An isotope dilution model for partitioning of phenylalanine and tyrosine uptake by the liver of lactating dairy cows.

An isotope dilution model to describe the partitioning of phenylalanine and tyrosine in the bovine liver was developed. The model comprises four intracellular and six extracellular pools and various flows connecting these pools and external blood. Conservation of mass principles were applied to generate the fundamental equations describing the behaviour of the system in the steady state. The model was applied to datasets from multi-catheterised dairy cattle during a constant infusion of [1-13C]phenylalanine and [2,3,5,6-2H]tyrosine tracers. Model solutions described the extraction of phenylalanine and tyrosine from the liver via the portal vein and hepatic artery. In addition, the exchange of free phenylalanine and tyrosine between extracellular and intracellular pools was explained and the hydroxylation of phenylalanine to tyrosine was estimated. The model was effective in providing information about the fates of phenylalanine and tyrosine in the liver and could be used as part of a more complex system describing amino acid metabolism in the whole animal.

A mechanistic model of small intestinal starch digestion and glucose uptake in the cow.

The high contribution of postruminal starch digestion (up to 50%) to total-tract starch digestion on energy-dense, starch-rich diets demands that limitations to small intestinal starch digestion be identified. A mechanistic model of the small intestine was described and evaluated with regard to its ability to simulate observations from abomasal carbohydrate infusions in the dairy cow. The 7 state variables represent starch, oligosaccharide, glucose, and pancreatic amylase in the intestinal lumen, oligosaccharide and glucose in the unstirred water layer at the intestinal wall, and intracellular glucose of the enterocyte. Enzymatic hydrolysis of starch was modeled as a 2-stage process involving the activity of pancreatic amylase in the lumen and of oligosaccharidase at the brush border of the enterocyte confined within the unstirred water layer. The Na+-dependent glucose transport into the enterocyte was represented along with a facilitative glucose transporter 2 transport system on the basolateral membrane. The small intestine is subdivided into 3 main sections, representing the duodenum, jejunum, and ileum for parameterization. Further subsections are defined between which continual digesta flow is represented. The model predicted nonstructural carbohydrate disappearance in the small intestine for cattle unadapted to duodenal infusion with a coefficient of determination of 0.92 and a root mean square prediction error of 25.4%. Simulation of glucose disappearance for mature Holstein heifers adapted to various levels of duodenal glucose infusion yielded a coefficient of determination of 0.81 and a root mean square prediction error of 38.6%. Analysis of model behavior identified limitations to the efficiency of small intestinal starch digestion with high levels of duodenal starch flow. Limitations to individual processes, particularly starch digestion in the proximal section of the intestine, can create asynchrony between starch hydrolysis and glucose uptake capacity.

An isotope dilution model for partitioning phenylalanine and tyrosine uptake by the mammary gland of lactating dairy cows.

An isotope dilution model for partitioning phenylalanine and tyrosine uptake by the mammary gland of the lactating dairy cow is constructed and solved in the steady state. The model contains four intracellular and four extracellular pools and conservation of mass principles are applied to generate the fundamental equations describing the behaviour of the system. The experimental measurements required for model solution are milk secretion and plasma flow rate across the gland in combination with phenylalanine and tyrosine concentrations and plateau isotopic enrichments in arterial and venous plasma and free and protein bound milk during a constant infusion of [1-(13)C]phenylalanine and [2,3,5,6-(2)H]tyrosine tracer. If assumptions are made, model solution enables determination of steady state flows for phenylalanine and tyrosine inflow to the gland, outflow from it and bypass, and flows representing the synthesis and degradation of constitutive protein and phenylalanine hydroxylation. The model is effective in providing information about the fates of phenylalanine and tyrosine in the mammary gland and could be used as part of a more complex system describing amino acid metabolism in the whole ruminant.

A dynamic mechanistic model of lactic acid metabolism in the rumen.

Current feed evaluation systems for ruminants are too imprecise to describe diets in terms of their acidosis risk. The dynamic mechanistic model described herein arises from the integration of a lactic acid (La) metabolism module into an extant model of whole-rumen function. The model was evaluated using published data from cows and sheep fed a range of diets or infused with various doses of La. The model performed well in simulating peak rumen La concentrations (coefficient of determination = 0.96; root mean square prediction error = 16.96% of observed mean), although frequency of sampling for the published data prevented a comprehensive comparison of prediction of time to peak La accumulation. The model showed a tendency for increased La accumulation following feeding of diets rich in nonstructural carbohydrates, although less-soluble starch sources such as corn tended to limit rumen La concentration. Simulated La absorption from the rumen remained low throughout the feeding cycle. The competition between bacteria and protozoa for rumen La suggests a variable contribution of protozoa to total La utilization. However, the model was unable to simulate the effects of defaunation on rumen La metabolism, indicating a need for a more detailed description of protozoal metabolism. The model could form the basis of a feed evaluation system with regard to rumen La metabolism.

