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Earlier reviews to discover research on interventions for children after neglect have concluded little was available, despite the well-documented prevalence and harmful effects of neglect on children. We revisited this question through a systematic literature review to discover the state of research on interventions for children who have experienced neglect. We searched MEDLINE, PsycINFO, ERIC, Sociological Abstracts and EMBASE for studies published between 2003 and 2021. Studies were included if neglect could be distinguished, and child outcomes reported. Eight reports describing six studies about six interventions were identified. These studies differed in interventions, age-groups, definitions of neglect, and outcomes. Four studies reported positive child outcomes though with varying degree of quality. More research is needed to inform a coherent theory of change following neglect. There remains an urgent need for research on interventions to help children recover from neglect., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Youth who have histories of trauma exposure face unique barriers and needs in navigating the juvenile justice system. Accordingly, reliance on recidivism as the primary "success" metric falls short for trauma-impacted youth and may actually prolong their justice involvement. Caregivers and juvenile justice professionals (i.e., judges, attorneys, detention and probation staff, case managers, and mental health clinicians) often struggle to identify and adequately address these challenges and pitfalls. This policy brief provides an overview of specialized considerations for traumatized youth with respect to common policies and practices, namely mandated placement, treatment, and timelines. Specific examples and actionable recommendations are provided to assist juvenile justice professionals and treatment providers with systemic efforts to more appropriately and effectively customize juvenile justice policies and programs for these extremely vulnerable youth., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zelechoski, Bohner and Perry.)

An Australia-wide consensus was reached on seven core concepts of physiology, one of which was "structure and function" with the descriptor "Structure and function are intrinsically related to all levels of the organism. In all physiological systems, the structure from a microscopic level to an organ level dictates its function." As a framework for the structure and function core concept, the renal system was unpacked by a team of 5 Australian Physiology educators from different universities with extensive teaching experience into hierarchical levels, with 5 themes and 25 subthemes up to 3 levels deep. Within theme 1 , the structures that comprise the renal system were unpacked. Within theme 2 , the physiological processes within the nephron such as filtration, reabsorption, and secretion were unpacked. Within theme 3 , the processes involved in micturition were unpacked. In theme 4 , the structures and processes involved in regulating renal blood flow and glomerular filtration were unpacked; and within theme 5 , the role of the kidney in red blood cell production was unpacked. Twenty-one academics rated the difficulty and importance of each theme/subtheme, and results were analyzed using a one-way ANOVA. All identified themes were validated as "essential" to "important"/"moderately important" and rated between "difficult" to "not difficult." A similar framework consisting of structure, physiological processes, physical processes, and regulation can be used to unpack other body systems. Unpacking of the body systems will provide a list of what students should be taught in curricula across Australian universities and inform assessment and learning activities. NEW & NOTEWORTHY This is the first attempt to unpack and validate the "structure and function" core concept in physiology with all Australian educators. We unpacked the renal system into themes with hierarchical levels, which were validated by an experienced team of Australian physiology educators. Our unpacking of the "structure and function" core concept provides a specific framework for educators to apply this important concept in physiology education.

Introduction: It has been proposed that an increased susceptivity to oxidative stress caused by the absence of the protein dystrophin from the inner surface of the sarcolemma is a trigger of skeletal muscle necrosis in the destructive dystrophin deficient muscular dystrophies. Here we use the mdx mouse model of human Duchenne Muscular Dystrophy to test the hypothesis that adding the antioxidant NAC at 2% to drinking water for six weeks will treat the inflammatory phase of the dystrophic process and reduce pathological muscle fiber branching and splitting resulting in a reduction of mass in mdx fast-twitch EDL muscles. Methods: Animal weight and water intake was recorded during the six weeks when 2% NAC was added to the drinking water. Post NAC treatment animals were euthanised and the EDL muscles dissected out and placed in an organ bath where the muscle was attached to a force transducer to measure contractile properties and susceptibility to force loss from eccentric contractions. After the contractile measurements had been made the EDL muscle was blotted and weighed. In order to assess the degree of pathological fiber branching mdx EDL muscles were treated with collagenase to release single fibers. For counting and morphological analysis single EDL mdx skeletal muscle fibers were viewed under high magnification on an inverted microscope. Results: During the six-week treatment phase NAC reduced body weight gain in three- to nine-week-old mdx and littermate control mice without effecting fluid intake. NAC treatment also significantly reduced the mdx EDL muscle mass and abnormal fiber branching and splitting. Discussion: We propose chronic NAC treatment reduces the inflammatory response and degenerative cycles in the mdx dystrophic EDL muscles resulting in a reduction in the number of complexed branched fibers reported to be responsible for the dystrophic EDL muscle hypertrophy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Redwan, Kiriaev, Kueh, Morley, Houweling, Perry and Head.)

The functioning of complex organisms requires a constant and delicate balance of processes both between and within cells, tissues, and organ systems. There is growing appreciation for the role of signalling crosstalk connecting different organ systems of the body, even from tissues traditionally classified as "inert" in terms of their capacity to produce chemical signals that can act on other organ systems. Many of these secreted molecules have been shown to contribute to, or exacerbate, a variety of functions and diseases in other organ systems, even if the two organs are not functionally linked. For example, there is a strong association with skeletal muscle atrophy and dysfunction in patients with chronic kidney disease (CKD). Identification of molecules produced and secreted by skeletal muscle has existed for some time, and there is emerging evidence that skeletal muscle may directly affect kidney function. Conversely, factors produced and secreted by the kidneys in various models of CKD have been shown to contribute to reduced muscle functionality. This review will focus on crosstalk in both directions between skeletal muscle and the kidneys. The emphasis will be on direct interaction between these organs using examples of secreted factors that are produced by the muscle or kidneys (including activin A, myostatin, microRNA's, irisin and mitsugumin 53), often under pathophysiological conditions. Our understanding of how the kidneys and skeletal muscle interact with each other is key to elucidating the pathophysiology processes that drive health and disease., Competing Interests: The authors have no conflicts of interest to declare., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

Small farmers produce most food in low- and middle-income countries and most small farmers rely on directly or indirectly working equids (WE). The lack of methods and metrics for assessing the role of WE hampers realisation of WE contributions. Based on literature review and a survey of WE welfare experts, we propose a framework for optimising WE potential based on two axes of sustainable development goals (SDGs) and value chains. WE contribute especially to earning and sparing income (largely in food production) (SDG 1), but also have roles in accessing health and hygiene services and products (SDG 3 and 5), providing edible products (SDG 2), and benefiting women (SDG 6), with lesser contributions to other SDGs, notably climate action (SDG 13). Experts identified barriers to appropriate appreciation of WE contributions, in order to target actions to overcome them. They found WE are neglected because they belong to farmers who are themselves neglected; because information on WE is inadequate; and, because the unique nature and roles of WE means systems, policies, investors, markets and service providers struggle to cater for them. Harnessing WE to optimally contribute to sustainable development will require generating better evidence on their contributions to SDGs, ensuring better integration into ongoing efforts to attain SDGs, and building the WE capacity among development actors., (© 2022. The Author(s).)

