Developmental programming: Impact of preconceptional and gestational exposure to a real-life environmental chemical mixture on maternal steroid, cytokine and oxidative stress milieus in sheep.

BACKGROUND: Gestational exposure to environmental chemicals (ECs) is associated with adverse, sex-specific offspring health effects of global concern. As the maternal steroid, cytokine and oxidative stress milieus can have critical effects on pregnancy outcomes and the programming of diseases in offspring, it is important to study the impact of real-life EC exposure, i.e., chronic low levels of mixtures of ECs on these milieus. Sheep exposed to biosolids, derived from human waste, is an impactful model representing the ECs humans are exposed to in real-life. Offspring of sheep grazed on biosolids-treated pasture are characterized by reproductive and metabolic disruptions. OBJECTIVE: To determine if biosolids exposure disrupts the maternal steroid, cytokine and oxidative stress milieus, in a fetal sex-specific manner. METHODS: Ewes were maintained before mating and through gestation on pastures fertilized with biosolids (BTP), or inorganic fertilizer (Control). From maternal plasma collected mid-gestation, 19 steroids, 14 cytokines, 6 oxidative stress markers were quantified. Unpaired t-test and ANOVA were used to test for differences between control and BTP groups (n = 15/group) and between groups based on fetal sex, respectively. Correlation between the different markers was assessed by Spearman correlation. RESULTS: Concentrations of the mineralocorticoids - deoxycorticosterone, corticosterone, the glucocorticoids - deoxycortisol, cortisol, cortisone, the sex steroids - androstenedione, dehydroepiandrosterone, 16-OH-progesterone and reactive oxygen metabolites were higher in the BTP ewes compared to Controls, while the proinflammatory cytokines IL-1ß and IL-17A and anti-inflammatory IL-36RA were decreased in the BTP group. BTP ewes with a female fetus had lower levels of IP-10. DISCUSSION: These findings suggest that pre-conceptional and gestational exposure to ECs in biosolids increases steroids, reactive oxygen metabolites and disrupts cytokines in maternal circulation, likely contributors to the aberrant phenotypic outcomes seen in offspring of BTP sheep - a translationally relevant precocial model.

Developmental programming: Preconceptional and gestational exposure of sheep to a real-life environmental chemical mixture alters maternal metabolome in a fetal sex-specific manner.

BACKGROUND: Everyday, humans are exposed to a mixture of environmental chemicals some of which have endocrine and/or metabolism disrupting actions which may contribute to non-communicable diseases. The adverse health impacts of real-world chemical exposure, characterized by chronic low doses of a mixture of chemicals, are only recently emerging. Biosolids derived from human waste represent the environmental chemical mixtures humans are exposed to in real life. Prior studies in sheep have shown aberrant reproductive and metabolic phenotypes in offspring after maternal biosolids exposure. OBJECTIVE: To determine if exposure to biosolids perturbs the maternal metabolic milieu of pregnant ewes, in a fetal sex-specific manner. METHODS: Ewes were grazed on inorganic fertilizer (Control) or biosolids-treated pastures (BTP) from before mating and throughout gestation. Plasma from pregnant ewes (Control n = 15, BTP n = 15) obtained mid-gestation were analyzed by untargeted metabolomics. Metabolites were identified using Agilent MassHunter. Multivariate analyses were done using MetaboAnalyst 5.0 and confirmed using SIMCA. RESULTS: Univariate and multivariate analysis of 2301 annotated metabolites identified 193 differentially abundant metabolites (DM) between control and BTP sheep. The DM primarily belonged to the super-class of lipids and organic acids. 15-HeTrE, oleamide, methionine, CAR(3:0(OH)) and pyroglutamic acid were the top DM and have been implicated in the regulation of fetal growth and development. Fetal sex further exacerbated differences in metabolite profiles in the BTP group. The organic acids class of metabolites was abundant in animals with male fetuses. Prenol lipid, sphingolipid, glycerolipid, alkaloid, polyketide and benzenoid classes showed fetal sex-specific responses to biosolids. DISCUSSION: Our study illustrates that exposure to biosolids significantly alters the maternal metabolome in a fetal sex-specific manner. The altered metabolite profile indicates perturbations to fatty acid, arginine, branched chain amino acid and one­carbon metabolism. These factors are consistent with, and likely contribute to, the adverse phenotypic outcomes reported in the offspring.