Exploring current undergraduate student perspectives on the introduction of the degree apprenticeship scheme in diagnostic radiography - a single institution study.

INTRODUCTION: The first degree apprenticeship programme in diagnostic radiography was launched in March 2020. This route into radiography runs in parallel with 'conventional' pre-registration programmes where students apply to a higher education institution (HEI) and undertake discrete clinical placements. The aim of this study was to explore the perspectives of pre-registration students on the diagnostic radiographer degree apprenticeship route. METHODS: A qualitative approach (online questionnaire) gathered attitudes and opinions of pre-registration students from a single HEI, regarding the degree apprenticeship programme. Participants were pre-registration medical imaging students from all stages of the programme (n = 204). Braun and Clarks's thematic analysis was employed for data analysis. RESULTS: A response rate of 21% (n = 44) was recorded. Four themes emerged from data analysis: (1) misunderstandings surrounding the degree apprenticeship, (2) financial implications and (3) practical experience associated with both degree courses and (4) the experience the pre-registration degree has to offer. CONCLUSION: There was an apparent lack of understanding regarding the degree apprenticeship leading students to misinterpret aspects of the course. Additionally, students highlighted the earning aspect of the apprenticeship to be an advantage in comparison to student debts associated with the traditional pre-registration programmes. Furthermore, students emphasised the advantage of the clinical focus practice associated with the degree apprenticeship. Nevertheless, students who have selected the HEI route still value what the traditional pre-registration degree offers. IMPLICATIONS FOR PRACTICE: As degree apprenticeship programmes become widely available, a greater awareness should, therefore, follow. In the interim, there is scope for HEIs to seek to raise awareness of degree apprenticeship provision. HEIs should seek to allay any concerns and highlight the benefits of having this alternative route into the profession.

Hemispheric asymmetry in ocean change and the productivity of ecosystem sentinels.

Climate change and other human activities are causing profound effects on marine ecosystem productivity. We show that the breeding success of seabirds is tracking hemispheric differences in ocean warming and human impacts, with the strongest effects on fish-eating, surface-foraging species in the north. Hemispheric asymmetry suggests the need for ocean management at hemispheric scales. For the north, tactical, climate-based recovery plans for forage fish resources are needed to recover seabird breeding productivity. In the south, lower-magnitude change in seabird productivity presents opportunities for strategic management approaches such as large marine protected areas to sustain food webs and maintain predator productivity. Global monitoring of seabird productivity enables the detection of ecosystem change in remote regions and contributes to our understanding of marine climate impacts on ecosystems.

Indirect genetic effects in a sex-limited trait: the case of breeding time in red-billed gulls.

Female reproductive performance can be strongly affected by male care, so that breeding time, a trait expressed only by females, can be seen as one trait determined by both male and female genotypes. Animal model analyses of a 46-year study of red-billed gulls (Larus novaehollandiae scopulinus) revealed that laying date was not heritable in females (h(2) = 0.001 +/- 0.030), but significantly so in males (h(2) = 0.134 +/- 0.029). Heritability of breeding time in males probably reflects genetic variability in some other trait such as courtship feeding ability. In line with predictions of evolutionary models incorporating indirect genetic effects, the strong and consistent directional selection for advanced breeding time has not resulted in detectable selection response in males. Our results demonstrate that a female trait is largely determined by genetic characteristics of its mate, and hence, any evolutionary change in red-billed gull breeding time depends critically on genetic variation in males.

Meeting Report: WHO Workshop on modelling global mortality and aetiology estimates of enteric pathogens in children under five. Cape Town, 28-29th November 2018.

