Inter- and intra-fractional stability of rectal gas in pelvic cancer patients during MRIgRT.

PURPOSE: Due to the electron return effect (ERE) during magnetic resonance imaging guided radiotherapy (MRIgRT), rectal gas during pelvic treatments can result in hot spots of over-dosage in the rectal wall. Determining the clinical impact of this effect on rectal toxicity requires estimation of the amount and mobility (and stability) of rectal gas during treatment. We therefore investigated the amount of rectal gas and local inter- and intra-fractional changes of rectal gas in pelvic cancer patients. METHODS: To estimate the volume of gas present at treatment planning, the rectal gas contents in the planning computed tomography (CT) scans of 124 bladder, 70 cervical and 2180 prostate cancer patients were calculated. To estimate inter- and intra-fractional variations in rectal gas, 174 and 131 T2-w MRIs for six cervical and eleven bladder cancer patients were used. These scans were acquired during four scan-sessions (~20-25 min each) at various time-points. Additionally, 258 T2-w MRIs of the first five prostate cancer patients treated using MRIgRT at our center, acquired during each fraction, were analyzed. Rectums were delineated on all scans. The area of gas within the rectum delineations was identified on each MRI slice using thresholding techniques. The area of gas on each slice of the rectum was used to calculate the inter- and intra-fractional group mean, systematic and random variations along the length of the rectum. The cumulative dose perturbation as a result of the gas was estimated. Two approaches were explored: accounting or not accounting for the gas at the start of the scan-session. RESULTS: Intra-fractional variations in rectal gas are small compared to the absolute volume of rectal gas detected for all patient groups. That is, rectal gas is likely to remain stable for periods of 20-25 min. Larger volumes of gas and larger variations in gas volume were observed in bladder cancer patients compared with cervical and prostate cancer patients. For all patients, local cumulative dose perturbations per beam over an entire treatment in the order of 60 % were estimated when gas had not been accounted for in the daily adaption. The calculated dose perturbation over the whole treatment was dramatically reduced in all patients when accounting for the gas in the daily set-up image. CONCLUSION: Rectal gas in pelvic cancer patients is likely to remain stable over the course of an MRIgRT fraction, and also likely to reappear in the same location in multiple fractions, and can therefore result in clinically relevant over-dosage in the rectal wall. The over-dosage is reduced when accounting for gas in the daily adaption.

Experimental verification the electron return effect around spherical air cavities for the MR-Linac using Monte Carlo calculation.

PURPOSE: Dose deposition around unplanned air cavities during magnetic resonance-guided radiotherapy (MRgRT) is influenced by the electron return effect (ERE). This is clinically relevant for gas forming close to or inside organs at risk (OARs) that lie in the path of a single beam, for example, intestinal track during pelvic treatment. This work aims to verify Monte Carlo calculations that predict the dosimetric effects of ERE around air cavities. For this, we use GafChromic EBT3 film inside poly-methyl methacrylate (PMMA) -air phantoms. METHOD: Four PMMA phantoms were produced. Three of the phantoms contained centrally located spherical air cavities (0.5, 3.5, 7.5 cm diameter), and one phantom contained no air. The phantoms were split to sandwich GafChromic EBT3 film in the center. The phantoms were irradiated on an Elekta Unity system using a single 10 × 10 cm2 7-MV photon beam under the influence of a 1.5-T transverse magnetic field. The measurements were replicated using the Elekta Monaco treatment planning system (TPS). Gamma analysis with pass criteria 3%/3 mm was used to compare the measured and calculated dose distributions. We also consider 3%/2 mm, 2%/3 mm, and 2%/2 mm pass criteria for interest. RESULTS: The gamma analysis showed that >95% of the points agreed between the TPS-calculated and measured dose distributions, using 3%/3 mm criteria. The phantom containing the largest air cavity had the lowest agreement, with most of the disagreeing points lying inside the air cavity (dose to air region). CONCLUSIONS: The dose effects due to ERE around spherical air cavities are being calculated in the TPS with sufficient accuracy for clinical use.

