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Progress in the development of compact high-energy pulsed laser- plasma wakefield accelerators is opening up the potential for using Very High Energy Electron (VHEEs) beams in the range of 150 - 250 MeV for biomedical studies. Initial experiments using VHEE for this purpose have been carried out using the ALPHA-X laser-plasma wakefield accelerator beam line at the University of Strathclyde, Glasgow, UK. The purpose of this investigation is to use Monte Carlo simulations to plan experiments and compare with characterization of the interaction of the VHEE beam using a dosimeter.An experiment using the VHEE beam to irradiate a muscle-equivalent BANG polymer gel dosimeter has been carried out. Simulations have been used to prepare for the experiments. These were undertaken using the expected average energy for a pulse set and an energy spread approximated by Gaussian distribution. The model was implemented in FLUKA Monte Carlo code with follow up modeling using the Geant4 toolkit. The results have been compared with 1mm̂3 voxel laser CT based measurements of the dose deposited in the BANG dosimeter and with measurement of the induced radioactivity.The results of the measured dose from induced radioactivity have been compared with data from the FLUKA simulations. The beam model based on an average energy of particles in irradiation gives an acceptable estimate of the induced radioactivity and the dose deposited in the BANG dosimeter. Comparison with the dosimeter scanned profiles shows that the structure of the spectra of VHEE beams in the experiment and secondary scattered particles in the beam line should be accounted for in any model. Such model description of the VHEE beam for the ALPHA-X beam line has been developed.Monte Carlo simulations using the FLUKA code is an efficient way to plan a VHEE experiment and analyze data from measurements.

Cows managed for extended lactations of 16 months duration were milked on a half-udder basis twice or thrice daily, commencing in lactation week 9. Mammary epithelial integrity (assessed by milk sodium[ratio ]potassium ratio) was greater in the half-udder which was milked thrice daily. This difference was evident throughout the lactation but became greater after week 41. Milk protein composition was assessed during late lactation (52±3 weeks). Casein number (casein as a proportion of total protein) was significantly higher in half-udders milked thrice daily, as were the relative amounts of α- and β-caseins, whilst those of κ- and γ-caseins were reduced. Two days of inverted milking frequency (i.e. thrice-milked udder halves now milked twice, and vice versa) only partly reversed these differences. We concluded that thrice-daily milking will help to prevent or ameliorate the usual decline in milk processing quality associated with late lactation. Part of this effect is due simply to reduced exposure to proteolytic enzymes as a result of decreased storage time in the udder, but part is due to a better maintenance of epithelial tight junction integrity as lactation advances, which restricts leakage of proteolytic enzymes from serum into milk.

Three galactopoietic stimuli, frequent milking (4X), bovine somatotrophin (bST) and thyroxine (T4) were used in an additive stair-step design to achieve maximum output (metabolic capacity) in six peak-lactation cows of high genetic merit (HT) and six of low genetic merit (LT). A further six of each merit were untreated controls (HC, LC). Milk yield was increased significantly by 4X, increased further by the combination of 4X and bST and increased further still and significantly by the full combination of 4X, bST and T4. The magnitude of the yield response to the sequence of treatments did not differ significantly between HT and LT. The yield response to 4X and bST was sustainable without significant loss of body weight or body condition score for the 6 weeks during which these stimuli were administered. The response to the full combination, which included T4, was accompanied by significantly elevated heart rate and significant loss of body weight and condition compared with the combination of 4X and bST. As a result, treatments were discontinued, on an individual cow basis, before completion of this 6-week phase. Time on experiment did not differ between HT and LT. The results do not support the commonly held belief that selective breeding of dairy cows for high milk production has rendered them markedly more susceptible to metabolic disturbances.

Peripheral and hypothalamic mechanisms underlying the hyperphagia of lactation have been investigated in sheep. Sheep were fed ad libitum and killed at 6 and 18 days of lactation; ad libitum-fed nonlactating sheep were killed as controls. Despite increased food intake, lactating ewes were in negative energy balance. Lactation decreased plasma leptin and adipose tissue leptin mRNA concentrations. OB-Rb gene expression, determined by in situ hybridization, was increased in the hypothalamic arcuate nucleus (ARC) and ventromedial hypothalamic nucleus (VMH) at both stages of lactation. Neuropeptide Y (NPY) was increased by lactation in both the ARC and dorsomedial hypothalamus (DMH), although increased gene expression in the DMH was only apparent at day 18 of lactation. Gene expression was decreased for cocaine- and amphetamine-regulated transcript (CART) in the ARC and VMH and for proopiomelanocortin in ARC during lactation. Agouti-related peptide gene expression was increased in the ARC, and melanocortin receptor expression was unchanged in both the ARC and VMH with lactation. Thus the hypoleptinemia of lactation may activate NPY orexigenic pathways and attenuate anorexigenic melanocortin and CART pathways in the hypothalamus to promote the hyperphagia of lactation.

Two critical windows in mammary development have been proposed. The first arises from observations in rodents that nutrition during fetal and neonatal periods can affect mammary ductular outgrowth, subsequent proliferative activity and, eventually, tumorigenesis, that is, potentially it could have a long-term effect on pathological outcome (breast cancer) in women. The second similarly involves early diet, but in this case the outcome is phenotypic, in that dairy heifers reared too quickly during the peripubertal period subsequently show impaired udder development and reduced milk yield persisting throughout life. Most mammary development occurs during pregnancy, but this period is usually thought of only in terms of the immediate outcome for the subsequent lactation; it is not believed to be a critical window, at least in terms of lifetime mammary productivity. This review examines the evidence underlying these various claims and attempts to define the mechanisms involved, and also considers whether derangements occurring earlier in life (prenatally) could also have long-term consequences for physiological or pathological mammary development.