Analysis of bovine blastocysts indicates ovarian stimulation does not induce chromosome errors, nor discordance between inner-cell mass and trophectoderm lineages.

Contemporary systems for oocyte retrieval and culture of both cattle and human embryos are suboptimal with respect to pregnancy outcomes following transfer. In humans, chromosome abnormalities are the leading cause of early pregnancy loss in assisted reproduction. Consequently, pre-implantation genetic testing for aneuploidy (PGT-A) is widespread and there is considerable interest in its application to identify suitable cattle IVP embryos for transfer. Here we report on the nature and extent of chromosomal abnormalities following transvaginal follicular aspiration (OPU) and IVP in cattle. Nine sexually mature Holstein heifers underwent nine sequential cycles of OPU-IVP (six non-stimulated and three stimulated cycles), generating 459 blastocysts from 783 oocytes. We adopted a SNP-array approach normally employed in genomic evaluations but reanalysed (Turner et al., 2019; Theriogenology125: 249) to detect levels of meiotic aneuploidy. Specifically, we asked whether ovarian stimulation increased the level of aneuploidy in either trophectoderm (TE) or inner-cell mass (ICM) lineages of blastocysts generated from OPU-IVP cycles. The proportion of Day 8 blastocysts of inseminated was greater (P < 0.001) for stimulated than non-stimulated cycles (0.712 ± 0.0288 vs. 0.466 ± 0.0360), but the overall proportion aneuploidy was similar for both groups (0.241 ± 0.0231). Most abnormalities consisted of meiotic trisomies. Twenty in vivo derived blastocysts recovered from the same donors were all euploid, thus indicating that 24 h of maturation is primarily responsible for aneuploidy induction. Chromosomal errors in OPU-IVP blastocysts decreased (P < 0.001) proportionately as stage/grade improved (from 0.373 for expanded Grade 2 to 0.128 for hatching Grade 1 blastocysts). Importantly, there was a high degree of concordance in the incidence of aneuploidy between TE and ICM lineages. Proportionately, 0.94 were "perfectly concordant" (i.e. identical result in both); 0.01 were imperfectly concordant (differing abnormalities detected); 0.05 were discordant; of which 0.03 detected a potentially lethal TE abnormality (false positives), leaving only 0.02 false negatives. These data support the use of TE biopsies for PGT-A in embryos undergoing genomic evaluation in cattle breeding. Finally, we report chromosome-specific errors and a high degree of variability in the incidence of aneuploidy between donors, suggesting a genetic contribution that merits further investigation.

Obesity risk factors in American Indians and Alaska Natives: a systematic review.

OBJECTIVES: We systematically reviewed the literature on risk factors for obesity in American Indians (AIs) and Alaska Natives (ANs) of all ages. STUDY DESIGN: We searched titles and abstracts in PubMed with combinations of the following terms: obesity, body mass index (BMI), American Indian, Alaska Native, and Native American. METHODS: We limited our review to articles that provided an empirically testable claim about a variable associated with obesity, measured obesity as a dependent variable, and provided data specific to AI/ANs. RESULTS: Our final sample included 31 articles; 20 examined AI/AN youth (<18 years), and 11 examined AI/AN adults (≥18 years). Risk factors for obesity varied by age. In infants, low birth weight, early termination of breastfeeding, and high maternal BMI, and maternal diabetes increased the risk of childhood obesity. In children and adolescents, parental obesity, sedentary behaviors, and limited access to fruits and vegetables were associated with obesity. In adulthood, sedentary behaviors, diets high in fats and carbohydrates, stress, verbal abuse in childhood, and the belief that health cannot be controlled were associated with obesity. CONCLUSIONS: Extant studies have three limitations: they do not apply a life course perspective, they lack nationally representative data and have limited knowledge of the resilience, resistance and resourcefulness of AI/ANs. Future studies that avoid these shortcomings are needed to inform interventions to reduce the prevalence of obesity in AI/ANs across the life course.

Antibiotic-eluting resorbable bone-void filler evaluated in a large animal infection prevention model.

