerize around the ingrown part of the nail and hold the gutter tube in place. The tubes are removed once the inflammation has subsided and the nail has grown appropriately (Int. J. Dermatol. 2004;43:759–65).

Surgery should not be performed on a patient with an ingrown toenail in a more advanced stage—more granulation tissue, significant pain, possible infection—until the level of inflammation has been reduced with salt soaks in warm water (as opposed to cold, because of the possibility of infection) and topical application of steroids three times a day for about a week, Dr. Daniel said. He doesn't use urea very often in these cases because it does not seem to work as well as it does for early-stage ingrown toenails.

Before surgery, leave plenty of time for anesthesia using a digital block or a distal approach to take effect. Premedication with NSAIDs, codeine, or dextropropoxyphene also may be appropriate, he said. Dr. Daniel uses a timer and does not keep a tourniquet on for more than 15 minutes; most procedures do not take longer than that (some surgeons do not use tourniquets).

To cut away the offending section of nail, an English anvil nail splitter is inserted under the nail plate and the cut is made all the way to the proximal nail fold. The hypertrophic, granulated tissue should be cut away as well. Many ingrown toenails are recurrent, so Dr. Daniel performs a chemical matricectomy in nearly all patients after making sure that the surgical field is dry and bloodless.

The proximal nail fold can be flared back to expose more of the proximal matrix if necessary. He inserts a Calgiswab coated with 88% phenol or 10% sodium hydroxide and applies the chemical for 30 seconds to the portion of the nail matrix that needs to be destroyed.

An Ellman electrode can be used to electrodesiccate the matrix, followed by curettage. The CO2 laser also has been used to perform a partial matricectomy after removal of the nail spicule and staining of the nail matrix with methylene blue (Dermatol. Surg. 2005;31:302–5).

An ingrown toenail is shown. ©Jeff Horn/Fotolia

WASHINGTON — Proper early management of ingrown toenails may help to decrease the risk of recurrence whether or not surgery is necessary, Dr. C. Ralph Daniel III said at the annual meeting of the American Academy of Dermatology.

"An ingrown nail is primarily acting as a foreign-body reaction. That rigid spicule penetrates soft surrounding tissue" and produces swelling, granulation tissue, and sometimes a secondary infection, said Dr. Daniel of the departments of dermatology at the University of Mississippi, Jackson, and the University of Alabama, Birmingham.

For the early management of stage I ingrown toenails in which some granulation tissue but no infection is present, Dr. Daniel has trained his nurse to push wisps of cotton gently under the involved ingrowing nail by using a 2-mm nail elevator or a 1− to 2-mm curette.

He also uses a technique for early-stage ingrown toenails in which dental floss is inserted under the ingrown nail corner without anesthesia and is kept there to separate the nail edge from adjacent soft tissue (J. Am. Acad. Dermatol. 2004;50:939–40).

Dr. Daniel formerly was on the board of directors for Doak Dermatologics, a subsidiary of Bradley Pharmaceuticals Inc., which manufactures urea-based products for nail care. He holds stock options and has served as a speaker, consultant, and investigator for the company.

A procedure that uses an acrylic-affixed gutter splint has been reported to be successful for avoiding surgery, Dr. Daniel said. A plastic gutter tube is set under the ingrown part of the nail and acrylic is sculpted and allowed to polymerize around the ingrown part of the nail and hold the gutter tube in place. The tubes are removed once the inflammation has subsided and the nail has grown appropriately (Int. J. Dermatol. 2004;43:759–65).

Surgery should not be performed on a patient with an ingrown toenail in a more advanced stage—more granulation tissue, significant pain, possible infection—until the level of inflammation has been reduced with salt soaks in warm water (as opposed to cold, because of the possibility of infection) and topical application of steroids three times a day for about a week, Dr. Daniel said. He doesn't use urea very often in these cases because it does not seem to work as well as it does for early-stage ingrown toenails.

Before surgery, leave plenty of time for anesthesia using a digital block or a distal approach to take effect. Premedication with NSAIDs, codeine, or dextropropoxyphene also may be appropriate, he said. Dr. Daniel uses a timer and does not keep a tourniquet on for more than 15 minutes; most procedures do not take longer than that (some surgeons do not use tourniquets).

To cut away the offending section of nail, an English anvil nail splitter is inserted under the nail plate and the cut is made all the way to the proximal nail fold. The hypertrophic, granulated tissue should be cut away as well. Many ingrown toenails are recurrent, so Dr. Daniel performs a chemical matricectomy in nearly all patients after making sure that the surgical field is dry and bloodless.

The proximal nail fold can be flared back to expose more of the proximal matrix if necessary. He inserts a Calgiswab coated with 88% phenol or 10% sodium hydroxide and applies the chemical for 30 seconds to the portion of the nail matrix that needs to be destroyed.