Background :  This paper describes a pilot study undertaken in 2018, to determine the key data needs of each of the different Ethiopian dairy sector stakeholder groups.  The study aimed to characterise the emerging trends of dairy product production, processing, retailing and consumption in Ethiopia, and to identify and characterise current and future data needs of different stakeholders. Methods :  The study undertook a mapping of the interactions between different stakeholders in the dairy sector, and an interactive evaluation of the institutional data repository and access options.  Focus group discussions and interviews were held in three regions of the country prior to a two-day workshop in the capital Addis Ababa.  Data needs were characterised by type, availability, format, level of detail, methods of dissemination, uptake and use, and the institutional arrangement, including the different roles of public and private sectors in decision making processes. Results :  The study highlighted the main data needs and identified several broader institutional issues constraining the further development of the Ethiopian dairy sector.  The stakeholder groups endorsed the reactivation of a national dairy board, independent of government but closely incorporating government, and with the buy-in and membership of private sector enterprises, including producers, processers, service providers and consumers, to provide clearer facilitative leadership on the dairy industry. Conclusions :  The study workshop provided a timely discussion between diverse stakeholders, including government, and several potential organisations were suggested to host and manage a national dairy database. Importantly, the reactivation of a national dairy board was strongly endorsed.  It was recommended that stakeholder links be established, sector-specific data needs be elevated to higher detail, and a national roll out of herd-specific data recording schemes was called for, to allow for effective evidence-based policies and decision making., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Perry BD et al.)

Background :  This paper describes a pilot study undertaken in 2018, to determine the key data needs of each of the different Ethiopian dairy sector stakeholder groups.  The study aimed to characterise the emerging trends of dairy product production, processing, retailing and consumption in Ethiopia, and to identify and characterise current and future data needs of different stakeholders. Methods :  The study undertook a mapping of the interactions between different stakeholders in the dairy sector, and an interactive evaluation of the institutional data repository and access options.  Focus group discussions and interviews were held in three regions of the country prior to a two-day workshop in the capital Addis Ababa.  Data needs were characterised by type, availability, format, level of detail, methods of dissemination, uptake and use, and the institutional arrangement, including the different roles of public and private sectors in decision making processes. Results :  The study highlighted the main data needs and identified several broader institutional issues constraining the further development of the Ethiopian dairy sector.  The stakeholder groups endorsed the reactivation of a national dairy board, independent of government but closely incorporating government, and with the buy-in and membership of private sector enterprises, including producers, processers, service providers and consumers, to provide clearer facilitative leadership on the dairy industry. Conclusions :  The study workshop provided a timely discussion between diverse stakeholders, including government, and several potential organisations were suggested to host and manage a national dairy database. Importantly, the reactivation of a national dairy board was strongly endorsed.  It was recommended that stakeholder links be established, sector-specific data needs be elevated to higher detail, and a national roll out of herd-specific data recording schemes was called for, to allow for effective evidence-based policies and decision making., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Perry BD et al.)

This paper reviews the rapidly changing global demands for animal-source foods, examines the agri-food systems behind these changes, and discusses the potential responses required by public-sector Veterinary Services to meet these new demands.

Minocycline, a tetracycline-class of antibiotic, has been tested with mixed effectiveness on neuromuscular disorders such as amyotrophic lateral sclerosis, autoimmune neuritis and muscular dystrophy. The independent effect of minocycline on skeletal muscle force production and signalling remain poorly understood. Our aim here is to investigate the effects of minocycline on muscle mass, force production, myosin heavy chain abundance and protein synthesis. Mice were injected with minocycline (40 mg/kg i.p.) daily for 5 days and sacrificed at day six. Fast-twitch EDL, TA muscles and slow-twitch soleus muscles were dissected out, the TA muscle was snap-frozen and the remaining muscles were attached to force transducer whilst maintained in an organ bath. In C2C12 myotubes, minocycline was applied to the media at a final concentration of 10 μg/mL for 48 h. In minocycline treated mice absolute maximal force was lower in fast-twitch EDL while in slow-twitch soleus there was an increase in the time to peak and relaxation of the twitch. There was no effect of minocycline treatment on the other contractile parameters measured in isolated fast- and slow-twitch muscles. In C2C12 cultured cells, minocycline treatment significantly reduced both myosin heavy chain content and protein synthesis without visible changes to myotube morphology. In the TA muscle there was no significant changes in myosin heavy chain content. These results indicate that high dose minocycline treatment can cause a reduction in maximal isometric force production and mass in fast-twitch EDL and impair protein synthesis during myogenesis in C2C12 cultured cells. These findings have important implications for future studies investigating the efficacy of minocycline treatment in neuromuscular or other muscle-atrophy inducing conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kiriaev, Perry, Mahns, Shortland, Redwan, Morley and Head.)

Background: Childhood adversity (CA) has previously been linked to various health problems in adulthood. Investigations into the differential impact of distinct types of CA on a wide range of outcomes are scarce. This study aimed to assess the impact of self-reported childhood family conflict and/or financial strain on health and social functioning in adulthood among Europeans, while taking into account the mediating role of adulthood socioeconomic disadvantage (SED) in these associations., Methods: Using the European Social Survey (ESS) collected in 2014, nationally representative cross-sectional data from 35 475 participants aged 15 years and older in 19 European countries were analysed. Logistic regressions were conducted to assess associations of retrospectively reported family conflict and/or financial strain in childhood with physical and mental health as well as health behaviours and social functioning in adulthood., Results: A quarter of the European population reported having experienced family conflict, financial strain or both in childhood. Financial strain was reported more among older age groups and conflict more among younger age groups. A dose-response pattern with increased risk was demonstrated for almost all physical, behavioral, mental and social outcomes for these aspects of CA compared with no CA, with the highest risk observed in those who experienced both financial strain and family conflict. Adulthood SED mediated a significant proportion of the associations with financial strain (ranging from 5.4% to 72.4%), but did not mediate the associations with conflict., Conclusion: Individuals reporting family conflict or financial strain during childhood are at increased risk of developing a wide range of health and social problems. Those who report financial strain in childhood are more likely to experience SED in adulthood, which in turn increases their risk of experiencing health and social problems. Reported family conflict during childhood conferred increased risk of health and social problems, but adulthood SED did not appear to operate as an indirect pathway., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Physical inactivity is a global health risk that can be addressed through application of exercise training suitable for an individual's health and age. People's willingness to participate in physical activity is often limited by an initially poor physical capability and early onset of fatigue. One factor associated with muscle fatigue during intense contractions is an inexcitability of skeletal muscle cells, reflecting impaired transmembrane Na + /K + exchange and membrane depolarization, which are regulated via the transmembranous protein Na + -K + -ATPase (NKA). This short review focuses on the plasticity of NKA in skeletal muscle in humans after periods of altered usage, exploring NKA upregulation with exercise training and downregulation with physical inactivity. In human skeletal muscle, the NKA content quantified by [ 3 H]ouabain binding site content shows robust, yet tightly constrained, upregulation of 8-22% with physical training, across a broad range of exercise training types. Muscle NKA content in humans undergoes extensive downregulation with injury that involves substantial muscular inactivity. Surprisingly, however, no reduction in NKA content was found in the single study that investigated short-term disuse. Despite clear findings that exercise training and injury modulate NKA content, the adaptability of the individual NKA isoforms in muscle (α 1-3 and β 1-3 ) and of the accessory and regulatory protein FXYD1 are surprisingly inconsistent across studies, for exercise training as well as for injury/disuse. Potential reasons for this are explored. Finally, we provide suggestions for future studies to provide greater understanding of NKA regulation during exercise training and inactivity in humans.

