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Correlation of paired liver biopsies in morbidly obese patients with suspected nonalcoholic fatty liver disease

Merriman, Raphael B; Ferrell, Linda D; Patti, Marco G; Weston, Shiobhan R; Pabst, Mark S; Aouizerat, Bradley E; Bass, Nathan M
In the absence of surrogate markers, the evaluation of suspected nonalcoholic fatty liver disease (NAFLD) is highly dependent on histological examination. The extent of sampling variability affecting the reliability of a single liver biopsy in patients with suspected NAFLD is poorly characterized. This prospective study aimed to correlate precise histological findings in paired biopsies--right and left lobe--in the diagnosis of NAFLD in morbidly obese subjects undergoing bariatric surgery employing both Brunt and Matteoni classifications and the NAFLD Activity Score (NAS). We also aimed to determine whether the composite histopathological findings of the two biopsies would improve diagnostic accuracy. Consecutive subjects had an intraoperative biopsy from both right and left lobes, evaluated and scored in a blinded manner. Intraobserver agreement was also assessed. Kappa coefficients of agreement were calculated. Forty-one subjects had acceptable biopsies. Agreement for steatosis was excellent and moderate for fibrosis. Concordance was only fair for most features of necroinflammation. Intraobserver agreement was only moderate for lobular inflammation. Excellent agreement was seen for the diagnosis of NASH using Brunt criteria and good agreement when using Matteoni and NAS scoring systems. Composite biopsy data particularly improved identification of hepatocyte ballooning. The diagnostic accuracy also improved substantially when composite features were compared with single-sided biopsy features, especially for the Matteoni and NAS scoring systems. In conclusion, significant sampling variability occurs in NAFLD, particularly for features of necroinflammation. This should be factored into the design of clinical trials and studies of the natural history of the disease.
PMID: 17006934
ISSN: 0270-9139
CID: 1564482

Subgroups of patients with cancer with different symptom experiences and quality-of-life outcomes: a cluster analysis

Miaskowski, Christine; Cooper, Bruce A; Paul, Steven M; Dodd, Marylin; Lee, Kathryn; Aouizerat, Bradley E; West, Claudia; Cho, Maria; Bank, Alice
PURPOSE/OBJECTIVES: To identify subgroups of outpatients with cancer based on their experiences with the symptoms of fatigue, sleep disturbance, depression, and pain; to explore whether patients in the subgroups differed on selected demographic, disease, and treatment characteristics; and to determine whether patients in the subgroups differed on two important patient outcomes: functional status and quality of life (QOL). DESIGN: Descriptive, correlational study. SETTING: Four outpatient oncology practices in northern California. SAMPLE: 191 outpatients with cancer receiving active treatment. METHODS: Patients completed a demographic questionnaire, Karnofsky Performance Status scale, Lee Fatigue Scale, General Sleep Disturbance Scale, Center for Epidemiological Studies Depression Scale, Multidimensional Quality-of-Life Scale Cancer, and a numeric rating scale of worst pain intensity. Medical records were reviewed for disease and treatment information. Cluster analysis was used to identify patient subgroups based on patients symptom experiences. Differences in demographic, disease, and treatment characteristics as well as in outcomes were evaluated using analysis of variance and chi square analysis. MAIN RESEARCH VARIABLES: Subgroup membership, fatigue, sleep disturbance, depression, pain, functional status, and QOL. FINDINGS: Four relatively distinct patient subgroups were identified based on patients experiences with four highly prevalent and related symptoms. CONCLUSIONS: The subgroup of patients who reported low levels of all four symptoms reported the best functional status and QOL. IMPLICATIONS FOR NURSING: The findings from this study need to be replicated before definitive clinical practice recommendations can be made. Until that time, clinicians need to assess patients for the occurrence of multiple symptoms that may place them at increased risk for poorer outcomes.
PMID: 16955115
ISSN: 1538-0688
CID: 1564492

The lipoprotein lipase gene in combined hyperlipidemia: evidence of a protective allele depletion