An Ellman electrode can be used to electrodesiccate the matrix, followed by curettage. The CO2 laser also has been used to perform a partial matricectomy after removal of the nail spicule and staining of the nail matrix with methylene blue (Dermatol. Surg. 2005;31:302–5).

An ingrown toenail is shown. ©Jeff Horn/Fotolia

WASHINGTON — Conditions in which patients have multiple lentigines commonly have an etiology that shares the same final molecular pathway that predisposes the patients to tumors, Dr. Constantine Stratakis said at a meeting of the Society for Pediatric Dermatology.

Understanding the common etiologic pathway in lentiginosis syndromes may help in developing therapeutic strategies and identifying individuals with less frequent or nonclassic presentations of such syndromes, said Dr. Stratakis, head of the section on endocrinology and genetics and chief of the heritable disorders branch at the National Institute of Child Health and Human Development, in Bethesda, Md.

Some inherited (and sporadic) lentiginoses such as a labial melanotic macule (J. Am. Acad. Dermatol. 1993;28:33–9) or genital lentiginosis (J. Am. Acad. Dermatol. 1990;22:453–60) are not tied to other lesions or tumors and are frequent in the population. Another condition not linked with tumors is benign lentiginosis, an autosomal dominant condition that is more frequently found in blacks and people of mixed race. Its molecular etiology is unknown. But other lentiginoses have more phenotypic variability and are associated with a predisposition to tumors:

▸ Peutz-Jeghers syndrome. Not all of the patients who have this autosomal dominant condition associated with mutations or deletions of the STK11/LKB1 gene have classic lip pigmentation.

“You really have to look for the distribution of unusual-looking pigmented lesions that may not be obvious,” Dr. Stratakis said. “The distribution of the lesions is very important. It's not just the classic pigmented macules that you all know from textbooks.” Other classic features of this condition include hamartomatous colonic polyps and a predisposition to a variety of neoplasms.

▸ LEOPARD syndrome. Many individuals who are affected by this condition may have only some of the phenotypic characteristics that have been described (Lentigines, ECG abnormalities, Ocular hypertension, Pulmonary stenosis, Abnormal genitalia, Retarded growth, and Deafness). For example, they may exhibit deafness and ECG abnormalities and no other phenotype.

Many patients thought to have LEOPARD syndrome have been recognized to have Watson syndrome, a condition that presents with pulmonary stenosis and inherited lentiginosis but is actually a form of neurofibromatosis type 1 (NF-1). It is now known that almost all the patients identified with pulmonary stenosis, multiple lentigines, and a predisposition to tumors have NF-1 gene mutations or deletions (Am J. Med. Genet. A. 2006;140:2749–56).

But patients with classic LEOPARD syndrome (without NF-1 gene mutations or deletions) have mutations in the same gene that causes Noonan's syndrome: the PTPN11 gene (which codes for a protein tyrosine phosphatase). There is some phenotype-genotype correlation in that mutations in slightly different locations of the PTPN11 gene are responsible for the LEOPARD and Noonan's syndromes.

“That explains why … whenever I was getting patients with Noonan's, I would almost always detect lentigines in these patients, except that very few of them had the density and the intensity of the pigmented lesions that the patients with classic LEOPARD have,” he said.

Since not all patients with LEOPARD or Noonan's fill all the diagnostic criteria for these disorders, one must make diagnosis using signs that are not classic for either condition. Patients with LEOPARD frequently have skeletal defects or joint hyperextensibility and other collagen disorder-like defects that can be seen in patients with Marfan syndrome, Ehlers-Danlos syndrome, and similar conditions.

“Almost all LEOPARD patients that I have seen have a form of skeletal dysplasia and/or some degree of flexibility,” he said.

▸ Cowden disease. The lentigines that are found in individuals with this disease are “for the most part indistinguishable from the lentigines in these other conditions,” Dr. Stratakis said. An autosomal dominant expression of a mutation in the PTEN gene (a protein tyrosine phosphatase) also causes this disease's characteristic multiple hamartomas and predisposition to a variety of tumors. Another condition with a PTEN gene mutation is the Ruvalcaba-Myhre-Smith syndrome, in which patients have penile lentiginosis.

“This gene can be mutated in a variety of phenotypes [called the PTEN mutation hamartoma syndromes] that don't necessarily make any sense,” Dr. Stratakis said. “Yet there is one thing that all these phenotypes have in common … and that is lentigines. All of these conditions that have multiple lentigines and have a predisposition to tumors in essence are candidates for PTEN testing,” he said.

▸ Carney's complex (CC). Patients with this multiple endocrine neoplasia syndrome have multiple lentigines, which do not necessarily have a distinct presence on the face. In Dr. Stratakis' experience with about 500 CC patients, it has become clear that they do not have the same type of pigmentation seen in Peutz-Jeghers patients, even though some features of the two conditions may be overlapping.

CC patients have “very distinct and purer labial macules, and some have no distinct pigmentation of the face,” except for a particular distribution and a few blue nevi on the saddle of the nose, which would be unusual for the general population, according to Dr. Stratakis.