Investment in vaccine product development should be guided by up-to-date and transparent global burden of disease estimates, which are also fundamental to policy recommendation and vaccine introduction decisions. For low- and middle-income countries (LMICs), vaccine prioritization is primarily driven by the number of deaths caused by different pathogens. Enteric diseases are known to be a major cause of death in LMICs. The two main modelling groups providing mortality estimates for enteric diseases are the Institute for Health Metrics and Evaluation (IHME) at the University of Washington, Seattle and the Maternal Child Epidemiology Estimation (MCEE) group, led by Johns Hopkins Bloomberg School of Public Health. Whilst previous global diarrhoea mortality estimates for under five-year-olds from these two groups were closely aligned, more recent estimates for 2016 have diverged, particularly with respect to numbers of deaths attributable to different enteric pathogens. This has impacted prioritization and investment decisions for vaccines in the development pipeline. The mission of the Product Development for Vaccines Advisory Committee (PDVAC) at the World Health Organisation (WHO) is to accelerate product development of vaccines and technologies that are urgently needed and ensure they are appropriately targeted for use in LMICs. At their 2018 meeting, PDVAC recommended the formation of an independent working group of subject matter experts to explore the reasons for the difference between the IHME and MCEE estimates, and to assess the respective strengths and limitations of the estimation approaches adopted, including a review of the data on which the estimates are based. Here, we report on the proceedings and recommendations from a consultation with the working group of experts, the IHME and MCEE modelling groups, and other key stakeholders. We briefly review the methodological approaches of both groups and provide a series of proposals for investigating the drivers for the differences in enteric disease burden estimates.

The development of lactic acid bacteria and Lactobacillus buchneri and their effects on the fermentation of alfalfa silage.

This study was conducted to document the development of populations of lactic acid bacteria (LAB) and Lactobacillus buchneri in alfalfa silage treated with various inoculants. Wilted and chopped alfalfa (45% dry matter) was treated with 1) distilled water (untreated, U), 2) Lactobacillus buchneri 40788 (4 x 10(5) cfu/g; LB), or 3) L. buchneri 40788 (4 x 10(5) cfu/g) and Pediococcus pentosaceus (1 x 10(5) cfu/g; LBPP). Forages were packed into triplicate vacuum-sealed, nylon-polyethylene bags per treatment, and ensiled for 2, 5, 45, 90, and 180 d. Viable (cfu) LAB in forage and silage were quantified by traditional plating on selective agar, and numbers of L. buchneri (cfu-equivalent, cfu-E) were quantified by real-time quantitative PCR. Fresh, untreated forage had 5.52 log cfu of LAB/g and 3.79 log cfu-E of L. buchneri/g. After 2 d of ensiling, numbers of LAB increased to >8 log cfu/g in all silages. In contrast, numbers of L. buchneri in U remained below 4 log cfu-E/g but reached approximately 7 log cfu-E/g in LB and LBPP. From d 5 onward, numbers of L. buchneri in U remained below 6 log cfu-E/g but approached 9 log cfu-E/g in LB and LBPP. The pH was lower in LBPP compared with U and LB after 2 and 5 d of ensiling, but pH was lower for U compared with LB and LBPP thereafter. Treatments LB and LBPP had more acetic acid than U at 45 d of ensiling, which coincided with detectable amounts of 1,2 propanediol. Inoculation with LBPP resulted in silage with the highest concentration of 1,2 propanediol after 180 d of ensiling. From d 45 onward, LB and LBPP silages had lower concentrations of residual water-soluble carbohydrates but had higher concentrations of ammonia-N than U. In conclusion, epiphytic L. buchneri can be detected in alfalfa but this population is unable to lead the silage fermentation. In contrast, when L. buchneri was added to silage as an inoculant, the numbers of L. buchneri (cfu-E) increased markedly but did not dictate fermentation until 45 d of ensiling. These findings help to explain why the response (in increased acetic acid) from the addition of L. buchneri in silages is not immediate.

Bovine coronary region keratinocyte colony formation is supported by epidermal-dermal interactions.

