The continuous intragastric enteral feeding protocol in the rat was a major development in alcohol-induced liver injury (ALI) research. Much of what has been learned to date involves inhibitors or nutritional manipulations that may not be specific. Knockout technology avoids these potential problems. Therefore, we used long-term intragastric cannulation in mice to study early ALI. Reactive oxygen species are involved in mechanisms of early ALI; however, their key source remains unclear. Cytochrome P-450 (CYP)2E1 is induced predominantly in hepatocytes by ethanol and could be one source of reactive oxygen species leading to liver injury. We aimed to determine if CYP2E1 was involved in ALI by adapting the enteral alcohol (EA) feeding model to CYP2E1 knockout (-/-) mice. Female CYP2E1 wild-type (+/+) or -/- mice were given a high-fat liquid diet with either ethanol or isocaloric maltose-dextrin as control continuously for 4 wk. All mice gained weight steadily over 4 wk, and there were no significant differences between groups. There were also no differences in ethanol elimination rates between CYP2E1 +/+ and -/- mice after acute ethanol administration to naive mice or mice receiving EA for 4 wk. However, EA stimulated rates 1.4-fold in both groups. EA elevated serum aspartate aminotransferase levels threefold to similar levels over control in both CYP2E1 +/+ and -/- mice. Liver histology was normal in control groups. In contrast, mice given ethanol developed mild steatosis, slight inflammation, and necrosis; however, there were no differences between the CYP2E1 +/+ and -/- groups. Chronic EA induced other CYP families (CYP3A, CYP2A12, CYP1A, and CYP2B) to the same extent in CYP2E1 +/+ and -/- mice. Furthermore, POBN radical adducts were also similar in both groups. Data presented here are consistent with the hypothesis that oxidants from CYP2E1 play only a small role in mechanisms of early ALI in mice. Moreover, this new mouse model illustrates the utility of knockout technology in ALI research.

Background and purpose Mechanisms of fatigue reported during radiotherapy are poorly defined but may include inflammatory cytokines and/or sleep disturbances. This prospective, longitudinal, phase II study assessed fatigue, sleep, and serum cytokine levels during radiotherapy for early-stage prostate cancer (PCa). Material and methods Twenty-eight men undergoing radiotherapy for early-stage PCa wore an Actiwatch Score to record fatigue level, sleep time, onset latency, efficiency and wake after sleep onset. Serum levels of IL-1α, IL-1β, TNF-α, IL-6, IL-8, IL-10 and VEGF were measured weekly during radiotherapy. Patient reported quality of life (QOL) metrics were collected before and after treatment. Linear mixed effects models examined trajectories across treatment weeks. Results Fatigue increased across treatment weeks (P < .01), and fatigue was associated with decreased patient-reported QOL. Sleep efficiency increased across treatment weeks (rate of change over time = .29, P = .03), and sleep onset latency decreased (rate of change over time = .86, P = .06). IL-6 tended to increase during treatment (P = 0.09), but none of the cytokine levels or sleep variables were significantly related to fatigue trajectories. Conclusions Despite increased sleep efficiency across treatment weeks, fatigue significantly increased. Although IL-6 increased during the course of radiotherapy, cytokines levels were not associated with fatigue scores or sleep disturbance. Further studies are needed to define the mechanisms for fatigue during radiotherapy.

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Prostate cancer patients undergoing localized external beam radiation therapy (EBRT) can experience a progressive increase in fatigue, which can affect physical functioning and quality of life. The purpose of this study was to develop a mouse EBRT prostate cancer treatment model with which to determine the role of pro-inflammatory cytokines in the genesis of EBRT-related fatigue. We assessed voluntary wheel-running activity (VWRA) as a proxy for fatigue, food intake and body weight in male C57BL/6 mice undergoing EBRT to the pelvis. In the first experiment, anesthetized male C57BL/6 mice underwent fractionated EBRT to the pelvis for a total dose of 68.2 Gy, thereby mimicking a clinically relevant therapeutic dose and frequency. The day after the last treatment, levels of IL-1β and TNF-α in plasma along with mRNA levels in liver, colon and whole brain were measured. EBRT-induced fatigue resulted in reduced body weight, diminished food intake, and increased plasma and tissue levels of IL-1β and TNF-α. In a follow-up experiment, we used TNF-α-deficient mice to further delineate the role of TNF-α signaling in EBRT-induced sickness behavior. EBRT-induced changes in fatigue, food intake and body weight were no different between TNF-α deficient mice and their wild-type counterparts. Taken together our data demonstrate that a clinically relevant localized irradiation of the pelvis induces a systemic IL-1β and TNF-α response and sickness behavior in mice, but the TNF-α signaling pathway alone does not independently mediate these effects.

The purpose of this study was the prospective comparison of objective and subjective effects of target volume region of interest (ROI) delineation using mousekeyboard and pen-tablet user input devices (UIDs). The study was designed as a prospective test/retest sequence, with Wilcoxon signed rank test for matchedpair comparison. Twenty-one physician-observers contoured target volume ROIs on four standardized cases (representative of brain, prostate, lung, and head and neck malignancies) twice: once using QWERTY keyboard/scroll-wheel mouse UID and once with pen-tablet UID (DTX2100, Wacom Technology Corporation, Vancouver, WA, USA). Active task time, ROI manipulation task data, and subjective survey data were collected. One hundred twenty-nine target volume ROI sets were collected, with 62 paired pen-tablet/mouse-keyboard sessions. Active contouring time was reduced using the pen-tablet UID, with mean ± SD active contouring time of 26 ±23 min, compared with 32 ± 25 with the mouse (p ≤ 0.01). Subjective estimation of time spent was also reduced from 31 ±26 with mouse to 27 ± 22 min with the pen (p = 0.02). Task analysis showed ROI correction task reduction (p = 0.045) and decreased panning and scrolling tasks (p < 0.01) with the pen-tablet; drawing, window/ level changes, and zoom commands were unchanged (p = n.s.) Volumetric analysis demonstrated no detectable differences in ROI volume nor intra-or inter-observer volumetric coverage. Fifty-two of 62 (84%) users preferred the tablet for each contouring task; 5 of 62 (8%) denoted no preference, and 5 of 62 (8%) chose the mouse interface. The pen-tablet UID reduced active contouring time and reduced correction of ROIs, without substantially altering ROI volume/coverage.