Multiple genital macules are present in CC patients, in contrast to one or two at most in the general population. Ear and outer canthal pigmentation is present in about one-third of CC patients but also occurs infrequently in Peutz-Jeghers patients.

CC patients have mutations in the PRKAR1A gene; PRKAR1A is a regulator of protein kinase A and mutations cause dysregulation of the catalytic subunit of the enzyme. A mouse model confirmed that the mutated gene could cause a variety of tumors. Subsequent experiments showed chromosomal instability and other features caused by PRKAR1A gene mutations in human and mouse cells.

If very different genes that do not seem to have a “functional connection” cause all of these inherited lentinginosis syndromes, “then they must have a common mediator of tumorigenesis,” Dr. Stratakis said. “It turns out that the common mediator is mTOR,” which is the mammalian target of rapamycin. Indeed, it appears that all of these conditions are associated with dysregulation of mTOR activity, which normally regulates other tumor suppressor genes and oncogenes. Rapamycin and its analogues are being tested in clinical trials of cancer patients, Dr. Stratakis noted.

This patient with Carney's complex shows lentigines on the eyelids as well as a small, red myxoma on the upper lid. Courtesy Dr. Constantine Stratakis

WASHINGTON — Conditions in which patients have multiple lentigines commonly have an etiology that shares the same final molecular pathway that predisposes the patients to tumors, Dr. Constantine Stratakis said at a meeting of the Society for Pediatric Dermatology.

Understanding the common etiologic pathway in lentiginosis syndromes may help in developing therapeutic strategies and identifying individuals with less frequent or nonclassic presentations of such syndromes, said Dr. Stratakis, head of the section on endocrinology and genetics and chief of the heritable disorders branch at the National Institute of Child Health and Human Development, in Bethesda, Md.

Some inherited (and sporadic) lentiginoses such as a labial melanotic macule (J. Am. Acad. Dermatol. 1993;28:33–9) or genital lentiginosis (J. Am. Acad. Dermatol. 1990;22:453–60) are not tied to other lesions or tumors and are frequent in the population. Another condition not linked with tumors is benign lentiginosis, an autosomal dominant condition that is more frequently found in blacks and people of mixed race. Its molecular etiology is unknown. But other lentiginoses have more phenotypic variability and are associated with a predisposition to tumors:

▸ Peutz-Jeghers syndrome. Not all of the patients who have this autosomal dominant condition associated with mutations or deletions of the STK11/LKB1 gene have classic lip pigmentation.

“You really have to look for the distribution of unusual-looking pigmented lesions that may not be obvious,” Dr. Stratakis said. “The distribution of the lesions is very important. It's not just the classic pigmented macules that you all know from textbooks.” Other classic features of this condition include hamartomatous colonic polyps and a predisposition to a variety of neoplasms.

▸ LEOPARD syndrome. Many individuals who are affected by this condition may have only some of the phenotypic characteristics that have been described (Lentigines, ECG abnormalities, Ocular hypertension, Pulmonary stenosis, Abnormal genitalia, Retarded growth, and Deafness). For example, they may exhibit deafness and ECG abnormalities and no other phenotype.

Many patients thought to have LEOPARD syndrome have been recognized to have Watson syndrome, a condition that presents with pulmonary stenosis and inherited lentiginosis but is actually a form of neurofibromatosis type 1 (NF-1). It is now known that almost all the patients identified with pulmonary stenosis, multiple lentigines, and a predisposition to tumors have NF-1 gene mutations or deletions (Am J. Med. Genet. A. 2006;140:2749–56).

But patients with classic LEOPARD syndrome (without NF-1 gene mutations or deletions) have mutations in the same gene that causes Noonan's syndrome: the PTPN11 gene (which codes for a protein tyrosine phosphatase). There is some phenotype-genotype correlation in that mutations in slightly different locations of the PTPN11 gene are responsible for the LEOPARD and Noonan's syndromes.

“That explains why … whenever I was getting patients with Noonan's, I would almost always detect lentigines in these patients, except that very few of them had the density and the intensity of the pigmented lesions that the patients with classic LEOPARD have,” he said.

Since not all patients with LEOPARD or Noonan's fill all the diagnostic criteria for these disorders, one must make diagnosis using signs that are not classic for either condition. Patients with LEOPARD frequently have skeletal defects or joint hyperextensibility and other collagen disorder-like defects that can be seen in patients with Marfan syndrome, Ehlers-Danlos syndrome, and similar conditions.

“Almost all LEOPARD patients that I have seen have a form of skeletal dysplasia and/or some degree of flexibility,” he said.

▸ Cowden disease. The lentigines that are found in individuals with this disease are “for the most part indistinguishable from the lentigines in these other conditions,” Dr. Stratakis said. An autosomal dominant expression of a mutation in the PTEN gene (a protein tyrosine phosphatase) also causes this disease's characteristic multiple hamartomas and predisposition to a variety of tumors. Another condition with a PTEN gene mutation is the Ruvalcaba-Myhre-Smith syndrome, in which patients have penile lentiginosis.

