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Electrocaloric effects have been experimentally studied in ferroelectrics and incipient ferroelectrics, but not incipient ferroelectrics driven ferroelectric using strain. Here we use optimally oriented interdigitated surface electrodes to investigate extrinsic electrocaloric effects in low-loss epitaxial SrTiO3films near the broad second-order 243 K ferroelectric phase transition created by biaxial in-plane coherent tensile strain from DyScO3substrates. Our extrinsic electrocaloric effects are an order of magnitude larger than the corresponding effects in bulk SrTiO3over a wide range of temperatures including room temperature, and unlike electrocaloric effects associated with first-order transitions they are highly reversible in unipolar applied fields. Additionally, the canonical Landau description for strained SrTiO3films works well if we set the low-temperature zero-field polarization along one of the in-plane pseudocubic <100> directions. In future, similar strain engineering could be exploited for other films, multilayers and bulk samples to increase the range of electrocaloric materials for energy efficient cooling.

AbstractThe developmental origins of health and disease (DOHaD) framework has highlighted the importance of the early life period on disease risk in later life with impacts that can span generations. A primary focus to date has been around maternal health and the ‘First Thousand Days’ as a key developmental window whereby an adverse environment can have lasting impacts on both mother and offspring. More recently, the impact of paternal health has gathered increasing traction as a key window for early life developmental programming. However, to date, adolescents, the next generation of parents, have attracted less attention as a key DOHaD window although many behavioural traits become entrained during adolescence and track into adulthood. This systematic review examined literature focused on identifying adolescent understanding of DOHaD concepts. Consistent across the eligible articles was that overall understanding of DOHaD-related concepts in adolescents was low. Three key themes emerged: 1. Individual-level awareness of DOHaD concepts (cognitive engagement and action of the adolescents themselves); 2. Interpersonal communication and social awareness of DOHaD concepts (cognitive engagement and communication of the DOHaD concepts to family and wider community); and 3. Health literacy and the promotion of adolescence as a key DOHaD life stage. These findings highlight the need to develop strategic approaches to increase DOHaD awareness that are not only appealing to adolescents but can also support sustained changes in health behaviour. Investment in today’s adolescents has the potential to act as a NCD ‘circuit breaker’ and thus will yield significant dividends for future generations.

AbstractObjective:Maternal obesity is associated with obesity and metabolic disorders in offspring. However, there remains a paucity of data on strategies to reverse the effects of maternal obesity on maternal and offspring health. With maternal undernutrition, taurine supplementation improves outcomes in offspring mediated in part via improved glucose–insulin homeostasis. The efficacy of taurine supplementation in the setting of maternal obesity on health and well-being of offspring is unknown. We examined the effects of taurine supplementation on outcomes related to growth and metabolism in offspring in a rat model of maternal obesity.Design:Wistar rats were randomised to: 1) control diet during pregnancy and lactation (CON); 2) CON with 1.5% taurine in drinking water (CT); 3) maternal obesogenic diet (MO); or 4) MO with taurine (MOT). Offspring were weaned onto the control diet for the remainder of the study.Results:At day 150, offspring body weights and adipose tissue weights were increased in MO groups compared to CON. Adipose tissue weights were reduced in MOT versus MO males but not females. Plasma fasting leptin and insulin were increased in MO offspring groups but were not altered by maternal taurine supplementation. Plasma homocysteine concentrations were reduced in all maternal taurine-supplemented offspring groups. There were significant interactions across maternal diet, taurine supplementation and sex for response to an oral glucose tolerance test , a high-fat dietary preference test and pubertal onset in offspring.Conclusions:These results demonstrate that maternal taurine supplementation can partially ameliorate adverse developmental programming effects in offspring in a sex-specific manner.

AbstractAn adverse early life environment is associated with increased cardiovascular disease in offspring. Work in animal models has shown that maternal undernutrition (UN) during pregnancy leads to hypertension in adult offspring, with effects thought to be mediated in part via altered renal function. We have previously shown that growth hormone (GH) treatment of UN offspring during the pre-weaning period can prevent the later development of cardiometabolic disorders. However, the mechanistic basis for these observations is not well defined. The present study examined the impact of GH treatment on renal inflammatory markers in adult male offspring as a potential mediator of these reversal effects. Female Sprague-Dawley rats were fed either a chow diet fed ad libitum(CON) or at 50% of CON intake (UN) during pregnancy. All dams were fed the chow diet ad libitumduring lactation. CON and UN pups received saline (CON-S/UN-S) or GH (2.5 µg/g/day; CON-GH/UN-GH) from postnatal day 3 until weaning (p21). Post-weaning males were fed a standard chow diet for the remainder of the study (150 days). Histological analysis was performed to examine renal morphological characteristics, and gene expression of inflammatory and vascular markers were assessed. There was evidence of renal hypotrophy and reduced nephron number in the UN-S group. Tumour necrosis factor-α, monocyte chemoattractant protein-1 (MCP-1), intercellular adhesion molecular-1 and vascular cell adhesion molecule-1 gene expression was increased in UN-S offspring and normalized in the UN-GH group. These findings indicate that pre-weaning GH treatment has the potential to normalize some of the adverse renal and cardiovascular sequelae that arise as a consequence of poor maternal nutrition.

