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Objective: Single nucleotide polymorphisms (SNPs) in intron 1 of fat mass- and obesity-associated gene (FTO) are strongly associated with human adiposity, whereas Fto(-/-) mice are lean and Fto(+/-) mice are resistant to diet-induced obesity. We aimed to determine whether FTO mutations are disproportionately represented in lean or obese humans and to use these mutations to understand structure-function relationships within FTO.Research Design and Methods: We sequenced all coding exons of FTO in 1,433 severely obese and 1,433 lean individuals. We studied the enzymatic activity of selected nonsynonymous variants.Results: We identified 33 heterozygous nonsynonymous variants in lean (2.3%) and 35 in obese (2.4%) individuals, with 8 mutations unique to the obese and 11 unique to the lean. Two novel mutations replace absolutely conserved residues: R322Q in the catalytic domain and R96H in the predicted substrate recognition lid. R322Q was unable to catalyze the conversion of 2-oxoglutarate to succinate in the presence or absence of 3-methylthymidine. R96H retained some basal activity, which was not enhanced by 3-methylthymidine. However, both were found in lean and obese individuals.Conclusions: Heterozygous, loss-of-function mutations in FTO exist but are found in both lean and obese subjects. Although intron 1 SNPs are unequivocally associated with obesity in multiple populations and murine studies strongly suggest that FTO has a role in energy balance, it appears that loss of one functional copy of FTO in humans is compatible with being either lean or obese. Functional analyses of FTO mutations have given novel insights into structure-function relationships in this enzyme. [ABSTRACT FROM AUTHOR]

The experience of 6 college-age women with bulimia nervosa was examined after they participated in an 8-week mindfulness-based eating disorder treatment group. This phenomenological study used individual interview and pre- and post-treatment self-portraits. Participants described their experience of transformation from emotional and behavioral extremes, disembodiment, and self-loathing to the cultivation of an inner connection with themselves resulting in greater self-awareness, acceptance, and compassion. They reported less emotional distress and improved abilities to manage stress. This treatment may help the 40% of women who do not improve with current therapies and might be useful to prevent symptoms in younger women. [ABSTRACT FROM AUTHOR]

BACKGROUND: Alcohol is a caloric compound that can contribute to energy intake. Therefore, peptides that regulate energy balance likely modify the motivation to consume alcohol. Melanin-concentrating hormone (MCH) regulates energy homeostasis and has been implicated in other behaviors that impact alcohol consumption (i.e., anxiety, fluid balance, and reward). We tested the hypothesis that MCH would decrease the motivation to consume alcohol secondarily to reducing anxiety. METHODS: Rats were trained to drink 10% ethanol or an isocaloric concentration of sucrose with use of a sucrose-fading technique. MCH (1, 5, or 10 microg) or its saline vehicle was administered into the third cerebral ventricle (i3vt), and intake of ethanol or sucrose and chow was assessed for 2 hr. Alcohol-naïve rats were evaluated in an elevated plus maze after i3vt MCH (10 microg), neuropeptide Y, or saline administration. RESULTS: Contrary to the hypothesis, MCH dose-dependently increased alcohol intake: saline = 0.7 +/- 0.1 g/kg, 1 microg MCH = 1.0 +/- 0.1 g/kg, 5 microg MCH = 1.2 +/- 0.1 g/kg, and 10 microg MCH = 1.8 +/- 0.3 g/kg (p < 0.01), and this was true whether water was simultaneously available or not. MCH also significantly increased sucrose intake (saline = 1.0 +/- 0.3 g/kg, 10 mug MCH = 1.4 +/- 0.5 g/kg; p < 0.05). MCH had no effect on time spent in the open arms (54.3 +/- 11.5 sec) relative to saline (58.2 +/- 23.8 sec), whereas neuropeptide Y, a known anxiolytic, increased time spent on the open arms (119.2 +/- 22 sec, p < 0.05). CONCLUSIONS: We conclude that MCH nonspecifically increases ingestive behavior. Furthermore, MCH had no apparent effect on anxiety. The ability of MCH to increase alcohol and/or sucrose intake may be explained by the effect of MCH on energy balance and/or reward processes. [ABSTRACT FROM AUTHOR]

BACKGROUND: Human dignity is an essential value of professional nursing education as well as a component of the American Nurses Association Code of Ethics. Nurses are exhorted to treat patients with dignity, and older adults want to be treated with dignity and die with dignity. Although dignity, particularly the dignity of older adults, is often discussed in the health care literature, its meaning is not always clear. AIM: The aim of this paper is to describe a concept analysis to develop a definition of dignity in older adults. METHODS: Data were collected using a literature review and five focus groups composed of older adults. The literature provided data about professionals' ideas of dignity and the focus groups provided qualitative data about the nature of dignity in older people. The literature review and focus groups were carried out concurrently, followed by synthesis of the findings. FINDINGS: Dignity is an inherent characteristic of being human, it can be subjectively felt as an attribute of the self, and is made manifest through behaviour that demonstrates respect for self and others. Dignity must be learned, and an individual's dignity is affected by the treatment received from others. CONCLUSIONS: A behavioural definition of dignity was constructed and this could provide the theoretical basis for nurses to develop interventions that foster dignity for older people. [ABSTRACT FROM AUTHOR]

