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1.  Lymph node shape in computed tomography imaging as a predictor for axillary lymph node metastasis in patients with breast cancer 
The aim of the present study was to evaluate whether preoperative computed tomography (CT) is a useful modality for the diagnosis of axillary lymph node metastasis. The axillary lymph node status was examined in patients with primary breast cancer who had undergone surgery. In total, 75 patients were analyzed with preoperative contrast CT images, following which the patients underwent an intraoperative sentinel lymph node biopsy to determine possible predictors of axillary lymph node metastasis. The lymph node shape was classified into three groups, which included fat-, clear-and obscure-types. Multivariate analysis revealed that clear-type lymph nodes in preoperative contrast CT imaging may be an independent predictor of lymph node metastasis (odds ratio, 15; P=0.003). Therefore, the results indicated that preoperative CT examination is useful to predict axillary lymph node metastasis.
PMCID: PMC4079443  PMID: 25009640
breast cancer; computed tomography; lymph node shape
2.  Glycated Albumin and Direct Low Density Lipoprotein Cholesterol Levels in Type 2 Diabetes Mellitus 
Diabetes mellitus is a major risk factor for coronary heart disease (CHD), renal failure, retinopathy, and neuropathy. Lowering glycosylated hemoglobin (HbA1c) as well as low-density lipoprotein-cholesterol (LDL-C) has been associated with a decreased risk of these complications. We evaluated the utility of glycated albumin (GA) and direct LDL-C, 2 novel assays, as compared to HbA1c and calculated LDL-C, in evaluating diabetes control and lipid in a heterogeneous population and in specific subgroups of patients with type 2 diabetes mellitus.
We obtained fasting blood samples and measured HbA1c, GA, and direct LDL-C, as well as other parameters, in a multi-ethnic population of 616 male and female patients with type 2 diabetes and 895 non-diabetic controls.
HbA1c and GA levels, which measure different periods of glycemia, had a correlation of r=0.70 (p<0.001), and mean values in patients were 38.7% and 43.4% higher, respectively, than controls in men, and 41.1% and 40.1% higher, respectively, than controls, in women (both p<0.001). Calculated and direct LDL-C values correlated very highly (r=0.96, p<0.001). The correlations between HbA1c and GA, and between calculated and direct LDL-C were similar for subgroups defined by gender, race, age, and other factors.
Calculated LDL-C provides an accurate assessment of fasting LDL-C compared with a direct measurement in most subjects, except for those with hypertriglyceridemia, and GA correlates with HbA1c in diabetic and non-diabetic subjects and may serve as a reasonable marker of short term diabetic control.
PMCID: PMC3927411  PMID: 19465013
glycated albumin; low density lipoprotein cholesterol; type 2 diabetes
3.  Small Dense Low Density Lipoprotein Cholesterol and Coronary Heart Disease: Results from the Framingham Offspring Study 
Clinical chemistry  2010;56(6):967-976.
A direct assay for small dense low density lipoprotein cholesterol (sdLDL-C) has been developed. Our goal was to establish normal ranges for this assay as well as to measure values in patients with established coronary heart disease (CHD) versus control subjects.
Direct LDL-C and sdLDL-C analyses were carried out on samples from 3,188 male and female participants of the Framingham Offspring Study, which included 173 male and 74 female CHD cases.
Male gender and female postmenopausal status were both associated with significantly (p<0.0001) higher sdLDL-C values. Use of cholesterol-lowering medications was significantly (p<0.0001) higher in CHD cases than in controls (46.8% versus 11.4% in men, and 35.1% versus 8.8% in women). Direct LDL-C levels were significantly lower in male CHD patients than in male controls (3.22 versus 3.51 mmol/L, p<0.0001), but their mean sdLDL-C levels were similar to those in controls (0.83 versus 0.84 mmol/L, p=0.609). Female CHD patients had similar LDL-C values to female controls (3.53 versus 3.46 mmol/L, p=0.543), but had significantly higher sdLDL-C values (0.83 versus 0.68 mmol/L, p=0.0015). Both male and female cases also had significantly (p<0.01) higher percentages of LDL-C as sdLDLC than controls.
