Sex-specific genetic architecture of human fatness in Chinese: the SAPPHIRe Study.

To dissect the genetic architecture of sexual dimorphism in obesity-related traits, we evaluated the sex-genotype interaction, sex-specific heritability and genome-wide linkages for seven measurements related to obesity. A total of 1,365 non-diabetic Chinese subjects from the family study of the Stanford Asia-Pacific Program of Hypertension and Insulin Resistance were used to search for quantitative trait loci (QTLs) responsible for the obesity-related traits. Pleiotropy and co-incidence effects from the QTLs were also examined using the bivariate linkage approach. We found that sex-specific differences in heritability and the genotype-sex interaction effects were substantially significant for most of these traits. Several QTLs with strong linkage evidence were identified after incorporating genotype by sex (G × S) interactions into the linkage mapping, including one QTL for hip circumference [maximum LOD score (MLS) = 4.22, empirical p = 0.000033] and two QTLs: for BMI on chromosome 12q with MLS 3.37 (empirical p = 0.0043) and 3.10 (empirical p = 0.0054). Sex-specific analyses demonstrated that these linkage signals all resulted from females rather than males. Most of these QTLs for obesity-related traits replicated the findings in other ethnic groups. Bivariate linkage analyses showed several obesity traits were influenced by a common set of QTLs. All regions with linkage signals were observed in one gender, but not in the whole sample, suggesting the genetic architecture of obesity-related traits does differ by gender. These findings are useful for further identification of the liability genes for these phenotypes through candidate genes or genome-wide association analysis.

Diagnosis of insulin resistance in hypertensive patients by the metabolic syndrome: AHA vs. IDF definitions.

BACKGROUND: Subjects with the metabolic syndrome are accompanied by insulin resistance (IR). However, it is not clear how well the newly defined metabolic syndrome identifies IR specifically in hypertensive subjects. AIMS: The purpose of the study was to evaluate the performance of the metabolic syndrome, defined by the American Heart Association (AHA) and the International Diabetes Federation (IDF) definitions, in identifying IR in hypertension. METHODS: The analysis is a cross-sectional study. Totally, 228 hypertensive patients and 92 non-diabetic normotensive controls who received insulin suppressive tests for direct evaluation of their insulin sensitivity were included from the Stanford Asia and Pacific Program for Hypertension and IR. McNemar's tests were used to compare sensitivity and specificity of the AHA-defined with the IDF-defined metabolic syndrome in diagnosis of IR. RESULTS: The sensitivity of the metabolic syndrome for IR in hypertension was 89.7% and the specificity 45.9% by the AHA definition. Using the IDF definition, the sensitivity was 77.6%, and the specificity increased to 63.5%. The diagnostic power of individual components of the syndrome was also modest. The predictive discrimination of wider waist circumference was similar to that of the AHA-defined metabolic syndrome. CONCLUSIONS: Use of the metabolic syndrome by the AHA definition provided good sensitivity, but low specificity to diagnose IR in hypertension. The IDF definition improved in false-positive rate, but it was still not specific enough to identify IR in hypertension.

A Point-based Mortality Prediction System for Older Adults with Diabetes.

The mortality prediction models for the general diabetic population have been well established, but the corresponding elderly-specific model is still lacking. This study aims to develop a mortality prediction model for the elderly with diabetes. The data used for model establishment were derived from the nationwide adult health screening program in Taiwan in 2007-2010, from which we applied a 10-fold cross-validation method for model construction and internal validation. The external validation was tested on the MJ health screening database collected in 2004-2007. Multivariable Cox proportional hazards models were used to predict five-year mortality for diabetic patients ≥65 years. A total of 220,832 older subjects with diabetes were selected for model construction, of whom 23,241 (10.5%) died by the end of follow-up (December 31, 2011). The significant predictors retained in the final model included age, gender, smoking status, body mass index (BMI), fasting glucose, systolic and diastolic blood pressure, leukocyte count, liver and renal function, total cholesterol, hemoglobin, albumin, and uric acid. The Harrell's C in the development, internal-, and external-validation datasets were 0.737, 0.746, and 0.685, respectively. We established an easy-to-use point-based model that could accurately predict five-year mortality risk in older adults with diabetes.

Primer Design Assistant (PDA): A web-based primer design tool.