“This gene can be mutated in a variety of phenotypes [called the PTEN mutation hamartoma syndromes] that don't necessarily make any sense,” Dr. Stratakis said. “Yet there is one thing that all these phenotypes have in common … and that is lentigines. All of these conditions that have multiple lentigines and have a predisposition to tumors in essence are candidates for PTEN testing,” he said.

▸ Carney's complex (CC). Patients with this multiple endocrine neoplasia syndrome have multiple lentigines, which do not necessarily have a distinct presence on the face. In Dr. Stratakis' experience with about 500 CC patients, it has become clear that they do not have the same type of pigmentation seen in Peutz-Jeghers patients, even though some features of the two conditions may be overlapping.

CC patients have “very distinct and purer labial macules, and some have no distinct pigmentation of the face,” except for a particular distribution and a few blue nevi on the saddle of the nose, which would be unusual for the general population, according to Dr. Stratakis.

Multiple genital macules are present in CC patients, in contrast to one or two at most in the general population. Ear and outer canthal pigmentation is present in about one-third of CC patients but also occurs infrequently in Peutz-Jeghers patients.

CC patients have mutations in the PRKAR1A gene; PRKAR1A is a regulator of protein kinase A and mutations cause dysregulation of the catalytic subunit of the enzyme. A mouse model confirmed that the mutated gene could cause a variety of tumors. Subsequent experiments showed chromosomal instability and other features caused by PRKAR1A gene mutations in human and mouse cells.

If very different genes that do not seem to have a “functional connection” cause all of these inherited lentinginosis syndromes, “then they must have a common mediator of tumorigenesis,” Dr. Stratakis said. “It turns out that the common mediator is mTOR,” which is the mammalian target of rapamycin. Indeed, it appears that all of these conditions are associated with dysregulation of mTOR activity, which normally regulates other tumor suppressor genes and oncogenes. Rapamycin and its analogues are being tested in clinical trials of cancer patients, Dr. Stratakis noted.

This patient with Carney's complex shows lentigines on the eyelids as well as a small, red myxoma on the upper lid. Courtesy Dr. Constantine Stratakis

WASHINGTON — Conditions in which patients have multiple lentigines commonly have an etiology that shares the same final molecular pathway that predisposes the patients to tumors, Dr. Constantine Stratakis said at a meeting of the Society for Pediatric Dermatology.

Understanding the common etiologic pathway in lentiginosis syndromes may help in developing therapeutic strategies and identifying individuals with less frequent or nonclassic presentations of such syndromes, said Dr. Stratakis, head of the section on endocrinology and genetics and chief of the heritable disorders branch at the National Institute of Child Health and Human Development, in Bethesda, Md.

Some inherited (and sporadic) lentiginoses such as a labial melanotic macule (J. Am. Acad. Dermatol. 1993;28:33–9) or genital lentiginosis (J. Am. Acad. Dermatol. 1990;22:453–60) are not tied to other lesions or tumors and are frequent in the population. Another condition not linked with tumors is benign lentiginosis, an autosomal dominant condition that is more frequently found in blacks and people of mixed race. Its molecular etiology is unknown. But other lentiginoses have more phenotypic variability and are associated with a predisposition to tumors:

▸ Peutz-Jeghers syndrome. Not all of the patients who have this autosomal dominant condition associated with mutations or deletions of the STK11/LKB1 gene have classic lip pigmentation.

“You really have to look for the distribution of unusual-looking pigmented lesions that may not be obvious,” Dr. Stratakis said. “The distribution of the lesions is very important. It's not just the classic pigmented macules that you all know from textbooks.” Other classic features of this condition include hamartomatous colonic polyps and a predisposition to a variety of neoplasms.

▸ LEOPARD syndrome. Many individuals who are affected by this condition may have only some of the phenotypic characteristics that have been described (Lentigines, ECG abnormalities, Ocular hypertension, Pulmonary stenosis, Abnormal genitalia, Retarded growth, and Deafness). For example, they may exhibit deafness and ECG abnormalities and no other phenotype.

Many patients thought to have LEOPARD syndrome have been recognized to have Watson syndrome, a condition that presents with pulmonary stenosis and inherited lentiginosis but is actually a form of neurofibromatosis type 1 (NF-1). It is now known that almost all the patients identified with pulmonary stenosis, multiple lentigines, and a predisposition to tumors have NF-1 gene mutations or deletions (Am J. Med. Genet. A. 2006;140:2749–56).

But patients with classic LEOPARD syndrome (without NF-1 gene mutations or deletions) have mutations in the same gene that causes Noonan's syndrome: the PTPN11 gene (which codes for a protein tyrosine phosphatase). There is some phenotype-genotype correlation in that mutations in slightly different locations of the PTPN11 gene are responsible for the LEOPARD and Noonan's syndromes.