Early-life stress (ELS) poses risks for developmental and mental health problems throughout the lifespan. More research is needed regarding how specific ELS experiences influence specific aspects of neurodevelopment. We examined the association between ELS, defined as severe adversity (e.g., domestic violence, caregiver drug use) and severe relational poverty (e.g., caregiver neglect, lack of caregiver attunement), occurring during the first 2 months of life and a variety of brain-related, clinician-rated functions, including self-regulation and relational capacities. Interdisciplinary clinicians using the Neurosequential Model of Therapeutics (NMT), an approach to clinical problem solving, reported on the timing and type of treatment-seeking children's ( N = 2,155; 8-10 years) stressful experiences during four developmental periods: Perinatal (0-2 months), Infancy (2-12 months), Early Childhood (13 months to 4 years), and Childhood (4-11 years). They also reported on children's current functioning in 32 brain-related domains (e.g., sleep, arousal, impulsivity, empathy, concrete cognition). Non-negative matrix factorization (NMF) was conducted on the 32 brain-related domains to identify latent factors, yielding four factors comprising Sensory Integration, Self-Regulation, Relational, and Cognitive functioning. Regularized hierarchical models were then used to identify associations between ELS and each latent factor while controlling for stress occurring during subsequent developmental periods, and children's current degree of relational health. ELS (stress occurring during the first 2 months of life), specifically a severe lack of positive relational experiences (e.g., caregiver neglect, lack of caregiver attunement), was associated with the Sensory Integration and Self-Regulation factors. The Relational factor was better explained by stress occurring during childhood, and the Cognitive factor by stress occurring during infancy and childhood. Implications for how the timing and type of stress experiences may influence brain-related outcomes that are observed in clinical settings are discussed. Future directions include longitudinal follow-ups and greater specification of environmental variables, such as types of interventions received and when they were received, that may interact with ELS experiences to influence brain-related outcomes.

Background: The association between developmental adversity and children's functioning is complex, particularly given the multifaceted nature of adverse experiences. The association between the timing of experience and outcomes is underresearched and clinically under-appreciated. We examine how the timing of both adverse (including potentially traumatic) events and relational poverty are associated with developmental outcomes., Method: Clinicians using the Neurosequential Model of Therapeutics (NMT), an approach to clinical problem solving, reported on the timing of children's developmental experiences, their degree of current relational health, and current functioning in key brain-mediated domains (N = 3523 6- to 13-year-old children). A regularized hierarchical model produced stable and generalizable estimates regarding associations between the timing of experiences across four developmental periods: Perinatal (0-2 mos), Infancy (2-12 mos), Early Childhood (13 mos to 4 years), and Childhood (4 to 11 years) and current functioning., Results: Perinatal developmental experiences were more strongly associated with compromised current functioning than such experiences occurring during other periods. Perinatal relational poverty was a stronger predictor than perinatal adversity. During subsequent developmental periods, the influence of relational poverty diminished, while the influence of adversity remained strong throughout early childhood. Current relational health, however, was the strongest predictor of functioning., Conclusion: Findings expand the understanding of the association between the timing of adversity and relationally impoverished experiences and children's functioning. Although early life experiences are significantly impactful, relationally enriched environments may buffer these effects., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Africa bears the brunt of many of the world's most devastating human and animal infectious diseases, a good number of which have no licensed or effective vaccines available. The continent's potential to generate novel interventions against these global health threats is however largely untapped. Strengthening Africa's vaccine research and development (R&D) sector could accelerate discovery, development and deployment of effective countermeasures against locally prevalent infectious diseases, many of which are neglected and have the capacity to spread to new geographical settings. Here, we review Africa's human and veterinary vaccine R&D sectors and identify key areas that should be prioritized for investment, and synergies that could be exploited from Africa's veterinary vaccine industry, which is surprisingly strong and has close parallels with human vaccine R&D., Competing Interests: No competing interests were disclosed., (Copyright: © 2018 Warimwe GM et al.)

Muscle atrophy in metabolic conditions like chronic kidney disease (CKD) and diabetes are associated with glucocorticoid production, dysfunctional insulin/Akt/FoxO3 signaling and increased myostatin expression. We recently found that CREB, a transcription factor proposed to regulate myostatin expression, is highly phosphorylated in some wasting conditions. Based on a novel Akt-PDE3/4 signaling paradigm, we hypothesized that reduced Akt signaling contributes to CREB activation and myostatin expression. C2C12 myotubes were incubated with dexamethasone (Dex), an atrophy-inducing synthetic glucocorticoid. Akt/CREB signaling and myostatin expression were evaluated by immunoblot and qPCR analyses. Inhibitors of Akt, phosphodiesterase (PDE)-3/4, and protein kinase A (PKA) signaling were used to test our hypothesis. Incubating myotubes with Dex for 3-24 h inhibited Akt phosphorylation and enhanced CREB phosphorylation as well as myostatin mRNA and protein. Inhibition of PI3K/Akt signaling with LY294002 similarly increased CREB phosphorylation. Isobutyl-methylxanthine (IBMX, a pan PDE inhibitor), milrinone (PDE3 inhibitor) and rolipram (PDE4 inhibitor) augmented CREB phosphorylation and myostatin expression. Inhibition of protein kinase A by PKI reverted Dex- or IBMX-induced CREB phosphorylation and myostatin expression. Our study provides evidence supporting a newly identified mechanism by which a glucocorticoid-related reduction in Akt signaling contributes to myostatin expression via CREB activation., (Published by Elsevier Inc.)