Primer Design Assistant (PDA) is a web interface primer design service combined with thermodynamic theory to evaluate the fitness of primers. It runs in a Linux-Apache-MySQL-PHP structure on a PC equipped with dual CPU (Intel Pentium III 1.4 GHz) and 512 Mb of RAM. A succinct user interface of PDA is accomplished by built-in parameters setting. Advanced options on 5' GC content, 3' GC content, dimer check and hairpin check are available. The option of covered region constrains the PCR product to cover a user-defined segment. PDA accepts single sequence query or multiple ones in FASTA format. It produces optimal and homogenous primer pairs that meet the need in experimental design with large-scaled PCR amplifications. Considering the system loading, the size of a submitted sequence is limited to 10 kb and the total sequence number in a query is limited to 20. The authors may be contacted regarding other requirements for primer design. The web application can be found at http://dbb.nhri.org.tw/primer/.

Stage migration influences on stage-specific survival comparison between D1 and D3 gastric cancer surgeries.

AIMS: We evaluate the influency stage migration in a randomised trial comparing D1 (N 1 lymphadenectomy) and D3 (N 1, 2 and 3 lymphadenectomy) dissections. METHODS: Two hundred and thirteen curatively resected patients were analysed, with this TNM data. RESULTS: After applying D3 patients' data according to simulated D1 staging, D3 resections were associated with up-staging to N2-3 levels in 8% of patients according to the N stage. The likelihood of N-status migration increased with increasing depth of invasion into the gastric wall. The increases in the calculated survival rate after stage migration on known 5-year survival rates were: 2% in stage IB, 1% in stage II, 4% in stage IIIA, and 1% in stage IIIB. CONCLUSIONS: Stage migration secondary to meticulous lymph node dissection affects stage-specific survival rates. True therapeutic survival benefit of D3 resection can only be assessed in this context.

Sibling-based association study of the PPARgamma2 Pro12Ala polymorphism and metabolic variables in Chinese and Japanese hypertension families: a SAPPHIRe study. Stanford Asian-Pacific Program in Hypertension and Insulin Resistance.

The peroxisome proliferator activated receptor (PPAR) gamma2 is a transcription factor that has been shown to be involved in adipocyte differentiation, adipogenesis, and insulin sensitivity. To address the role of PPARgamma2 in glucose homeostasis and insulin sensitivity, among many other objectives, we conducted a sibling-controlled association study in a multicenter program - the Stanford Asian-Pacific Program in Hypertension and Insulin Resistance (SAPPHIRe). Approximately 2525 subjects in 734 Chinese and Japanese families have been recruited from six field centers for SAPPHIRe. In total, 1702 subjects including parents and siblings from 449 families have been genotyped for PPARgamma2, of which 328 families were Chinese and 121 Japanese. Only 88 subjects of the 1525 siblings screened for the P12A polymorphism were found to be carriers of the A variant, the most common variant of the PPARgamma2 gene. A variant frequencies of the siblings were 4.27% in Chinese and 2.72% in Japanese. A sibling-controlled association study was performed through genetically discordant sibships (i.e., P/P genotype vs. P/A + A/A genotypes). Specifically, we examined whether there were differences in metabolic variables between the discordant siblings within families. In total, 88 subjects carrying either 1 or 2 A alleles had at least one sibling who was discordant for the P12A polymorphism, yielding a total of 180 individuals from 47 families for analyses, among which 92 siblings were homozygous for wild-type P allele. Siblings with the A variant tended to have lower levels of fasting plasma glucose (OG-10), and lower glucose levels at 60 min following oral glucose loading after adjusting for age, gender, and body mass index. Using a mixed model treating family as a random effect, we found that P12A polymorphism of the PPARgamma2 gene contributes significantly to the variance in fasting plasma glucose, glucose level at 60 min, and insulin-resistance homeostasis model assessment. Our results suggest that within families siblings with the A variant in the PPARgamma2 gene may be more likely to have better glucose tolerance and insulin sensitivity independent of obesity in Chinese and Japanese populations.

Correlates of antibiotic use in Taiwan hospitals.

OBJECTIVE: To determine factors that correlate with increased antibiotic use among adult inpatients in Taiwan. DESIGN: Retrospective survey of medical records. SETTING: 14 acute-care hospitals (8 regional hospitals, 6 medical centers) in Taiwan. PARTICIPANTS: A systematic probability sample from each hospital, totaling 663 adult inpatients who were discharged or had died in early 1999. MEASUREMENTS: Infectious disease physicians at the 14 hospitals collected data from medical records regarding patient demographics, hospitalization, discharge diagnosis, and antibiotics received. RESULTS: A total of 447 (67%) patients received antibiotics for an overall rate of 813 antibiotic-days (number of days patients received each antibiotic)/1,000 patient-days. Both the proportion of beds in intensive care units ([ICUs] Pearson correlation coefficient [r], 0.67; 95% confidence interval [CI 95], 0.36-0.89; P<.01) and the proportion of patients admitted to surgical services (r, 0.66; CI 95, 0.20-0.88; P=.01) correlated with the mean patient rate of antibiotic-days/hospital-day (MPAUD). In contrast, we found no correlation between the proportion of patients who received antibiotics and the MPAUD. Using multiple linear regression, medical center status was the only independent predictor for increased MPAUD (regression coefficient [b], 0.15; CI 95, 0.05-0.24; P<.01). There was no correlation between pooled rates of antibiotic-days/hospital-day and any hospital demographic factors. First-generation cephalosporin (39%) and aminoglycoside (24%) use accounted for the majority of antibiotic-days. CONCLUSIONS: Antibiotic use is greater in medical centers than in regional hospitals and appears to be independent of surgical case mix or the proportion of ICU beds. Determination of multiple, independent measures of antibiotic use may be necessary to understand the relation between antibiotic use and resistance in hospital.