Optimal early development in most species is dependent upon a stable relationship between the mother and her infant. The research described here focuses on the reciprocal nature of this dyad in rodents and humans, with respect to the regulation of responsiveness to stress in both mother and offspring. Dietary influences are critical not only to regulate infant growth but also to modulate the response of the neuroendocrine system to stress and, possibly, to influence some aspects of brain development. In particular, we discuss the role of leptin, a protein produced in the adipose tissue and present in maternal milk, that reduces responses to stress in the infant. We suggest that leptin acts on both central (hypothalamus and hippocampus) and peripheral (pituitary, adrenal gland) targets in the infant to reduce exposure to glucocorticoids and enhance hippocampal development during a sensitive period of brain development. There is also evidence to support the reverse regulatory influence, in which maternal state is profoundly affected by stimulation from the young. During the period of lactation, mothers exhibit lower neuroendocrine and behavioural responses to several types of stressors, except possibly those representing a threat to the infant. This ability to 'filter' relevant from irrelevant stimuli while caring for their young might be viewed as adaptive for the mother-infant dyad, and the inability to filter adequately stressful stimuli could at least in part be associated with the development of postpartum depression. [ABSTRACT FROM AUTHOR]

Background: Evidence is needed to understand factors that influence child development and caregiving experiences, especially in marginalized contexts, to inform the development and implementation of early childhood development (ECD) interventions. This study explores caregiving practices for young children in an urban informal settlement with Kenyans and embedded refugees, and identifies factors shaping these caregiving experiences, to inform the design and development of potentially appropriate ECD interventions., Methods: A qualitative formative study, which included 14 focus group discussions (n = 125 participants), and 13 key informant interviews was conducted between August and October 2018. Purposive sampling approaches were used to select a diverse range of respondents including caregivers of children below three years of age and stakeholders of Kenyan nationality and refugees. Data were analysed using a thematic approach and the Nurturing Care Framework was used as an interpretative lens., Results: There was a fusion of traditional, religious and modern practices in the care for young children, influenced by the caregivers' culture, and financial disposition. There were mixed views/practices on nutrition for young children. For example, while there was recognition of the value for breastfeeding, working mothers, especially in the informal economy, found it a difficult practice. Stimulation through play was common, especially for older children, but gaps were identified in aspects such as reading, and storytelling in the home environment. Some barriers identified included the limited availability of a caregiver, insecurity, and confined space in the informal settlement, all of which made it difficult for children to engage in play activities. Physical and psychological forms of discipline were commonly mentioned, although few caregivers practiced and recognized the need for using non-violent approaches. Some overarching challenges for caregivers were unemployment or unstable sources of income, and, particularly for refugee caregivers, their legal status., Conclusion: These findings point to the interplay of various factors affecting optimal caregiving for young children in an urban informal settlement with Kenyans and refugees. Integrated ECD interventions are needed for such a mixed population, especially those that strive to anchor along caregivers' social support system, co-designed together with community stakeholders, that ideally focus on parent skills training promoting nurturing care and economic empowerment., (© 2024. The Author(s).)

Background: Worldwide, the climate is changing and affecting the health and well-being of children in many ways. In this review, we provided an overview of how climate change-related events may affect child and adolescent health and well-being, including children's mental and physical health, nutrition, safety and security, learning opportunities, and family caregiving and connectedness., Methods: In this narrative review, we highlighted and discussed peer-reviewed evidence from 2012-23, primarily from meta-analyses and systematic reviews. The search strategy used a large and varied number of search terms across three academic databases to identify relevant literature., Results: There was consistent evidence across systematic reviews of impact on four themes. Climate-related events are associated with a) increases in posttraumatic stress and other mental health disorders in children and adolescents, b) increases in asthma, respiratory illnesses, diarrheal diseases and vector-borne diseases, c) increases in malnutrition and reduced growth and d) disruptions to responsive caregiving and family functioning, which can be linked to poor caregiver mental health, stress and loss of resources. Evidence of violence against children in climate-related disaster contexts is inconclusive. There is a lack of systematic review evidence on the associations between climate change and children's learning outcomes., Conclusions: Systematic review evidence consistently points to negative associations between climate change and children's physical and mental health, well-being, and family functioning. Yet, much remains unknown about the causal pathways linking climate-change-related events and mental and physical health, responsive relationships and connectedness, nutrition, and learning in children and adolescents. This evidence is urgently needed so that adverse health and other impacts from climate change can be prevented or minimised through well-timed and appropriate action., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests., (Copyright © 2024 by the Journal of Global Health. All rights reserved.)