This paper discusses the sustainability of livestock systems, emphasising bidirectional relations with animal health. We review conventional and contrarian thinking on sustainability and argue that in the most common approaches to understanding sustainability, health aspects have been under-examined. Literature review reveals deep concerns over the sustainability of livestock systems; we recognise that interventions are required to shift to more sustainable trajectories, and explore approaches to prioritising in different systems, focusing on interventions that lead to better health. A previously proposed three-tiered categorisation of 'hot spots', 'cold spots' and 'worried well' animal health trajectories provides a mental model that, by taking into consideration the different animal health status, animal health risks, service response needs and key drivers in each system, can help identify and implement interventions. Combining sustainability concepts with animal health trajectories allows for a richer analysis, and we apply this to three case studies drawn from North Africa and the Middle East; Bangladesh; and the Eastern Cape of South Africa. We conclude that the quest for sustainability of livestock production systems from the perspective of human and animal health is elusive and difficult to reconcile with the massive anticipated growth in demand for livestock products, mainly in low- and middle-income countries, as well as the aspirations of poor livestock keepers for better lives. Nevertheless, improving the health of livestock can contribute to health sustainability both through reducing negative health impacts of livestock and increasing efficiency of production. However, the choice of the most appropriate options must be under-pinned by an understanding of agro-ecology, economy and values. We argue that a new pillar of One Health should be added to the three traditional sustainability pillars of economics, society and environment when addressing livestock systems.

Saturated fatty acids, such as palmitate, are elevated in metabolically dysfunctional conditions like type 2 diabetes mellitus. Palmitate has been shown to impair insulin sensitivity and suppress protein synthesis while upregulating proteolytic systems in skeletal muscle. Increased sarco/endoplasmic reticulum (ER) stress and subsequent activation of the unfolded protein response may contribute to the palmitate-induced impairment of muscle protein synthesis. In some cell types, ER stress occurs through activation of the Toll-like receptor 4 (TLR4). Given the link between ER stress and suppression of protein synthesis, we investigated whether palmitate induces markers of ER stress and protein synthesis by activating TLR4 in cultured mouse C2C12 myotubes. Myotubes were treated with vehicle, a TLR4-specific ligand (lipopolysaccharides), palmitate, or a combination of palmitate plus a TLR4-specific inhibitor (TAK-242). Inflammatory indicators of TLR4 activation (IL-6 and TNFα) and markers of ER stress were measured, and protein synthesis was assessed using puromycin incorporation. Palmitate substantially increased the levels of IL-6, TNF-α, CHOP, XBP1s, and ATF 4 mRNAs and augmented the levels of CHOP, XBP1s, phospho-PERK and phospho-eIF2α proteins. The TLR4 antagonist attenuated both acute palmitate and LPS-induced increases in IL-6 and TNFα, but did not reduce ER stress signaling with either 6 h or 24 h palmitate treatment. Similarly, treating myotubes with palmitate for 6 h caused a 43% decline in protein synthesis consistent with an increase in phospho-eIF2α, and the TLR4 antagonist did not alter these responses. These results suggest that palmitate does not induce ER stress through TLR4 in muscle, and that palmitate impairs protein synthesis in skeletal muscle in part by induction of ER stress.

Lipid accumulation in skeletal muscle results in dysregulation of protein metabolism and muscle atrophy. We previously reported that treating C2C12 myotubes with palmitate (PA), a saturated fatty acid, increases the overall rate of proteolysis via activation of the ubiquitin-proteasome and autophagy systems; co-treatment with the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) prevents the PA-induced responses. Others have reported that PA induces endoplasmic reticulum (ER) stress which initiates the unfolded protein response (UPR), a collective group of responses that can lead to activation of caspase-mediated proteolysis and autophagy. Presently, we tested the hypothesis that DHA protects against PA-induced ER stress/UPR and its atrophy-related responses in muscle cells. C2C12 myotubes were treated with 500  μ mol/L PA and/or 100  μ mol/L DHA for 24 h. Proteins and mRNA associated with ER stress/UPR, autophagy, and caspase-3 activation were evaluated. PA robustly increased the phosphorylation of protein kinase R (PKR)-like ER kinase (PERK) and eukaryotic initiation factor 2 α (eIF2 α ). It also increased the mRNAs encoding activating transcription factor 4 (ATF4), spliced X-box binding protein 1 (XBP1s), C/EBP homologous protein (CHOP), and autophagy-related 5 (Atg5) as well as the protein levels of the PERK target nuclear factor erythroid 2-related factor (Nrf2), CHOP, and cleaved (i.e., activated) caspase-3. Co-treatment with DHA prevented all of the PA-induced responses. Our results indicate that DHA prevents PA-induced muscle cell atrophy, in part, by preventing ER stress/UPR, a process that leads to activation of caspase-mediated proteolysis and an increase in expression of autophagy-related genes., (Published 2017. This article is a U.S. Government work and is in the public domain in the USA. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Young adults typically adapt to intense exercise training with an increased skeletal muscle Na + ,K + -ATPase (NKA) content, concomitant with reduced extracellular potassium concentration [K + ] during exercise and enhanced exercise performance. Whether these changes with longitudinal training occur in older adults is unknown and was investigated here. Fifteen older adults (69.4 ± 3.5 years, mean ± SD) were randomized to either 12 weeks of intense interval training (4 × 4 min at 90-95% peak heart rate), 3 days/week (IIT, n  = 8); or no exercise controls ( n  = 7). Before and after training, participants completed an incremental cycle ergometer exercise test until a rating of perceived exertion of 17 (very hard) on a 20-point scale was attained, with measures of antecubital venous [K + ] v Participants underwent a resting muscle biopsy prior to and at 48-72 h following the final training session. After IIT, the peak exercise work rate (25%), oxygen uptake (16%) and heart rate (6%) were increased ( P  < 0.05). After IIT, the peak exercise plasma [K + ] v tended to rise ( P  = 0.07), while the rise in plasma [K + ] v relative to work performed (nmol.L -1 J -1 ) was unchanged. Muscle NKA content increased by 11% after IIT ( P  < 0.05). Single fiber measurements, increased in NKA α 2 isoform in Type II fibers after IIT (30%, P  < 0.05), with no changes to the other isoforms in single fibers or homogenate. Thus, intense exercise training in older adults induced an upregulation of muscle NKA, with a fiber-specific increase in NKA α 2 abundance in Type II fibers, coincident with increased muscle NKA content and enhanced exercise performance., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Purpose: Salbutamol inhalation is permissible by WADA in athletic competition for asthma management and affects potassium regulation, which is vital for muscle function. Salbutamol effects on arterial potassium concentration ([K + ] a ) during and after high-intensity continuous exercise (HI cont ) and intermittent exercise comprising repeated, brief sprints (HI int ), and on performance during HI int are unknown and were investigated., Methods: Seven recreationally active men participated in a double-blind, randomised, cross-over design, inhaling 1000 µg salbutamol or placebo. Participants cycled continuously for 5 min at 40 % [Formula: see text]O 2peak and 60 % [Formula: see text]O 2peak , then HI cont (90 s at 130 % [Formula: see text]O 2peak ), 20 min recovery, and then HI int (3 sets, 5 × 4 s sprints), with 30 min recovery., Results: Plasma [K + ] a increased throughout exercise and subsequently declined below baseline (P < 0.001). Plasma [K + ] a was greater during HI cont than HI int (P < 0.001, HI cont 5.94 ± 0.65 vs HI int set 1, 4.71 ± 0.40 mM); the change in [K + ] a from baseline (Δ[K + ] a ) was 2.6-fold greater during HI cont than HI int (P < 0.001). The Δ[K + ] throughout the trial was less with salbutamol than placebo (P < 0.001, treatment main effect, 0.03 ± 0.67 vs 0.22 ± 0.69 mM, respectively); and remained less after correction for fluid shifts (P < 0.001). The Δ[K + ] during HI cont was less after salbutamol (P < 0.05), but not during HI int . Blood lactate, plasma pH, and the work output during HI int did not differ between trials., Conclusions: Inhaled salbutamol modulated the [K + ] a rise across the trial, comprising intense continuous and intermittent exercise and recovery, lowering Δ[K + ] during HI cont . The limited [K + ] a changes during HI int suggest that salbutamol is unlikely to influence systemic [K + ] during periods of intense effort in intermittent sports.