Background: High levels within the normal range of plasma C-reactive protein (CRP), an acute phase reactant, are associated with the incidence of coronary heart disease. The heritability of CRP is [...]

Abstract Objective To investigate whether including a placebo arm in a clinical trial of hormone replacement therapy influenced women's stated willingness to participate. Design Quasirandomised, interview based study. Setting 10 [...]

AbstractSmall Island Developing States (SIDS) are island nations that experience specific social, economic and environmental vulnerabilities associated with small populations, isolation and limited resources. Globally, SIDS exhibit exceptionally high rates of non-communicable disease (NCD) risk and incidence. Despite this, there is a lack of context-specific research within SIDS focused on life course approaches to NCD prevention, particularly the impact of the early-life environment on later disease risk as defined by the Developmental Origins of Health and Disease (DOHaD) framework. Given that globalization has contributed to significant nutritional transitions in these populations, the DOHaD paradigm is highly relevant. SIDS in the Pacific region have the highest rates of NCD risk and incidence globally. Transitions from traditional foods grown locally to reliance on importation of Western-style processed foods high in fat and sugar are common. The Cook Islands is one Pacific SIDS that reports this transition, alongside rising overweight/obesity rates, currently 91%/72%, in the adult population. However, research on early-life NCD prevention within this context, as in many low- and middle-income countries, is scarce. Although traditional research emphasizes the need for large sample sizes, this is rarely possible in the smaller SIDS. In these vulnerable, high priority countries, consideration should be given to utilizing ‘small’ sample sizes that encompass a high proportion of the total population. This may enable contextually relevant research, crucial to inform NCD prevention strategies that can contribute to improving health and well-being for these at-risk communities.

An adverse early life environment can increase the risk of metabolic and other disorders later in life. Genetic variation can modify an individual’s susceptibility to these environmental challenges. These gene by environment interactions are important, but difficult, to dissect. The nucleus is the primary organelle where environmental responses impact directly on the genetic variants within the genome, resulting in changes to the biology of the genome and ultimately the phenotype. Understanding genome biology requires the integration of the linear DNA sequence, epigenetic modifications and nuclear proteins that are present within the nucleus. The interactions between these layers of information may be captured in the emergent spatial genome organization. As such genome organization represents a key research area for decoding the role of genetic variation in the Developmental Origins of Health and Disease.

Obesity is a global epidemic, affecting both developed and developing countries. The related metabolic consequences that arise from being overweight or obese are a paramount global health concern, and represent a significant burden on healthcare systems. Furthermore, being overweight or obese during pregnancy increases the risk of offspring developing obesity and other related metabolic complications in later life, which can therefore perpetuate a transgenerational cycle of obesity. Obesity is associated with a chronic state of low-grade metabolic inflammation. However, the role of maternal obesity-mediated alterations in inflammatory processes as a mechanism underpinning developmental programming in offspring is less understood. Further, the use of anti-inflammatory agents as an intervention strategy to ameliorate or reverse the impact of adverse developmental programming in the setting of maternal obesity has not been well studied. This review will discuss the impact of maternal obesity on key inflammatory pathways, impact on pregnancy and offspring outcomes, potential mechanisms and avenues for intervention.

Health before conception, and periconceptional nutritional environments, contribute to conditioning of later-life health and disease. Health behaviors developed during adolescence continue into adulthood. Thus, even when the gap between pregnancy and adolescence is substantial, behaviors developed during adolescence influence later-life non-communicable disease (NCD) vulnerability in offspring. Consequently, adolescence is an important life phase where development of positive health behaviors can contribute to disruption of transgenerational cycles of NCD risk. Schooling is a core activity during adolescence. Modern curricula focus on development of capabilities associated with critical, engaged citizenship, empowering learning that supports action-based engagement in complex issues. Contexts relevant to adolescents and their communities, such as the NCD epidemic, are used to facilitate learning. Thus, engaging the education sector as participants in the work of the Developmental Origins of Health and Disease community offers an important strategy to capture the potential of adolescence as a life stage for transgenerational primary prevention of obesity and NCD risk.

There are now significant data to support the hypothesis that early life nutrition in the fetus, infant and young child can have profound effects on long-term health. This review considers some of this evidence with specific reference to the current burden of disease in Australia and New Zealand. As the findings of further research become available, recommendations on optimizing early life nutrition should be formulated and made widely available as part of the preventative health policy agenda in both Australia and New Zealand.