Periprosthetic infection in total knee arthroplasty is a difficult-to-treat complication. Current implant revision procedures use non-degradable, antibiotic-loaded bone cement for local antimicrobial delivery. As a permanent foreign body, antibiotic-loaded bone cement is susceptible to bacterial colonisation after antibiotic release. In this first step, of a multi-study approach, an infection prevention model assessed a resorbable, antibiotic-eluting bone-void filler for preventing infection in a large animal model. Four groups of sheep were utilised to monitor antibiotic-eluting bone-void filler-induced osteoconductivity, infection prevention, and implant resorption. Explanted bone and surrounding tissues were evaluated using quantitative microbiology, backscattered electron microscopy, bone mineral apposition, and Sanderson's staining at the 12-week endpoint. Control groups received commercially available bone-void filler, implanted into a surgically created defect on the right medial femoral condyle. Experimental groups received six antibiotic-eluting bone-void filler devices placed into identically sized defects. One control and one experimental group tested osteoconductivity. An additional control and experimental group were each inoculated with 5 × 105 colony forming units/mL Staphylococcus aureus during implant placement for bactericidal effects. Osteoconductivity was confirmed for both antibiotic-eluting bone-void filler and commercially available bone-void filler. The experimental group inoculated with S. aureus showed no detectable bacteria at the study's 12-week endpoint, while infection controls required euthanasia 6-11 d post-inoculation due to infection. This large animal study validated this antibiotic-eluting bone-void filler as osteoconductive, in situ degradable, and bactericidal. All groups, except the infection control, exhibited bone formation comparable to commercial filler ProOsteon®500R.

Added dietary cobalt or vitamin B12, or injecting vitamin B12 does not improve performance or indicators of ketosis in pre- and post-partum Holstein-Friesian dairy cows.

Vitamin B12 is synthesised in the rumen from cobalt (Co) and has a major role in metabolism in the peri-paturient period, although few studies have evaluated the effect of the dietary inclusion of Co, vitamin B12 or injecting vitamin B12 on the metabolism, health and performance of high yielding dairy cows. A total of 56 Holstein-Friesian dairy cows received one of four treatments from 8 weeks before calving to 8 weeks post-calving: C, no added Co; DC, additional 0.2 mg Co/kg dry matter (DM); DB, additional 0.68 mg vitamin B12/kg DM; IB, intra-muscular injection of vitamin B12 to supply 0.71 mg/cow per day prepartum and 1.42 mg/cow per day post-partum. The basal and lactation rations both contained 0.21 mg Co/kg DM. Cows were weighed and condition scored at drying off, 4 weeks before calving, within 24 h of calving and at 2, 4 and 8 weeks post-calving, with blood samples collected at drying off, 2 weeks pre-calving, calving and 2, 4 and 8 weeks post-calving. Liver biopsy samples were collected from all animals at drying off and 4 weeks post-calving. Live weight changed with time, but there was no effect of treatment (P>0.05), whereas cows receiving IB had the lowest mean body condition score and DB the highest (P0.05) with mean values of 21.6 kg/day, 39.6 kg/day and 40.4 g/kg, respectively. Cows receiving IB had a higher plasma vitamin B12 concentration than those receiving any of the other treatments (P0.05) of treatment on homocysteine or succinate concentrations, although mean plasma methylmalonic acid concentrations were lower (P=0.019) for cows receiving IB than for Control cows. Plasma ß-hydroxybutyrate concentrations increased sharply at calving followed by a decline, but there was no effect of treatment. Similarly, there was no effect (P>0.05) of treatment on plasma non-esterified fatty acids or glucose. Whole tract digestibility of DM and fibre measured at week 7 of lactation were similar between treatments, and there was little effect of treatment on the milk fatty acid profile except for C15:0, which was lower in cows receiving DC than IB (P<0.05). It is concluded that a basal dietary concentration of 0.21 mg Co/kg DM is sufficient to meet the requirements of high yielding dairy cows during the transition period, and there is little benefit from additional Co or vitamin B12.

Radiographic assessment of the skeletons of Dolly and other clones finds no abnormal osteoarthritis.