Physical training increases skeletal muscle Na + ,K + -ATPase content (NKA) and improves exercise performance, but the effects of inactivity per se on NKA content and isoform abundance in human muscle are unknown. We investigated the effects of 23-day unilateral lower limb suspension (ULLS) and subsequent 4-wk resistance training (RT) on muscle function and NKA in 6 healthy adults, measuring quadriceps muscle peak torque; fatigue and venous [K + ] during intense one-legged cycling exercise; and skeletal muscle NKA content ([ 3 H]ouabain binding) and NKA isoform abundances (immunoblotting) in muscle homogenates (α 1-3 , β 1-2 ) and in single fibers (α 1-3 , β 1 ). In the unloaded leg after ULLS, quadriceps peak torque and cycling time to fatigue declined by 22 and 23%, respectively, which were restored with RT. Whole muscle NKA content and homogenate NKA α 1-3 and β 1-2 isoform abundances were unchanged with ULLS or RT. However, in single muscle fibers, NKA α 3 in type I (-66%, P = 0.006) and β 1 in type II fibers (-40%, P = 0.016) decreased after ULLS, with other NKA isoforms unchanged. After RT, NKA α 1 (79%, P = 0.004) and β 1 (35%, P = 0.01) increased in type II fibers, while α 2 (76%, P = 0.028) and α 3 (142%, P = 0.004) increased in type I fibers compared with post-ULLS. Despite considerably impaired muscle function and earlier fatigue onset, muscle NKA content and homogenate α 1 and α 2 abundances were unchanged, thus being resilient to inactivity induced by ULLS. Nonetheless, fiber type-specific downregulation with inactivity and upregulation with RT of several NKA isoforms indicate complex regulation of muscle NKA expression in humans., (Copyright © 2016 the American Physiological Society.)

Research on early intervention for young children (infants and toddlers) with fetal alcohol spectrum disorders (FASD), particularly children with comorbid maltreatment experiences, is limited. Existing research has primarily focused on structuring environments to be responsive to the needs experienced by children with FASD rather than improving their functioning. The purpose of this study is to present outcomes from an early psychosocial intervention with 10 adopted, maltreated young children diagnosed with FASD, aged 10-53 months (M = 35 months), and their adoptive parents. The potential for early, targeted interventions to improve developmental outcomes for children with prenatal alcohol exposure was examined, as well as improving the skills of and reducing stress experienced by their adoptive parents. Based on the outcomes of a neurodevelopmentally informed assessment protocol, the 10 children whose data are presented were recommended to receive a range of regulatory, somatosensory, relational, and cognitive enrichments. As part of their treatment, children and caregivers received Child-Parent Psychotherapy (CPP), and caregivers (here, adoptive parents) also received Mindful Parenting Education (MPE). Related-samples Wilcoxon signed-rank tests indicated that scores of several measures of child developmental functioning improved from pre- to post-intervention and that parents' caregiving skills improved while their caregiving stress decreased. Reliable change analyses indicated that change observed from pre- to post-intervention was reliable. The promise of using neurodevelopmentally informed assessment strategies to sequence interventions for young children with diverse neurodevelopmental insults is discussed., (© The Author(s) 2016.)

Inactivity negatively impacts on skeletal muscle function mainly through muscle atrophy. However, recent evidence suggests that the quality of individual muscle fibers is also altered. This study examined the effects of 23 days of unilateral lower limb suspension (ULLS) on specific force and sarcoplasmic reticulum (SR) Ca(2+) content in individual skinned muscle fibers. Muscle biopsies of the vastus lateralis were taken from six young healthy adults prior to and following ULLS. After disuse, the endogenous SR Ca(2+) content was ∼8% lower in type I fibers and maximal SR Ca(2+) capacity was lower in both type I and type II fibers (-11 and -5%, respectively). The specific force, measured in single skinned fibers from three subjects, decreased significantly after ULLS in type II fibers (-23%) but not in type I fibers (-9%). Western blot analyses showed no significant change in the amounts of myosin heavy chain (MHC) I and MHC IIa following the disuse, whereas the amounts of sarco(endo)plasmic reticulum Ca(2+)-ATPase 1 (SERCA1) and calsequestrin increased by ∼120 and ∼20%, respectively, and the amount of troponin I decreased by ∼21%. These findings suggest that the decline in force and power occurring with muscle disuse is likely to be exacerbated in part by reductions in maximum specific force in type II fibers, and in the amount of releasable SR Ca(2+) in both fiber types, the latter not being attributable to a reduced calsequestrin level. Furthermore, the ∼3-wk disuse in human elicits change in SR properties, in particular a more than twofold upregulation in SERCA1 density, before any fiber-type shift., (Copyright © 2016 the American Physiological Society.)