Study Design: Single-subject repeated measures design., Objectives: To explore the impacts of a novel individualized interdisciplinary pain self-management program for persons living with spinal cord injury pain., Setting: A large rehabilitation institute for adults with physical disabilities in Quebec city (Quebec, Canada)., Methods: Six persons having sustained a spinal cord injury and experiencing chronic pain participated. Following a five-week pre-intervention phase (baseline repeated measures) and a clinical evaluation, individualized intervention objectives were developed in collaboration with each participant. Then, participants completed a ten-week intensive intervention and a six-month consolidation phase. The program included cognitive behavioral therapy, and physical and pharmacological interventions, which were group- and individual-based. Outcome measures were the Canadian Occupational Performance Measure (COPM), the French-Canadian Chronic Pain Self-efficacy Scale (FC-CPSES), the Brief Pain Inventory (BPI), and the Hospital Anxiety and Depression Scale (HADS)., Results: For five out of the six participants, a majority of outcomes improved during either of the intervention phases or both. Improvements in occupational performance were clinically significant for three participants. Pain interference and anxiety improved significantly in five participants, while pain self-efficacy and depressive symptoms improved in four participants., Conclusions: The results suggest that the pain self-management program was effective to reduce the impact of spinal cord injury pain. Further research is needed to replicate these results in a larger study and comprehend the factors favoring or undermining improvements with such programs, as well as their persistence over time., (© 2023. The Author(s), under exclusive licence to International Spinal Cord Society.)

Children in urban informal settlements experience high risks for poor health and development. Understanding health seeking behaviors and childcare patterns of caregivers in urban informal settlements is important for devising effective interventions. This study describes household characteristics and aspects of nurturing care among caregivers of children aged 0-2 years in Dagoretti informal settlement, Nairobi-Kenya. In this cross sectional study, data were collected on household socio-demographic characteristics, antenatal care and child delivery practices, infant and young child feeding practices, activities that promote play, learning and school readiness, and on childcare and protection practices. Descriptive statistics of proportions and means were used to summarize the data. The study covers a total of 458 Kenyan and 118 immigrant households. Caregivers from immigrant households, with low education and from the younger age-group (less than 20 years) were vulnerable to sub-optimal caregiving and health seeking practices, including relatively lower rates of age-appropriate breastfeeding and poor dietary diversity. Seventy-five percent of expectant mothers attended less than four antenatal care visits. Households surveyed had limited possession of children's books (2% with three or more books), limited access to play materials (43% had two or more play materials), and low paternal involvement in child stimulation and early learning activities (14%). One-third and half of the children were left with inadequate care and disciplined using both violent and non-violent methods, respectively. Our findings highlight the urgent need for contextually appropriate and integrated interventions anchored in the WHO's nurturing care framework. These interventions can benefit from extensive involvement of caregivers, facility and community-based healthcare workers, policy makers, and other relevant stakeholders., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2022 Ssewanyana et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: The COVID-19 pandemic has brought significant changes to family life, society and essential health and other services. A rapid review of evidence was conducted to examine emerging evidence on the effects of the pandemic on three components of nurturing care, including responsive caregiving, early learning, and safety and security., Design: Two academic databases, organisational websites and reference lists were searched for original studies published between 1 January and 25 October 2020. A single reviewer completed the study selection and data extraction with verification by a second reviewer., Interventions: We included studies with a complete methodology and reporting on quantitative or qualitative evidence related to nurturing care during the pandemic., Primary and Secondary Outcome Measures: Studies reporting on outcomes related to responsive caregiving, early learning, and safety and security were included., Results: The search yielded 4410 citations in total, and 112 studies from over 30 countries met our eligibility criteria. The early evidence base is weighted towards studies in high-income countries, studies related to caregiver mental health and those using quantitative survey designs. Studies reveal issues of concern related to increases in parent and caregiver stress and mental health difficulties during the pandemic, which was linked to harsher and less warm or responsive parenting in some studies. A relatively large number of studies examined child safety and security and indicate a reduction in maltreatment referrals. Lastly, studies suggest that fathers' engagement in caregiving increased during the early phase of the pandemic, children's outdoor play and physical activity decreased (while screen time increased), and emergency room visits for child injuries decreased., Conclusion: The results highlight key evidence gaps (ie, breastfeeding support and opportunities for early learning) and suggest the need for increased support and evidence-based interventions to ensure young children and other caregivers are supported and protected during the pandemic., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Community engagement is crucial for the design and implementation of community-based early childhood development (ECD) programmes. This paper aims to share key components and learnings of a community engagement process for an integrated ECD intervention. The lessons shared are drawn from a case study of urban informal settlement with embedded refugees in Nairobi, Kenya., Methods: We conducted three stakeholder meetings with representatives from the Ministry of Health at County and Sub-County, actors in the ECD sector, and United Nations agency in refugee management, a transect walk across five villages (Ngando, Muslim, Congo, Riruta and Kivumbini); and, six debrief meetings by staff from the implementing organization. The specific steps and key activities undertaken, the challenges faced and benefits accrued from the community engagement process are highlighted drawing from the implementation team's perspective., Results: Context relevant, well-planned community engagement approaches can be integrated into the five broad components of stakeholder engagement, formative research, identification of local resources, integration into local lives, and shared control/leadership with the local community. These can yield meaningful stakeholder buy-in, community support and trust, which are crucial for enabling ECD programme sustainability., Conclusion: Our experiences underscore that intervention research on ECD programmes in urban informal settlements requires a well-planned and custom-tailored community engagement model that is sensitive to the needs of each sub-group within the community to avoid unintentionally leaving anyone out., (© 2022. The Author(s).)

