Publications

BACKGROUND

AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme that is evolutionarily conserved from yeast to mammals and functions to maintain cellular and whole body energy homeostasis. Studies in experimental animals demonstrate that activation of AMPK in skeletal muscle protects against insulin resistance, type 2 diabetes and obesity. The regulatory gamma(3) subunit of AMPK is expressed exclusively in skeletal muscle; however, its importance in controlling overall AMPK activity is unknown. While evidence is emerging that gamma subunit mutations interfere specifically with AMP activation, there remains some controversy regarding the impact of gamma subunit mutations. Here we report the first gain-of-function mutation in the muscle-specific regulatory gamma(3) subunit in humans.

METHODS AND FINDINGS

We sequenced the exons and splice junctions of the AMPK gamma(3) gene (PRKAG3) in 761 obese and 759 lean individuals, identifying 87 sequence variants including a novel R225W mutation in subjects from two unrelated families. The gamma(3) R225W mutation is homologous in location to the gamma(2)R302Q mutation in patients with Wolf-Parkinson-White syndrome and to the gamma(3)R225Q mutation originally linked to an increase in muscle glycogen content in purebred Hampshire Rendement Napole (RN-) pigs. We demonstrate in differentiated muscle satellite cells obtained from the vastus lateralis of R225W carriers that the mutation is associated with an approximate doubling of both basal and AMP-activated AMPK activities. Moreover, subjects bearing the R225W mutation exhibit a approximately 90% increase of skeletal muscle glycogen content and a approximately 30% decrease in intramuscular triglyceride (IMTG).

CONCLUSIONS

We have identified for the first time a mutation in the skeletal muscle-specific regulatory gamma(3) subunit of AMPK in humans. The gamma(3)R225W mutation has significant functional effects as demonstrated by increases in basal and AMP-activated AMPK activities, increased muscle glycogen and decreased IMTG. Overall, these findings are consistent with an important regulatory role for AMPK gamma(3) in human muscle energy metabolism.

BACKGROUND

Certain medications are identified by the U.S. Food and Drug Administration (FDA) as class D or X because they increase the risk for birth defects if used during pregnancy.

OBJECTIVE

To assess pregnancy rates and the frequency of contraceptive counseling documented with prescriptions for class D or X drugs filled by women of reproductive age.

DESIGN

Description of prescriptions filled in 2001.

SETTING

A large health maintenance organization in northern California in 2001.

PATIENTS

488,175 women age 15 to 44 years who filled a total of 1,011,658 class A, B, D, or X prescriptions.

MEASUREMENTS

Medications dispensed, contraceptive counseling, and pregnancy testing.

RESULTS

A class D or X prescription was filled by 1 of every 6 women studied. Women who filled a prescription for class D or X medications were no more likely than women who filled prescriptions for safer, class A or B medications to have received contraceptive counseling, filled a contraceptive prescription, or been sterilized (48% vs. 51% of prescriptions). There was little variation by clinical indication in rates of contraceptive counseling with class D or X prescriptions, except for isotretinoin. Women who filled a class D or X prescription were only slightly less likely to have a pregnancy documented within 3 months than women filling a class A or B prescription (1.0% vs. 1.4% of prescriptions).

LIMITATIONS

International Classification of Diseases, Ninth Revision, codes underestimate contraceptive counseling. Documentation of a positive pregnancy test after filling a prescription may overestimate medication use in early pregnancy. Women who filled several prescriptions are overrepresented in prescription analyses.

CONCLUSION

Prescriptions for potentially teratogenic medications are frequently filled by women of childbearing age without documentation of contraceptive counseling.

INTRODUCTION

Studies show that the recommendations of a primary care physician for colorectal cancer screening may be one important influence on an individual's use of screening. However, another possible influence, the effect of regional differences in physicians' beliefs and recommendations on screening use, has not been assessed.

METHODS

We linked data from the National Health Interview Survey on the use of colorectal cancer screening by respondents aged 50 years or older, by hospital-referral region, with data from the Survey of Colorectal Cancer Screening Practices on the colorectal cancer screening recommendations of primary care physicians, by region. Our principal independent variables were the proportion of physicians in a region who recommended screening at age 50 and continuing screening at the recommended frequency.

RESULTS

On average, 53.3% of physicians in a region correctly recommended initiating colorectal cancer screening, and 64.8% advised screening at the recommended frequency. Of adults who lived in regions where less than 30% of physicians correctly recommended initiating screening, 47.3% had been screened, in contrast to 54.8% in areas where 70% or more of physicians made correct recommendations. Seventy-one percent of respondents living in regions where less than 30% of physicians advised screening at the recommended frequency were current on screening, in contrast to 79.9% of respondents living in regions where 70% or more of physicians made this recommendation. These differences were statistically significant after adjustment for individual characteristics.

CONCLUSION

Strategies to improve colorectal cancer screening recommendations of primary care physicians may improve the use of screening for millions of Americans.

The permeability barrier is required for terrestrial life and is localized to the stratum corneum, where extracellular lipid membranes inhibit water movement. The lipids that constitute the extracellular matrix have a unique composition and are 50% ceramides, 25% cholesterol, and 15% free fatty acids. Essential fatty acid deficiency results in abnormalities in stratum corneum structure function. The lipids are delivered to the extracellular space by the secretion of lamellar bodies, which contain phospholipids, glucosylceramides, sphingomyelin, cholesterol, and enzymes. In the extracellular space, the lamellar body lipids are metabolized by enzymes to the lipids that form the lamellar membranes. The lipids contained in the lamellar bodies are derived from both epidermal lipid synthesis and extracutaneous sources. Inhibition of cholesterol, fatty acid, ceramide, or glucosylceramide synthesis adversely affects lamellar body formation, thereby impairing barrier homeostasis. Studies have further shown that the elongation and desaturation of fatty acids is also required for barrier homeostasis. The mechanisms that mediate the uptake of extracutaneous lipids by the epidermis are unknown, but keratinocytes express LDL and scavenger receptor class B type 1, fatty acid transport proteins, and CD36. Topical application of physiologic lipids can improve permeability barrier homeostasis and has been useful in the treatment of cutaneous disorders.