Our recent report detailing the health status of cloned sheep concluded that the animals had aged normally. This is in stark contrast to reports on Dolly (first animal cloned from adult cells) whose diagnoses of osteoarthritis (OA) at 5½ years of age led to considerable scientific concern and media debate over the possibility of early-onset age-related diseases in cloned animals. Our study included four 8-year old ewes derived from the cell line that gave rise to Dolly, yet none of our aged sheep showed clinical signs of OA, and they had radiographic evidence of only mild or, in one case, moderate OA. Given that the only formal record of OA in Dolly is a brief mention of a single joint in a conference abstract, this led us to question whether the original concerns about Dolly's OA were justified. As none of the original clinical or radiographic records were preserved, we undertook radiographic examination of the skeletons of Dolly and her contemporary clones. We report a prevalence and distribution of radiographic-OA similar to that observed in naturally conceived sheep, and our healthy aged cloned sheep. We conclude that the original concerns that cloning had caused early-onset OA in Dolly were unfounded.

Epigenetics and developmental programming of welfare and production traits in farm animals.

The concept that postnatal health and development can be influenced by events that occur in utero originated from epidemiological studies in humans supported by numerous mechanistic (including epigenetic) studies in a variety of model species. Referred to as the 'developmental origins of health and disease' or 'DOHaD' hypothesis, the primary focus of large-animal studies until quite recently had been biomedical. Attention has since turned towards traits of commercial importance in farm animals. Herein we review the evidence that prenatal risk factors, including suboptimal parental nutrition, gestational stress, exposure to environmental chemicals and advanced breeding technologies, can determine traits such as postnatal growth, feed efficiency, milk yield, carcass composition, animal welfare and reproductive potential. We consider the role of epigenetic and cytoplasmic mechanisms of inheritance, and discuss implications for livestock production and future research endeavours. We conclude that although the concept is proven for several traits, issues relating to effect size, and hence commercial importance, remain. Studies have also invariably been conducted under controlled experimental conditions, frequently assessing single risk factors, thereby limiting their translational value for livestock production. We propose concerted international research efforts that consider multiple, concurrent stressors to better represent effects of contemporary animal production systems.

Healthy ageing of cloned sheep.

The health of cloned animals generated by somatic-cell nuclear transfer (SCNT) has been of concern since its inception; however, there are no detailed assessments of late-onset, non-communicable diseases. Here we report that SCNT has no obvious detrimental long-term health effects in a cohort of 13 cloned sheep. We perform musculoskeletal assessments, metabolic tests and blood pressure measurements in 13 aged (7-9 years old) cloned sheep, including four derived from the cell line that gave rise to Dolly. We also perform radiological examinations of all main joints, including the knees, the joint most affected by osteoarthritis in Dolly, and compare all health parameters to groups of 5-and 6-year-old sheep, and published reference ranges. Despite their advanced age, these clones are euglycaemic, insulin sensitive and normotensive. Importantly, we observe no clinical signs of degenerative joint disease apart from mild, or in one case moderate, osteoarthritis in some animals. Our study is the first to assess the long-term health outcomes of SCNT in large animals.

Mesenchymal Stromal Cells are Readily Recoverable from Lung Tissue, but not the Alveolar Space, in Healthy Humans.

Stromal support is critical for lung homeostasis and the maintenance of an effective epithelial barrier. Despite this, previous studies have found a positive association between the number of mesenchymal stromal cells (MSCs) isolated from the alveolar compartment and human lung diseases associated with epithelial dysfunction. We hypothesised that bronchoalveolar lavage derived MSCs (BAL-MSCs) are dysfunctional and distinct from resident lung tissue MSCs (LT-MSCs). In this study, we comprehensively interrogated the phenotype and transcriptome of human BAL-MSCs and LT-MSCs. We found that MSCs were rarely recoverable from the alveolar space in healthy humans, but could be readily isolated from lung transplant recipients by bronchoalveolar lavage. BAL-MSCs exhibited a CD90Hi , CD73Hi , CD45Neg , CD105Lo immunophenotype and were bipotent, lacking adipogenic potential. In contrast, MSCs were readily recoverable from healthy human lung tissue and were CD90Hi or Lo , CD73Hi , CD45Neg , CD105Int and had full tri-lineage potential. Transcriptional profiling of the two populations confirmed their status as bona fide MSCs and revealed a high degree of similarity between each other and the archetypal bone-marrow MSC. 105 genes were differentially expressed; 76 of which were increased in BAL-MSCs including genes involved in fibroblast activation, extracellular matrix deposition and tissue remodelling. Finally, we found the fibroblast markers collagen 1A1 and α-smooth muscle actin were increased in BAL-MSCs. Our data suggests that in healthy humans, lung MSCs reside within the tissue, but in disease can differentiate to acquire a profibrotic phenotype and migrate from their in-tissue niche into the alveolar space. Stem Cells 2016;34:2548-2558.