Objective : A population-level, randomized controlled trial was conducted to test the effectiveness of a parent recruitment package for increasing initial engagement into a school-based parenting program and to identify strategies responsible for effects. Method : Participants were caregivers of kindergarten- to third-grade students ( N = 1,276) attending one of five schools serving ethnically diverse families living in mostly low-income, urban conditions. First, families were randomly assigned to be recruited for research surveys or not, and then to a parenting program recruitment condition: 1) Engagement-as-usual (EAU) informational flyer; 2) EAU + testimonial booklet; 3) EAU + teacher endorsement; 4) EAU + recruitment call; or 5) all strategies (full package). Caregivers were offered a free parenting program at their child's school. Primary dependent variables were parenting program enrollment and attending at least one session (initiation). Exploratory analyses were conducted on program completion, attendance across sessions, homework completion, and in-session participation. Results : In the population-level sample, enrollment and initiation were higher for the full package compared to all other conditions except the recruitment call condition. Enrollment, initiation, and program completion were higher for the recruitment call and full package conditions compared to the EAU condition. In the subsample of initiators, parents in the full package condition attended fewer parenting sessions than in the EAU condition. Controlling for attendance across sessions, there were no condition effects on homework completion or in-session participation. Conclusions : The recruitment call can increase the public health impact of evidence-based parenting programs by improving enrollment, initiation, and program completion.

Purpose: This systematic review aimed to assess the scientific evidence on the effects of waiting for outpatient physiotherapy services in persons with musculoskeletal disorders., Methods: A literature search was conducted in three databases (Medline, CINAHL, and Embase) for articles assessing the effects of waiting for outpatient physiotherapy services in persons with musculoskeletal disorders. Clinical and health system outcomes were analyzed., Results: Sixteen studies met the inclusion criteria for this review. The studies varied in designs, settings, and populations. The definition of waiting also varied between studies. The studies were of low to high methodological quality. Waiting for outpatient physiotherapy services was shown to have mixed results on clinical and health system outcomes. Results from included studies suggest the possible detrimental effects of waiting on pain, disability, quality of life, and psychological symptoms in persons with musculoskeletal disorders. There was also evidence of higher healthcare utilization and costs for patients who wait longer before physiotherapy services., Conclusions: This review provides mixed evidence that suggest potential detrimental effects on the health of individuals with MSDs and at the health system level. Further high-quality studies are needed, such as longitudinal studies specifically addressing the effects of waiting due to lack of access to physiotherapy services.IMPLICATIONS FOR REHABILITATIONThe findings from this review suggest potential detrimental effects on health outcomes when patients wait longer before receiving physiotherapy services.The findings also suggest higher healthcare utilization and costs for patients with longer wait times compared to those who receive physiotherapy services more rapidly.This review suggests the need to assess and implement strategies and policies to ensure timely access to physiotherapy.

Forced displacement worldwide is at its highest in decades and millions of young children are living in conflict zones, in transitional or enduring refugee contexts, and in demographically diverse marginalized and informal settlements. There is a huge unmet need for delivering early childhood development interventions to ensure the safety and continued development of young children in these vulnerable contexts. In this paper, we discuss nurturing care as an important entry point for multisectoral collaborations to support families and reach young children. Nurturing care is a basic right of every child and encompasses health, nutrition, security and safety, responsive caregiving, and early learning. We review key elements of the biological and psychological development of children important to nurturing care and illustrate their application in case studies of war and displacement in Angola and Kenya. Building on long-term benefits of early interventions, scaled up support is essential to improve the health, development, and well-being of young children in contexts of conflict, violence, and insecurity. Not only do early childhood development interventions support the development of young children, but they also provide a potential pathway to violence reduction and a way to achieve more peaceful families, communities, and societies., (© 2018 Wiley Periodicals, Inc.)

Purpose: Little is known about the physical activity of adolescents born prematurely. This study aimed to: 1) describe relationships between moderate to vigorous physical activity (MVPA) in adolescents born prematurely and various factors and, 2) compare their MVPA level to guidelines., Method: A secondary analysis was performed using data from 64 adolescents (16.1 ± 2.5 years old, born £29 weeks gestation; 57.8% girls). Time spent in MVPA was based on accelerometry data. Sociodemographic, prematurity and comorbidity variables were based on questionnaire data or, for movement difficulty, from the results of the Movement Assessment Battery for Children-Second Edition., Results: Multiple regression analysis showed that participants who were older (b = -4.52, p < .001), female (b = 14.18, p = .014), with movement difficulty (b = 18.64, p = .014), with health problems (b = 11.78, p = .036) and without hyperactive behavior (trend, b = 2.04, p = .099) spent less time in MVPA. Together these variables explained 44.4% of the variance in MVPA. Most participants (79.7%) did not meet Canadian MVPA guidelines., Conclusion: Study results suggest that physical activity interventions should especially target adolescents born prematurely who are older, female, with health problems, and with marked movement difficulties.