Despite four fold greater cholesterol lowering therapy use, CHD patients had mean LDL-C values well above the LDL-C goal of < 2.6 mmol/L or 100 mg/dl, and male CHD cases had similar sdLDL C values and female CHD cases had significantly higher values than controls. These findings may explain some of the high residual risk of future CHD events in CHD patients.
PMCID: PMC3791882  PMID: 20431054
small dense LDL-cholesterol; coronary heart disease; risk factor; Framingham Offspring Study; obesity
4.  Direct assessment of plasma low density lipoprotein and high density lipoprotein cholesterol levels and coronary heart disease: results from the Framingham Offspring Study 
Atherosclerosis  2010;213(1):251-255.
We evaluated direct low density lipoprotein (LDL) cholesterol (C) and high density lipoprotein (HDL) cholesterol (C) versus standard methods using fasting plasma samples from participants in cycle 6 of the Framingham Offspring Study.
Direct LDL-C and HDL-C measurements were performed on fasting plasma from male (1335 controls, 173 CHD cases) and female (1606 controls, 74 cases) participants, and compared with LDL-C, as calculated with the Friedewald formula, and HDL-C, as measured after dextran-Mg2+ precipitation.
Values for direct LDL-C and HDL-C correlated well with standard methods (both about r2=0.94, p<0.001) with similar absolute values. Biases of > 10% were present for 7.7% of samples for LDL-C, while for HDL-C this value was 8.5%. Despite higher use of cholesterol lowering medication in CHD cases, calculated or direct LDL-C values were still well above recommended values [< 2.6 mmol/L, (100 mg/dl)] in CHD cases, especially in females.
Direct assays for both LDL-C and HDL-C provide an acceptable guide for lipid treatment. In the Framingham Offspring Study participants, most CHD cases have LDL-C levels above the recommended target.
PMCID: PMC3707385  PMID: 20863498
cholesterol; LDL; HDL; coronary heart disease; Framingham Offspring Study
5.  Adiponectin: an Independent Risk Factor for Coronary Heart Disease in the Framingham Offspring Study 
Atherosclerosis  2011;217(2):543-548.
Our aim was to determine whether a low plasma adiponectin level is an independent predictor of coronary heart disease (CHD).
Methods and Results
We measured adiponectin levels in frozen plasma samples (−80°C) in a total of 3,188 male and female participants in cycle 6 of the Framingham Offspring Study, using a novel full-automated assay. CHD cases at baseline were excluded, and participants were followed for a mean of 7.5 years (mean age was 57 years in both men and women, and mean BMI 28.5 kg/m2 in men and 27.3 kg/m2 in women). Plasma adiponectin levels (median [25percentile, 75percentile]) were significantly higher in female than male controls (14.8 [10.7, 20.5] μg/mL versus 9.0 [7.0, 12.2] μg/mL, p< 0.001). After adjustment for age, body mass index, smoking status, systolic blood pressure, treatment for hypertension, diabetes status, use of cholesterol-lowering medication, total cholesterol level, and high-density lipoprotein cholesterol level. A decreased plasma adiponectin level was a highly significant predictor of future CHD events (n =117) in men, with a hazards ratio of 0.4728 (p=0.0024). A bottom-quartile value of < 7.0 μg/mL doubled the risk of CHD in men. The identical trend was observed in women; however, the statistical significance of these associations disappeared after multivariate adjustments, possibly due to a low number of female CHD cases (n=60).
An adiponectin level of < 7.0 μg/mL is a powerful independent predictor of CHD in men in the United States.
PMCID: PMC3662557  PMID: 21741045
adiponectin; coronary heart disease; risk factor; Framingham Offspring Study; obesity
6.  Biomarkers for Insulin Resistance and Inflammation and the Risk for All-Cause Dementia and Alzheimer Disease 
Archives of neurology  2012;69(5):10.1001/archneurol.2011.670.
