Carotid MRI Detection of Intraplaque Hemorrhage at 3T and 1.5T.

BACKGROUND AND PURPOSE: Carotid intraplaque hemorrhage leads to plaque progression and ischemic events. Detection can be accomplished with 3T T1w sequences, but may be limited by false-positive lipid/necrosis. The purpose of this study was threefold: (1) to determine if magnetization-prepared rapid acquisition with gradient-echo (MPRAGE) detects intraplaque hemorrhage versus lipid/necrosis; (2) if 3T MPRAGE image quality is retained at 1.5T; and (3) to determine observer agreement. METHODS: MPRAGE positive areas were compared to hemorrhage and lipid/necrosis areas from 100 carotid endarterectomy slides in 12 subjects using multivariable linear regression. Image quality was determined between 3T and 1.5T in 716 carotid arteries using t-tests and multivariable linear regression. Kappa analysis was used to determine agreement. RESULTS: Intraplaque hemorrhage, not lipid/necrosis, was a significant predictor of MPRAGE positive area before and after adjusting for confounders (slope = .52 vs. .51, P < .001). Image quality at 3T was slightly lower than 1.5T (mean 3.87 vs. 4.34, P < .0001). 3T image quality remained slightly decreased before and after adjusting for confounders (slope = -.46 vs. -.41, P < .001). Kappa values for inter-/intraobserver agreement were .807/.919 at 3T and .803/.871 at 1.5T. CONCLUSIONS: Carotid MPRAGE detects intraplaque hemorrhage, not lipid/necrosis. 3T image quality was retained at 1.5T with very good observer agreement.

Diagnostic accuracy studies of fine-needle aspiration show wide variation in reporting of study population characteristics: implications for external validity.

CONTEXT: Study comparisons rest on the assessment of applicability or external validity. Population characteristics are an important component of external validity and, although there has been a heightened awareness of deficiencies in reporting in diagnostic test accuracy (DTA) studies, the reporting of populations in DTA studies has not been investigated. OBJECTIVE: To assess the quality of reporting of population descriptions in DTA studies for fine-needle aspiration cytology (FNAC). DESIGN: Literature survey of common population parameters and usage patterns in FNAC DTA studies. We randomly selected 20 FNAC DTA studies in 4 categories (salivary glands, lung, thyroid, and pancreas) and determined the frequency of parameter usage. RESULTS: Studies showed considerable variability in reporting patterns. On average, studies reported 2 to 4 parameters to describe study populations. Age, sex, and lesion size were most frequently reported. Sixteen percent of studies did not provide any population description. Population parameters were used to describe the sample population more frequently than to describe the selection process (P = .001). There were significant differences in the number of parameters specified by anatomic site (P = .001). Only 21% of studies provided a flow diagram. Thirty-three percent of studies mentioned the target population. CONCLUSIONS: Studies show considerable variability in the description of sample populations and the population selection process. Studies often fail to provide flow diagrams or to provide a clear statement of the research problem. There is considerable opportunity for studies to improve both descriptions of sample populations and the process used to select them.

Ceramide mediates vascular dysfunction in diet-induced obesity by PP2A-mediated dephosphorylation of the eNOS-Akt complex.

Vascular dysfunction that accompanies obesity and insulin resistance may be mediated by lipid metabolites. We sought to determine if vascular ceramide leads to arterial dysfunction and to elucidate the underlying mechanisms. Pharmacological inhibition of de novo ceramide synthesis, using the Ser palmitoyl transferase inhibitor myriocin, and heterozygous deletion of dihydroceramide desaturase prevented vascular dysfunction and hypertension in mice after high-fat feeding. These findings were recapitulated in isolated arteries in vitro, confirming that ceramide impairs endothelium-dependent vasorelaxation in a tissue-autonomous manner. Studies in endothelial cells reveal that de novo ceramide biosynthesis induced protein phosphatase 2A (PP2A) association directly with the endothelial nitric oxide synthase (eNOS)/Akt/Hsp90 complex that was concurrent with decreased basal and agonist-stimulated eNOS phosphorylation. PP2A attenuates eNOS phosphorylation by preventing phosphorylation of the pool of Akt that colocalizes with eNOS and by dephosphorylating eNOS. Ceramide decreased the association between PP2A and the predominantly cytosolic inhibitor 2 of PP2A. We conclude that ceramide mediates obesity-related vascular dysfunction by a mechanism that involves PP2A-mediated disruption of the eNOS/Akt/Hsp90 signaling complex. These results provide important insight into a pathway that represents a novel target for reversing obesity-related vascular dysfunction.

Carotid magnetization-prepared rapid acquisition with gradient-echo signal is associated with acute territorial cerebral ischemic events detected by diffusion-weighted MRI.