The effect of concentrate supplementation on milk production and cow traffic in early and late lactation in a pasture-based automatic milking system.

The objective of this experiment was to establish the effect of low-concentrate (LC) and high-concentrate (HC) supplementation in the early and late periods of lactation on milk production and cow traffic in a pasture-based automatic milking (AM) system. In total, 40 cows (10 primiparous and 30 multiparous) were randomly assigned to one of the two treatments. The experimental periods for the early and late lactation trials extended from 23 February to 12 April 2015 and 31 August to 18 October 2015, respectively (49 days in each trial period). The early lactation supplement levels were 2.3 and 4.4 kg/cow per day for LC and HC, respectively, whereas the late lactation supplement levels were 0.5 and 2.7 kg/cow per day for LC and HC, respectively. Variables measured included milking frequency, milking interval, milking outcome and milking characteristics, milk yield/visit and per day, wait time/visit and per day, return time/visit and the distribution of gate passes. As the herd was seasonal (spring) calving, the experimental periods could not run concurrently and as a result no statistical comparison between the periods was conducted. There was no significant effect of treatment in the early lactation period on any of the milk production, milking characteristics or cow traffic variables. However, treatment did significantly affect the distribution of gate passes, with the HC cows recording significantly more gate passes in the hours preceding the gate time change such as hours 7 (P<0.01), 15 (P<0.05), 20, 21 (P<0.001), and 22 (P<0.05), whereas the LC treatment recorded significantly more gate passes in the hours succeeding the gate time change, such as time points 2 (P<0.01) and 10 (P<0.05). There was a significant effect of treatment in late lactation, with HC having a greater milk yield (P<0.01), milking duration and activity/day (P<0.05), while also having a significantly shorter milking interval (P<0.05) and return time/visit (P<0.01). The distribution of gate passes were similar to the early lactation period, with HC also recording a significantly greater number of gate passes during the early morning period (P<0.01) when visitations were at their lowest. Any decision regarding the supplementing of dairy cows with concentrates needs to be examined from an economic perspective, to establish if the milk production and cow traffic benefits displayed in late lactation outweigh the cost of the concentrate; thereby ensuring that the decision to supplement is financially prudent.

Daily and seasonal trends of electricity and water use on pasture-based automatic milking dairy farms.

The objective of this study was to identify the major electricity and water-consuming components of a pasture-based automatic milking (AM) system and to establish the daily and seasonal consumption trends. Electricity and water meters were installed on 7 seasonal calving pasture-based AM farms across Ireland. Electricity-consuming processes and equipment that were metered for consumption included milk cooling components, air compressors, AM unit(s), auxiliary water heaters, water pumps, lights, sockets, automatic manure scrapers, and so on. On-farm direct water-consuming processes and equipment were metered and included AM unit(s), auxiliary water heaters, tubular coolers, wash-down water pumps, livestock drinking water supply, and miscellaneous water taps. Data were collected and analyzed for the 12-mo period of 2015. The average AM farm examined had 114 cows, milking with 1.85 robots, performing a total of 105 milkings/AM unit per day. Total electricity consumption and costs were 62.6 Wh/L of milk produced and 0.91 cents/L, respectively. Milking (vacuum and milk pumping, within-AM unit water heating) had the largest electrical consumption at 33%, followed by air compressing (26%), milk cooling (18%), auxiliary water heating (8%), water pumping (4%), and other electricity-consuming processes (11%). Electricity costs followed a similar trend to that of consumption, with the milking process and water pumping accounting for the highest and lowest cost, respectively. The pattern of daily electricity consumption was similar across the lactation periods, with peak consumption occurring at 0100, 0800, and between 1300 and 1600 h. The trends in seasonal electricity consumption followed the seasonal milk production curve. Total water consumption was 3.7 L of water/L of milk produced. Water consumption associated with the dairy herd at the milking shed represented 42% of total water consumed on the farm. Daily water consumption trends indicated consumption to be lowest in the early morning period (0300-0600 h), followed by spikes in consumption between 1100 and 1400 h. Seasonal water trends followed the seasonal milk production curve, except for the month of May, when water consumption was reduced due to above-average rainfall. This study provides a useful insight into the consumption of electricity and water on a pasture-based AM farms, while also facilitating the development of future strategies and technologies likely to increase the sustainability of AM systems.