To investigate the contribution of biomarkers of glucose homeostasis (adiponectin, glucose, glycated albumin, and insulin levels) and inflammation (high-sensitivity C-reactive protein and lipoprotein-associated phospholipase A2 levels) to the risk of developing Alzheimer disease (AD) and all-cause dementia.
Prospective cohort study.
Dementia-free Framingham Heart Study participants had sera measured for these biomarkers at the 19th biennial examination (1985–1988) and were followed up prospectively for the development of AD and all-cause dementia.
Eight hundred forty (541 women, median age of 76 years) subjects participated in the study.
Main Outcome Measures
We used sex-pooled and sex-specific multivariable Cox proportional hazards models adjusted for age, education, body mass index, recent change in weight, APOE ε4 allele status, and plasma docosahexaenoic acid levels to determine association of these biomarkers with the development of all-cause dementia and AD.
Over a mean follow-up period of 13 years, 159 persons developed dementia (including 125 with AD). After adjustment for other risk factors, only adiponectin in women was associated with an increased risk of all-cause dementia (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.00–1.66; P=.054) and AD (HR, 1.33; 95% CI, 1.00–1.76; P=.050) per 1-SD increase in adiponectin level. Women with baseline adiponectin values more than the median had a higher risk of all-cause dementia (HR, 1.63; 95% CI, 1.03–2.56; P=.04) and AD (HR, 1.87; 95% CI, 1.13–3.10; P=.01) as compared with those with values less than the median.
In women, increased plasma adiponectin levels are an independent risk factor for the development of both all-cause dementia and AD.
PMCID: PMC3512190  PMID: 22213409
7.  Altering dietary lysine:arginine ratio has little effect on cardiovascular risk factors and vascular reactivity in moderately hypercholesterolemic adults 
Atherosclerosis  2009;210(2):555-562.
Information is scarce regarding the effect of dietary protein type, with specific focus on the lysine to arginine (Lys:Arg) ratio, on cardiovascular risk factors and vascular reactivity in humans.
Determine effect of dietary Lys:Arg ratio on cardiovascular risk factors and vascular reactivity in moderately hypercholesterolemic adults.
Randomized cross-over design of two 35-day diet phases; thirty adults (21 females and 9 males, ≥50 y, LDL cholesterol ≥120 mg/dL). Diets had 20% energy (E) protein, 30%E fat, 50%E carbohydrate and were designed to have low (0.7) or high (1.4) Lys:Arg ratio. Measures included fasting and postprandial lipid, lipoprotein, apolipoprotein concentrations; fasting high sensitivity C-reactive protein (hsCRP), small dense LDL (sdLDL)-cholesterol, remnant lipoprotein cholesterol (RemLC), glycated albumin, adiponectin and immunoreactive insulin concentrations, endogenous cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyl transferase (LCAT) activities; cholesterol fractional synthesis rate (FSR); and flow mediated dilation (FMD) and peripheral artery tonometry (PAT).
No differences were observed in fasting and/or postprandial total, LDL, HDL and sdLDL cholesterol, RemLC, Lp(a) or apo B concentrations, LCAT and CETP activities, FSR, glycated albumin, immunoreactive insulin, FMD or PAT. The low, relative to the high, Lys:Arg ratio diet resulted in lower postprandial VLDL cholesterol (−24%, P=0.001) and triglycerides (−23%, P=0.001), and small but significant differences in fasting (−3%, P=0.003) and postprandial (−3%, P=0.018) apo AI, and fasting adiponectin concentrations (+7%, P=0.035). Fasting and postprandial hsCRP concentrations were 23% lower after the low Lys:Arg ratio diet (P=0.020 for both).
Diets differing in Lys:Arg ratios had no or small effects on cardiovascular risk factors and vascular reactivity.