Delineating the factors that orchestrate keratinocyte growth and differentiation in the claw is pivotal to understanding the quality of hoof horn production in health and disease. The specific objectives of this investigation were to establish an in vitro culture system for bovine coronary region keratinocytes and dermal fibroblasts, determine the colony-forming capacity of epidermal keratinocytes in the coronary region, and characterize transcriptional changes in specific cytokine, growth factor, and receptor genes during colony formation in coculture. Fibroblasts and keratinocytes from the coronary region of the lateral, hind limb claw were collected, and 5.0 x 10(3) and 7.5 x 10(3) keratinocytes were cultured in the presence or absence of fibroblast monolayers, respectively. The 2 densities of keratinocytes formed 144 +/- 15.8 and 183 +/- 26.9 colonies, respectively, in the presence of dermal fibroblasts, whereas no colonies developed in the absence of dermal fibroblasts. Keratinocytes with the ability to show colony formation comprised 1.09% +/- 0.16 to 1.77% +/- 0.28 of the keratinocyte population isolated from the coronary region. Keratinocyte-fibroblast cocultures developed a time-dependent increased expression of several growth factors, cytokines, and receptors. These findings demonstrated that keratinocytes from the bovine coronary region formed colonies in vitro and that colony formation occurred with an absolute dependence on dermal fibroblasts. Colony growth was associated with increased transcriptional expression of cytokine, growth factor, and receptor expression known to drive keratinocyte colony formation in other species. The results indicate that horn-producing keratinocytes must interact with dermal fibroblasts during normal tissue homeostasis in the bovine claw.

Age, segment, and horn disease affect expression of cytokines, growth factors, and receptors in the epidermis and dermis of the bovine claw.

The aim of this study was to examine changes in RNA expression for growth factors, cytokines, and receptors in epidermal-dermal tissues of the bovine claw relative to host age, claw segment, and disease state of the horn. Epidermal-dermal tissues were collected from the coronary, wall, sole, and bulb segments of 8- to 9-mo-old Holstein fetuses, normal adult cows, and adult cows with sole ulceration. Anatomic and pathologic characteristics were determined in tissues stained with eosin and hematoxylin, and RNA expression levels were evaluated using real-time, quantitative PCR. In normal tissues, certain RNA expression levels were clearly affected by host age: 290.0-, 610.0-, 53.4-, and 8.1-fold greater expression of granulocyte-macrophage colony stimulating factor was observed in fetal coronary, wall, sole, and bulb segment relative to adult tissues, respectively. A claw segment effect was also observed in that IL-1alpha expression was greater (1.59-fold) in the normal adult wall relative to the coronary segment, and IL-18 expression was greater (16.2-fold) in the normal adult sole compared with the coronary segment and 2.88 greater in the fetal sole relative to the bulb segment. Sole ulceration was associated with hemorrhage, thrombosis, inflammation, and striking increases in IL-1beta, IL-18, and inducible nitric oxide synthase, and with less dramatic, albeit measurable, changes in IL-1 type I receptor, IL-1 receptor antagonist, and tumor necrosis factor-alpha. Amidst striking increases in keratinocyte growth factor receptor (i.e., 21.0-fold, 10.4-fold, 0, and 21.6-fold in the coronary, wall, sole, and bulb segments, respectively), a concomitant decrease occurred in keratinocyte growth factor (i.e., 0.80-, 0.54-, 0.56-, and 0.72-fold, respectively). The results demonstrated changes in disease state and, to a lesser extent, claw segment and were accompanied by alterations in the RNA expression of several cytokines, growth factors, and receptors present in the normal claw.

A comparison of neural network approaches for on-line prediction in IGRT.

Image-guided radiation therapy aims to improve the accuracy of treatment delivery by tracking tumor position and compensating for observed movement. Due to system latency it is sometimes necessary to predict tumor trajectory evolution in order to facilitate changes in beam delivery. Neural networks (NNs) have previously been investigated for predicting future tumor position because of their ability to model non-linear systems. However, no attempt has been made to optimize the NN training algorithms, and no mention has been made of potential errors which can be caused by using NNs for extrapolation purposes. In this work, after giving a brief explanation of NN theory, a comparison is made between 4 different adaptive algorithms for training time-series prediction NNs. New error criteria are introduced which highlight error maxima. Results are obtained by training the NNs using previously published data. A hybrid algorithm combining Bayesian regularization with conjugate-gradient backpropagation is demonstrated to give the best average prediction accuracy, whilst a generalized regression NN is shown to reduce the possibility of isolated large prediction errors.

Alterations in immunoregulatory T cell subsets in active systemic lupus erythematosus.

To determine whether imbalance among subsets of human T cells exists in patients with systemic lupus erythematosus (SLE), we analyzed peripheral blood lymphocytes in SLE patients during active and inactive stages of disease. For this analysis, we used monoclonal antibodies to the surface antigens of inducer (T4) and suppressor (T5/T8) T cell subsets, as well as a common T cell antigen (T3). In contrast to normal and inactive SLE patients, the percentage of T3+ cells was reduced in all active SLE patients. More importantly, there was a selective decrease in T5+/T8+ suppressor T cells in 12 of 14 active patients, including 1 of 2 patients with drug-induced SLE. Serial analysis of three SLE patients showed a significant correlation between the presence of T5+/T8+ subset and clinical disease activity in all patients. We conclude that aberrations in suppressor T cell subsets are an important correlate of disease in patients with SLE.