Does preoperative breast MRI significantly impact on initial surgical procedure and re-operation rates in patients with screen-detected invasive lobular carcinoma?

AIM: To investigate whether magnetic resonance imaging (MRI) changes the management of patients with screen-detected invasive lobular carcinoma (ILC). MATERIALS AND METHODS: A retrospective, controlled, single-centre analysis of 138 cases of screen-detected ILC was performed. All patients were assessed by a single multidisciplinary team as to whether preoperative MRI altered the initial management decision or reduced re-operation rates. RESULTS: Forty-three percent of patients had preoperative MRI. MRI guided surgical management in 40.7% patients. Primary mastectomy rates were not significantly different between the MRI and non-MRI groups (32% and 30% respectively, p=0.71). The MRI group had a lower secondary surgery rate (6.8% versus 15.2%); however, the results did not reach statistical significance, and there were no unnecessary mastectomies. CONCLUSION: MRI can be used appropriately to guide primary surgery in screen-detected ILC cases and affects the initial management decision in 40.7% of patients. It does not significantly affect the overall mastectomy rate or re-operation rates, but reduces the likelihood of the latter. As a result of this review, the authors' local policy for the use of MRI in screen-detected ILC patients has been modified. For patients undergoing mastectomy for ILC, MRI is no longer performed routinely to search for contralateral malignancy as this has no proven added benefit.

Molecular determinants of a competent bovine corpus luteum: first- vs final-wave dominant follicles.

Reproductive management in cattle requires the synchrony of follicle development and oestrus before insemination. However, ovulation of follicles that have not undergone normal physiological maturation can lead to suboptimal luteal function. Here, we investigated the expression of a targeted set of 47 genes in (a) a first-wave vs final-wave dominant follicle (DF; the latter destined to ovulate spontaneously) and (b) 6-day-old corpora lutea (CLs) following either spontaneous ovulation or induced ovulation of a first-wave DF to ascertain their functional significance for competent CL development. Both the mass and progesterone-synthesising capacity of a CL formed following induced ovulation of a first-wave DF were impaired. These impaired CLs had reduced expression of steroidogenic enzymes (e.g. STAR and HSD3B1), luteotrophic receptors (LHCGR) and angiogenic regulators (e.g. VEGFA) and increased expression of BMP2 (linked to luteolysis). Relative to final-wave DFs, characteristic features of first-wave DFs included reduced oestradiol concentrations and a reduced oestradiol:progesterone ratio in the face of increased expression of key steroidogenic enzymes (i.e. CYP11A1, HSD3B1 and CYP19A1) in granulosa cells and reduced expression of the HDL receptor SCARB1 in thecal cells. Transcripts for further components of the TGF and IGF systems (e.g. INHA, INHBA, IGF2R and IGFBP2) varied between the first- and final-wave DFs. These results highlight the importance of hormones such as progesterone interacting with local components of both the TGF and IGF systems to affect the maturation of the ovulatory follicle and functional competency of the subsequent CL.

Utility of field-based techniques to assess Indigenous Australians' functional fitness and sedentary time.

OBJECTIVE: To examine the utility of field-based techniques to assess functional exercise capacity and sedentary time in Indigenous and non-Indigenous regional Australian adults. STUDY DESIGN: Observational, analytic cohort study. METHODS: Ninety six adults residing in regional and remote Australian communities participated in this study (Indigenous n = 61 and non-Indigenous Australians n = 35). Participants undertook a field-based test of functional exercise capacity (6 min walk test; 6 MWT) and wore an accelerometer during waking hours for seven days, provided self-report data on physical activity and sedentary time and rated experiences in regard to the ease of complying with study protocols. RESULTS: There were high levels of compliance in this study (Indigenous: 91% and non-Indigenous: 97%). Functional exercise capacity was lower in Indigenous Australians (P < 0.001), and independently associated with advancing age, higher BMI, and indigeneity, with 45% of variability in the 6 MWT distance explained by these factors. The relationship between accelerometer and self-report measures of sedentary behaviour was significant (P < 0.001) but only explained 17% of the total variation. CONCLUSIONS: This study demonstrated very good compliance for the methods utilised and is the first to report reduced functional exercise capacity in Indigenous people. IMPLICATIONS: The field-based techniques from this study demonstrate good utility for larger scale implementation in regional Indigenous populations.