Wung, Shu-Fen; Kulkarni, Medha V; Pullinger, Clive R; Malloy, Mary J; Kane, John P; Aouizerat, Bradley E
BACKGROUND: Lipoprotein Lipase (LPL), a key enzyme in lipid metabolism, catalyzes the hydrolysis of triglycerides (TG) from TG-rich lipoproteins, and serves a bridging function that enhances the cellular uptake of lipoproteins. Abnormalities in LPL function are associated with pathophysiological conditions, including familial combined hyperlipidemia (FCH). Whereas two LPL susceptibility alleles were found to co-segregate in a few FCH kindred, a role for common, protective alleles remains unexplored. The LPL Ser447Stop (S447X) allele is associated with anti-atherogenic lipid profiles and a modest reduction in risk for coronary disease. We hypothesize that significant depletion of the 447X allele exists in combined hyperlipidemia cases versus controls. A case-control design was employed. The polymorphism was assessed by restriction assay in 212 cases and 161 controls. Genotypic, allelic, and phenotypic associations were examined. RESULTS: We found evidence of significant allelic (447Xcontrol: 0.130 vs. 447Xcase: 0.031, chi2 = 29.085; 1df; p < 0.001) and genotypic association (SS: 0.745 vs. 0.939, and SX+XX: 0.255 vs. 0.061) in controls and cases, respectively (chi2 = 26.09; 1df; p < 0.001). In cases, depletion of the 447X allele is associated with a significant elevation in very-low-density lipoprotein cholesterol (VLDL-C, p = 0.045). Consonant with previous studies of this polymorphism, regression models predict that carriers of the 447X allele displayed significantly lower TG, low-density lipoprotein cholesterol (LDL-C) and TG/high-density lipoprotein cholesterol (HDL-C) ratio. CONCLUSION: These findings suggest a role for the S447X polymorphism in combined hyperlipidemia and demonstrate the importance of evaluating both susceptibility and protective genetic risk factors.
PMCID:1538992
PMID: 16822320
ISSN: 1476-511x
CID: 1564502

Genetic variation of PLTP modulates lipoprotein profiles in hypoalphalipoproteinemia

Aouizerat, Bradley E; Engler, Mary B; Natanzon, Yanina; Kulkarni, Medha; Song, James; Eng, Celeste; Huuskonen, Jarkko; Rivera, Christopher; Poon, Annie; Bensley, Matt; Sehnert, Amy; Zellner, Christian; Malloy, Mary; Kane, John; Pullinger, Clive R
Phospholipid transfer protein (PLTP) participates in key processes in lipoprotein metabolism, including interparticle phospholipid transfer, remodeling of HDL, cholesterol and phospholipid efflux from peripheral tissues, and the production of hepatic VLDL. The impact of PLTP on reverse cholesterol transport suggests that the gene may harbor sequence anomalies that contribute to disorders of HDL metabolism. The human PLTP gene was screened for sequence anomalies by DNA melting analysis in 276 subjects with hypoalphalipoproteinemia (HA) and 364 controls. The association with plasma lipid parameters was evaluated. We discovered 18 sequence variations, including four missense mutations and a novel polymorphism (c.-34G > C). In healthy controls, the c.-34G > C minor allele was associated with higher high density lipoprotein-cholesterol (HDL-C) and was depleted in subjects with HA. Linear regression models predict that possession of the rare allele decreases plasma triglyceride (TG) and TG/HDL-C and increases HDL-C independent of TG. Decreased PLTP activity was observed in one (p.R235W) of four (p.E72G, p.S119A, p.S124Y, and p.R235W) mutations in an in vitro activity assay. These findings indicate that PLTP gene variation is an important determinant of plasma lipoproteins and affects disorders of HDL metabolism.
PMID: 16388083
ISSN: 0022-2275
CID: 1564512