The UN Sustainable Development Goals provide a historic opportunity to implement interventions, at scale, to promote early childhood development. Although the evidence base for the importance of early childhood development has grown, the research is distributed across sectors, populations, and settings, with diversity noted in both scope and focus. We provide a comprehensive updated analysis of early childhood development interventions across the five sectors of health, nutrition, education, child protection, and social protection. Our review concludes that to make interventions successful, smart, and sustainable, they need to be implemented as multi-sectoral intervention packages anchored in nurturing care. The recommendations emphasise that intervention packages should be applied at developmentally appropriate times during the life course, target multiple risks, and build on existing delivery platforms for feasibility of scale-up. While interventions will continue to improve with the growth of developmental science, the evidence now strongly suggests that parents, caregivers, and families need to be supported in providing nurturing care and protection in order for young children to achieve their developmental potential., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: High-quality preschools are known to prepare children for success in primary school. Over half of Indonesia's children now pass through preschools whose quality and effectiveness are unknown. Our goal was to evaluate two government preschool models, namely kindergarten (TK) and the less formal health-post (PAUD), with and without capacity-building efforts of a non-governmental organization (NGO-Plan), on children's language and math skills., Methods: Thirteen TK and 17 PAUD Plan-supported and the same number of government-supported preschools were randomly selected from East Nusa Tenggara, Indonesia. Five children from each (n = 292) and five who had graduated from each and were now in first grade (n = 241) were randomly selected and tested on language and math measures. The Plan-supported preschools were assessed for quality. Mothers reported on their family's socio-demographic situation and their child's preventive health practices, illnesses and diet over the previous two weeks., Results: Analyses of covariance adjusting for clusters indicated that children attending Plan-supported preschools performed better overall, and especially those in TK preschools. Plan-supported TKs were observed to have higher quality than Plan-supported PAUDs. First graders who graduated from Plan-supported preschools, both TK and PAUD, achieved higher scores on language and math tests than government-supported graduates. Preventive health practices were better in the Plan group, though diet and height-for-age were poor overall., Conclusions: Upgrades to the government preschool program are needed to raise its quality and effectiveness, specifically by introducing a mix of instructional and indoor free-choice play, resources and teacher training to support children's learning.

Engineered nanoparticles (ENP) are increasingly being incorporated into consumer products and reaching the environment at a growing rate. Unfortunately, few analytical techniques are available that allow the detection of ENP in complex environmental matrices. The major limitations with existing techniques are their relatively high detection limits and their inability to distinguish ENP from other chemical forms (e.g. ions, dissolved) or from natural colloids. Of the matrices that are considered to be a priority for method development, ENP are predicted to be found at relatively high concentrations in wastewaters and wastewater biosolids. In this paper, we demonstrate the capability of hydrodynamic chromatography (HDC) coupled to inductively coupled plasma mass spectrometry (ICPMS), in its classical and single particle modes (SP ICPMS), to identify ENP in wastewater influents and effluents. The paper first focuses on the detection of standard silver nanoparticles (Ag NP) and their mixtures, showing that significant dissolution of the Ag NP was likely to occur. For the Ag NP, detection limits of 0.03 μg L(-1) were found for the HDC ICPMS whereas 0.1 μg L(-1) was determined for the HDC SP ICPMS (based on results for the 80 nm Ag NP). In the second part of the paper, HDC ICPMS and HDC SP ICPMS were performed on some unspiked natural samples (wastewaters, river water). While nanosilver was below detection limits, it was possible to identify some (likely natural) Cu nanoparticles using the developed separation technology.

Formation of embryonic vasculature involves vasculogenesis as endothelial cells differentiate and aggregate into vascular cords and angiogenesis which includes branching from the existing vessels. In the zebrafish which has emerged as an advantageous model to study vasculogenesis, cranial vasculature is thought to originate by a combination of vasculogenesis and angiogenesis, but how these processes are coordinated is not well understood. To determine how angioblasts assemble into cranial vasculature, we generated an etsrp:GFP transgenic line in which GFP reporter is expressed under the promoter control of an early regulator of vascular and myeloid development, etsrp/etv2. By utilizing time-lapse imaging we show that cranial vessels originate by angiogenesis from angioblast clusters, which themselves form by the mechanism of vasculogenesis. The two major pairs of bilateral clusters include the rostral organizing center (ROC) which gives rise to the most rostral cranial vessels and the midbrain organizing center (MOC) which gives rise to the posterior cranial vessels and to the myeloid and endocardial lineages. In Etsrp knockdown embryos initial cranial vasculogenesis proceeds normally but endothelial and myeloid progenitors fail to initiate differentiation, migration and angiogenesis. Such angioblast cluster-derived angiogenesis is likely to be involved during vasculature formation in other vertebrate systems as well., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Signaling pathways controlling vasculogenesis, angiogenesis, and myelopoiesis are still poorly understood, in part because not all genes important for vasculature or myeloid cell formation have been characterized. To identify novel potential regulators of vasculature and myeloid cell formation we performed microarray analysis of zebrafish embryos that overexpress Ets1-related protein (Etsrp/Etv2/ER71), sufficient to induce vasculogenesis and myelopoiesis (Sumanas and Lin [2006] Development 121:3141-3150; Lee [2008] Cell Stem Cell 2:497-507; Sumanas et al. [2008] Blood 111:4500-4510). We performed sequence homology and expression analysis for up-regulated genes that were novel or previously unassociated with the zebrafish vasculature formation. Angiotensin II type 2 receptor (agtr2), src homology 2 domain containing E (she), mannose receptor C1 (mrc1), endothelial cell-specific adhesion molecule (esam), yes-related kinase (yrk/fyn), zinc finger protein, multitype 2b (zfpm2b/fog2b), and stabilin 2 (stab2) were specifically expressed in vascular endothelial cells during early development while keratin18 expression was localized to the myeloid cells. Identification of vasculature and myeloid-specific genes will be important for dissecting molecular mechanisms of vasculogenesis/angiogenesis and myelopoiesis., ((c) 2009 Wiley-Liss, Inc.)

