Identification cholesterol metabolites altered before the onset of nonalcoholic steatohepatitis by targeted metabolomics.

Nonalcoholic steatohepatitis (NASH) is a disease with symptoms similar to those of alcoholic liver inflammation without alcohol intake. As an effective treatment strategy has not been established for this disease, a detailed understanding of the pathological progression mechanism is required. We focused on cholesterol metabolites, which are suspected to regulate NASH pathology, and investigated their relationship with the pathological progression in the early stages of NASH. First, the LC/MS/MS methods for bile acids and sterols were optimized and validated. Next, NASH model mice were established by feeding a choline-deficient, methionine-reduced high-fat diet, and the levels of hepatic cholesterol metabolites were measured. As a result, before the onset of NASH, desmosterol, 4ß-hydroxycholesterol, campesterol, sitosterol, secondary bile acids such as taurodeoxycholic acid significantly decreased by up to 1/38 of NASH model group. Autoxidation-generated sterols significantly increased 2- to 5-fold, and various primary bile acids such as conjugated ß-muricholic acids and cholic acids significantly increased 2- to 7-fold. In this study, the levels of cholesterol metabolites changed in the before the onset of NASH. These metabolic alterations involved in inflammation induction and detoxification for NASH may help the discovery of early diagnostic biomarkers in the future.

Altered bile acid composition and disposition in a mouse model of non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) is a progressive inflammatory and fibrotic disease. However, the progression mechanism of NASH is not well understood. Bile acids are endogenous molecules that regulate cholesterol homeostasis, lipid solubilization in the intestinal lumen, and metabolic signaling via several receptors. In this study, we investigated the relationship between bile acid composition and NASH-associated fibrosis using a mouse model fed choline-deficient, L-amino-acid-defined, high-fat diet with 0.1% methionine (CDAHFD). C57BL/6 J mice fed CDAHFD developed NASH and fibrosis within few weeks. With the progress of NASH-associated liver fibrosis, altered bile acid composition was observed in the liver, bile, and peripheral plasma. Decreased mRNA levels of bile acid metabolizing enzymes such as Cyp7a1 and Baat were observed in contrast to increased Sult2a1 level in the liver. Increased mRNA levels of Ostß and Abcc4 and decreased in mRNA levels of Bsep, Abcc2, Ntcp, and Oatp1b2, suggesting that bile acids efflux from hepatocytes into the peripheral plasma rather than into bile. In conclusion, the changes in bile acid metabolizing enzymes and transporters expression, resulting in increasing the total bile acid concentration in the plasma, signify a protection mechanism by the hepatocyte to reduce hepatotoxicity during disease progression to NASH but may promote liver fibrosis.

[Comparison of image distortion between three magnetic resonance imaging systems of different magnetic field strengths for use in stereotactic irradiation of brain].

In this study, we evaluated the image distortion of three magnetic resonance imaging (MRI) systems with magnetic field strengths of 0.4 T, 1.5 T and 3 T, during stereotactic irradiation of the brain. A quality assurance phantom for MRI image distortion in radiosurgery was used for these measurements of image distortion. Images were obtained from a 0.4-T MRI (APERTO Eterna, HITACHI), a 1.5-T MRI (Signa HDxt, GE Healthcare) and a 3-T MRI (Signa HDx 3.0 T, GE Healthcare) system. Imaging sequences for the 0.4-T and 3-T MRI were based on the 1.5-T MRI sequence used for stereotactic irradiation in the clinical setting. The same phantom was scanned using a computed tomography (CT) system (Aquilion L/B, Toshiba) as the standard. The results showed mean errors in the Z direction to be the least satisfactory of all the directions in all results. The mean error in the Z direction for 1.5-T MRI at －110 mm in the axial plane showed the largest error of 4.0 mm. The maximum errors for the 0.4-T and 3-T MRI were 1.7 mm and 2.8 mm, respectively. The errors in the plane were not uniform and did not show linearity, suggesting that simple distortion correction using outside markers is unlikely to be effective. The 0.4-T MRI showed the lowest image distortion of the three. However, other items, such as image noise, contrast and study duration need to be evaluated in MRI systems when applying frameless stereotactic irradiation.

[Method for evaluating the positional accuracy of a six-degrees-of-freedom radiotherapy couch using high definition digital cameras].

PURPOSE: In this study, we proposed and evaluated a positional accuracy assessment method with two high-resolution digital cameras for add-on six-degrees-of-freedom radiotherapy (6D) couches. METHODS AND MATERIALS: Two high resolution digital cameras (D5000, Nikon Co.) were used in this accuracy assessment method. These cameras were placed on two orthogonal axes of a linear accelerator (LINAC) coordinate system and focused on the isocenter of the LINAC. Pictures of a needle that was fixed on the 6D couch were taken by the cameras during couch motions of translation and rotation of each axis. The coordinates of the needle in the pictures were obtained using manual measurement, and the coordinate error of the needle was calculated. The accuracy of a HexaPOD evo (Elekta AB, Sweden) was evaluated using this method. RESULTS: All of the mean values of the X, Y, and Z coordinate errors in the translation tests were within ±0.1 mm. However, the standard deviation of the Z coordinate errors in the Z translation test was 0.24 mm, which is higher than the others. In the X rotation test, we found that the X coordinate of the rotational origin of the 6D couch was shifted. CONCLUSIONS: We proposed an accuracy assessment method for a 6D couch. The method was able to evaluate the accuracy of the motion of only the 6D couch and revealed the deviation of the origin of the couch rotation. This accuracy assessment method is effective for evaluating add-on 6D couch positioning.

Effect of daily setup errors on individual dose distribution in conventional radiotherapy: an initial study.

Recent linear accelerators can perform cone-beam computed tomography to correct setup errors immediately before dose delivery. We calculated the dose distribution with setup errors acquired from cone-beam computed tomography to determine a more realistic and individual effect of setup errors. The differences in dose distribution were analyzed. The setup errors of three patients who were irradiated in the neck, esophagus, and pelvic area were obtained retrospectively. We found that the maximum dose variances for the three cases were 19.9-35.9%. The maximum dose variance points were relatively far from the isocenter. The volume of the 10% dose difference had widths of 1.3-1.85 cm around the beam edges. The V95 and mean doses at the clinical target volume were mostly unchanged. Doses around the beam edges were more varied than those around the isocenter for every case. The dose on the spinal cord located near the beam edges varied by 5-10% compared with the dose of the radiotherapy plan in two of the cases. We demonstrated the individual dose distributions of the cases affected by daily setup errors for all fractions.

The effects of a timolol maleate gel-forming solution on normotensive beagle dogs.

The effects of a timolol maleate gel-forming solution (TMGS) on intraocular pressure (IOP), blood pressure (BP), and pupil size (PS) were evaluated in normotensive dogs. TMGS was administered once daily to six normotensive beagle dogs. TMGS administration reduced IOP and PS. The hypotensive effect persisted for 24 hr after the administration. The mean reduction in IOP was 5.3 mm Hg (P<0.01). The changes in BP and PS were not significant. These results suggest that TMGS can potentially be used in the treatments of glaucoma and ocular hypertension in dogs.