Human infection with novel G3P[25] rotavirus strain in Taiwan.

Genotype P[25] rotaviruses are rare and to date have been reported to occur only in a few countries of mainland Asia. Here we report the molecular characterization of a novel human rotavirus genotype combination, G3P[25], detected in a 17-month-old child hospitalized due to severe gastroenteritis during 2009 in central Taiwan. Sequencing and phylogenetic analysis of the VP4 gene demonstrated a distinct origin from other strains bearing the P[25] VP4 gene, whereas the VP7, VP6 and NSP4 gene phylogenies identified common origins with cognate genes of other, presumed human-porcine reassortment Taiwanese strains. These results suggest that interactions between human and animal strains appear to contribute to the generation of genetic and antigenic diversity of rotavirus strains, with potential public health importance in Taiwan.

Bivariate genome-wide scan for metabolic phenotypes in non-diabetic Chinese individuals from the Stanford, Asia and Pacific Program of Hypertension and Insulin Resistance Family Study.

AIMS/HYPOTHESIS: Hypertension, obesity, impaired glucose tolerance and dyslipidaemia are metabolic abnormalities that often cluster together more often than expected by chance alone. Since these metabolic variables are highly heritable and are at least partially genetically determined, the clustering of defects in these traits implies that pleiotropic effects, where a common set of genes influences more than one trait simultaneously, are likely. METHODS: We conducted bivariate linkage analyses for highly correlated traits, aiming to dissect the genetic architecture affecting these traits, in 411 Chinese families participating in the Stanford Asia-Pacific Program of Hypertension and Insulin Resistance Study. RESULTS: We confirmed the pleiotropic effects of the locus at 37 cM on chromosome 20 on the following pairs: (1) fasting insulin and insulin AUC (empirical p = 0.0006); (2) fasting insulin and homeostasis model assessment of beta cell function (HOMA-beta) (empirical p = 0.0051); and (3) HOMA of insulin resistance (IR) and HOMA-beta (empirical p = 0.0044). In addition, the peak logarithm of the odds (LOD) scores of linkage between a chromosomal locus and a trait for the pair fasting insulin and HOMA-IR rose to 5.10 (equivalent LOD score in univariate analysis, LOD([1]) = 4.01, empirical p = 8.0 x 10(-5)) from 3.67 and 3.42 respectively for these two traits in univariate analysis. Additional significant linkage evidence, not shown in single-trait analysis, was identified at 45 cM on chromosome 16 for the pair 1 h insulin and the AUC for insulin, with a LOD score of 4.29 (or LOD([1]) = 3.27, empirical p = 2.0 x 10(-4)). This new locus is also likely to harbour the common genes regulating these two traits (p = 1.73 x 10(-6)). CONCLUSIONS/INTERPRETATION: These data help provide a better understanding of the genomic structure underlying the metabolic syndrome.

Betel nut chewing and other risk factors associated with obesity among Taiwanese male adults.

OBJECTIVE: The research aimed at examining betel nut chewing and other risk factors associated with obesity among Taiwanese male adults. DESIGN: The research analyzed the data obtained by the 2001 National Health Interview Survey in Taiwan that covered all the administrative divisions in Taiwan. Multistage stratified systematic sampling design was adopted for survey. All members of a sampled household received the interview. SUBJECTS: The research analyzed questionnaires answered by nonaboriginal male respondents aged between 20 and 59 years old, and the total number of samples analyzed read 6126. Since very few female subjects chewed betel nut, they were excluded from the analysis. MEASUREMENTS: Criteria of obesity was defined as body mass index > or = 27 kg/m2. The variables incorporated for analysis included the respondents' status of betel nut chewing, age, educational background, presence of hypertension and diabetes mellitus, drinking and smoking status, exercise status, and demand for physical strength at job. Generalized estimating equations model was employed to estimate the odd ratios (with 95% CI) of obesity of each independent variable. RESULTS: Approximately 16.2% of respondents were obese. The distribution of betel nut chewing was current chewers 15.9%, ex-chewers 4.3%, and nonchewers 79.8%. After controlling above-mentioned independent variables, hypertension, diabetes mellitus, betel nut chewing, never exercising, and sedentary jobs were closely associated with obesity. CONCLUSION: The research found that betel nut chewing closely associated with obesity. The increased appetite of betel nut chewers is speculated as the underlying cause. The prospective study is needed to clarify this issue. In addition to increasing the risk of developing oral cancer, betel nut chewing seemed to be related with another health hazard: obesity.