PMCID: PMC2878850  PMID: 20042191
lysine:arginine ratio; lipoproteins; small dense LDL (sdLDL)-cholesterol; remnant lipoprotein cholesterol (RemLC); cholesterol fractional synthesis rate (FSR); flow mediated dilation (FMD); peripheral artery tonometry (PAT)
8.  Familial Combined Hyperlipidemia is Associated with Alterations in the Cholesterol Synthesis Pathway 
Familial combined hyperlipidemia (FCH) is a common familial lipid disorder characterized by increases in plasma total cholesterol, triglyceride and apolipoprotein B-100 levels. In light of prior metabolic and genetic research, our purpose was to ascertain whether FCH cases had significant abnormalities of plasma markers of cholesterol synthesis and absorption as compared to unaffected kindred members.
Methods and Results
Plasma levels of squalene, desmosterol and lathosterol (cholesterol synthesis markers) and campesterol, sitosterol and cholestanol (cholesterol absorption markers) were measured by gas-liquid chromatography in 103 FCH patients and 240 normolipidemic relatives (NLR). Squalene, desmosterol, and lathosterol levels were 6% (0.078), 31%, (p<0.001) and 51% (p<0.001) higher in FCH as compared to NLR, and these differences were especially pronounced in women. An interaction with obesity was also noted for a subset of these markers. We did not observe any apparent differences for the cholesterol absorption markers among FCH patients and NLR.
Our data indicate that both men and women with FCH have alterations in the cholesterol synthesis pathway, resulting in 51% higher levels of lathosterol (and additionally desmosterol in women). Plasma levels of the cholesterol precursor sterol squalene were only slightly increased (6%), suggesting enhanced conversion of squalene to lathosterol in this disorder.
PMCID: PMC2813691  PMID: 19834104
Cholesterol; Lipids; Sterols; Familial Combined Hyperlipidemia
9.  Substitution of vegetable oil for a partially-hydrogenated fat favorably alters cardiovascular disease risk factors in moderately hypercholesterolemic postmenopausal womena,b 
Atherosclerosis  2009;207(1):208-212.
Compared to vegetable oils in their unmodified state, partially-hydrogenated fat is associated with less favorable effects on cardiovascular disease (CVD) risk factors. Acceptable alternatives must be adjudicated. Our objective was to assess the effect of a recent commercial fat substitution, corn oil for partially-hydrogenated soybean oil.
Using a double-blind cross-over design, 30 postmenopausal women ≥50 y with LDL-cholesterol concentrations ≥120 mg/dL were randomly assigned to each of two 35-day phases; all food and beverage was provided to maintain body weight. Corn or partially-hydrogenated soybean oil was incorporated throughout the diet and contributed two-thirds of fat. Primary outcomes included fasting and non-fasting lipid, lipoprotein, apolipoprotein, and fasting high sensitivity C-reactive protein (hsCRP) concentrations; secondary outcomes included fasting small dense LDL (sdLDL)-cholesterol, remnant lipoprotein cholesterol (RemLC), glycated albumin, adiponectin and immunoreactive insulin concentrations, and endogenous cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyl transferase (LCAT) activities.
Relative to the partially-hydrogenated soybean oil-enriched diet, the corn oil enriched diet resulted in lower fasting total cholesterol (7%; P<0.0001), LDL-cholesterol (10%; P<0.0001), VLDL-cholesterol (7%; P=0.052), apo B (9%; P<0.0001), Lp(a) (5%; P=0.024), sdLDL-cholesterol (17%; P=0.001), and RemLC (20%; P=0.007) concentrations, and no significant effect on the other outcomes. Changes in postprandial (4-h post-meal) lipid, lipoprotein and apolipoprotein concentrations were similar to the fasting state.
The replacement of partially-hydrogenated soybean oil with corn oil favorably affects a range of CVD risk factors and is an appropriate option to decrease cardiovascular disease risk factors in moderately hypercholesterolemic individuals.