The evidence underpinning the developmental origins of health and disease (DOHaD) is overwhelming. As the emphasis shifts more towards interventions and the translational strategies for disease prevention, it is important to capitalize on collaboration and knowledge sharing to maximize opportunities for discovery and replication. DOHaD meetings are facilitating this interaction. However, strategies to perpetuate focussed discussions and collaborations around and between conferences are more likely to facilitate the development of DOHaD research. For this reason, the DOHaD Society of Australia and New Zealand (DOHaD ANZ) has initiated themed Working Groups, which convened at the 2014–2015 conferences. This report introduces the DOHaD ANZ Working Groups and summarizes their plans and activities. One of the first Working Groups to form was the ActEarly birth cohort group, which is moving towards more translational goals. Reflecting growing emphasis on the impact of early life biodiversity – even before birth – we also have a Working Group titled Infection, inflammation and the microbiome. We have several Working Groups exploring other major non-cancerous disease outcomes over the lifespan, including Brain, behaviour and development and Obesity, cardiovascular and metabolic health. The Epigenetics and Animal Models Working Groups cut across all these areas and seeks to ensure interaction between researchers. Finally, we have a group focussed on ‘Translation, policy and communication’ which focusses on how we can best take the evidence we produce into the community to effect change. By coordinating and perpetuating DOHaD discussions in this way we aim to enhance DOHaD research in our region.

Obesity and its related non-communicable diseases (NCDs), such as type 2 diabetes, heart disease and cancer, impose huge burdens on society, particularly the healthcare system. Until recently, public health and policy were primarily focused on secondary prevention and treatment of NCDs. However, epidemiological and experimental evidence indicates that early-life exposures influence the risk of childhood obesity and related diseases later in life, and has now focused attention on the health of both mother and child. During pregnancy and the early neonatal period, individuals respond to their environment by establishing anatomical, physiological and biochemical trajectories that shape their future health. This period of developmental plasticity provides an early window of opportunity to mitigate the environmental insults that may increase an individual’s sensitivity to, or risk of, developing obesity or related diseases later in life. Although much investigation has already occurred in the area of Developmental Origins of Health and Diseaseresearch, the science itself is still in its infancy. It remains for researchers to tackle the important outstanding questions and translate their knowledge into workable solutions for the public good. The challenge, however, is to decide which areas to focus on. With these opportunities and challenges in mind, the 2014 Gravida Summit convened to examine how its early-life research program can determine which areas of research into mechanisms, biomarkers and interventions could contribute to the international research strategy to fight childhood obesity and its related diseases.

The recent pilot studies of chlamydia screening in Portsmouth and the Wirral show that there is a substantial burden of chlamydial infection in young women and that high uptake of [...]

Crack-free transparent thin films of ferroelectric Pb(Zr0.3, Ti0.7)O3(PZT) with the perovskite structure were prepared by spin-coating a solution of complex alkoxides, followed by drying and then firing at the temperatures less than 500°C. The preparation of stock solution, drymg, and firing of films are described. The coatings with selective orientations have been prepared by using selective processing parameters. The influence of low-temperature processing steps on texture development will be reported. The formation and growth of polymeric particles in the hydrolysis and condensation of PZT sol-gel precursor solutions have been investigated by using photon correlation spectroscopy (PCS), small angle x-ray scattering (SAXS) and by measuring their rheological properties. It has been possible to follow the growth of the particles in the sol by the different techniques used from initial values of <4nm up to ca 100nm. It has been shown that the particles are rods rather than spheres. The effects of particle shape and solution chemistry on the crystal phase formation and texture development will be discussed.

In 1994 the UK Clinical Standards Advisory Group recommended eight treatment standards for back pain.[1] In 1995 availability of these services to general practitioners was generally poor.[2] We conducted another [...]

A life-course approach to reduction of risk of non-communicable diseases (NCD) suggests that early-life interventions may be more effective than lifestyle modifications in middle age. Knowledge translation to develop understanding of the Developmental Origins of Health and Disease (DOHaD) within the community offers the potential to encourage informed diet and lifestyle choices supporting reduction of NCD risk in current and future generations. Many women do not make sustained dietary change before or during pregnancy, therefore appropriate nutritional behaviours need to be established prior to adulthood. This makes adolescence an appropriate stage for interventions to establish suitable dietary and lifestyle behaviours. Therefore, we engaged adolescents in a school-based educational intervention, and assessed the value of this in development of understanding of DOHaD concepts to support behaviour change that could lead to NCD risk reduction in the next generation. Modules of course work were written for 11–14 year olds and trialled in nine schools. Matched pre- and post-intervention questionnaire responses from 238 students and 99 parents, and post-intervention interviews evaluated the intervention. Understanding of a link between maternal diet during pregnancy and the health of the foetus in adulthood increased from 46% to 76% following intervention. Post-intervention evidence suggests the programme facilitated discussion of diet, lifestyle and DOHaD concepts in most families. The intervention was effective in improving understanding of DOHaD concepts and in some cases led to appropriate behaviour change. However, the sustainability of these changes remains to be determined through on-going evaluation of attitudes and behaviour within this cohort.