There is an increasing interest in determining the impact of vaccine technologies developed using public funding targeted at international development, and understanding the factors and ingredients which contribute to the success and impacts of such vaccines. This paper chronicles the development of a live vaccine against East Coast fever, a tick-borne disease of cattle caused by Theileria parva . The paper describes the technological innovation, commonly known as infection-and-treatment, which was developed some 40 years ago, explores the institutional settings in which the vaccine was developed and refined, and discusses the political dynamics of both during the decades from first development to field deployment and impacts. The paper also analyses the direct and indirect indicators of success of ITM and the many qualifiers of these, the impacts that the emerging technology has had, both in positive and negative terms, and maps the key contributors and milestones on the research-to-impact pathway.

Muscle atrophy is caused by an imbalance in contractile protein synthesis and degradation which can be triggered by various conditions including Type 2 Diabetes Mellitus (T2DM). Reduced muscle quality in patients with T2DM adversely affects muscle function, the capacity to perform activities of daily living, quality of life and ultimately may increase the risk of premature mortality. Systemic inflammation initiated by obesity and prolonged overnutrition not only contributes to insulin resistance typical of T2DM, but also promotes muscle atrophy via decreased muscle protein synthesis and increased ubiquitin-proteasome, lysosomal-proteasome and caspase 3- mediated protein degradation. Emerging evidence suggests that the inflammation-sensitive Nuclear Factor κ B (NF-κB) and Signal Transducer and Activator of Transcription 3 (STAT3) pathways may contribute to muscle atrophy in T2DM. In contrast, exercise appears to be an effective tool in promoting muscle hypertrophy, in part due to its effect on systemic and local (skeletal muscle) inflammation. The current review discusses the role inflammation plays in muscle atrophy in T2DM and the role of exercise training in minimising the effect of inflammatory markers on skeletal muscle. We also report original data from a cohort of obese patients with T2DM compared to age-matched controls and demonstrate that patients with T2DM have 60% higher skeletal muscle expression of the atrophy transcription factor FoxO1. This review concludes that inflammatory pathways in muscle, in particular, NF-κB, potentially contribute to T2DM-mediated muscle atrophy. Further in-vivo and longitudinal human research is required to better understand the role of inflammation in T2DM-mediated atrophy and the anti-inflammatory effect of exercise training under these conditions., (Copyright © 2015 International Society of Exercise and Immunology. All rights reserved.)

Many societies are spoiled for choice when they purchase meat and other livestock products, and around the globe food choice has grown dramatically in the last two decades. What is more, besides the cost and obvious health concerns influencing commodity section, an increasing proportion of choices is made to contribute to the achievement of certain ideals, such as natural resource management, climate change mitigation, animal welfare concerns and personal lifestyle. At the same time, human health considerations are becoming more important for consumption choices as richer societies, and increasingly the urban poor in low- and middle-income countries, face an unprecedented epidemic of over-consumption and associated diet-related non-communicable diseases. Animal source foods are considered significant contributors to this trend. This paper reviews this complicated arena, and explores the range of considerations that influence consumers' preferences for meat and other animal source foods. This paper also argues that deeper drivers of consumption behaviour of many foods may act in opposition to the articulated preferences for choices around animal source food consumption. We review how the returns to different causes are being valued, how emerging metrics are helping to manage and influence consumption behaviours, and draw conclusions regarding options which influence food choice.

-Reactive oxygen species (ROS) produced in skeletal muscle may play a role in potentiating the beneficial responses to exercise; however, the effects of exercise-induced ROS on insulin action and protein signaling in humans has not been fully elucidated. Seven healthy, recreationally active participants volunteered for this double-blind, randomized, repeated-measures crossover study. Exercise was undertaken with infusion of saline (CON) or the antioxidant N-acetylcysteine (NAC) to attenuate ROS. Participants performed two 1-h cycling exercise sessions 7-14 days apart, 55 min at 65% V̇o2peak plus 5 min at 85%V̇o2peak, followed 3 h later by a 2-h hyperinsulinemic euglycemic clamp (40 mIU·min(-1)·m(2)) to determine insulin sensitivity. Four muscle biopsies were taken on each trial day, at baseline before NAC infusion (BASE), after exercise (EX), after 3-h recovery (REC), and post-insulin clamp (PI). Exercise, ROS, and insulin action on protein phosphorylation were evaluated with immunoblotting. NAC tended to decrease postexercise markers of the ROS/protein carbonylation ratio by -13.5% (P = 0.08) and increase the GSH/GSSG ratio twofold vs. CON (P < 0.05). Insulin sensitivity was reduced (-5.9%, P < 0.05) by NAC compared with CON without decreased phosphorylation of Akt or AS160. Whereas p-mTOR was not significantly decreased by NAC after EX or REC, phosphorylation of the downstream protein synthesis target kinase p70S6K was blunted by 48% at PI with NAC compared with CON (P < 0.05). We conclude that NAC infusion attenuated muscle ROS and postexercise insulin sensitivity independent of Akt signaling. ROS also played a role in normal p70S6K phosphorylation in response to insulin stimulation in human skeletal muscle., (Copyright © 2015 the American Physiological Society.)

While training upregulates skeletal muscle Na(+), K(+)-ATPase (NKA), the effects of knee injury and associated disuse on muscle NKA remain unknown. This was therefore investigated in six healthy young adults with a torn anterior cruciate ligament, (KI; four females, two males; age 25.0 ± 4.9 years; injury duration 15 ± 17 weeks; mean ± SD) and seven age- and BMI-matched asymptomatic controls (CON; five females, two males). Each participant underwent a vastus lateralis muscle biopsy, on both legs in KI and one leg in CON. Muscle was analyzed for muscle fiber type and cross-sectional area (CSA), NKA content ([(3)H]ouabain binding), and α1-3 and β1-2 isoform abundance. Participants also completed physical activity and knee function questionnaires (KI only); and underwent quadriceps peak isometric strength, thigh CSA and postural sway assessments in both injured and noninjured legs. NKA content was 20.1% lower in the knee-injured leg than the noninjured leg and 22.5% lower than CON. NKA α2 abundance was 63.0% lower in the knee-injured leg than the noninjured leg, with no differences in other NKA isoforms. Isometric strength and thigh CSA were 21.7% and 7.1% lower in the injured leg than the noninjured leg, respectively. In KI, postural sway did not differ between legs, but for two-legged standing was 43% higher than CON. Hence, muscle NKA content and α2 abundance were reduced in severe knee injury, which may contribute to impaired muscle function. Restoration of muscle NKA may be important in rehabilitation of muscle function after knee and other lower limb injury., (© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