Comparison of 50 kV facilities for contact radiotherapy.

The radiation characteristics of a short source to surface distance (SSD) contact therapy tube in clinical use at the Centre Antoine-Lacassagne, Nice and a long SSD unit at the Clatterbridge Centre for Oncology were compared. The output from the tube at Nice had a dose rate of approximately double that of the tube at Clatterbridge, whereas the tube at Clatterbridge had a slightly higher value of the half value layer. Depth dose measurements were made with GafChromic MD55 film and SSD corrected depth dose curves showed good agreement between centres. Profiles at 2mm depth also showed comparable levels of flatness and uniformity.

Increased susceptibility to maternal aneuploidy demonstrated by comparative genomic hybridization analysis of human MII oocytes and first polar bodies.

Single cell comparative genomic hybridization (CGH) was employed to extensively investigate 24 unfertilized or in vitromatured meiosis II oocytes and their corresponding first polar bodies (PBs), to determine how and whether all 23 chromosomes participate in female meiosis I errors and to accurately estimate the aneuploidy rate in the examined cells. Results were obtained for 15 oocytes and 16 PBs, representing 23 eggs (MII oocyte-PB complexes) donated from 15 patients (average age 32.2 years). Abnormalities were detected in ten eggs, giving an overall aneuploidy rate of 43.5%. In all, fourteen anomalies were scored, with the fertilized oocyte being at risk of monosomy in eight cases and at risk of trisomy in six; chromosomes of various sizes participated. CGH was able to give a comprehensive aneuploidy rate, as both absence of chromosomal material and the presence of extra copies were accurately scored. The aneuploidy mechanisms determined were: classical whole univalent non-disjunction; chromatid predivision prior to anaphase I, leading to metaphase II imbalance. There was also evidence of germinal mosaicism for a trisomic cell line. Three patients appeared to be predisposed to meiosis I errors, based on the presence of either multiple abnormalities in one or more of their examined cells, or of the same type of abnormality in all of their cells. Exclusion of these susceptible patients reduces the aneuploidy rate to 20%. Various hypotheses are put forward to explain these observations in order to stimulate research into the complex nature of female meiotic regulation.

Late onset systemic lupus erythematosus.

This study describes the clinical and laboratory features and the natural history of 31 patients with late onset (in the sixth decade or later) systemic lupus erythematosus (SLE). Patients with late onset SLE constitute a distinct subset of the general lupus population that accounts for approximately 12 per cent of the cases. Advanced age modifies the expression of SLE in terms of clinical presentation (pleuritis and/or pericarditis are the most common presenting manifestations) and pattern of organ involvement (pulmonary abnormalities are more common, whereas lymphadenopathy, Raynaud's phenomenon, neuropsychiatric disease, alopecia and skin rash are less common). Because SLE is not usually considered to be a disease that affects the elderly, and because the pattern of SLE in the older age group may differ substantially from the seen in younger patients, there is often a delay in diagnosis (median of 10 months, with a delay of over one year in 32 per cent of patients). In light of the high incidence of steroid complications in older patients (40 per cent in our series), and because these patients with SLE have a relatively good prognosis (five year survival of 92.3 per cent; nine year survival of 83.1 per cent), therapy should be more conservative in late onset SLE.

Accommodation of couch constraints for coplanar intensity modulated radiation therapy.