Randomized clinical trial of morbidity after D1 and D3 surgery for gastric cancer.

BACKGROUND: A randomized comparison of D1 (level 1 lymphadenectomy) and D3 (levels 1, 2 and 3 lymphadenectomy) dissection was performed to evaluate morbidity and effects on survival from gastric cancer. METHODS: A total of 221 patients were studied after resection for gastric cancer, 110 after D1 surgery and 111 after D3 surgery. RESULTS: The morbidity rate was higher after D3 than after D1 resection (17.1 (95 per cent confidence interval (c.i.) 10.1 to 24.1) versus 7.3 (95 per cent c.i. 2.4 to 12.2) per cent respectively; P = 0.012). The difference was largely related to abdominal abscess (8.1 per cent after D3 versus none after D1 resection; P = 0.003). The D3 group had an anastomotic leak rate of 4.5 per cent whereas there was no leakage in the D1 group (P = 0.060). All anastomotic leaks were minor and were managed non-operatively with nutritional support. Patients who had D3 resection had longer operating times, greater blood loss and postoperative drain outputs, and more patients needed blood transfusion. There was no death in either group. The hospital stay was longer after D3 than D1 surgery (mean(s.d.) 19.6(13.9) (range 10-98) versus 15.0(4.0) (range 10-30) days; P = 0.001). CONCLUSION: Extended lymphadenectomy for gastric cancer is associated with more complications than limited lymphadectomy but this does not lead to significant mortality.

Genetic epistasis of adiponectin and PPARgamma2 genotypes in modulation of insulin sensitivity: a family-based association study.

AIMS/HYPOTHESIS: Genetic interactions in modulating the phenotypes of a complex trait, such as insulin sensitivity, were usually taken for granted. However, this has not been commonly shown. Previous studies have suggested that both PPARgamma2 and adiponectin genes could influence insulin sensitivity. Therefore it is likely that they could modulate insulin sensitivity through gene to gene interactions. METHODS: We genotyped 1793 subjects of Chinese and Japanese descendents from 601 hypertensive families recruited in Sapphire study for a T94G in the adiponectin gene exon 2 and the PPARgamma2 Pro12Ala polymorphisms. Serum insulin concentrations and insulin resistance index (HOMA(IR)) were used as the markers of insulin sensitivity. RESULTS: We found that the T allele of adiponectin gene was associated with a higher Ins60 and higher area under curve of insulin (AUCi) in OGTT utilizing all subjects in a mixed model that corrected for family effects. Important interactions between adiponectin and PPARgamma2 genotypes were found in fasting insulin concentrations (Ins0), insulin concentrations at 2-h (Ins120) in OGTT and insulin resistance index (HOMA(IR)). The main effects of the PPARgamma2 genotypes were in the plasma glucose concentrations in OGTT. In contrast, the main effects of adiponectin genotypes were in every insulin variable, including Ins0, Ins60, Ins120, AUCi and HOMA(IR). The subjects carrying the adiponectin G allele and the PPARgamma2 Ala12 allele seemed to be more insulin sensitive. CONCLUSION/INTERPRETATION: These results showed that adiponectin is a genetic factor associated with insulin sensitivity. Interactions with PPARgamma2 genotypes modified this association.

Weekly CAF chemotherapy for advanced breast cancer patients.

In a prospective phase II study, 102 women with advanced breast cancer were treated with low doses of cyclophosphamide, Adriamycin and 5-fluorouracil (CAF) at weekly intervals by intravenous injection. Seventy-five patients were evaluable for treatment response and the overall response rate was 52% (95% confidence interval, 41-63%). Of the evaluable patients, 15% had complete response and 37% had partial response. The median survival after therapy was 15.6 months, the median time to progression was 6.8 months and the median duration of response was 9.1 months. The main toxicities were mild vomiting and moderate myelosuppression. There was only 1 patient who experienced heart failure. Weekly CAF appears to have an efficacy with tolerable side effects comparable to standard CAF with an every-3-week schedule.