We quantified the between-village transmission rate, β (the rate of transmission of H5N1 HPAI virus per effective contact), and the reproductive number, Re (the average number of outbreaks caused by one infectious village during its entire infectious period), of H5N1 highly pathogenic avian influenza (HPAI) virus in Nigeria using outbreak data collected between December 2005 and July 2008. We classified the outbreaks into two phases to assess the effectiveness of the control measures implemented. Phase 1 (December 2005-October 2006) represents the period when the Federal Government of Nigeria managed the HPAI surveillance and response measures, while Phase 2 (November 2006-July 2008) represents the time during which the Nigeria Avian Influenza Control and Human Pandemic Preparedness project (NAICP), funded by a World Bank credit of US$ 50 million, had taken over the management of most of the interventions. We used a total of 204 outbreaks from 176 villages that occurred in 78 local government areas of 25 states. The compartmental susceptible-infectious model was used as the analytical tool. Means and 95% percentile confidence intervals were obtained using bootstrapping techniques. The overall mean β (assuming a duration of infectiousness, T, of 12 days) was 0.07/day (95% percentile confidence interval: 0.06-0.09). The first and second phases of the epidemic had comparable β estimates of 0.06/day (0.04-0.09) and 0.08/day (0.06-0.10), respectively. The Re of the virus associated with these β and T estimates was 0.9 (0.7-1.1); the first and second phases of the epidemic had Re of 0.84 (0.5-1.2) and 0.9 (0.6-1.2), respectively. We conclude that the intervention measures implemented in the second phase of the epidemic had comparable effects to those implemented during the first phase and that the Re of the epidemic was low, indicating that the Nigeria H5N1 HPAI epidemic was unstable., (© 2012 Blackwell Verlag GmbH.)

We review the global dynamics of livestock disease over the last two decades. Our imperfect ability to detect and report disease hinders assessment of trends, but we suggest that, although endemic diseases continue their historic decline in wealthy countries, poor countries experience static or deteriorating animal health and epidemic diseases show both regression and expansion. At a mesolevel, disease is changing in terms of space and host, which is illustrated by bluetongue, Lyme disease, and West Nile virus, and it is also emerging, as illustrated by highly pathogenic avian influenza and others. Major proximate drivers of change in disease dynamics include ecosystem change, ecosystem incursion, and movements of people and animals; underlying these are demographic change and an increasing demand for livestock products. We identify three trajectories of global disease dynamics: (i) the worried well in developed countries (demanding less risk while broadening the circle of moral concern), (ii) the intensifying and market-orientated systems of many developing countries, where highly complex disease patterns create hot spots for disease shifts, and (iii) the neglected cold spots in poor countries, where rapid change in disease dynamics is less likely but smallholders and pastoralists continue to struggle with largely preventable and curable livestock diseases.

Knee osteoarthritis (OA) is a debilitating disorder prevalent in older populations that is accompanied by declines in muscle mass, strength, and physical activity. In skeletal muscle, the Na(+)-K(+) pump (NKA) is pivotal in ion homeostasis and excitability and is modulated by disuse and exercise training. This study examined the effects of OA and aging on muscle NKA in 36 older adults (range 55-81 yr), including 19 with OA (69.9 ± 6.5 yr, mean ± SD) and 17 asymptomatic controls (CON, 66.8 ± 6.4 yr). Participants completed knee extensor strength testing and a physical activity questionnaire. A vastus lateralis muscle biopsy was analyzed for NKA content ([(3)H]ouabain binding sites), α1-3- and β1-3-isoform protein abundance (immunoblotting), and mRNA (real-time RT-PCR). The association between age and NKA content was investigated within the OA and CON groups and in pooled data. The NKA content was also contrasted between subgroups below and above the median age of 68.5 yr. OA had lower strength (-40.8%, P = 0.005), but higher NKA α2- (∼34%, P = 0.006) and α3-protein (100%, P = 0.016) abundance than CON and performed more incidental physical activity (P = 0.035). No differences were found between groups for NKA content, abundance of other NKA isoforms, or gene expression. There was a negative correlation between age and NKA content within OA (r = -0.63, P = 0.03) and with both groups combined (r = -0.47, P = 0.038). The NKA content was 25.5% lower in the older (69-81 yr) than in the younger (55-68 yr) subgroup. Hence older age, but not knee OA, was related to lowered muscle NKA content in older adults.

Aging is associated with reduced muscle mass, weakness, and increased fatigability. In skeletal muscle, the Na(+)-K(+) pump (NKA) is important in regulating Na(+)-K(+) gradients, membrane excitability, and thus contractility, but the effects of aging on muscle NKA are unclear. We investigated whether aging is linked with reduced muscle NKA by contrasting muscle NKA isoform gene expression and protein abundance, and NKA total content in 17 Elderly (66.8 ± 6.4 yr, mean ± SD) and 16 Young adults (23.9 ± 2.2 yr). Participants underwent peak oxygen consumption assessment and a vastus lateralis muscle biopsy, which was analyzed for NKA α(1)-, α(2)-, α(3)-, β(1)-, β(2)-, and β(3)-isoform gene expression (real-time RT-PCR), protein abundance (immunoblotting), and NKA total content ([(3)H]ouabain binding sites). The Elderly had lower peak oxygen consumption (-36.7%, P = 0.000), strength (-36.3%, P = 0.001), NKA α(2)- (-24.4%, 11.9 ± 4.4 vs. 9.0 ± 2.7 arbitrary units, P = 0.049), and NKA β(3)-protein abundance (-23.0%, P = 0.041) than Young. The β(3)-mRNA was higher in Elderly compared with Young (P = 0.011). No differences were observed between groups for other NKA isoform mRNA or protein abundance, or for [(3)H]ouabain binding site content. Thus skeletal muscle in elderly individuals was characterized by decreased NKA α(2)- and β(3)-protein abundance, but unchanged α(1) abundance and [(3)H]ouabain binding. The latter was likely caused by reduced α(2) abundance with aging, preventing an otherwise higher [(3)H]ouabain binding that might occur with a greater membrane density in smaller muscle fibers. Further study is required to verify reduced muscle NKA α(2) with aging and possible contributions to impaired exercise capability and daily living activities.

Animal disease outbreaks pose significant threats to livestock sectors throughout the world, both from the standpoint of the economic impacts of the disease itself and the measures taken to mitigate the risk of disease introduction. These impacts are multidimensional and not always well understood, complicating effective policy response. In the developing world, livestock diseases have broader, more nuanced effects on markets, poverty, and livelihoods, given the diversity of uses of livestock and complexity of livestock value chains. In both settings, disease control strategies, particularly those informed by ex ante modeling platforms, often fail to recognize the constraints inherent among farmers, veterinary services, and other value chain actors. In short, context matters. Correspondingly, an important gap in the animal health economics literature is the explicit incorporation of behavior and incentives in impact analyses that highlight the interactions of disease with its socio-economic and institutional setting. In this paper, we examine new approaches and frameworks for the analysis of economic and poverty impacts of animal diseases. We propose greater utilization of "bottom-up" analyses, highlighting the strengths and weaknesses of value chain and information economics approaches in impact analyses and stressing the importance of improved integration between the epidemiology of disease and its relationships with economic behavior., (Copyright © 2010 Elsevier B.V. All rights reserved.)