PURPOSE: Three treatment couches, henceforth referred to as the standard, the variable standard and the C-arm couch, each based on a different supporting frame system, were investigated for their suitability for the delivery of a high number of coplanar beams (> or =5) as may be required for intensity-modulated radiation therapy treatments. MATERIALS AND METHODS: A number of equispaced beam arrangements (five to nine) were examined in combination with two circular target sizes (Phi6 and Phi10 cm) at different locations within an elliptical body on the investigated couches, resulting in 70 different plans per couch. A rule based advisory system determined possible intersections of the beam paths with the supporting frames of the respective treatment couch and suggested a suitable constellation for the supporting frames. In cases of intersection, a beam-couch collision was eliminated by minimal rotation of the beams from the initial equispaced beam arrangement. To investigate the effect of a rotation of the posterior-oblique beams for five, seven and nine initially equispaced beams by an angle of 10 degrees, a prostate plan was generated and compared with equispaced beam arrangement. RESULTS: Initial beam paths intersected with the standard couch in 63% of the plans, necessitating a rotation of one or two beams. It was necessary to modify the beam angles in 34% of the cases on the variable standard couch to avoid an intersection of the beams with the couch. All the plans would have been delivered satisfactorily on the C-arm couch without a rotation of beams. Simulation studies showed that the dose distribution for a prostate treatment could be affected significantly, but not detrimentally, by the rotation of the two posterior-oblique beam orientations by an angle of 10 degrees.

Optimization of beam orientation in radiotherapy using planar geometry.

This paper proposes a new geometrical formulation of the coplanar beam orientation problem combined with a hybrid multiobjective genetic algorithm. The approach is demonstrated by optimizing the beam orientation in two dimensions, with the objectives being formulated using planar geometry. The traditional formulation of the objectives associated with the organs at risk has been modified to account for the use of complex dose delivery techniques such as beam intensity modulation. The new algorithm attempts to replicate the approach of a treatment planner whilst reducing the amount of computation required. Hybrid genetic search operators have been developed to improve the performance of the genetic algorithm by exploiting problem-specific features. The multiobjective genetic algorithm is formulated around the concept of Pareto optimality which enables the algorithm to search in parallel for different objectives. When the approach is applied without constraining the number of beams, the solution produces an indication of the minimum number of beams required. It is also possible to obtain non-dominated solutions for various numbers of beams, thereby giving the clinicians a choice in terms of the number of beams as well as in the orientation of these beams.

Reversal of female sterilisation: a comparative study.

In 80 women who had reversal of sterilisation, a study was made of their clinical features at the time of sterilisation and of the factors related to successful outcome. Compared with controls at the time of sterilisation, the women requesting reversal were younger, of lower social class and of higher parity; in addition they were more likely to have an unstable relationship and to have been sterilised following a recent pregnancy. After reversal, intrauterine pregnancy occurred in 26/80 (32.5%) and ectopic pregnancy in 6/80 (7.5%), the majority of successful pregnancies occurring in younger women within one year of reversal following a non-destructive method of tubal occlusion. There was no evidence that techniques of management, including the use of an operating microscope, significantly influenced outcome, and controlled trials will be required to establish their efficacy.

PIP: In 80 women who had reversal of sterilization, a study was made of their clinical features at the time of sterilization and of the factors related to successful outcome. Compared with controls at the time of sterilization, the women requesting reversal were younger, of lower social class and of higher parity; in addition they were more likely to have an unstable relationship and to have been sterilized following a recent pregnancy. Only 24% were still in their original marriage. Most of these gave regret as the reason for their request, while the rest had lost children. The remaining women wished reversal because of a change of partner; 2/5 had remarried, while 3/5 were single, widowed, separated or divorced, but cohabiting. It is clear that sterilization at delivery may be in response to severe social pressure, but it may not always be in the patients' longterm interests to yield to such pressure. After reversal, intrauterine pregnancy occurred in 32.5% and ectopic pregnancy in 7.5%, the majority of successful pregnancies occurring in younger women within 1 year of reversal following a non-destructive method of tubal occlusion. There was no evidence that techniques of management, including the use of an operating microscope, significantly influenced outcome; controlled trials will be required to establish their efficacy.

Use of the linear quadratic model in order to accommodate a small reduction in the number of fractions of a standard radiotherapy treatment regime.

Use of the linear quadratic model is considered for reduction, by one or two fractions, of the number of fractions in a daily fractionated reference schedule while maintaining a continuous regime. The cases of maintaining late or early tumour reacting tissue are considered with the inclusion of time effects. The reduction of biologically effective dose (BED) to early-tumour type tissue is shown to be overestimated for both cases if time effects are not taken into account. A third option is outlined, which equates the magnitude of the fractional reduction of BED for early-tumour-reacting tissue to the fractional increase in BED for late-reacting tissue without accounting for time effects. Using this option, the resulting variations in BED for late- and early-tumour tissue are compared with the accepted tolerances in physical dose delivery and some examples presented. The overestimated prediction of the variation in BED for early-tumour tissue still applies in this option, suggesting that this is the way the linear quadratic model should be applied to such a schedule change.