Genetic influences in nonalcoholic fatty liver disease

Merriman, Raphael B; Aouizerat, Bradley E; Bass, Nathan M
Nonalcoholic fatty liver disease (NAFLD) is a metabolic liver disease with widely variable phenotypes extending from simple steatosis, through nonalcoholic steatohepatitis (NASH) to cirrhosis and hepatocellular carcinoma. Inevitably, this reflects the interplay of well-recognized environmental factors and disease associations such as obesity and insulin resistance with host genetic factors, which are polygenic or complex in nature. Most of the observed phenotypic variability will probably be explained by variations in single nucleotide polymorphism frequency, although knowledge of the effect of most polymorphisms on biologic function is currently limited. Several observational studies of kindred with NASH suggest a genetic contribution. Most data characterizing genetic variation in different NAFLD phenotypes is derived from case-control association studies involving putative candidate genes. These candidate genes have been selected largely based upon the "two-hit hypothesis" of the pathogenesis of NAFLD, although other hypothesis-independent approaches can also be informative in gene selection. Thus far, candidate gene association studies have had significant limitations such as small cohort sizes and poor reproducibility. Rapid technologic developments are increasing the capability of detecting genetic variation. Identification of the genetic contribution to NAFLD will inform theories of disease pathogenesis and progression and ultimately improve management.
PMID: 16540764
ISSN: 0192-0790
CID: 1564522

Identification of four gene variants associated with myocardial infarction

Shiffman, Dov; Ellis, Stephen G; Rowland, Charles M; Malloy, Mary J; Luke, May M; Iakoubova, Olga A; Pullinger, Clive R; Cassano, June; Aouizerat, Bradley E; Fenwick, Raymond G; Reitz, Richard E; Catanese, Joseph J; Leong, Diane U; Zellner, Christian; Sninsky, John J; Topol, Eric J; Devlin, James J; Kane, John P
Family history is a major risk factor for myocardial infarction (MI). However, known gene variants associated with MI cannot fully explain the genetic component of MI risk. We hypothesized that a gene-centric association study that was not limited to candidate genes could identify novel genetic associations with MI. We studied 11,053 single-nucleotide polymorphisms (SNPs) in 6,891 genes, focusing on SNPs that could influence gene function to increase the likelihood of identifying disease-causing gene variants. To minimize false-positive associations generated by multiple testing, two studies were used to identify a limited number of nominally associated SNPs; a third study tested the hypotheses that these SNPs are associated with MI. In the initial study (of 340 cases and 346 controls), 637 SNPs were associated with MI (P<.05); these were evaluated in a second study (of 445 cases and 606 controls), and 31 of the 637 SNPs were associated with MI (P<.05) and had the same risk allele as in the first study. For each of these 31 SNPs, we tested the hypothesis that it is associated with MI, using a third study (of 560 cases and 891 controls). We found that four of these gene variants were associated with MI (P<.05; false-discovery rate <10%) and had the same risk allele as in the first two studies. These gene variants encode the cytoskeletal protein palladin (KIAA0992 [odds ratio (OR) 1.40]), a tyrosine kinase (ROS1 [OR 1.75]), and two G protein-coupled receptors (TAS2R50 [OR 1.58] and OR13G1 [OR 1.40]); all ORs are for carriers of two versus zero risk alleles. These findings could lead to a better understanding of MI pathophysiology and improved patient risk assessment.
PMCID:1275608
PMID: 16175505
ISSN: 0002-9297
CID: 1564532

Do women in the community recognize hereditary and sporadic breast cancer risk factors?

Katapodi, Maria C; Aouizerat, Bradley E
PURPOSE/OBJECTIVES: To describe knowledge of hereditary, familial, and sporadic breast cancer risk factors among women in the community and to identify characteristics associated with this knowledge. DESIGN: Descriptive, cross-sectional. SETTING: Community settings in the San Francisco Bay Area. SAMPLE: 184 women who had never been diagnosed with cancer, were 30-85 years old (mean = 47 + 12), and agreed to complete a questionnaire in English. Participants were from diverse racial and cultural backgrounds (i.e., 43% European descent, 27% African descent, 16% Asian descent, and 14% Hispanic descent). Many (49%) were college graduates, and 24% had a median annual family income of $30,000-$50,000. METHODS: Survey. MAIN RESEARCH VARIABLES: Knowledge of hereditary, familial, and sporadic breast cancer risk factors and characteristics associated with this knowledge. FINDINGS: Although most women recognized heredity as a risk factor, some did not understand the impact of paternal family history on risk. Some women did not recognize the relationship between breast and ovarian cancer, risk factors associated with the Gail model, and that aging increases risk. Education level was the most important characteristic associated with knowledge of risk factors. CONCLUSIONS: Although age and family history are independent predictors of sporadic, hereditary, and familial breast cancer risk, women in the community could not distinguish between the three forms of the disease. Although the sample included a large number of educated women, their knowledge of breast cancer risk factors appeared incomplete. IMPLICATIONS FOR NURSING: Advanced practice nurses should provide individualized risk assessment and education regarding breast cancer risk factors.
PMID: 15897936
ISSN: 1538-0688
CID: 1564542