The effect of concentrate allocation on traffic and milk production of pasture-based cows milked by an automatic milking system.

Increased economic, societal and environmental challenges facing agriculture are leading to a greater focus on effective way to combine grazing and automatic milking systems (AMS). One of the fundamental aspects of robotic milking is cows' traffic to the AMS. Numerous studies have identified feed provided, either as fresh grass or concentrate supplement, as the main incentive for cows to return to the robot. The aim of this study was to determine the effect of concentrate allocation on voluntary cow traffic from pasture to the robot during the grazing period, to highlight the interactions between grazed pasture and concentrate allocation in terms of substitution rate and the subsequent effect on average milk yield and composition. Thus, 29 grazing cows, milked by a mobile robot, were monitored for the grazing period (4 months). They were assigned to two groups: a low concentrate (LC) group (15 cows) and a high concentrate (HC) group (14 cows) receiving 2 and 4 kg concentrate/cow per day, respectively; two allocations per day of fresh pasture were provided at 0700 and 1600 h. The cows had to go through the AMS to receive the fresh pasture allocation. The effect of concentrate level on robot visitation was calculated by summing milkings, refusals and failed milkings/cow per day. The impact on average daily milk yield and composition was also determined. The interaction between lactation number and month was used as an indicator of pasture availability. Concentrate allocation increased significantly robot visitations in HC (3.60±0.07 visitations/cow per day in HC and 3.10±0.07 visitations/cow per day in LC; P<0.001) while milkings/cow per day were similar in both groups (LC: 2.37±0.02/day and HC: 2.39±0.02/day; Ns). The average daily milk yield over the grazing period was enhanced in HC (22.39±0.22 kg/cow per day in HC and 21.33±0.22 kg/cow per day in LC; P<0.001). However the gain in milk due to higher concentrate supply was limited with regards to the amount of provided concentrates. Milking frequency in HC primiparous compared with LC was increased. In the context of this study, considering high concentrate levels as an incentive for robot visitation might be questioned, as it had no impact on milking frequency and limited impact on average milk yield and composition. By contrast, increased concentrate supply could be targeted specifically to primiparous cows.

Investment appraisal of automatic milking and conventional milking technologies in a pasture-based dairy system.

The successful integration of automatic milking (AM) systems and grazing has resulted in AM becoming a feasible alternative to conventional milking (CM) in pasture-based systems. The objective of this study was to identify the profitability of AM in a pasture-based system, relative to CM herringbone parlors with 2 different levels of automation, across 2 farm sizes, over a 10-yr period following initial investment. The scenarios which were evaluated were (1) a medium farm milking 70 cows twice daily, with 1 AM unit, a 12-unit CM medium-specification (MS) parlor and a 12-unit CM high-specification (HS) parlor, and (2) a large farm milking 140 cows twice daily with 2 AM units, a 20-unit CM MS parlor and a 20-unit CM HS parlor. A stochastic whole-farm budgetary simulation model combined capital investment costs and annual labor and maintenance costs for each investment scenario, with each scenario evaluated using multiple financial metrics, such as annual net profit, annual net cash flow, total discounted net profitability, total discounted net cash flow, and return on investment. The capital required for each investment was financed from borrowings at an interest rate of 5% and repaid over 10-yr, whereas milking equipment and building infrastructure were depreciated over 10 and 20 yr, respectively. A supporting labor audit (conducted on both AM and CM farms) showed a 36% reduction in labor demand associated with AM. However, despite this reduction in labor, MS CM technologies consistently achieved greater profitability, irrespective of farm size. The AM system achieved intermediate profitability at medium farm size; it was 0.5% less profitable than HS technology at the large farm size. The difference in profitability was greatest in the years after the initial investment. This study indicated that although milking with AM was less profitable than MS technologies, it was competitive when compared with a CM parlor of similar technology.