PMCID: PMC2905850  PMID: 19423109
cardiovascular disease; trans fatty acids; polyunsaturated fatty acids; lipoproteins; partially-hydrogenated fat; vegetable oil; LDL-cholesterol; HDL-cholesterol; hsCRP; CETP; LCAT
10.  Extended-release niacin alters the metabolism of plasma apolipoprotein (apo) A-I- and apoB-containing lipoproteins 
Extended-release niacin effectively lowers plasma TG levels and raises plasma HDL cholesterol levels, but the mechanisms responsible for these effects are unclear.
Methods and Results
We examined the effects of extended-release niacin (2 g/d) and extended-release niacin (2 g/d) plus lovastatin (40 mg/d), relative to placebo, on the kinetics of apolipoprotein (apo) A-I and apoA-II in HDL, apoB-100 in TG-rich lipoproteins (TRL), intermediate-density lipoproteins (IDL) and LDL, and apoB-48 in TRL in five men with combined hyperlipidemia. Niacin significantly increased HDL cholesterol and apoA-I concentrations, associated with a significant increase in apoA-I production rate (PR) and no change in fractional catabolic rate (FCR). Plasma TRL apoB-100 levels were significantly lowered by niacin, accompanied by a trend toward an increase in FCR and no change in PR. Niacin treatment significantly increased TRL apoB-48 FCR but had no effect on apoB-48 PR. No effects of niacin on concentrations or kinetic parameters of IDL and LDL apoB-100 and HDL apoA-II were noted. The addition of lovastatin to niacin promoted a lowering in LDL apoB-100 due to increased LDL apoB-100 FCR.
Niacin treatment was associated with significant increases in HDL apoA-I concentrations and production, as well as enhanced clearance of TRL apoB-100 and apoB-48.
PMCID: PMC2761712  PMID: 18566298
11.  Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans 
The Journal of Clinical Investigation  2009;119(5):1322-1334.
Studies in animals have documented that, compared with glucose, dietary fructose induces dyslipidemia and insulin resistance. To assess the relative effects of these dietary sugars during sustained consumption in humans, overweight and obese subjects consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks. Although both groups exhibited similar weight gain during the intervention, visceral adipose volume was significantly increased only in subjects consuming fructose. Fasting plasma triglyceride concentrations increased by approximately 10% during 10 weeks of glucose consumption but not after fructose consumption. In contrast, hepatic de novo lipogenesis (DNL) and the 23-hour postprandial triglyceride AUC were increased specifically during fructose consumption. Similarly, markers of altered lipid metabolism and lipoprotein remodeling, including fasting apoB, LDL, small dense LDL, oxidized LDL, and postprandial concentrations of remnant-like particle–triglyceride and –cholesterol significantly increased during fructose but not glucose consumption. In addition, fasting plasma glucose and insulin levels increased and insulin sensitivity decreased in subjects consuming fructose but not in those consuming glucose. These data suggest that dietary fructose specifically increases DNL, promotes dyslipidemia, decreases insulin sensitivity, and increases visceral adiposity in overweight/obese adults.
PMCID: PMC2673878  PMID: 19381015
12.  Endogenous Reactive Oxygen Species Is an Important Mediator of Miconazole Antifungal Effect 
Antimicrobial Agents and Chemotherapy  2002;46(10):3113-3117.
We investigated the significance of endogenous reactive oxygen species (ROS) produced by fungi treated with miconazole. ROS production in Candida albicans was measured by a real-time fluorogenic assay. The level of ROS production was increased by miconazole at the MIC (0.125 μg/ml) and was enhanced further in a dose-dependent manner, with a fourfold increase detected when miconazole was used at 12.5 μg/ml. This increase in the level of ROS production was completely inhibited by pyrrolidinedithiocarbamate (PDTC), an antioxidant, at 10 μM. In a colony formation assay, the decrease in cell viability associated with miconazole treatment was significantly prevented by addition of PDTC. Moreover, the level of ROS production by 10 clinical isolates of Candida species was inversely correlated with the miconazole MIC (r = −0.8818; P < 0.01). These results indicate that ROS production is important to the antifungal activity of miconazole.
PMCID: PMC128784  PMID: 12234832

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