BACKGROUND: Carotid intraplaque hemorrhage has been associated with symptomatic stroke and can be accurately detected with magnetization-prepared rapid acquisition with gradient-echo (MPRAGE). Currently, there are no studies analyzing carotid MPRAGE signal and territorial ischemic events defined by diffusion restriction in the acute setting. Our aim was to determine the association of carotid MPRAGE signal with acute territorial ischemic events using carotid MPRAGE and brain diffusion tensor imaging. METHODS AND RESULTS: After the addition of the MPRAGE sequence to the neck MR angiographic protocol, 159 patients with suspected acute stroke were evaluated with both brain diffusion tensor imaging and carotid MPRAGE sequences over 2 years, providing 318 carotid artery and paired brain images for analysis. Forty-eight arteries were excluded due to extracarotid sources of brain ischemia and 4 were excluded due to carotid occlusion. Two hundred sixty-six arteries were eligible for data analysis. Carotid MPRAGE-positive signal was associated with an acute cerebral territorial ischemic event with a relative risk of 6.4 (P<0.001). The relative risk of a diffusion tensor imaging-positive territorial ischemic event with carotid MPRAGE-positive signal was increased in mild, moderate, and severe stenosis categories (10.3, P<0.001; 2.9, P=0.01; and 2.2, P=0.01, respectively). CONCLUSIONS: In the workup of acute stroke, carotid MPRAGE-positive signal was associated with an increased risk of territorial cerebral ischemic events as detected objectively by brain diffusion tensor imaging. The relative risk of stroke was increased in all carotid stenosis categories but was most elevated in the mild stenosis category.

Methods specification for diagnostic test accuracy studies in fine-needle aspiration cytology: a survey of reporting practice.

Diagnostic test accuracy (DTA) studies on fine-needle aspiration cytology (FNAC) often show considerable variability in diagnostic accuracy between study centers. Many factors affect the accuracy of FNAC. A complete description of the testing parameters would help make valid comparisons between studies and determine causes of performance variation. We investigated the manner in which test conditions are specified in FNAC DTA studies to determine which parameters are most commonly specified and the frequency with which they are specified and to see whether there is significant variability in reporting practice. We identified 17 frequently reported test parameters and found significant variation in the reporting of these test specifications across studies. On average, studies reported 5 of the 17 items that would be required to specify the test conditions completely. A more complete and standardized reporting of methods, perhaps by means of a checklist, would improve the interpretation of FNAC DTA studies.

Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance.

Insulin resistance occurs in 20%-25% of the human population, and the condition is a chief component of type 2 diabetes mellitus and a risk factor for cardiovascular disease and certain forms of cancer. Herein, we demonstrate that the sphingolipid ceramide is a common molecular intermediate linking several different pathological metabolic stresses (i.e., glucocorticoids and saturated fats, but not unsaturated fats) to the induction of insulin resistance. Moreover, inhibition of ceramide synthesis markedly improves glucose tolerance and prevents the onset of frank diabetes in obese rodents. Collectively, these data have two important implications. First, they indicate that different fatty acids induce insulin resistance by distinct mechanisms discerned by their reliance on sphingolipid synthesis. Second, they identify enzymes required for ceramide synthesis as therapeutic targets for combating insulin resistance caused by nutrient excess or glucocorticoid therapy.

Solenopsin, the alkaloidal component of the fire ant (Solenopsis invicta), is a naturally occurring inhibitor of phosphatidylinositol-3-kinase signaling and angiogenesis.

Phosphatidylinositol-3-kinase (PI3K), and its downstream effector Akt, or protein kinase Balpha (PKBalpha), play a major regulatory role in control of apoptosis, proliferation, and angiogenesis. PI3K and Akt are amplified or overexpressed in a number of malignancies, including sarcomas, ovarian cancer, multiple myeloma, and melanoma. This pathway regulates production of the potent angiogenic factor vascular endothelial growth factor (VEGF), and protects tumor cells against both chemotherapy and reactive oxygen-induced apoptosis through phosphorylation of substrates such as apoptotic peptidase-activating factor-1 (APAF-1), forkhead proteins, and caspase 9. Given its diverse actions, compounds that suppress the PI3K/Akt pathway have potential pharmacologic utility as angiogenesis inhibitors and antineoplastic agents. Using the SVR angiogenesis assay, a screen of natural products, we isolated the alkaloid solenopsin, and found that it is a potent angiogenesis inhibitor. We also found that solenopsin inhibits the PI3K signaling pathway in cells upstream of PI3K, which may underlie its affects on angiogenesis. Consistent with inhibition of the activation of PI3K, solenopsin prevented the phosphorylation of Akt and the phosphorylation of its substrate forkhead box 01a (FOXO1a), a member of the forkhead family of transcription factors. Interestingly, solenopsin also inhibited Akt-1 activity in an ATP-competitive manner in vitro without affecting 27 of 28 other protein kinases tested.