Introducing the MUC16 gene: implications for prevention and early detection in epithelial ovarian cancer

McLemore, Monica R; Aouizerat, Bradley
More than 24,000 women in the United States are diagnosed with ovarian cancer every year, and half of these women die from their disease. Stage 1 ovarian cancer is curable in 95% of cases; however, due to inadequate screening tools and lack of symptoms in early disease, ovarian cancer is generally at Stage 3 or 4 when finally diagnosed. CA125 is a tumor antigen used to monitor the progression and regression of epithelial ovarian cancer. When its levels are elevated postsurgery (hysterectomy/salpingo-oophorectomy with or without peritoneal washings and lymph node biopsy) and postchemotherapy, it is suggestive of recurrent disease. Due to its similarly elevated levels in some nonmalignant conditions, however, it is not specific enough to be used for population screening. The CA125 molecule is considered a very large glycoprotein because of its molecular weight, and it has three domains: the carboxy terminal domain, the extracellular domain, and the amino terminal domain. MUC16 is the gene that encodes the peptide moiety of the CA125 molecule. MUC16 domains provide novel opportunities to develop new assays and refine current tools to improve the sensitivity and specificity of CA125 for population-based screening guidelines.
PMID: 15788735
ISSN: 1099-8004
CID: 1564552

Influences of apolipoprotein E polymorphism on the risk for breast cancer and HER2/neu status in Taiwan

Chang, Nai-Wen; Chen, Dar-Ren; Wu, Chen-Ten; Aouizerat, Bradley E; Chen, Fei-Na; Hung, Shin-Jer; Wang, Shiuan-Huei; Wei, Ming-Feng; Chang, Cheng-Shyong
Apolipoprotein E (APOE) polymorphism plays an important role in lipid metabolism. Preliminary evidence suggests that APOE genotype appears to be a risk factor for not only cardiovascular disease, but also Alzheimer's disease and cancer. We screened the APOE genotype in 290 breast cancer patients and 232 non-cancer controls and determined the relationship between APOE gene polymorphism and breast cancer in Taiwan. We found risk for breast cancer was associated with the APOE genotype (xi(2) = 8.652, p = 0.013). Carriers of the epsilon4 allele were more common in breast cancer cases than carriers of epsilon3 allele (p = 0.004, OR = 1.786, 95% CI: 1.197-2.664). In addition, the epsilon4 allele is also associated with HER2/neu negative status in breast cancer patients (p = 0.006, OR = 0.277, 95% CI: 0.111-0.693). No significant associations between APOE genotype and tumor grade, TN classification, progesterone receptor, estrogen receptor, lymphatic invasion, or recurrence of breast cancer were in evidence. These results suggest that the APOE epsilon4 allele may be a risk factor for breast cancer and correlates with HER2/neu negative status.
PMID: 15830139
ISSN: 0167-6806
CID: 1564562

Replicated association of a purinergic receptor variant with risk of myocardial infarction [Meeting Abstract]

Young, BA; Bare, LA; Malloy, MJ; Arellano, AR; Short, ML; Luke, MM; Rowland, CM; Iakoubova, OA; Cassano, J; Aouizerat, BE; Pullinger, CR; Devlin, JJ; Ellis, SG; Sninsky, JJ; Kane, JP
ISI:000226808201791
ISSN: 0735-1097
CID: 1565062