Direct enzyme-substrate affinity determination by real-time hyperpolarized (13)C-MRS.

A specialized kinetic analysis of real-time hyperpolarized [1,1,2,2-D4, 1-(13)C]choline (13)C-magnetic resonance spectroscopy enabled the determination of initial rates of metabolic enzyme activity (choline oxidase), enzyme-substrate affinity (Km), and inhibition. In a clinical MRI scanner, metabolite levels lower than 16 µM were detected at a temporal resolution of 1 s.

Observations of body mass index in Duchenne muscular dystrophy: a longitudinal study.

BACKGROUND/OBJECTIVES: Nutritional issues that are associated with Duchenne muscular dystrophy (DMD) remain poorly understood. The aim of this analysis was to describe and explore longitudinal observations of body mass index (BMI) in a cohort of children with DMD. SUBJECTS/METHODS: Anthropometric and clinical characteristics were collected retrospectively and longitudinally for boys with DMD seen in two large neuromuscular clinics. BMI Z-scores were determined using the Centers for Disease Control and Prevention reference values for children (2000). RESULTS: Medical records (n=193) were examined from which 75% were included for analysis. The mean age of the cohort at the time of data collection was 11.9 years, with 72% of patients currently or previously using steroids. The highest prevalence of obesity based on the BMI Z-score was 50% at the age of 10 years. Longitudinally, BMI Z-scores from the age of 2 to 12 years plot approximately one s.d. above the mean, after which there is a marked and progressive decline. BMI gainers were identified for whom BMI Z-score increased by 1.65 units compared with the 0.09 units in non-gainers. BMI gainers were younger when they had their first BMI measurement (5.9 vs 7.2 years), and this measure was significantly lower compared with the non-gainers (BMI Z-score: 0.04 vs 1.17). In this cohort, BMI was associated with age, ambulatory status and lung function. CONCLUSIONS: This study demonstrates that boys with DMD using steroid therapy experience shifts in BMI. A declining BMI appears to be associated with increasing age. Interpretation of growth patterns is limited here by a lack of normative growth references in DMD.

Reducing dietary protein in dairy cow diets: implications for nitrogen utilization, milk production, welfare and fertility.

In light of increasing global protein prices and with the need to reduce environmental impact of contemporary systems of milk production, the current review seeks to assess the feasibility of reducing levels of dietary CP in dairy cow diets. At CP levels between 140 and 220 g/kg DM there is a strong positive relationship between CP concentration and dry matter intake (DMI). However, such effects are modest and reductions in DMI when dietary CP is below 180 g/kg DM can be at least partially offset by improving the digestibility and amino acid profile of the undegradable protein (UDP) component of the diet or by increasing rumen fermentable energy. Level and balance of intestinally absorbable amino acids, in particular methionine and lysine, may become limiting at lower CP concentrations. In general the amino acid composition of microbial protein is superior to that of UDP, so that dietary strategies that aim to promote microbial protein synthesis in the rumen may go some way to correcting for amino acid imbalances in low CP diets. For example, reducing the level of NDF, while increasing the proportion of starch, can lead to improvements in nitrogen (N) utilisation as great as that achieved by reducing dietary CP to below 150 g/kg. A systematic review and meta-analysis of responses to rumen protected forms of methionine and lysine was conducted for early/mid lactation cows fed diets containing ⩽150 g CP/kg DM. This analysis revealed a small but significant (P=0.002) increase in milk protein yield when cows were supplemented with these rumen protected amino acids. Variation in milk and milk protein yield responses between studies was not random but due to differences in diet composition between studies. Cows fed low CP diets can respond to supplemental methionine and lysine so long as DMI is not limiting, metabolisable protein (MP) is not grossly deficient and other amino acids such as histidine and leucine do not become rate limiting. Whereas excess dietary protein can impair reproduction and can contribute to lameness, there is no evidence to indicate that reducing dietary CP levels to around 140 to 150 g CP/kg DM will have any detrimental effect on either cow fertility or health. Contemporary models that estimate MP requirements of dairy cows may require refinement and further validation in order to predict responses with low CP diets.