An adverse prenatal environment may induce long-term metabolic consequences, in particular hypertension and cardiovascular disease. A maternal low-protein (LP) diet is well known to result in increased blood pressure (BP) in offspring. Choline has been shown to have direct BP-reducing effects in humans and animals. It has been suggested that endogenous choline synthesis via phosphatidylcholine is constrained during maternal LP exposure. The present study investigates the effect of choline supplementation to mothers fed a LP diet during pregnancy on systolic BP (SBP) in offspring as measured by tail-cuff plethysmography. Wistar rats were assigned to one of three diets to be fed ad libitumthroughout pregnancy: (1) control diet (CONT, 20% protein); (2) an LP diet (9% protein); and (3) LP supplemented with choline (LP + C). Dams were fed the CONT diet throughout lactation and offspring were fed the CONT diet from weaning for the remainder of the trial. At postnatal day 150, SBP and retroperitoneal fat mass was significantly increased in LP offspring compared with CONT animals and was normalized in LP + C offspring. Effects of LP + C reduction in SBP were similar in both males and females. Plasma choline and phosphatidylcholine concentrations were not different across treatment groups, but maternal choline supplementation resulted in a significant reduction in homocysteine concentrations in LP + C offspring compared with LP and CONT animals. The present trial shows for the first time that maternal supplementation with dietary choline during periods of LP exposure can normalize increased SBP and fat mass observed in offspring in later life.

Maternal obesity during pregnancy is often characterized by fetal macrosomia but it can also result in fetal growth restriction in a subset of pregnancies. We hypothesized that mechanisms of this growth restriction may include adverse effects of maternal high fat (HF) intake on placental growth and function. Female rats (100 days old) were time-mated and randomly assigned to either a control (Con) or HF diet ad libitumthroughout gestation. At E21, dams were killed; litter size and fetal and placental weights were recorded and maternal and fetal samples collected for further analyses. The HF diet resulted in a 54% increase in maternal body weight gain during gestation. In contrast, male and female fetal weights were reduced in HF pregnancies (P< 0.05), as were the weights of the junctional zone of the placenta (P= 0.013), whereas labyrinth zone weights were unaffected. The HF diet increased maternal and fetal plasma leptin levels (P< 0.05), but maternal and fetal insulin and fetal glucose levels were unaffected. Labyrinthine expression of PPAR? and total VEGFa mRNA, both markers of placental vascular development, were unaffected by consumption of the HF diet in placentas of male and female fetuses. Furthermore, maternal HF nutrition did not alter phosphorylated protein levels of either mammalian target of rapamycin or its downstream signaling factor eIF4E binding protein 1 (4E-BP1). These data show that in the rat, maternal HF nutrition results in fetal and placental junctional zone growth restriction, maternal and fetal hyperleptinemia but did not alter gene expression of markers of placental vascular development.

We previously reported that a maternal high fat (HF) diet resulted in adult offspring with increased adiposity and hyperleptinemia. As leptin has an inhibitory effect on adrenal steroidogenesis and a stimulatory effect on epinephrine synthesis, we hypothesized that key adrenal steroidogenic and catecholaminergic enzymes would be altered in these offspring. Wistar rats were randomized into three groups at weaning: (1) control dams fed a standard control chow diet from weaning and throughout pregnancy and lactation (CON), (2) dams fed a HF diet from weaning and throughout pregnancy and lactation (MHF) and (3) dams fed standard control chow diet throughout life until conception, then fed a HF diet in pregnancy and lactation (PLHF). Dams were mated at day 100 (P100). After birth at P22 (weaning), male offspring were fed a standard control chow (con) or high fat (hf) diet. At P160, plasma samples and adrenal tissues were collected. Postweaning hf diet significantly elevated plasma corticosterone concentrations in PLHF-hf offspring compared to PLHF-con. MHF nutrition increased adrenal adrenocorticotrophic hormone receptor (ACTH-R) mRNA levels compared to CON-con. 3ß-hydroxysteroid dehydrogenase (3ßHSD) mRNA levels were decreased in MHF compared to PLHF offspring. Phenylethanolamine N-methyltransferase (PNMT) mRNA levels were increased in MHF-hf offspring compared to MHF-con. Plasma homocysteine (HCY) concentrations were significantly elevated in CON-hf and MHF-hf offspring compared to chow-fed offspring, associated with elevated intakes of methionine and reduced intakes of pyridoxine. Immunoreactive leptin receptor (ObRb) and PNMT were colocalized in medullary chromaffin cells. This study suggests that a postweaning HF diet in offspring induced changes in adrenal gene expression levels that are dependent upon the level of maternal nutrition.

