Background-Altered vascular mechanics resulting from changes in collagen and integrins may influence resistance artery structure and function and, therefore, peripheral resistance and blood pressure in spontaneously hypertensive rats (SHR). Methods and Results-Effects of age, angiotensin-converting enzyme inhibition (fosinopril, 10 to 30 mg/kg per day), and AT 1 -receptor antagonism (irbesartan, 50 mg/kg per day) on vascular structure, mechanics, and composition were assessed in SHR. Systolic blood pressure was elevated in young SHR (130Ϯ2 mm Hg) compared with Wistar-Kyoto (WKY) rats (106Ϯ2 mm Hg). In adult SHR, the rise in systolic blood pressure (44Ϯ3 mm Hg) was blunted by fosinopril (18Ϯ1 mm Hg) and irbesartan (9Ϯ3 mm Hg). Lumen diameter of mesenteric resistance arteries was smaller and media/lumen ratio was greater in young and adult SHR versus WKY rats. Growth index was 24% in untreated adult SHR versus WKY rats; these values were Ϫ35% for fosinopril-treated and Ϫ29% for irbesartan-treated SHR versus untreated SHR. Isobaric wall stiffness was normal despite increased stiffness of wall components in adult SHR vessels. Irbesartan partially prevented stiffening of wall components in SHR. The collagen/elastin ratio was greater in adult SHR vessels (6.5Ϯ1.3) than in WKY (3.2Ϯ0.4) vessels. Expression of ␣ v ␤ 3 and ␣ 5 ␤ 1 integrins was increased in SHR aged 20 versus 6 weeks. Expression of ␣ 5 ␤ 1 integrins was lower in young SHR, and ␣ v ␤ 3 integrins were overexpressed in adult SHR versus WKY rats. Irbesartan and fosinopril attenuated differences in the collagen/elastin ratio and integrin expression. Conclusions-Wall components of mesenteric resistance arteries stiffen with age in SHR. Interrupting the renin-angiotensin system has normalizing effects on integrin expression and composition, stiffness, and growth of the arterial wall.

Aims: Increased fructose consumption predisposes the liver to nonalcoholic fatty liver disease (NAFLD), but the mechanisms are elusive. Thioredoxin-interacting protein (TXNIP) links oxidative stress to NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome activation and this signaling axis may be involved in fructose-induced NAFLD. Here, we explore the role of reactive oxygen species (ROS)-induced TXNIP overexpression in fructose-mediated hepatic NLRP3 inflammasome activation, inflammation, and lipid accumulation. Results: Rats were fed a 10% fructose diet for 8 weeks and treated with allopurinol and quercetin during the last 4 weeks. Five millimolars of fructose-exposed hepatocytes (primary rat hepatocytes, rat hepatic parenchymal cells [RHPCs], HLO2, HepG2) were co-incubated with antioxidants or caspase-1 inhibitor or subjected to TXNIP or NLRP3 siRNA interference. Fructose induced NLRP3 inflammasome activation and proinflammatory cytokine secretion, janus-activated kinase 2/signal transducers and activators of transcription 3-mediated inflammatory signaling, and expression alteration of lipid metabolism-related genes in cultured hepatocytes and rat livers. NLRP3 silencing and caspase-1 suppression blocked these effects in primary rat hepatocytes and RHPCs, confirming that inflammasome activation alters hepatocyte lipid metabolism. Hepatocellular ROS and TXNIP were increased in animal and cell models. TXNIP silencing blocked NLRP3 inflammasome activation, inflammation, and lipid metabolism perturbations but not ROS induction in fructoseexposed hepatocytes, whereas antioxidants addition abrogated TXNIP induction and diminished the detrimental effects in fructose-exposed hepatocytes and rat livers. Innovation and Conclusions: This study provides a novel mechanism for fructose-induced NAFLD pathogenesis by which the ROS-TXNIP pathway mediates hepatocellular NLRP3 inflammasome activation, inflammation and lipid accumulation. Antioxidant-based interventions can inhibit the ROS-TXNIP pathway. Antioxid. Redox Signal. 22, 848-870.

The Monte Carlo method enables accurate dose calculation for radiation therapy treatment planning and has been implemented in some commercial treatment planning systems. Unlike conventional dose calculation algorithms that provide patient dose information in terms of dose to water with variable electron density, the Monte Carlo method calculates the energy deposition in different media and expresses dose to a medium. This paper discusses the differences in dose calculated using water with different electron densities and that calculated for different biological media and the clinical issues on dose specification including dose prescription and plan evaluation using dose to water and dose to medium. We will demonstrate that conventional photon dose calculation algorithms compute doses similar to those simulated by Monte Carlo using water with different electron densities, which are close (<4% differences) to doses to media but significantly different (up to 11%) from doses to water converted from doses to media following American Association of Physicists in Medicine (AAPM) Task Group 105 recommendations. Our results suggest that for consistency with previous radiation therapy experience Monte Carlo photon algorithms report dose to medium for radiotherapy dose prescription, treatment plan evaluation and treatment outcome analysis.