Receptor reserve analysis of the human CCR3 receptor in eosinophils and CCR3-transfected cells.

A novel pharmacological study of CCR3 receptor reserve in a CCR3-transfected cell (CREM3) and human eosinophils was done; functional responses measured were increases in intracellular calcium and chemotaxis. Eotaxin, eotaxin-2, monocyte chemoattractant protein-4 (MCP-4), RANTES, and MCP-3 induced similar maximal eosinophil chemotaxis, whereas MCP-3 and RANTES induced submaximal calcium responses in eosinophils compared to eotaxin, MCP-4, and eotaxin-2. This suggested a receptor reserve in the chemotaxis response. Receptor reserve was quantitated for eotaxin. Occupancy of all CCR3 receptors was required for a maximal calcium response in both CREM3 and eosinophils (reserve = 1.0 or 0.17, respectively); the stimulus-calcium response relationship was linear, indicating no receptor reserve. In contrast, in eosinophils a large receptor reserve (6.5) was found for chemotaxis, where occupancy of 15% receptors drove half-maximal responses. These studies indicate that CCR3 interacts with G-proteins that are poorly coupled to the calcium response, whereas coupling efficiency and/or amplification to the chemotaxis apparatus in human eosinophils is significantly greater.

Effects of cyclosporin A and dinactin on T-cell proliferation, interleukin-5 production, and murine pulmonary inflammation.

We compared the effects of cyclosporin A (CSA) and a macrotetrolide antibiotic, dinactin, on human T-cell proliferation and cytokine production induced by stimulation of the T-cell receptor alone (monoclonal antibody [mAb] directed against CD3) or in combination with costimulatory signals (mAbs directed against CD3 and CD28). These agents were also examined in a murine model of interleukin (IL)-5-mediated pulmonary inflammation. Dinactin inhibited T-cell proliferation induced by IL-2, by mAb to CD3, and by mAbs to CD3 plus alpha-CD28 with identical dose-response curves (IC50 = 10-20 ng/ml). Dinactin inhibited cytokine production with IC50 values of 10 ng/ml for IL-4 and IL-5 and 30 or 60 ng/ml for interferon-gamma or IL-2, respectively. Unlike CSA, exogenous IL-2 did not alter the dinactin-mediated effects on T cells, and nuclear run-on and steady-state messenger RNA (mRNA) analysis showed that dinactin inhibited cytokine production through a post-transcriptional mechanism. CSA selectively blocked T-cell receptor-induced T-cell proliferation and cytokine production (IC50 = 10 ng/ml). Under costimulatory conditions, IL-5 synthesis was only minimally inhibited by high concentrations of CSA, and at CSA concentrations of less than 125 ng/ml, IL-5 was significantly increased above control values. Dinactin and CSA reduced pulmonary eosinophilia when administered within 1 d of airway antigen challenge. Of the cytokine mRNAs examined in the lungs of CSA-pretreated, antigen-challenged mice, IL-5 mRNA levels were the least reduced, paralleling the resistance of IL-5 to CSA observed in vitro and suggesting a role for CD28 in the in vivo induction of IL-5.

Interleukins 6 and 11 protect mice from mortality in a staphylococcal enterotoxin-induced toxic shock model.

BALB/By mice given doses of D-galactosamine plus Staphylococcus aureus enterotoxin B die within 48 h of administration. The cause of death is a syndrome much like toxic shock syndrome in humans. We used this model to investigate the role of two cytokines, interleukin 6 and interleukin 11, which share the signal transducing subunit, gp130, of their respective receptors. We observed that pretreatment of mice with antibody to interleukin 6 increased mortality from 55% to nearly 90% (P < 0.001), while pretreatment with either cytokine reduced death. The protection was dose dependent; however, interleukin 6 was about 10-fold more potent that interleukin 11. These data indicate that endogenous interleukin 6 plays a protective role in attenuating acute inflammatory responses; furthermore, interleukin 6 and interleukin 11 can abrogate T-cell activation due to triggering by superantigen. A possible clinical role for these cytokines in the treatment of toxic shock merits further investigation.