“That explains why … whenever I was getting patients with Noonan's, I would almost always detect lentigines in these patients, except that very few of them had the density and the intensity of the pigmented lesions that the patients with classic LEOPARD have,” he said.

Since not all patients with LEOPARD or Noonan's fill all the diagnostic criteria for these disorders, one must make diagnosis using signs that are not classic for either condition. Patients with LEOPARD frequently have skeletal defects or joint hyperextensibility and other collagen disorder-like defects that can be seen in patients with Marfan syndrome, Ehlers-Danlos syndrome, and similar conditions.

“Almost all LEOPARD patients that I have seen have a form of skeletal dysplasia and/or some degree of flexibility,” he said.

▸ Cowden disease. The lentigines that are found in individuals with this disease are “for the most part indistinguishable from the lentigines in these other conditions,” Dr. Stratakis said. An autosomal dominant expression of a mutation in the PTEN gene (a protein tyrosine phosphatase) also causes this disease's characteristic multiple hamartomas and predisposition to a variety of tumors. Another condition with a PTEN gene mutation is the Ruvalcaba-Myhre-Smith syndrome, in which patients have penile lentiginosis.

“This gene can be mutated in a variety of phenotypes [called the PTEN mutation hamartoma syndromes] that don't necessarily make any sense,” Dr. Stratakis said. “Yet there is one thing that all these phenotypes have in common … and that is lentigines. All of these conditions that have multiple lentigines and have a predisposition to tumors in essence are candidates for PTEN testing,” he said.

▸ Carney's complex (CC). Patients with this multiple endocrine neoplasia syndrome have multiple lentigines, which do not necessarily have a distinct presence on the face. In Dr. Stratakis' experience with about 500 CC patients, it has become clear that they do not have the same type of pigmentation seen in Peutz-Jeghers patients, even though some features of the two conditions may be overlapping.

CC patients have “very distinct and purer labial macules, and some have no distinct pigmentation of the face,” except for a particular distribution and a few blue nevi on the saddle of the nose, which would be unusual for the general population, according to Dr. Stratakis.

Multiple genital macules are present in CC patients, in contrast to one or two at most in the general population. Ear and outer canthal pigmentation is present in about one-third of CC patients but also occurs infrequently in Peutz-Jeghers patients.

CC patients have mutations in the PRKAR1A gene; PRKAR1A is a regulator of protein kinase A and mutations cause dysregulation of the catalytic subunit of the enzyme. A mouse model confirmed that the mutated gene could cause a variety of tumors. Subsequent experiments showed chromosomal instability and other features caused by PRKAR1A gene mutations in human and mouse cells.

If very different genes that do not seem to have a “functional connection” cause all of these inherited lentinginosis syndromes, “then they must have a common mediator of tumorigenesis,” Dr. Stratakis said. “It turns out that the common mediator is mTOR,” which is the mammalian target of rapamycin. Indeed, it appears that all of these conditions are associated with dysregulation of mTOR activity, which normally regulates other tumor suppressor genes and oncogenes. Rapamycin and its analogues are being tested in clinical trials of cancer patients, Dr. Stratakis noted.

This patient with Carney's complex shows lentigines on the eyelids as well as a small, red myxoma on the upper lid. Courtesy Dr. Constantine Stratakis

WASHINGTON – Medicine and health are so often in the news that it may be worthwhile to be prepared to do interviews in a variety of media, Ms. Patricia A. Clark said at a meeting of the Society for Pediatric Dermatology.

“The physician today cannot possibly get through his or her entire career professionally without talking to the media, so you better be ready,” said Ms. Clark, a communications expert in media training, speech coaching, and message development from Ogden Dunes, Ind. “You do have a good story to tell, right? So the trick is how to tell it.”

Before one tries to get a particular message across during an interview, it is necessary to understand the medium through which the message is delivered (television, radio, print) and the messenger.

“If you don't understand the medium you're working with … and if you aren't an appealing messenger–and I don't mean handsome or beautiful, I mean eager, avid, happy to be here,” she said, then the interview “won't matter. We will have 'remoted' you out before you get to the message.”

Stories on the evening news are packaged into preset lengths: a 90-second story, which normally provides 10–20 seconds for commentary from the physician; or a 110-second story, which could provide 30–40 seconds if the sound bite is good or just 10–20 seconds if it is not. When a person goes on and on and does not deliver a succinct message in those time frames, the media will pull out a piece of what was said when they are putting the story together, leaving the potential for misquotation.

“You're going to say, 'You misquoted me. You took me out of context,' while the media will say, 'No, we tried to save you,'” Ms. Clark said.

The television camera diminishes appearance and does not catch subtlety, so it is necessary to restore what it takes away by increasing your smile, perk, and warmth. And on television, “every time you look away, you give away: You give away believability,” she said.

The media likes conflict and controversy, visuals, and emotion, which “for doctors means pulling patients out of your pocket … and putting a face on the complex issues” rather than drawing attention to yourself and your or your specialty's problems, she said.

