Citations

Health promotion programs may target a variety of behaviors including weight loss, exercise, stress, nutrition, or other risk factors. Comparing the outcomes of diverse programs is hampered by the absence of a common metric. Overall self-rated health has been used as a health outcome measure in population studies and in some primary care studies, but its potential use to monitor the outcomes of health programs is unexplored. The purpose of this study was to compare the outcomes of 4 health promotion programs using change in overall self-rated health as a common metric. Program-specific metrics used were weight change, change in minutes of exercise, change in stress management activities, and change in healthy nutrition practices. We found that, although all of our lifestyle interventions positively affected the program-specific metrics, only the weight loss and exercise programs showed improvement in specific metrics correlated with improvements in overall self-rated health. ( Population Health Management 2010;13:91–95)

A recently identified variant within the fat mass and obesity-associated ( FTO ) gene is carried by 46% of Western Europeans and is associated with an ~1.2 kg higher weight, on average, in adults and an ~1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of ~8% in the frontal lobes and 12% in the occipital lobes—these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly.

We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH ( P < 10 −75 ), ARMS2 ( P < 10 −59 ), C2/CFB ( P < 10 −20 ), C3 ( P < 10 −9 ), and CFI ( P < 10 −6 ). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 × 10 −11 ), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci ( LIPC , P = 1.3 × 10 −7 ; CETP , P = 7.4 × 10 −7 ) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c—associated alleles near LPL ( P = 3.0 × 10 −3 ) and ABCA1 ( P = 5.6 × 10 −4 ). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.

Abstract Mortality in National Heart, Lung and Blood Institute–sponsored clinical trials of treatments for acute lung injury (ALI) has decreased dramatically during the past two decades. As a consequence, design of such trials based on a mortality outcome requires ever-increasing numbers of patients. Recognizing that advances in clinical trial design might be applicable to these trials and might allow trials with fewer patients, the National Heart, Lung and Blood Institute convened a workshop of extramural experts from several disciplines. The workshop assessed the current state of clinical research addressing ALI, identified research needs, and recommended: (1) continued performance of trials evaluating treatments of patients with ALI; (2) development of strategies to perform ALI prevention trials; (3) observational studies of patients without ALI undergoing prolonged mechanical ventilation; and (4) development of a standardized format for reporting methods, endpoints, and results of ALI trials.

To further characterize spontaneous diabetes mellitus in cynomolgus macaques ( Macaca fascicularis) as a model for human non-insulin-dependent diabetes mellitus (NIDDM), we evaluated the morphologic characteristics of the endocrine pancreas of 4 diabetic and 12 age-matched nondiabetic cynomolgus macaques. In addition, the cDNA-predicted amino acid sequence for islet amyloid polypeptide (IAPP) of this species was determined. Islet amyloid deposits exhibiting typical congophilia and green birefringence were found in 4/4 diabetic animals and in 8/12 nondiabetics. Islet amyloid deposits were significantly more extensive in the diabetic macaques ( P = 0.001), in which they occupied a mean of 60% of the islet area. In contrast, in the nondiabetic group the maximum islet area occupied by amyloid was 24% (group mean = 6.8%), with four animals having no detectable islet amyloid. Amyloid deposits consistently showed immunoreactivity for IAPP but not for insulin. Comparisons between group means for diabetic versus nondiabetic macaques showed significantly greater islet area ( P = 0.01, 85,390 versus 36,540 μm 2 ) and significantly greater islet area fraction ( P = 0.02, 0.065 versus 0.032) for the diabetic group. The cDNA-predicted amino acid sequence for cynomolgus IAPP was identical to that previously reported for pig-tail macaques ( M. nemestrina) and had 92%, 86%, and 84% amino acid sequence identity with human, domestic cat, and murine IAPPs, respectively. These findings support the use of cynomolgus macaques as an animal model of human NIDDM.

Abstract Pancreatic cancer is the fourth leading cause of cancer deaths in the United States, with an overall 5-year survival rate of &lt;5%. Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, is highly resistant to conventional chemotherapies, underscoring the critical need for new molecular targets for pancreatic cancer chemotherapy. The KRAS proto-oncogene is mutated in &gt;90% of PDAC. Protein kinase Cι (PKCι) is required for the oncogenic Ras–mediated transformed growth of lung cancer and intestinal epithelial cells. However, little is known about the role of PKCι in pancreatic cancer. In this study, we evaluated the expression of PKCι in human pancreatic cancer and the requirement for PKCι for the transformed growth and tumorigenicity of PDAC cells. We find that PKCι is significantly overexpressed in human pancreatic cancer, and high PKCι expression correlates with poor patient survival. Inhibition of PKCι expression blocks PDAC cell transformed growth in vitro and tumorigenicity in vivo. Inhibition of PKCι expression in pancreatic tumors also significantly reduces tumor angiogenesis and metastasis. Analysis of downstream PKCι effectors implicates the Rac1-MEK/ERK1/2 signaling axis in PKCι-mediated transformed growth and cellular invasion. Taken together, our data show a required role for PKCι in the transformed growth of pancreatic cancer cells and reveal a novel role for PKCι in pancreatic cancer cell metastasis and angiogenesis in vivo. Our results strongly indicate that PKCι will be an effective target for pancreatic cancer therapy. Cancer Res; 70(5); 2064–74