Lipoprotein Genotype and Conserved Pathway for Exceptional Longevity in Humans

Alteration of single genes involved in nutrient and lipoprotein metabolism increases longevity in several animal models. Because exceptional longevity in humans is familial, it is likely that polymorphisms in genes favorably influence certain phenotypes and increase the likelihood of exceptional longevity. A group of Ashkenazi Jewish centenarians ( n = 213), their offspring ( n = 216), and an age-matched Ashkenazi control group ( n = 258) were genotyped for 66 polymorphisms in 36 candidate genes related to cardiovascular disease (CVD). These genes were tested for association with serum lipoprotein levels and particle sizes, apolipoprotein A1, B, and C-3 levels and with outcomes of hypertension, insulin resistance, and mortality. The prevalence of homozygosity for the −641C allele in the APOC3 promoter (rs2542052) was higher in centenarians (25%) and their offspring (20%) than in controls (10%) ( p = 0.0001 and p = 0.001, respectively). This genotype was associated with significantly lower serum levels of APOC3 and a favorable pattern of lipoprotein levels and sizes. We found a lower prevalence of hypertension and greater insulin sensitivity in the −641C homozygotes, suggesting a protective effect against CVD and the metabolic syndrome. Finally, in a prospectively studied cohort, a significant survival advantage was demonstrated in those with the favorable −641C homozygote ( p < 0.0001). Homozygosity for the APOC3 −641C allele is associated with a favorable lipoprotein profile, cardiovascular health, insulin sensitivity, and longevity. Because modulation of lipoproteins is also seen in genetically altered longevity models, it may be a common pathway influencing lifespan from nematodes to humans

Morbid Obesity as Early Manifestation of Occult Hypothalamic-Pituitary LCH with Delay in Treatment

Morbid obesity presents unique challenges in managing additional disease processes. A 16-year-old male with a history of central diabetes insipidus (DI) and hypothyroidism developed destructive lesions in both his right mandible and brain, which were not discovered until the patient presented for tinnitus, 8 years after his initial diagnosis with DI. Langerhans cell histiocytosis (LCH) was diagnosed on pathologic biopsy. The patient’s initial body mass index (BMI) was 54.5 kg/m2 so a unique treatment approach with single agent cladribine (2-CdA) was offered as traditional steroid therapy could worsen his endocrine dysfunction. The patient presented with neurodegenerative sequelae from the central LCH, possibly due to a delay in diagnosis and therapy. This case highlights difficulties in managing obese patients in an oncology setting and provides an illustrative case of how obesity may mask other comorbid conditions. Close supervision of complex obese patients with coordinated endocrinology and oncology care is vital. For the primary care practitioner, monitoring abrupt changes in BMI with serial cranial imaging may lead to a prompt diagnosis and prevention of further neurodegenerative effects. The use of 2-CdA was found to successfully bring the patient’s LCH into remission without the additional risks of steroid therapy in a morbidly obese patient

Promoting Active Living and Healthy Eating among Inner-City Youth through Community Health Workers: From Clinic to Neighborhood

The promotion of physical activity and healthy eating to prevent obesity among youth is a pressing challenge. The current study examined the feasibility of community health workers (CHWs) con-ducting a physical activity (PA) and healthy eating intervention strategy with links to community supports and programs. Youth aged 10- 18 years were recruited from three clinical sites serving inner-city families. Trained CHWs conducted assessment and counseling for PA and healthy eating among youth and their families and provided customized plans and navigation to neighborhood PA and nutrition programs. Measures of daily PA by self-report, weekday and weekend day se-dentary behaviors, fruit and vegetable intake, avoidance of fatty foods, and avoidance of sugary drinks were assessed at baseline and follow-up. Twenty-five patients (mean age = 12.9 years) were exposed to ~9 months of intervention from baseline. Pre- and post-assessments revealed significant changes in reported PA, sedentary behaviors on weekdays, sedentary behaviors on weekend days, fruit and vegetable intake, avoidance of fatty foods, and avoidance of sugary drinks