There is a critical need for safer and more convenient treatments for organ transplant rejection and autoimmune disorders such as rheumatoid arthritis. Janus tyrosine kinases (JAK1, JAK3) are expressed in lymphoid cells and are involved in the signaling of multiple cytokines important for various T cell functions. Blockade of the JAK1/JAK3-STAT pathway with a small molecule was anticipated to provide therapeutic immunosuppression/immunomodulation. The Pfizer compound library was screened against the catalytic domain of JAK3 resulting in the identification of a pyrrolopyrimidine-based series of inhibitors represented by CP-352,664 (2a). Synthetic analogues of 2a were screened against the JAK enzymes and evaluated in an IL-2 induced T cell blast proliferation assay. Select compounds were evaluated in rodent efficacy models of allograft rejection and destructive inflammatory arthritis. Optimization within this chemical series led to identification of CP-690,550 1, a potential first-in-class JAK inhibitor for treatment of autoimmune diseases and organ transplant rejection.

Objective: The CCR2 receptor plays a crucial role in monocyte recruitment and has been implicated as a contributing factor to atherosclerosis. CCR2 receptor deletion leads to significant inhibition of lesion development. Our objective was to determine if CCR2 receptor blockade with a small molecule would have a beneficial effect of decreasing established lesions., Methods and Results: We demonstrated that CCR2 blockade had no significant effect on advanced lesions or the progression of fatty streaks. CCR2 blockade in mice resulted in elevations in plasma CCL2 levels and a significant reduction in the plasma Ly-6C(hi) subpopulations of monocytes expressing the CCR2 receptor. Neither CCL2 elevation nor margination of the Ly-6C(hi) population was observed in CCR2(-/-) mice., Conclusions: CCR2 receptor blockade with a small molecule antagonist at dose levels showing efficacy in several inflammatory models did not show a beneficial effect in murine models of atherosclerosis. Elevations in CCL2 and margination of Ly-6C(hi) cells demonstrate that the role of CCR2 in controlling monocyte levels goes beyond the control of monocyte emigration., (Copyright 2009. Published by Elsevier Ireland Ltd.)

Foot-and-mouth disease (FMD) remains one of the most important livestock diseases of the world, given its highly infectious nature, its broad economic impacts on animal wellbeing and productivity, and its implications for successful access to domestic and export markets for livestock and products. The impacts of the disease vary markedly between developed and developing countries, and also within many developing countries. These differences in impact shape some markedly heterogeneous incentives for FMD control and eradication, which become of particular importance when setting priorities for poverty reduction in developing countries. Some consider that the benefits from FMD control accrue only to the better off in such societies and, as such, may not be a priority for investments targeted at poverty reduction. But is that view justified? Others see the control of FMD as a major development opportunity in a globalised environment. In this paper, Brian Perry and Karl Rich summarise the differential impacts of FMD and its control, and link these findings with the growing understanding of how the control of this globally important disease may contribute to the processes of pro-poor growth in certain countries of the developing world.

The current system for the certification of internationally traded animal commodities can act as a barrier to developing countries accessing high-value international markets. In this Viewpoint article, Gavin Thomson and colleagues discuss the situation as it stands and identify inconsistencies with respect to the certification process. They suggest ways to address the lack of capacity for credible certification in some developing countries that will encourage market access for livestock commodities. They emphasise the role of mechanisms other than demonstrating that an area of production is free from a range of animal diseases, arguing that this could be of significant benefit to developing regions and countries, but that a reliable and independent system of certification based on international standards is essential.

Background: Childhood maltreatment has been linked to a variety of changes in brain structure and function and stress-responsive neurobiological systems. Epidemiological studies have documented the impact of childhood maltreatment on health and emotional well-being., Methods: After a brief review of the neurobiology of childhood trauma, we use the Adverse Childhood Experiences (ACE) Study as an epidemiological "case example" of the convergence between epidemiologic and neurobiological evidence of the effects of childhood trauma. The ACE Study included 17,337 adult HMO members and assessed 8 adverse childhood experiences (ACEs) including abuse, witnessing domestic violence, and serious household dysfunction. We used the number of ACEs (ACE score) as a measure of cumulative childhood stress and hypothesized a "dose-response" relationship of the ACE score to 18 selected outcomes and to the total number of these outcomes (comorbidity)., Results: Based upon logistic regression analysis, the risk of every outcome in the affective, somatic, substance abuse, memory, sexual,and aggression-related domains increased in a graded fashion as the ACE score increased (P <0.001). The mean number of comorbid outcomes tripled across the range of the ACE score., Conclusions: The graded relationship of the ACE score to 18 different outcomes in multiple domains theoretically parallels the cumulative exposure of the developing brain to the stress response with resulting impairment in multiple brain structures and functions.

This paper discusses the role of integrated epidemiology and economics modelling in animal health planning, with particular reference to the evaluation of national level interventions that involve the vaccination of livestock. Well-integrated epidemiology and economics is considered essential if model outputs are to be of value in national animal disease control planning. The different approaches to the use of modelling in priority setting and resource allocation in animal health are reviewed and discussed. The authors conclude that this particular application of modelling is poorly developed, due in part to the complexities involved. Much more has been done to develop models that evaluate the merits of different intervention scenarios for a given single disease, and examples of these are presented. However, the authors conclude that despite the widespread use of such models, there is still considerable scope for the development of a more standardised approach, incorporating consideration of both direct and indirect implications of intervention options. In discussing the changing demands on animal health economics modelling, the authors propose that increased attention should be given to the valuation of "externalities", the calculation and interpretation of the distribution of costs and benefits, the evaluation of the impact of disease control on poverty reduction, and the development of real-time economics modelling techniques, to assist particularly in the effective management of disease outbreaks.

Because of its requirement for signaling by multiple cytokines, Janus kinase 3 (JAK3) is an excellent target for clinical immunosuppression. We report the development of a specific, orally active inhibitor of JAK3, CP-690,550, that significantly prolonged survival in a murine model of heart transplantation and in cynomolgus monkeys receiving kidney transplants. CP-690,550 treatment was not associated with hypertension, hyperlipidemia, or lymphoproliferative disease. On the basis of these preclinical results, we believe JAK3 blockade by CP-690,550 has potential for therapeutically desirable immunosuppression in human organ transplantation and in other clinical settings.