Stories on the radio are not too much different from television, but the lack of a visual element puts more focus on what is said, so verbs and nouns have to be more illustrative and carry more weight.

Newspaper stories are now smaller than ever, and interview subjects may get only an inch or two of space–the media savvy will be higher in the story while those who are not end up at the bottom, a place fewer people read and that is more likely to be cut for space, according to Ms. Clark.

You are apt to be stuck at the bottom of a story if you are called at 9 a.m. to do an interview and the reporter's deadline is 3 p.m., but you decide to call the reporter back at 2:50 p.m. By doing this, you've hurt yourself and your colleagues. The story is blank at 9 a.m., but it's all ready to go at 2:50 p.m., and other sources have already weighed in with their interpretations of the issue. Your quote will be stuck at the bottom because it is too late to try to integrate it into the story, she said.

“Start thinking about what the press needs rather than what you need, because when you figure out what [they] need, you'll figure out how to get what you need,” Ms. Clark said.

Easy practice may be found in the form of a cable access channel that few people watch. Volunteer to be on a show and talk about clinical topics you know well. Talk or call-in radio is another option. Every time you take a call, practice bridging back to your core message, she said.

WASHINGTON – Medicine and health are so often in the news that it may be worthwhile to be prepared to do interviews in a variety of media, Ms. Patricia A. Clark said at a meeting of the Society for Pediatric Dermatology.

“The physician today cannot possibly get through his or her entire career professionally without talking to the media, so you better be ready,” said Ms. Clark, a communications expert in media training, speech coaching, and message development from Ogden Dunes, Ind. “You do have a good story to tell, right? So the trick is how to tell it.”

Before one tries to get a particular message across during an interview, it is necessary to understand the medium through which the message is delivered (television, radio, print) and the messenger.

“If you don't understand the medium you're working with … and if you aren't an appealing messenger–and I don't mean handsome or beautiful, I mean eager, avid, happy to be here,” she said, then the interview “won't matter. We will have 'remoted' you out before you get to the message.”

Stories on the evening news are packaged into preset lengths: a 90-second story, which normally provides 10–20 seconds for commentary from the physician; or a 110-second story, which could provide 30–40 seconds if the sound bite is good or just 10–20 seconds if it is not. When a person goes on and on and does not deliver a succinct message in those time frames, the media will pull out a piece of what was said when they are putting the story together, leaving the potential for misquotation.

“You're going to say, 'You misquoted me. You took me out of context,' while the media will say, 'No, we tried to save you,'” Ms. Clark said.

The television camera diminishes appearance and does not catch subtlety, so it is necessary to restore what it takes away by increasing your smile, perk, and warmth. And on television, “every time you look away, you give away: You give away believability,” she said.

The media likes conflict and controversy, visuals, and emotion, which “for doctors means pulling patients out of your pocket … and putting a face on the complex issues” rather than drawing attention to yourself and your or your specialty's problems, she said.

Stories on the radio are not too much different from television, but the lack of a visual element puts more focus on what is said, so verbs and nouns have to be more illustrative and carry more weight.

Newspaper stories are now smaller than ever, and interview subjects may get only an inch or two of space–the media savvy will be higher in the story while those who are not end up at the bottom, a place fewer people read and that is more likely to be cut for space, according to Ms. Clark.

You are apt to be stuck at the bottom of a story if you are called at 9 a.m. to do an interview and the reporter's deadline is 3 p.m., but you decide to call the reporter back at 2:50 p.m. By doing this, you've hurt yourself and your colleagues. The story is blank at 9 a.m., but it's all ready to go at 2:50 p.m., and other sources have already weighed in with their interpretations of the issue. Your quote will be stuck at the bottom because it is too late to try to integrate it into the story, she said.

“Start thinking about what the press needs rather than what you need, because when you figure out what [they] need, you'll figure out how to get what you need,” Ms. Clark said.

Easy practice may be found in the form of a cable access channel that few people watch. Volunteer to be on a show and talk about clinical topics you know well. Talk or call-in radio is another option. Every time you take a call, practice bridging back to your core message, she said.

WASHINGTON – Medicine and health are so often in the news that it may be worthwhile to be prepared to do interviews in a variety of media, Ms. Patricia A. Clark said at a meeting of the Society for Pediatric Dermatology.

“The physician today cannot possibly get through his or her entire career professionally without talking to the media, so you better be ready,” said Ms. Clark, a communications expert in media training, speech coaching, and message development from Ogden Dunes, Ind. “You do have a good story to tell, right? So the trick is how to tell it.”

Before one tries to get a particular message across during an interview, it is necessary to understand the medium through which the message is delivered (television, radio, print) and the messenger.

“If you don't understand the medium you're working with … and if you aren't an appealing messenger–and I don't mean handsome or beautiful, I mean eager, avid, happy to be here,” she said, then the interview “won't matter. We will have 'remoted' you out before you get to the message.”

