Evidence for age as a modifier of genetic associations for lipid levels

In order to identify novel genetic variants that influence plasma lipid concentrations, we performed a genome-wide association study (GWAS) comprised of 411 children under 18 years of age, ascertained at St. Jude Children's Research Hospital, all of whom were of European, African, or Mexican descent. Promising associations (p < 10(-5)) were subsequently examined in 1040 additional youths and 3508 adults from the Third National Health and Nutrition Examination Survey (NHANES III), a diverse population-based study. Three genotype-phenotype associations replicated in NHANES III youths and three associated in NHANES III adults at p < 0.05; however, no single association was significant in both youths and adults. The most significant association (p= 0.009) in NHANES III youths was between low-density lipoprotein cholesterol (LDL-C) and intronic rs2429917 among participants of African descent. Given the known age dependency of lipid levels, we also tested for gene-age interactions in NHANES III participants across all ages. We identified a significant (p= 0.024) age-dependent association between SGSM2 rs2429917 and LDL-C. This finding illustrates the utility of using children to discover novel variants associated with complex phenotypes and the importance of considering age-dependent genetic effects in association studies of lipid levels.     

Developmental expression of cell cycle regulators in the baboon fetal adrenal gland

Although the human and the nonhuman primate fetal adrenal glands undergo a highly unique pattern of cortical zone-specific intrauterine growth and development, studies of the regulatory components of the cell cycle responsible for this growth have not been conducted. Therefore, the present study determined expression of the cell cycle regulators, cyclin D1 and cyclin E, and their cyclin-dependent kinases, Cdk2, Cdk4, and Cdk6, and Ki67 a marker of cell proliferation within the baboon fetal adrenal cortex during advancing stages of gestation. Fetal adrenal glands were obtained on days 60 (early), 100 (mid), and 160-170 (late) of gestation (term = 184 days). Mean (+/- s.e.) cyclin D1 mRNA levels, determined by RT-PCR and expressed relative to 18S rRNA, were similar at early (0.85 +/- 0.09) and mid (1.04 +/- 0.08) gestation, then decreased (P < 0.001, ANOVA) approximately 50% by late gestation (0.57 +/- 0.04). Cyclin E mRNA levels were also similar at early (2.03 +/- 0.07) and mid (1.63 +/- 0.31) gestation, and decreased by 70% (P < 0.001) in late gestation (0.53 +/- 0.09). Coinciding with the decrease in cyclin D1 and cyclin E, the percentage of Ki67 positive cells in the definitive zone decreased twofold (P < 0.01) between mid (28.2 +/- 3.6) and late (13.8 +/- 1.7) gestation. The cyclin D1 and cyclin E proteins, determined by immunocytochemistry, were expressed at high levels in the definitive zone of baboon fetal adrenal gland, where they decreased between mid- and late gestation. In contrast, immunocytochemical expression of the functionally important steroidogenic enzyme Delta(5)-3beta-hydroxysteroid dehydrogenase (3beta-HSD) became abundant in the definitive and transitional zones with advancing pregnancy. However, fetal adrenal Cdk2, Cdk4, and Cdk6 mRNA levels and protein immunoexpression were similar in the baboon fetal adrenal at early-, mid-, and late gestation. In summary, expression of cyclin D1, cyclin E, and Ki67 decreased, while 3beta-HSD expression increased, in the fetal adrenal cortex, particularly in the definitive zone, between mid- and late-baboon gestation. We propose that a developmental decline in cellular proliferation permits functional differentiation of fetal adrenal cortical cells, leading to increased production of steroid hormones important for placental estrogen synthesis and maturation of organ systems within the developing fetus.     

The “polymorphous” history of a polymorphous skull bone: the sphenoid

For a long time, because of its location at the skull base level, the sphenoid bone was rather mysterious as it was too difficult for anatomists to reach and to elucidate its true configuration. The configuration of the sphenoid bone led to confusion regarding its sutures with the other skull bones, its shape, its detailed anatomy, and the vascular and nervous structures that cross it. This article takes the reader on a journey through time and space, charting the evolution of anatomists’ comprehension of sphenoid bone morphology from antiquity to its conception as a bone structure in the eighteenth century, and ranging from ancient Greece to modern Italy and France. The journey illustrates that many anatomists have attempted to name and to best describe the structural elements of this polymorphous bone.     

MANAGEMENT OF NIDDM BY FAMILY DOCTORS IN HONG KONG: A QUESTIONNAIRE SURVEY

The management approach to non-insulin-dependent diabetes mellitus among family doctors in Hong Kong was studied using two case histories. In 1996, all 804 fellows, members and associate members of the Hong Kong College of Family Physicians were sent a letter and a questionnaire. Of the 512 who responded, 405 were male and 95 were female (12 were discarded) with ages ranging from 24 to 77 years (median 40). For the 48-year-old obese man who showed improvements in blood glucose and symptoms after diet for 6 weeks (Case 1), most respondents suggested adding a sulphonylurea (39.0%) or metformin (21.1%), or continuing diet (35.2%). Younger and more junior doctors tended to use metformin plus diet. Of 192 respondents who wanted to use a sulphonylurea, gliclazide (45.8%) and glibenclamide (42.7%) were chosen most often. For the 76-year-old overweight woman with symptomatic diabetes despite diet therapy (Case 2), most respondents suggested adding a sulphonylurea (41.9%), metformin (25.6%) or both (19.2%). Younger and more junior doctors tended to use metformin plus diet, whereas older doctors tended to use insulin plus diet. Older and more experienced doctors tended to use diet plus metformin and sulphonylurea. Of 208 respondents who wanted to use a sulphonylurea, gliclazide (47.8%) and glibenclamide (30.1%) were chosen most often. The management approach to NIDDM varied with the age and experience of the doctor.