FTO is a nuclear protein belonging to the AlkB-related non-haem iron- and 2-oxoglutarate-dependent dioxygenase family. Although polymorphisms within the first intron of the FTO gene have been associated with obesity, the physiological role of FTO remains unknown. Here we show that a R316Q mutation, inactivating FTO enzymatic activity, is responsible for an autosomal-recessive lethal syndrome. Cultured skin fibroblasts from affected subjects showed impaired proliferation and accelerated senescence. These findings indicate that FTO is essential for normal development of the central nervous and cardiovascular systems in human and establish that a mutation in a human member of the AlkB-related dioxygenase family results in a severe polymalformation syndrome.

Objective: Evidence links the hypothalamic fatty acid synthase (FAS) pathway to the regulation of food intake and body weight. This includes pharmacological inhibitors that potently reduce feeding and body weight. The mammalian target of rapamycin (mTOR) is an intracellular fuel sensor whose activity in the hypothalamus is also linked to the regulation of energy balance. The purpose of these experiments was to determine whether hypothalamic mTOR complex 1 (mTORC1) signaling is involved in mediating the effects of FAS inhibitors., Research Design and Methods: We measured the hypothalamic phosphorylation of two downstream targets of mTORC1, S6 kinase 1 (S6K1) and S6 ribosomal protein (S6), after administration of the FAS inhibitors C75 and cerulenin in rats. We evaluated food intake in response to FAS inhibitors in rats pretreated with the mTOR inhibitor rapamycin and in mice lacking functional S6K1 (S6K1(-/-)). Food intake and phosphorylation of S6K1 and S6 were also determined after C75 injection in rats maintained on a ketogenic diet., Results: C75 and cerulenin increased phosphorylation of S6K1 and S6, and their anorexic action was reduced in rapamycin-treated rats and in S6K1(-/-) mice. Consistent with our previous findings, C75 was ineffective at reducing caloric intake in ketotic rats. Under ketosis, C75 was also less efficient at stimulating mTORC1 signaling., Conclusions: These findings collectively indicate an important interaction between the FAS and mTORC1 pathways in the central nervous system for regulating energy balance, possibly via modulation of neuronal glucose utilization.

Individual cells must carefully regulate their energy flux to ensure nutrient levels are adequate to maintain normal cellular activity. The same principle holds in multicellular organisms. Thus, for mammals to perform necessary physiological functions, sufficient nutrients need to be available. It is more complex, however, to understand how the energy status of different cells impacts on the overall energy balance of the entire organism. We propose that the central nervous system is the critical organ for the coordination of intracellular metabolic processes that are essential to guarantee energy homeostasis at the organismal level. In particular, we suggest that in specific hypothalamic neurons, evolutionarily conserved fuel sensors, such as adenosine monophosphate-activated protein kinase and mammalian target of rapamycin (mTOR), integrate sensory input from nutrients, including those derived from recently ingested food or those that are stored in adipose tissue, to regulate effector pathways responsible for fuel intake and utilization. The corollary to this hypothesis is that dysregulation of these fuel-sensing mechanisms in the brain may contribute to metabolic dysregulation underlying diseases, such as obesity and type 2 diabetes.

The mammalian Target of Rapamycin (mTOR) protein is a serine-threonine kinase that regulates cell-cycle progression and growth by sensing changes in energy status. We demonstrated that mTOR signaling plays a role in the brain mechanisms that respond to nutrient availability, regulating energy balance. In the rat, mTOR signaling is controlled by energy status in specific regions of the hypothalamus and colocalizes with neuropeptide Y and proopiomelanocortin neurons in the arcuate nucleus. Central administration of leucine increases hypothalamic mTOR signaling and decreases food intake and body weight. The hormone leptin increases hypothalamic mTOR activity, and the inhibition of mTOR signaling blunts leptin's anorectic effect. Thus, mTOR is a cellular fuel sensor whose hypothalamic activity is directly tied to the regulation of energy intake.