Pathological, entomological and avian investigations were conducted during the summer of 2002, in a horse farm that had four cases of West Nile virus (WNV) infection in horses. All the four horses had encephalitis and WNV infection was confirmed by RT-PCR and in situhybridization procedure. Forty-seven per cent of house sparrows that resided on the farm were tested positive for WNV infection. Mosquitoes (98Culex pipiens) collected by trapping at the farm, during this period were positive for WNV. The meteorological data for year 2002 were compared to previous 16?years. The precipitation and atmospheric temperature were found to be reduced and higher respectively, indicating a drier summer than the prior 16?years, which may have been a contributing factor for the outbreak. None of the horses on these premises had been vaccinated for WNV disease.

Strain relaxation has been studied for the 10-period quantum well (QW) heterostructures grown by MOVPE, In0.16Ga0.84N/GaN and In0.2Ga0.8N/GaN, both emitting with high efficiency in the blue and green regions, respectively. Additionally, a set of high-In content InGaN/GaN QW structures, where growth parameters were kept constant but QW numbers varied between 1 and 10, were also analysed by TEM, XRD and PL. For the highly-efficient green and the set of variable QW samples, TEM structural studies identified large well-width fluctuations and misfit dislocations that thread into the sample surface and are generated in the quantum well stack. This contrasts with similar observations of blue-emitting MQWs where misfit dislocations are not seen. PL measurements have been carried out for the In-rich QW series and did not reveal a greater degradation of the optical properties with increasing numbers of quantum wells in the stack. (© 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

This paper reports the first example of the fabrication of KNO3, K2CO3, CuSO4, NaOH, and mixed‐inorganic‐salt (KNO3and KOH) patterns using a transfer‐printing (TP) technique. The transfer quality is found to be related to the concentration of the salt solutions. By varying the immersion time, it is possible to control the heights of the raised features of the transfer‐printed salts from the nanoscale to the submicrometer scale. Utilizing these inorganic salts as water‐soluble masks for microfabrication is demonstrated using patterned NaOH films. The use of water as a developer solvent demonstrates the potential utility of the patterning of inorganic salts as a low‐cost, simple, and, more importantly, environmentally friendly route towards accurate patterning of different materials.

SynopsisEnvironmental degradation including deforestation is of great concern in the whole of sub-Saharan Africa, even in many protected areas. One of them is Lake Malawi National Park (LMNP), which encases the most populated village in Malawi, Chembe. The rise in population has increased the pressure to utilize natural resources in LMNP, and the collection of firewood for domestic use as well as for commercial purposes has led to woodland degradation in the park area. To assist LMNP and its stakeholders in combating deforestation, World Wide Fund for Nature (WWF) Finland has promoted organic matter fuel briquettes as a substitute to firewood since 2001.This article is the result of data collection related to the monitoring of the briquette project and forest management practices in LMNP. Results showed that illegal firewood collection inside park area is widespread and its control inefficient. It was also found that despite interest towards fuel briquettes, cost is the limiting factor when people choose their fuel source. Stronger marketing efforts are needed to increase the viability of the briquette business. Another alternative would be to teach families how to make briquettes for household use. Concentrated efforts to regulate “free” fuel wood collection inside park area are needed to reverse deforestation.

The effect of ZrO₂ addition on the properties of MgB₂ has been studied using in situ and ex situ processes. The in situ process was performed by introducing ZrO₂ from the milling tools into MgB₂ throughout the planetary ball milling, whereas the ex situ process was accomplished by mixing ZrO₂ from the milling tools with MgB₂ by hand grinding in a mortar. A detectable amount of ZrO₂ was present in MgB₂ after 4 h of milling during the in situ process and its content increased with milling time as expected. The 400 h milled powder was partially amorphized and showed the formation of a minority ZrB₂ phase. For milling up to 100 h, diamagnetism of MgB₂ was significantly reduced while T_c remained unchanged. Superconductivity was totally destroyed after 148 h of milling. The loss of superconductivity is attributed to the effect of disordering induced by mechanical milling. As a result of in situ ZrO₂ addition, the initial T_c and crystal structure of MgB₂ could not be restored upon annealing. With increasing milling time, the expansion of lattice parameters in both the a-axis and c-axis may be due to possible substitution of Mg or B by Zr. The result from the magnetic measurement shows that J_c of MgB₂ is deteriorated by in situ ZrO₂ addition. On the other hand, ex situ ZrO₂ addition with annealing did not degrade the T_c of MgB₂.

We discuss the results of a study of MgB₂ multifilamentary conductors and coated conductors from the point of view of their future dc and ac applications. The correlation between the slope of the irreversibility line induced by neutron irradiation defects and in situ structural imperfections and the critical temperature and critical current density is discussed with respect to the conductor performance and applicability. We debate the possible origin of the observed anomalous decrease of ac susceptibility at 50 K in copper clad in situ powder-in-tube MgB₂ wires. Different conductor preparation methods and conductor architectures, and attainable critical current densities are presented. Some numerical results on critical currents, thermal stability and ac losses of future MgB₂ multifilamentary and coated conductors with magnetic cladding of their filaments are also discussed.