Stories on the evening news are packaged into preset lengths: a 90-second story, which normally provides 10–20 seconds for commentary from the physician; or a 110-second story, which could provide 30–40 seconds if the sound bite is good or just 10–20 seconds if it is not. When a person goes on and on and does not deliver a succinct message in those time frames, the media will pull out a piece of what was said when they are putting the story together, leaving the potential for misquotation.

“You're going to say, 'You misquoted me. You took me out of context,' while the media will say, 'No, we tried to save you,'” Ms. Clark said.

The television camera diminishes appearance and does not catch subtlety, so it is necessary to restore what it takes away by increasing your smile, perk, and warmth. And on television, “every time you look away, you give away: You give away believability,” she said.

The media likes conflict and controversy, visuals, and emotion, which “for doctors means pulling patients out of your pocket … and putting a face on the complex issues” rather than drawing attention to yourself and your or your specialty's problems, she said.

Stories on the radio are not too much different from television, but the lack of a visual element puts more focus on what is said, so verbs and nouns have to be more illustrative and carry more weight.

Newspaper stories are now smaller than ever, and interview subjects may get only an inch or two of space–the media savvy will be higher in the story while those who are not end up at the bottom, a place fewer people read and that is more likely to be cut for space, according to Ms. Clark.

You are apt to be stuck at the bottom of a story if you are called at 9 a.m. to do an interview and the reporter's deadline is 3 p.m., but you decide to call the reporter back at 2:50 p.m. By doing this, you've hurt yourself and your colleagues. The story is blank at 9 a.m., but it's all ready to go at 2:50 p.m., and other sources have already weighed in with their interpretations of the issue. Your quote will be stuck at the bottom because it is too late to try to integrate it into the story, she said.

“Start thinking about what the press needs rather than what you need, because when you figure out what [they] need, you'll figure out how to get what you need,” Ms. Clark said.

Easy practice may be found in the form of a cable access channel that few people watch. Volunteer to be on a show and talk about clinical topics you know well. Talk or call-in radio is another option. Every time you take a call, practice bridging back to your core message, she said.

CHICAGO – An investigational gabapentin prodrug may be an effective therapy for symptoms and sleep problems associated with restless legs syndrome, Dr. Arthur S. Walters reported at the annual meeting of the American Neurological Association.

The active compound gabapentin has already been shown to improve the sensory and motor symptoms of restless legs syndrome (RLS) and decrease periodic leg movements during sleep, but the drug is approved only for treating epilepsy and postherpetic neuralgia, according to Dr. Walters of the Seton Hall University School of Graduate Medical Education, Edison, N.J.

The gabapentin prodrug XP13512 has several potential advantages over standard gabapentin for treating RLS: The agent has linear pharmacokinetics, doesn't reach a saturation point, and is formulated for sustained release. The capacity for once-daily dosing differentiates gabapentin prodrug XP13512 from the active compound gabapentin (Neurontin), which cannot be manufactured in a sustained-release delivery and must be taken three to four times per day, Dr. Walters discussed on his poster at the meeting.

XenoPort Inc., the drug's manufacturer, has sponsored two phase II, randomized, double-blind trials. One of these trials was a crossover study with 38 patients testing 1,800 mg XP13512 against placebo. The other trial compared XP13512 at 600 mg and 1,200 mg and placebo in 95 patients without any crossover. In both studies, patients had RLS symptoms at least 4 nights during a 7-day baseline period and had a score of at least 15 (out of a possible 40) on the International RLS Study Group rating scale (IRLS). Most patients were white, and mean age was about 50 years.

Compared with patients given placebo, patients treated with the gabapentin prodrug had significantly greater improvement (decreases) in IRLS scores at doses of 1,800 mg (20.4–8.4 vs. 20.4–18.5) and 1,200 mg (22.4–6.3 vs. 22.4–13.5) at the end of the 2-week trial. The patients who received XP13512 at 1,200 mg also had significantly greater improvement than those who received 600 mg. Clinical global impressions of change from both patients and investigators followed the same trend and were significantly in favor of patients who received XP13512, reported Dr. Walters, who received compensation for consulting with XenoPort.

Polysomnographic assessments in the crossover study found that patients had significantly more total sleep time (25 minutes) while receiving the gabapentin prodrug than with placebo. In both studies, patients who received XP13512 had significantly fewer awakenings and spent less time awake per night because of RLS symptoms.

More than 30% of patients who received either 1,200 mg or 1,800 mg of XP13512 experienced somnolence. Dizziness also occurred in 28% of patients at 1,800 mg and in 18% at 1,200 mg. In most cases, the events were transient and mild. Other adverse events occurred at much lower rates, and none were serious.

CHICAGO – An investigational gabapentin prodrug may be an effective therapy for symptoms and sleep problems associated with restless legs syndrome, Dr. Arthur S. Walters reported at the annual meeting of the American Neurological Association.

