Dominant mutations in the amyloid precursor protein (APP) gene are associated with rare cases of familial Alzheimer's disease; however, the normal functions of APP and related proteins remain unclear. The nematode Caenorhabditis elegans has a single APP-related gene, apl-1, that is expressed in multiple tissues. Loss of apl-1 disrupts several developmental processes, including molting and morphogenesis, and results in larval lethality. The apl-1 lethality can be rescued by neuronal expression of the extracellular domain of APL-1. These data highlight the importance of the extracellular domain of an APP family member and suggest that APL-1 acts noncell-autonomously during development. Overexpression of APL-1 also causes several defects, including a high level of larval lethality. Decreased activity of sel-12, a C. elegans homologue of the human ␥-secretase component presenilin 1, partially rescues the lethality associated with APL-1 overexpression, suggesting that SEL-12 activity regulates APL-1 activity either directly or indirectly. Determining the in vivo functions of APP in mammals is complicated by the presence of two APP-related genes, APLP1 and APLP2 (for review see ref. 5). APP and APP-related proteins share two conserved domains in the extracellular region (E1 and E2) and one in the cytoplasmic domain, but the APP-related proteins do not contain the ␤-amyloid peptide (5). Mice in which APP, APLP1, or APLP2 is inactivated are viable and have minor behavioral and growth deficits (6-8). However, inactivation of APLP2 and either APP or APLP1 results in early postnatal lethality (6,8), indicating that the APP family is essential for viability. The brains of double knockout animals exhibit no obvious morphological defects (6, 8). By contrast, animals in which the entire APP gene family is inactivated show cortical dysplasia and type 2 lissencephaly, indicating that the APP gene family is necessary for neurodevelopment and adhesion (9).Although no APP gene has been identified in Drosophila melanogaster or Caenorhabditis elegans, each organism contains a single APP-related gene (10, 11). Inactivation of the Drosophila APP-related gene, Appl, causes abnormal synaptic differentiation (12), axonal transport (13,14), and phototactic behavior (15), the latter of which can be partially rescued with a human APP transgene (15). Expression of human APP in Drosophila wing imaginal discs results in a blistered wing phenotype, showing that overexpression of APP can disrupt cell adhesion in the transgenic animals (16).In this article, we examine the role of apl-1 in C. elegans. Zambrano et al. (17) have reported mild pharyngeal defects when apl-1 activity is decreased by dsRNA-mediated interference by feeding. We genetically inactivated apl-1 and found that, like the mammalian APP gene family, apl-1 has an essential role in C. elegans. In particular, APL-1 is necessary for proper molting and morphogenesis. Furthermore, expression of the extracellular domain of APL-1 in neurons is sufficient to rescue the apl-1 lethality. Th...

OBJECTIVEThe purpose of this study was to describe the incidence of type 1 diabetes in children in Philadelphia from 2000–2004, compare the epidemiology to the previous three cohorts in the Philadelphia Pediatric Diabetes Registry, and, for the first time, describe the incidence of type 2 diabetes.RESEARCH DESIGN AND METHODSDiabetes cases were obtained through a retrospective population-based registry. Hospital inpatient and outpatient records were reviewed for cases of type 1 and type 2 diabetes diagnosed from 1 January 2000 to 31 December 2004. The secondary source of validation was the School District of Philadelphia. Time series analysis was used to evaluate the changing pattern of incidence over the 20-year period.RESULTSThe overall age-adjusted incidence rate in 2000–2004 of 17.0 per 100,000 per year was significantly higher than that of previous cohorts, with an average yearly increase of 1.5% and an average 5-year cohort increase of 7.8% (P = 0.025). The incidence in white children (19.2 per 100,000 per year) was 48% higher than in the previous cohort. Children aged 0–4 years had a 70% higher incidence (12.2 per 100,000 per year) than the original cohort; this increase was most marked in young black children. The overall age-adjusted incidence of type 2 diabetes was 5.8 per 100,000 per year and was significantly higher in black children.CONCLUSIONSThe incidence of type 1 diabetes is rising among children in Philadelphia. The incidence rate has increased by 29% since the 1985–1989 cohort. The most marked increases were among white children ages 10–14 years and black children ages 0–4 years. The incidence of type 1 diabetes is 18 times higher than that of type 2 in white children but only 1.6 times higher in black children.

These discordant findings suggest a differential effect of vitamin D on cardiovascular risk factors such as oxidative stress and insulin resistance. To confirm these findings, further prospective studies with larger sample size and longer follow-up are warranted.