Patients with type 2 diabetes have high levels of triglyceride-rich lipoproteins (TRLs), including apolipoprotein B-48 (apoB-48)-containing TRLs of intestinal origin, but the mechanism leading to overaccumulation of these lipoproteins remains to be fully elucidated. Therefore, the objective of this study was to examine the in vivo kinetics of TRL apoB-48 and VLDL, intermediate density lipoprotein (IDL), and LDL apoB-100 in type 2 diabetic subjects (n 5 11) and nondiabetic controls (n 5 13) using a primedconstant infusion of L-[5,5,5-D 3 ]leucine for 12 h in the fed state. Diabetic subjects had significantly higher fasting glycemia, higher fasting insulinemia, higher plasma triglyceride, and lower HDL-cholesterol levels than controls. Compared with controls, diabetic subjects had increased TRL apoB-48, VLDL apoB-100, and IDL apoB-100 pool sizes as a result of increased production rates (PRs) and reduced fractional catabolic rates of these lipoprotein subfractions. Furthermore, multiple linear regression analyses revealed that the diabetic/control status was an independent predictor of TRL apoB-48 PR and represented nearly 35% of its variance. These results suggest that the overaccumulation of TRLs seen in patients with type 2 diabetes is attributable to increased PRs of both intestinally derived apoB-48-containing lipoproteins and TRL apoB-100 of hepatic origin and to decreased catabolism of these

Objective-To examine the impact of ezetimibe, a selective inhibitor of intestinal cholesterol absorption, on the in vivo kinetics of apolipoproteins (apo) B-48 and B-100 in humans. Methods and Results-Kinetics of triglyceride-rich lipoprotein (TRL) apoB-48 and very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) apoB-100 labeled with a stable isotope were assessed at baseline and at the end of 8 weeks of treatment with 10 mg/d of ezetimibe in 8 men with moderate primary hypercholesterolemia. Data were fit to a multicompartmental model using SAAMII to calculate fractional catabolic rate (FCR) and production rate (PR). Ezetimibe significantly decreased total and LDL cholesterol concentrations by Ϫ14.5% and Ϫ22.0% (Pϭ0.004), respectively, with no significant change in plasma triglyceride and high-density lipoprotein (HDL) cholesterol levels. Ezetimibe had no significant effect on TRL apoB-48 kinetics and pool size (PS). However, VLDL and IDL apoB-100 FCRs were significantly increased (ϩ31.2%, Pϭ0.02 and ϩ20.8%, Pϭ0.04, respectively) with a concomitant elevation of VLDL apoB-100 PR (ϩ20.9%, Pϭ0.04).

Background Screening clinical breast examination (cbe) is controversial; the use of cbe is declining not only as a

Sixteen hyperlipidemic men were enrolled in a randomized, placebo-controlled, double-blind, cross-over study to evaluate the effect of ezetimibe 10 mg and simvastatin 40 mg, coadministered and alone, on the in vivo kinetics of apolipoprotein (apo) B-48 and B-100 in humans. Subjects underwent a primed-constant infusion of a stable isotope in the fed state. The coadministration of simvastatin and ezetimibe significantly reduced plasma concentrations of cholesterol (243.0%), LDL-C (253.6%), and triglycerides (244.0%). Triglyceride-rich lipoproteins (TRL) apoB-48 pool size (PS) was significantly decreased (248.9%) following combination therapy mainly through a significant reduction in TRL apoB-48 production rate (PR) (238.0%). The fractional catabolic rate (FCR) of VLDL and LDL apoB-100 were significantly increased with all treatment modalities compared with placebo, leading to a significant reduction in the PS of these fractions. We also observed a positive correlation between changes in TRL apoB-48 PS and changes in TRL apoB-48 PR (r 5 0.85; P , 0.0001) with combination therapy. Our results indicate that treatment with simvastatin plus ezetimibe is effective in reducing plasma TRL apoB-48 levels and that this effect is most likely mediated by a reduction in the intestinal secretion of TRL apoB-48. Our study also indicated that the reduction in LDL-C concentration following combination therapy is mainly driven by an increase in FCR of apoB-100 containing lipoproteins.-Tremblay, A. J., B. Lamarche, J-C. Hogue, and P. Couture. Effects of ezetimibe and simvastatin on apolipoprotein B metabolism in males with mixed hyperlipidemia. J. Lipid Res.