Photon beams of 4, 6 and 15 MV from Varian Clinac 2100C and 2300C/D accelerators were simulated using the EGS4/BEAM code system. The accelerators were modelled as a combination of component modules (CMs) consisting of a target, primary collimator, exit window, flattening filter, monitor chamber, secondary collimator, ring collimator, photon jaws and protection window. A full phase space file was scored directly above the upper photon jaws and analysed using beam data processing software, BEAMDP, to derive the beam characteristics, such as planar fluence, angular distribution, energy spectrum and the fractional contributions of each individual CM. A multiple-source model has been further developed to reconstruct the original phase space. Separate sources were created with accurate source intensity, energy, fluence and angular distributions for the target, primary collimator and flattening filter. Good agreement (within 2%) between the Monte Carlo calculations with the source model and those with the original phase space was achieved in the dose distributions for field sizes of 4 cm x 4 cm to 40 cm x 40 cm at source surface distances (SSDs) of 80-120 cm. The dose distributions in lung and bone heterogeneous phantoms have also been found to be in good agreement (within 2%) for 4, 6 and 15 MV photon beams for various field sizes between the Monte Carlo calculations with the source model and those with the original phase space.

IMRT is associated with a decrease in severity of acute desquamation compared with a matched control group treated with conventional radiation therapy. As with conventional radiation, breast size remains the most important prognostic factor for acute skin toxicity. The CTC grading system for acute radiation dermatitis is not sensitive when applied to modern breast cancer treatment because of its dependence of subjective rating of erythema and inability to gauge variations in desquamation. Further study of patient symptoms, quality of life, and cosmesis is needed to evaluate the benefit of IMRT for breast cancer.

Conventional IMRT dose verification using film and ion chamber measurements is useful but limited with respect to the actual dose distribution received by the patient. The Monte Carlo simulation has been introduced as an independent dose verification tool for IMRT using the patient CT data and MLC leaf sequence files, which validates the dose calculation accuracy but not the plan delivery accuracy. In this work, we propose a Monte Carlo based IMRT dose verification method that reconstructs the patient dose distribution using the patient CT, actual beam data based on the information from the record and verify system (R/V), and the MLC log files obtained during dose delivery that record the MLC leaf positions and MUs delivered. Comparing the Monte Carlo dose calculation with the original IMRT plan using these data simultaneously validates the accuracy of both the IMRT dose calculation and beam delivery. Such log file based Monte Carlo simulations are expected to be employed as a useful and efficient IMRT QA modality to validate the dose delivered to the patient. We have run Monte Carlo simulations for eight IMRT prostate plans using this method and the results for the target dose were consistent with the original CORVUS treatment plans to within 3.0% and 2.0% with and without heterogeneity corrections in the dose calculation. However, significant dose deviations in nearby critical structures have been observed. The results showed that up to 9.0% of the bladder dose and up to 38.0% of the rectum dose, to which leaf position errors were found to contribute <2%, were underestimated by the CORVUS treatment planning system. The concept of average leaf position error has been defined to analyze MLC leaf position errors for an IMRT plan. A linear correlation between the target dose error and the average position error has been found based on log file based Monte Carlo simulations, showing that an average position error of 0.2 mm can result in a target dose error of about 1.0%.

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A method for deriving the electron and photon energy spectra from electron beam central axis percentage depth dose (PDD) curves has been investigated. The PDD curves of 6, 12 and 20 MeV electron beams obtained from the Monte Carlo full phase space simulations of the Varian linear accelerator treatment head have been used to test the method. We have employed a 'random creep' algorithm to determine the energy spectra of electrons and photons in a clinical electron beam. The fitted electron and photon energy spectra have been compared with the corresponding spectra obtained from the Monte Carlo full phase space simulations. Our fitted energy spectra are in good agreement with the Monte Carlo simulated spectra in terms of peak location, peak width, amplitude and smoothness of the spectrum. In addition, the derived depth dose curves of head-generated photons agree well in both shape and amplitude with those calculated using the full phase space data. The central axis depth dose curves and dose profiles at various depths have been compared using an automated electron beam commissioning procedure. The comparison has demonstrated that our method is capable of deriving the energy spectra for the Varian accelerator electron beams investigated. We have implemented this method in the electron beam commissioning procedure for Monte Carlo electron beam dose calculations.