Oleoylethanolamide (OEA), a lipid synthesized in the intestine, reduces food intake and stimulates lipolysis through peroxisome proliferator-activated receptor-alpha. OEA also activates transient receptor potential vanilloid type 1 (TRPV1) in vitro. Because the anorexigenic effect of OEA is associated with delayed feeding onset and reduced locomotion, we examined whether intraperitoneal administration of OEA results in nonspecific behavioral effects that contribute to the anorexia in rats. Moreover, we determined whether circulating levels of other gut hormones are modulated by OEA and whether CCK is involved in OEA-induced anorexia. Our results indicate that OEA reduces food intake without causing a conditioned taste aversion or reducing sodium appetite. It also failed to induce a conditioned place aversion. However, OEA induced changes in posture and reduced spontaneous activity in the open field. This likely underlies the reduced heat expenditure and sodium consumption observed after OEA injection, which disappeared within 1 h. The effects of OEA on motor activity were similar to those of the TRPV1 agonist capsaicin and were also observed with the peroxisome proliferator-activated receptor-alpha agonist Wy-14643. Plasma levels of ghrelin, peptide YY, glucagon-like peptide 1, and apolipoprotein A-IV were not changed by OEA. Finally, antagonism of CCK-1 receptors did not affect OEA-induced anorexia. These results suggest that OEA suppresses feeding without causing visceral illness and that neither ghrelin, peptide YY, glucagon-like peptide 1, apolipoprotein A-IV, nor CCK plays a critical role in this effect. Despite that OEA-induced anorexia is unlikely to be due to impaired motor activity, our data raise a cautionary note in how specific behavioral and metabolic effects of OEA should be interpreted.

Death is a unique experience for each human being, yet there is tremendous societal pressure on a dying person to be a "goodpatient " while trying to experience the "good death. " These pressures shape patient, caregiver, and family choices in end-of-life situations. The purpose of this literature review was twofold: first, to develop an understanding of "dying with dignity" to enhance the end-of-life care received by dying patients, and second, to contribute to a concept analysis of dignity to improve the clarity and consistency of future research related to dignity in aging individuals. Articles pertaining to dying with dignity from the disciplines of nursing, medicine, ethics, psychology, and sociology were reviewed using a matrix method. A dichotomy surrounding dying with dignity emerged from this review. The definition of dignity in dying identifies not only an intrinsic, unconditional quality of human worth, but also the external qualities of physical comfort, autonomy, meaningfulness, usefulness, preparedness, and interpersonal connection. For many elderly individuals, death is a process, rather than a moment in time, resting on a need for balance between the technology of science and the transcendence of spirituality.

Mindfulness-based stress reduction (MBSR) programs may mitigate the effects of stress and disease. This integrative review identified 21 clinical studies on MBSR interventions. Although preliminary findings suggest health enhancement from MBSR, controlled, randomized studies, the operationalization of constructs, and qualitative research are needed.

Leptin regulates food intake in adult mammals by stimulating hypothalamic anorexigenic pathways and inhibiting orexigenic ones. In developing rodents, fat stores are low, yet circulating leptin levels are high and do not appear to regulate food intake. We determined whether two appetite-related neuropeptides [neuropeptide Y (NPY) and proopiomelanocortin (POMC)] and food intake behavior are sensitive to leptin [3 mg/kg body weight (BW), ip] in neonates. We measured the effects of 1) acute leptin administration (3 mg/kg BW, ip, 3 h before testing) on food intake on postnatal day (PND) 5, 8, and 10; and 2) chronic leptin treatment (3 mg/kg BW, ip, daily PND3-PND10) on BW gain and fat pads weight on PND10. In addition to hypothalamic POMC and NPY expression, we determined the expression of suppressor of cytokine signaling-3, all subtypes of leptin receptors, and corticotropin-releasing factor receptor-2 mRNA in PND10 pups receiving either an acute (PND10) or a chronic (PND 3-10) leptin (3 mg/kg BW, ip) or vehicle treatment. Brains were removed 30 or 120 min after the last injection. Acute leptin administration did not affect food intake at any age tested. Chronic leptin treatment did not change BW but decreased fat pad weight significantly. In the arcuate nucleus (ARC), acute leptin increased SOCS-3 and POMC mRNA levels, but decreased NPY mRNA levels in the rostral part of ARC. Chronic leptin down-regulated all subtypes of leptin receptors mRNA and decreased NPY mRNA levels in the caudal ARC but had no further effect on POMC expression. Chronic leptin increased corticotropin-releasing factor receptor-2 mRNA levels in the ventromedial hypothalamus. We conclude that despite adult-like effects of leptin on POMC, NPY, and CRFR-2 expression in neonates, leptin does not regulate food intake during early development.

WKHA rats constitute a recombinant inbred rat strain derived by phenotypic selection of the progeny of hybrid F2 crosses between SHR and WKY rats. WKHA are normotensive and show some features of hyperactivity and of hyper-reactivity to stress, but their utility as model of attention deficit/hyperactivity disorder (ADHD) has not yet been settled. To address these questions, we performed behavioral and neurochemical evaluations of WKHA, and compared them to both WKY and Wistar (WIS) rats. In locomotor activity tests, the respective scores for each strain were WKY