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Previous studies have shown that 4-54% of breast lesions reported on core biopsies as atypical ductal hyperplasia (ADH) are upgraded on further excision to ductal carcinoma in situ (DCIS) or invasive carcinoma. We evaluated the rate of upgrading ADH to carcinoma at surgery for ADH diagnosed by percutaneous biopsy, and examined characteristics associated with malignancy. We identified 13,488 consecutive biopsies conducted at one center over a nine-year period. A total of 422 biopsies with ADH in 415 patients were included. DCIS or invasive carcinoma was found in 132 cases (31.3% upgrading). Multivariate model revealed that ipsilateral breast symptoms, mammographic lesion other than microcalcifications alone, 14G core needle biopsy, papilloma co-diagnosis, severe ADH and pathologists with lower volume of ADH diagnosis were factors statistically associated with malignancy. However, no subgroups were identified for safe clinical-only follow-up. Surgery is recommended in all cases of ADH diagnosed by percutaneous breast biopsy.

Early radiokinetic studies revealed that the classical metabolic defect in patients with familial hypercholesterolemia (FH) is hypocatabolism of LDL due to decreased LDL receptor activity. However, recent studies have suggested that hepatic oversecretion of apolipoprotein B-100 (apoB-100)-containing lipoproteins could also contribute to the markedly elevated plasma concentrations of LDL-cholesterol found in FH. The aim of this study was to examine the kinetics of apoB-100 labeled with a stable isotope ( l -[5,5,5-D 3 ] leucine) in five normolipidemic controls and in seven well-characterized FH subjects that included six FH heterozygotes and one FH homozygote carrying the same null LDL receptor gene mutation. As compared with controls, the VLDL apoB-100 production rate was increased by 50% in the FH heterozygotes and by 109% in the FH homozygote. Furthermore, FH subjects had significantly higher LDL apoB-100 pool size and lower LDL apoB-100 fractional catabolic rate than controls. These results indicate that the elevation of plasma LDL-cholesterol found in FH is attributable to both decreased clearance of LDL and increased hepatic production of apoB-100-containing lipoproteins. -Tremblay, A. J., B. Lamarche, I. L. Ruel, J-C. Hogue, J. Bergeron, C. Gagné, and P. Couture. Increased production of VLDL apoB-100 in subjects with familial hypercholesterolemia carrying the same null LDL receptor gene mutation. J. Lipid Res. 2004. 45: 866-872.Supplementary key words apolipoprotein B-100 • gas chromatography/mass spectrometry • kinetic Apolipoprotein B-100 (apoB-100) is a large glycoprotein of hepatic origin that plays an indispensable role in the assembly, secretion, and intravascular transport of distinct classes of lipoproteins. The role of the LDL receptor in the hepatic removal of apoB-containing lipoproteins is well established. ApoB-100 contains the domain required for interaction with the LDL receptor (1) responsible for approximately two-thirds of the clearance of apoB-containing lipoproteins (2). The importance of the LDL receptor in mediating hepatic uptake of apoB-containing lipoproteins is well illustrated in patients with heterozygous familial hypercholesterolemia (FH), in whom the presence of a mutant LDL receptor allele leads to a 2-to 3-fold increase of plasma levels of atherogenic apoB-containing lipoproteins and to premature coronary artery disease (3). Recently, a possible new role for the LDL receptor in the regulation of hepatic production of apoB-100 has been proposed on the basis of animal studies (4, 5). These studies suggest that the LDL receptor modulates the hepatic secretion of apoB-100 by promoting presecretory degradation of apoB-100 and by mediating the reuptake of newly secreted nascent apoB-100-containing lipoproteins, resulting in internalization and subsequent turnover of apoB-100. Therefore, the potential interaction between the LDL receptor and apoB-100 within the secretory pathway would impact upon hepatic apoB-100 secretion in a unique manner and would be expected to influe...

Metastases of breast ILC to atypical sites might be more frequent than previously reported. Clinicians should keep a high level of suspicion when a patient with a history of ILC develops digestive symptoms. It is important to differentiate metastases from a primary GI tumor by using immunohistochemical markers. J. Surg. Oncol. 2016;114:543-547. © 2016 Wiley Periodicals, Inc.