Determination and comparison of radiotherapy dose responses for hepatocellular carcinoma and metastatic colorectal liver tumours.

OBJECTIVE: The purpose of this study was to seek radiation dose responses separately for primary hepatocellular carcinoma (HCC) and metastatic (MET) colorectal liver tumours to establish tumour control probabilities (TCPs) for radiotherapy (RT) of liver tumours. METHODS: The records of 36 HCC and 26 MET colorectal liver tumour patients were reviewed. The median dose per fraction and total dose were 4 Gy (2-10 Gy) and 52 Gy (29-83 Gy) for the HCC group and 3.6 Gy (2.0-13.0 Gy) and 55 Gy (30-80 Gy) for the MET group, respectively. Median tumour diameter was 6.6 cm (3.0-18.0 cm) and 5.0 cm (1.0-13.0 cm) for the HCC and MET groups, respectively. A logistic TCP model was fitted to the response data for each group using the maximum likelihood method. RESULTS: 50% and 90% probabilities of 6-month local control were estimated to be achievable by 2 Gy per fraction equivalent doses (α/ß=10 Gy) of 53 Gy and 84 Gy for the HCC group and 70 Gy and 95 Gy for the MET group, respectively. Actuarial 1-year local control for the HCC and MET groups was 65% (45-85%) and 32% (6-58%), respectively, whereas median time to failure was 543 days (374-711 days) and 183 days (72-294 days), respectively. CONCLUSION: Dose-response relationships were found and modelled for the HCC and MET patient groups, with a higher dose required to control MET tumours. RT offers better local control for HCC than for MET colorectal liver tumours at our institution. ADVANCES IN KNOWLEDGE: An improved understanding of radiation dose-response relationships for primary and MET colorectal liver tumours will help inform future dose prescriptions.

Effects of exposure to environmental chemicals during pregnancy on the development of the male and female reproductive axes.

There is a large body of literature describing effects of environmental chemicals (ECs), many of them anthropogenic with endocrine-disrupting properties, on development in rodent laboratory species, some of which lead to impaired reproduction and adverse health. This literature joins extensive human epidemiological data and opportunistic wildlife findings on health effects of ECs. In contrast, the effect of endocrine disruption on foetal development and reproductive performance in domestic species is less extensively documented. This applies both to domestic farm and to companion species even though the former is critical to food production and the latter share our homes and many aspects of the modern developed human lifestyle. In domestic species, the nature of chemicals exposure in utero and their consequences for animal health and production are poorly understood. A complication in our understanding is that the pace of development, ontogeny and efficiency of foetal and maternal hepatic and placental activity differs between domestic species. In many ways, this reflects the difficulties in understanding human exposure and consequences of that exposure for the foetus and subsequent adult from epidemiological and largely rodent-based data. It is important that domestic species are included in research into endocrine disruption because of their (i) wide variety of exposure to such chemicals, (ii) greater similarity of many developmental processes to the human, (iii) economic importance and (iv) close similarities to developed world human lifestyle in companion species.

Development of a broad spectrum polymer-released antimicrobial coating for the prevention of resistant strain bacterial infections.

More than 400,000 primary hip and knee replacement surgeries are performed each year in the United States. From these procedures, approximately 0.5-3% will become infected and when considering revision surgeries, this rate has been found to increase significantly. Antibiotic-resistant bacterial infections are a growing problem in patient care. This in vitro research investigated the antimicrobial potential of the polymer released, broad spectrum, Cationic Steroidal Antimicrobial-13 (CSA-13) for challenges against 5 × 10(8) colony forming units (CFU) of methicillin-resistant Staphylococcus aureus (MRSA). It was hypothesized that a weight-to-weight (w/w) concentration of 18% CSA-13 in silicone would exhibit potent bactericidal potential when used as a controlled release device coating. When incorporated into a polymeric device coating, the 18% (w/w) broad-spectrum polymer released CSA-13 antimicrobial eliminated 5 × 10(8) CFU of MRSA within 8 h. In the future, these results will be utilized to develop a sheep model to assess CSA-13 for the prevention of perioperative device-related infections in vivo.