Leptin modifies the activity of the hypothalamic-pituitary-adrenal axis in adult rodents and inhibits the production of glucocorticoids from human and rat adrenals in vitro. During development, high levels of circulating leptin and low levels of corticosterone secretion are observed together with adrenal hyporesponsiveness to stress. As chronic neonatal leptin administration reduced stress-induced corticotropin-releasing factor mRNA expression and ACTH secretion in pups, we determined whether elevated leptin levels enhanced the feedback effect of glucocorticoids on the hypothalamic-pituitary-adrenal axis. In naive pups we found a highly significant inverse relationship between plasma levels of leptin and corticosterone (P < 0.01) during postnatal d 6-20. We tested the ability of dexamethasone (1 or 10 microg/kg BW, ip, -3 h before stress) to suppress ether-induced ACTH secretion in 10-d-old pups that were treated during the neonatal period (d 2-9) with either vehicle or leptin (1 or 3 mg/kg BW, ip, daily). The expressions of brain GR and MR in vehicle- or leptin-treated neonates were determined by in situ hybridization and Western blotting. Chronic leptin treatment enhanced the ability of dexamethasone to suppress ACTH secretion after stress, and the low dose of dexamethasone was discriminant. Leptin treatment increased GR mRNA levels in the hypothalamic paraventricular nucleus (P < 0.05) and in the dentate gyrus of the hippocampus in a dose-dependent fashion. Hippocampal GR protein concentrations were increased by leptin treatment (P < 0.05). Expression of MR mRNA was not modified. Thus, the ability of leptin to enhance glucocorticoid feedback in pups is mediated in part by changes in brain GR. The high circulating leptin concentrations found in developing pups might be critical to regulate glucocorticoid production, GR levels, and stress responses. As leptin levels in pups vary with maternal diet, leptin might represent an important mediator of the maternal environment on the infant.

Coproporphyrinogen oxidase (EC 1.3.3.3), protoporphyrinogen oxidase (EC 1.3.3.4), and ferrochelatase (EC 4.99.1.1) catalyze the terminal three steps of the heme biosynthetic pathway. All three are either bound to or associated with the inner mitochondrial membrane in higher eukaryotic cells. A current model proposes that these three enzymes may participate in some form of multienzyme complex with attendant substrate channeling (Grand-champ, B., Phung, N., & Nordmann, Y., 1978, Biochem. J. 176, 97-102; Ferreira, G.C., et al., 1988, J. Biol. Chem. 263, 3835-3839). In the present study we have examined this question in isolated mouse mitochondria using two experimental approaches: one that samples substrate and product levels during a timed incubation, and a second that follows dilution of radiolabeled substrate by pathway intermediates. When isolated mouse mitochondria are incubated with coproporphyrinogen alone there is an accumulation of free protoporphyrin. When Zn is added as a substrate for the terminal enzyme, ferrochelatase, along with coproporphyrinogen, there is formation of Zn protoporphyrin with little accumulation of free protoporphyrin. When EDTA is added to this incubation mixture with Zn, Zn protoporphyrin formation is eliminated and protoporphyrin is formed. We have examined the fate of radiolabeled substrates in vitro to determine if exogenously supplied pathway intermediates can compete with the endogenously produced compounds. The data demonstrate that while coproporphyrinogen is efficiently converted to heme in vitro when the pathway is operating below maximal capacity, exogenous protoporphyrinogen can compete with endogenously formed protoporphyrinogen in heme production.(ABSTRACT TRUNCATED AT 250 WORDS)

As a result of the inability to resolve the heterogeneous mixture of G protein beta gamma subunits present in tissues, it has not been possible to compare different beta gamma subunits of the G proteins in terms of their proposed roles in receptor-effector coupling. This study was undertaken to establish the utility of the baculovirus expression system in producing homogeneous beta gamma subunits of defined composition for the comparative analysis of these subunits in reconstitution systems. In this study we report the expression, and appropriate post-translational processing, of recombinant beta 2, gamma 2 and gamma 3 subunits. In addition, we show that the recombinant beta gamma subunits can be readily purified, and can functionally interact with the alpha subunits of the G proteins.

Protoporphyrinogen oxidase (EC 1.3.3.4) (PPO) is the penultimate enzyme of the heme biosynthetic pathway. Mouse PPO has been purified in low yield and kinetically characterized by this laboratory previously. A new more rapid purification procedure is described herein, and with this protein we detect a noncovalently bound flavin moiety. This flavin is present at approximately stoichiometric amounts in the purified enzyme and has been identified by its fluorescence spectrum and high performance liquid chromatography as flavin mononucleotide (FMN). Fluorescence quenching studies on the flavin yielded a Stern-Volmer quenching constant of 12.08 M-1 for iodide and 1.1 M-1 for acrylamide. Quenching of enzyme tryptophan fluorescence resulted in quenching constants of 6 M-1 and 10 M-1 for iodide and acrylamide, respectively. Plasma scans performed on purified enzyme preparations did not reveal the presence of stoichiometric amounts of protein-bound metal ions, and we were unable to detect any protein-associated pyrroloquinoline quinone (PQQ). Data from circular dichroism studies predict a secondary structure of the native protein consisting of 30.5% alpha helix, 40.5% beta sheet, 13.7% turn, and 15.3% random coil. Denaturation of PPO with urea resulted in a biphasic curve when ellipticity is plotted against urea concentration, typical of amphipathic proteins.