The active compound gabapentin has already been shown to improve the sensory and motor symptoms of restless legs syndrome (RLS) and decrease periodic leg movements during sleep, but the drug is approved only for treating epilepsy and postherpetic neuralgia, according to Dr. Walters of the Seton Hall University School of Graduate Medical Education, Edison, N.J.

The gabapentin prodrug XP13512 has several potential advantages over standard gabapentin for treating RLS: The agent has linear pharmacokinetics, doesn't reach a saturation point, and is formulated for sustained release. The capacity for once-daily dosing differentiates gabapentin prodrug XP13512 from the active compound gabapentin (Neurontin), which cannot be manufactured in a sustained-release delivery and must be taken three to four times per day, Dr. Walters discussed on his poster at the meeting.

XenoPort Inc., the drug's manufacturer, has sponsored two phase II, randomized, double-blind trials. One of these trials was a crossover study with 38 patients testing 1,800 mg XP13512 against placebo. The other trial compared XP13512 at 600 mg and 1,200 mg and placebo in 95 patients without any crossover. In both studies, patients had RLS symptoms at least 4 nights during a 7-day baseline period and had a score of at least 15 (out of a possible 40) on the International RLS Study Group rating scale (IRLS). Most patients were white, and mean age was about 50 years.

Compared with patients given placebo, patients treated with the gabapentin prodrug had significantly greater improvement (decreases) in IRLS scores at doses of 1,800 mg (20.4–8.4 vs. 20.4–18.5) and 1,200 mg (22.4–6.3 vs. 22.4–13.5) at the end of the 2-week trial. The patients who received XP13512 at 1,200 mg also had significantly greater improvement than those who received 600 mg. Clinical global impressions of change from both patients and investigators followed the same trend and were significantly in favor of patients who received XP13512, reported Dr. Walters, who received compensation for consulting with XenoPort.

Polysomnographic assessments in the crossover study found that patients had significantly more total sleep time (25 minutes) while receiving the gabapentin prodrug than with placebo. In both studies, patients who received XP13512 had significantly fewer awakenings and spent less time awake per night because of RLS symptoms.

More than 30% of patients who received either 1,200 mg or 1,800 mg of XP13512 experienced somnolence. Dizziness also occurred in 28% of patients at 1,800 mg and in 18% at 1,200 mg. In most cases, the events were transient and mild. Other adverse events occurred at much lower rates, and none were serious.

CHICAGO – An investigational gabapentin prodrug may be an effective therapy for symptoms and sleep problems associated with restless legs syndrome, Dr. Arthur S. Walters reported at the annual meeting of the American Neurological Association.

The active compound gabapentin has already been shown to improve the sensory and motor symptoms of restless legs syndrome (RLS) and decrease periodic leg movements during sleep, but the drug is approved only for treating epilepsy and postherpetic neuralgia, according to Dr. Walters of the Seton Hall University School of Graduate Medical Education, Edison, N.J.

The gabapentin prodrug XP13512 has several potential advantages over standard gabapentin for treating RLS: The agent has linear pharmacokinetics, doesn't reach a saturation point, and is formulated for sustained release. The capacity for once-daily dosing differentiates gabapentin prodrug XP13512 from the active compound gabapentin (Neurontin), which cannot be manufactured in a sustained-release delivery and must be taken three to four times per day, Dr. Walters discussed on his poster at the meeting.

XenoPort Inc., the drug's manufacturer, has sponsored two phase II, randomized, double-blind trials. One of these trials was a crossover study with 38 patients testing 1,800 mg XP13512 against placebo. The other trial compared XP13512 at 600 mg and 1,200 mg and placebo in 95 patients without any crossover. In both studies, patients had RLS symptoms at least 4 nights during a 7-day baseline period and had a score of at least 15 (out of a possible 40) on the International RLS Study Group rating scale (IRLS). Most patients were white, and mean age was about 50 years.

Compared with patients given placebo, patients treated with the gabapentin prodrug had significantly greater improvement (decreases) in IRLS scores at doses of 1,800 mg (20.4–8.4 vs. 20.4–18.5) and 1,200 mg (22.4–6.3 vs. 22.4–13.5) at the end of the 2-week trial. The patients who received XP13512 at 1,200 mg also had significantly greater improvement than those who received 600 mg. Clinical global impressions of change from both patients and investigators followed the same trend and were significantly in favor of patients who received XP13512, reported Dr. Walters, who received compensation for consulting with XenoPort.

Polysomnographic assessments in the crossover study found that patients had significantly more total sleep time (25 minutes) while receiving the gabapentin prodrug than with placebo. In both studies, patients who received XP13512 had significantly fewer awakenings and spent less time awake per night because of RLS symptoms.

More than 30% of patients who received either 1,200 mg or 1,800 mg of XP13512 experienced somnolence. Dizziness also occurred in 28% of patients at 1,800 mg and in 18% at 1,200 mg. In most cases, the events were transient and mild. Other adverse events occurred at much lower rates, and none were serious.