In 1989, the UK Medical Research Council (MRC) agreed that, if feasible, a randomized controlled trial to assess the long-term risks and benefits of hormone replacement therapy (HRT) was a priority. Feasibility work began in 1990 and demonstrated that a large-scale multicenter trial was possible. An application for funding for a main trial was submitted to MRC in 1993 and, after extensive review, funding was released in late 1996. Set-up work for the trial - the Women's International Study of long Duration Oestrogen after Menopause (WISDOM) - began in 1997 with recruitment in 1999. In October 2002, following the early discontinuation of one arm of the US Women's Health Initiative HRT trial, the MRC decided to stop the WISDOM trial. This article, by the principal UK investigators of WISDOM, sets out the background and history of the trial.

Surveys of human mutant cells exhibit a few individuals with relatively high “outlying” values, which might be explained by rare mutations occurring during development. To estimate how commonly this occurs, mutant red cell frequencies at the glycophorin A locus in 135 neonates and 109 children and adolescents from three research centers are compared with simulations in which mutations arise from successive cycles of binary fission. The simulations predict the data most accurately when the mutation rate in stem cell precursors is about 2–4 × 10−7per division cycle, which is similar to previous estimates from adult stem cell divisions. If these mutation rates are accurate, and the number of stem cell divisions during adult life is as low as previously estimated, it is predicted that up to one‐sixth of mutant stem cells over a lifetime arose in early life. However, these mutant stem cells would be difficult to detect in surveys because their distribution within the general population is so skewed. Environ. Mol. Mutagen. 39:333–341, 2002. © 2002 Wiley‐Liss, Inc.

AIM: To establish the efficacy of oral formulations of ivermectin and moxidectin against naturally acquired abomasal nematode infections on a North Island sheep farm.METHODS: Two controlled slaughter trials were undertaken. In the first, 30 sheep on pasture were randomly allocated on the basis of faecal egg count to 1 of 3 groups, comprising an untreated control group and 2 treatment groups. One treatment group was given a single oral dose of ivermectin and the other a single oral dose of moxidectin, both at the manufacturer's recommended dose rates of 0.2 mg/kg liveweight. Six days after treatment, all animals were slaughtered and their abomasa recovered for worm counting. The second trial, which involved 47 animals, was essentially the same as the first except that, as well as involving the slaughter of 30 sheep from all 3 groups, 6 days after treatment, it also included a further 8 untreated control animals and 9 moxidectin treated animals which were slaughtered 27 days after treatment.RESULTS: At 6 days after treatment, moxidectin was highly effective against all 3 of the abomasal nematodes present. While ivermectin was similarly effective against Trichostrongylus axei 6 days after treatment, it was not effective against either Ostertagia circumcinta or Haemonchus contortus, against which average efficacies of only 63.6% and 61.6%, respectively, were recorded. At 27 days after treatment, moxidectin, was also highly effective against T. axei (97.3% reduction) but not against either H. contortus (71.4% reduction) or O. circumcinta (61.0% reduction).CONCLUSIONS: These results provide the first record of macrocyclic lactone resistance in H. contortus in sheep or in any other host in New Zealand, and the first case where such resistance has been exhibited in more than one parasite species at a time. Although the therapeutic efficacy of moxidectin was high against these resistant H. contortus and O. circumcincta strains, resistance to moxidectin was indicated by its diminished prophylactic activity against them. It is suggested that this reduction in the prophylactic activity of moxidectin is also likely to reduce its apparent current high therapeutic efficacy.CLINICAL RELEVANCE: As well as providing further evidence that it can no longer be automatically assumed that macrocylic lactone anthelmintics will be effective on sheep farms in this country, these findings also present a warning that increasingly complex parasite control options may have to be faced in the future.

FUI1 and function unknown now 26 (FUN26) are proteins of uncertain function with sequence similarities to members of the uracil/allantoin permease and equilibrative nucleoside transporter families of transporter proteins, respectively. [(3)H]Uridine influx was eliminated by disruption of the gene encoding FUI1 (fui1) and restored by expression of FUI1 cDNA, whereas influx in transport-competent and fui1-negative yeast were unaffected, respectively, by disruption of the FUN26 gene or overexpression of FUN26 cDNA. FUI1 transported uridine with high affinity (K(m), 22 +/- 3 micrometer) and was unaffected or inhibited only partially by high concentrations (1 mm) of a variety of ribo- and deoxyribonucleosides or nucleobases. When FUN26 cDNA was expressed in oocytes of Xenopus laevis, inward fluxes of [(3)H]uridine, [(3)H]adenosine, and [(3)H]cytidine were stimulated, and uridine influx was independent of pH and not inhibited by dilazep, dipyridamole, or nitrobenzylmercaptopurine ribonucleoside. Fractionation of yeast membranes containing immunotagged recombinant FUN26 (shown to be functional in oocytes) demonstrated that the protein was primarily in intracellular membranes. These results indicated that FUI1 has high selectivity for uracil-containing ribonucleosides and imports uridine across cell-surface membranes, whereas FUN26 has broad nucleoside selectivity and most likely functions to transport nucleosides across intracellular membranes.