Survival Analysis according to <i>APOC3</i> Genotypes

<div><p>Of the 381 participants we genotyped since 1998, 64 had the −641 CC genotype. To describe the relationship between genotype and death, we plotted the Kaplan–Meier survival function estimates of probands and controls by <i>APOC3</i> genotype. Offspring were excluded in this analysis because all participants are currently alive and offspring genotype/phenotype is not independent of the probands. </p> <p>Log-Rank ( <i>p</i> = 0.0008); Wilcoxon ( <i>p</i> = 0.0007). </p> <p>CC, homozygous for (−641) C; CA/AA, homozygous and heterozygous for (−641) A.</p></div

Distribution of “Favorable” Gene Polymorphisms of <i>APOC3, APOA4,</i> and <i>CETP</i> in the Study Population

<p>The genotype frequencies of the favorable gene polymorphisms of <i>APOC3 C(</i>− <i>641)A</i> and <i>CETP</i> I405V were analyzed in controls and probands (60 to 100 y old). (Offspring were not included in this analysis due to the genotype dependency of this group on proband genotypes.) The frequency of these two variants was found to be higher among centenarians, with a monotonic increase with age. Other polymorphisms in these same genes ( <i>APOC3</i> (−455) TT, <i>APOA4</i> 347 TT, and <i>APOA4</i> 360 EE) showed no differences in genotype frequency with age. </p

Haplotype Structure of <i>APOC3</i> and <i>APOA4</i> and <i>CETP</i>

<div><p>Ordinal arrangement of 15 SNP associated with CVD and lipoprotein metabolism, according to their position on chromosomes with LD (number in boxes) where the highest rate is represented in red and no LD in lilac. Blocks define potential haplotypes between two clustered genes.</p> <p>(A) <i>APOC3</i> and <i>APOA4.</i></p> <p>(B) <i>CETP.</i></p></div

Genotype Distribution of <i>APOC3</i> C(−641)A and Serum APOC3 Concentrations

<div><p>(A) <i>APOC3</i> C(−641)A. </p> <p>(B) Serum APOC3.</p> <p>* <i>p</i> < 0.05, ** <i>p</i> = 0.001 versus control. </p> <p>CC, homozygous for (−641) C; AA, homozygous for (−641) A; CA, heterozygous for (−641) C/A.</p></div

Identifying Gaps in the Performance of Pediatric Trainees Who Receive Marginal/Unsatisfactory Ratings

Purpose To perform a derivation study to determine in which subcompetencies marginal/unsatisfactory pediatric residents had the greatest deficits compared with their satisfactorily performing peers and which subcompetencies best discriminated between marginal/unsatisfactory and satisfactorily performing residents. Method Multi-institutional cohort study of all 21 milestones (rated on four or five levels) reported to the Accreditation Council for Graduate Medical Education, and global marginal/unsatisfactory versus satisfactory performance reported to the American Board of Pediatrics. Data were gathered in 2013-2014. For each level of training (postgraduate year [PGY] 1, 2, and 3), mean differences between milestone levels of residents with marginal/unsatisfactory and satisfactory performance adjusted for clustering by program and C-statistics (area under receiver operating characteristic curve) were calculated. A Bonferroni-corrected significance threshold of.0007963 was used to account for multiple comparisons. Results Milestone and overall performance evaluations for 1,704 pediatric residents in 41 programs were obtained. For PGY1s, two subcompetencies had almost a one-point difference in milestone levels between marginal/unsatisfactory and satisfactory trainees and outstanding discrimination (≥ 0.90): organize/prioritize (0.93; C-statistic: 0.91) and transfer of care (0.97; C-statistic: 0.90). The largest difference between marginal/unsatisfactory and satisfactory PGY2s was trustworthiness (0.78). The largest differences between marginal/unsatisfactory and satisfactory PGY3s were ethical behavior (1.17), incorporating feedback (1.03), and professionalization (0.96). For PGY2s and PGY3s, no subcompetencies had outstanding discrimination. Conclusions Marginal/unsatisfactory pediatric residents had different subcompetency gaps at different training levels. While PGY1s may have global deficits, senior residents may have different performance deficiencies requiring individualized counseling and targeted performance improvement plans