In the spontaneously hypertensive rat (SHR) fetal growth and metabolism are abnormal. It has been speculated that maternal hypertension may be the cause of these abnormalities. Captopril treatment, which reduces maternal blood pressure, during pregnancy and lactation, is reported to have a beneficial effect postnatally, normalizing the blood pressure of offspring in the SHR. In the present study, the effects of maternal captopril treatment on fetal growth and plasma metabolites were investigated in the fetuses of two rat strains (SHR and Wistar-Kyoto (WKY)), in order to determine whether normalizing maternal blood pressure also normalized abnormalities in fetal growth and metabolism. On fetal Day 20, SHR fetuses were lighter and placentae were heavier than for the corresponding WKY. Captopril had no effect on fetal weight in the SHR, but decreased it in the WKY. There was no effect of captopril on placental weight. Fetal plasma insulin levels were higher in the SHR than in the WKY and were decreased by captopril treatment in both strains. Fetal blood glucose was elevated and fetal blood lactate was decreased in captopril-treated litters from both strains. Captopril had no effect on fetal plasma IGF-1 but fetal plasma IGF-2 levels were lower in the captopril-treated SHR than in the captopril-treated WKY. These findings suggest that maternal captopril treatment decreases insulin secretion in the fetal rat. High levels of fetal plasma insulin suggest that the SHR fetus is insulin resistant. Fetal insulin levels may contribute to the adverse consequences of gestational captopril treatment observed in many species. The differences in the effect of captopril on the two strains suggest that there are underlying endocrine differences in the SHR.

We investigated whether a recombinant follicle stimulating hormone (FSH) (Puregon) can be administered less frequently and at lower doses during ovulation induction than is current practice. Patients (20-35 years, body mass index <30 kg/m(2)) with infertility and chronic anovulation secondary to polycystic ovarian syndrome and resistant to previous clomiphene treatment received (Puregon); 100 IU, n = 17 patients, or 50 IU, n = 10 patients) on alternate days. After 2 weeks and in the absence of follicular recruitment, doses were increased stepwise at weekly intervals (50 IU/alternate days). Twenty-two cycles out of 27 were ovulatory. There were six pregnancies, five from Puregon (100 IU) and one from Puregon (50 IU); four pregnancies proceeded to term. The duration of stimulation (mean, range) with Puregon (100 IU) was 16.4, 7-29 and Puregon (50 IU) 19.1, 8-38 days. The gonadotrophin doses administered (mean; range) were 689, 200-1800 IU (Puregon 50 IU) and 939, 400-2300 IU (Puregon 100 IU). We conclude that low dose alternate day Puregon treatment is suitable for this difficult patient group.

In the sol-gel processing of the ferroelectric thin films of PbZrxTi1-xO3 (PZT), solution precursor characteristics have been long considered as a factor, which affects thin film microstructure and orientation. In this study, we used a hybrid solvent of acetic acid and methanol to prepare PZT precursor sols. The structures of PZT precursor sols before and after hydrolysis were characterised by using NMR (nuclear magnetic resonance), PCS (photon correlation spectroscopy), and SAXS (small angle X-ray scattering) techniques. We also measured the rheological properties of the PZT precursor solutions. The measurements revealed that methoxy ligands, which were bonding to metals, were completely replaced by acetate ligands in the unhydrolysed sols. The particles in our PZT sols are chain-like and their average size increases linearly on a logarithmic scale after extra water was added due to the hydrolysis and condensation reactions. To examine the relationship between the film crystallisation and the particle size in the precursor sols, the films were fabricated with different particle sizes and then annealed at 480°C. The crystallisation of the thin films was investigated using X-ray diffraction. Under the identical fabrication conditions, pyrochlore phase appeared in the films prepared with the solutions of larger particle sizes. Ferroelectric properties were degraded when using the solutions with large particles.

OBJECTIVE: To investigate whether including a placebo arm in a clinical trial of hormone replacement therapy influenced women's stated willingness to participate. DESIGN: Quasirandomised, interview based study. Setting: 10 group practices in the Medical Research Council's General Practice Research Framework. PARTICIPANTS: 436 postmenopausal women aged 45-64 who had not had a hysterectomy. MAIN OUTCOME MEASURES: Stated willingness to enter a trial and reasons for the decisions made. RESULTS: Of 218 women told about the trial without a placebo arm, 85 (39%) indicated their willingness to enter compared with 65 (30%) of the 218 women told about the trial with the placebo arm (P=0.06). Part of this difference was due to explicit reluctance to take a placebo. Altruism and personal benefit were the reasons most frequently given for wanting to take part in a trial. The reasons most frequently cited for not wanting to take part were reluctance to restart periods, not wanting to take unknown or unnecessary tablets, or not wanting to interfere with present good health. CONCLUSION: For preventive trials the inclusion of a placebo arm may reduce patients' willingness to participate.

We investigated whether a recombinant follicle stimulating hormone (FSH) (Puregon®) can be administered less frequently and at lower doses during ovulation induction than is current practice. Patients (20–35 years, body mass index <30 kg/m2) with infertility and chronic anovulation secondary to polycystic ovarian syndrome and resistant to previous clomiphene treatment received (Puregon®; 100 IU, n = 17 patients, or 50 IU, n = 10 patients) on alternate days. After 2 weeks and in the absence of follicular recruitment, doses were increased stepwise at weekly intervals (50 IU/alternate days). Twenty-two cycles out of 27 were ovulatory. There were six pregnancies, five from Puregon® (100 IU) and one from Puregon® (50 IU); four pregnancies proceeded to term. The duration of stimulation (mean, range) with Puregon® (100 IU) was 16.4, 7–29 and Puregon® (50 IU) 19.1, 8–38 days. The gonadotrophin doses administered (mean; range) were 689, 200–1800 IU (Puregon® 50 IU) and 939, 400–2300 IU (Puregon® 100 IU). We conclude that low dose alternate day Puregon® treatment is suitable for this difficult patient group.

The primary lesions of eastern equine encephalomyelitis (EEE) virus infection in the horse are limited to the brain and spinal cord. Intestinal lesions in addition to the changes in the central nervous system were found in a 6-month-old male Tennessee Walking Horse. One week prior to death, this colt was vaccinated for EEE virus, western equine encephalomyelitis virus, influenza virus, equine rhinopneumonitis virus, and tetanus. The clinical signs consisted of ataxia and rear-end weakness, with a body temperature of 102.8 F. Gross lesions consisted of yellowish discoloration, swelling, edema, and hemorrhage of the brain stem and dark discoloration of the gray matter of the spinal cord. Microscopic lesions in the small intestine were mainly in the muscular layer and consisted of multifocal areas of myonecrosis and lymphomonocytic infiltration with a few focal areas of mild fibrous connective tissue proliferation. Occasional focal mild perivascular lymphocytic infiltration was observed in the submucosa. Lesions in the brain and spinal cord consisted of widespread areas of perivascular lymphomonocytic cuffing, focal areas of necrosis, neutrophilic infiltration, hemorrhage, neuronal degeneration, and gliosis. Hepatic changes consisted of periportal lymphocytic infiltration and mild vacuolar degeneration of hepatocytes. EEE virus was isolated from the intestine and detected by DNA in situ hybridization.

We recently reported the presence of four genes lying between the human alpha-globin gene cluster and the telomere of the short arm of chromosome 16 (16p). We now report that one of these genes encodes 3-methyladenine DNA glycosylase, an enzyme important in the repair of DNA after damage by alkylating agents. The gene comprises five exons, representation of which differs in independently isolated cDNA clones. Although the gene is widely expressed, the abundance of its mRNA is considerably higher in a colon adenocarcinoma cell line (HT29) than in other cell lines that were tested. The major positive erythroid-specific regulatory element controlling alpha-globin gene expression lies equidistant between the promoters of the alpha-globin genes and the 3-methyladenine DNA glycosylase gene. Interestingly, in contrast to the alpha-globin genes, expression of the 3-methyladenine DNA glycosylase gene is not influenced by the regulatory element in the human erythroleukemia cell line K562.

Histamine, selective histamine H1- and H2-receptor agonists, and chemical analogues of these compounds lacking activity at histamine receptors, were tested as inhibitors of phytohaemagglutinin-induced human lymphocyte proliferation and zymosan-induced release of lysosomal enzymes from human polymorphs. No correlation was found between their inhibitory potency in these systems and their relative activity at histamine H1- or H2-receptors.

Histamine, injected subcutaneously (0.3–10 mg/kg), produced a dose-related inhibition of the primary and secondary inflammation, and the development of the secondary lesions of rat adjuvant arthritis. Histamine was effective when given for short periods around the time of adjuvant administration and could also delay and possibly reverse an established arthritic response. The histamine H1-agonist, 2-(2-pyridyl)-ethylamine, inhibited rat adjuvant arthritis, whereas the histamine H2-agonists, impromidine and dimaprit, failed to affect the response. Metiamide, a histamine H2-antagonist (5 mg/kg), reduced the inflammation in the uninjected hind-paw and the development of secondary lesions.

We have studied the effect of clonidine on gastric motility, by examining the effect on gastric emptying of indigestible solids. In Wistar rats, either clonidine or saline was injected intraperitoneally, and ten steel balls (1.0 mm in diameter) were inserted into the stomach. Gastric emptying was examined at 3 h. Clonidine delayed gastric emptying of steel balls (ED50=0.0071 [95% confidence interval: 0.0033–0.013) mg kg⁻¹). Yohimbine, but not naloxone, significantly antagonized the inhibitory effect of clonidine. We conclude that clonidine inhibits gastric motility through the alpha2 adrenoceptor.