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BACKGROUND: Prevalence rates of overweight are higher among American Indian children than among any other ethnic group, but little research has explored contributing influences. OBJECTIVE: The objective was to determine the prevalence and predictors of body mass index (BMI; in kg/m2) > or = 85th percentile in American Indian children in Wisconsin. DESIGN: A retrospective analysis was conducted with linked pediatric and pregnancy nutrition surveillance systems and birth records from 1997 through 2001. Participants were American Indian mothers and children (aged 0-3 y) who were participating in the Special Supplemental Nutrition Program for Women, Infants, and Children in Wisconsin. Outcome measurements included indicators of BMI > or = 85th percentile identified by using binary logistic regression. RESULTS: Of the 3-y-olds, 22.2% were overweight and 18.7% were at risk of overweight. Of their mothers, 42.5% had smoked during pregnancy. Smoking at the initial prenatal visit significantly predicted overweight and risk of overweight in children at age 3 y (odds ratio: 2.16; 95% CI: 1.05, 4.47). Despite being smaller at birth, the children of smoking mothers had a significantly (P < 0.05) greater increase in weight-for-length z score between birth and age 3 y than did children of nonsmokers. This greater increase was due to a significantly (P < 0.02) greater increase in weight in children of smokers than in those of nonsmokers and not to a relatively slower increase in height. CONCLUSIONS: Our findings suggest the early influence of maternal smoking on the prevalence of overweight at age 3 y in a high-risk American Indian population and provide evidence that interventions to reduce smoking in pregnant women may be warranted. Copyright © 2005 American Society for Clinical Nutrition [ABSTRACT FROM AUTHOR]

After a clinical study at Kilifi District hospital had shown a high prevalence of geophagy among pregnant women, and a strong association of geophagy, anaemia and iron depletion, 52 pregnant women from the same hospital, and 4 traditional healers from the surroundings of Kilifi in Kenya were interviewed on the topic of soil-eating and its perceived causes and consequences. The findings were substantiated by results from an earlier anthropological study on maternal health and anaemia in the same study area. Most of the pregnant women (73%) ate soil regularly. They mainly ate the soil from walls of houses, and their estimated median daily ingestion was 41.5 g. They described soil-eating as a predominantly female practice with strong relations to fertility and reproduction. They made associations between soil-eating, the condition of the blood and certain bodily states: pregnancy, lack of blood (upungufu wa damu), an illness called safura involving 'weak' blood, and worms (minyolo). The relationships the women described between soil-eating and illness resemble to some extent the causalities explored in biomedical research on soil-eating, anaemia and intestinal worm infections. However the women did not conceptualise the issue in terms of the single causal links characteristic of most scientific thought. Instead, they acknowledged the existence of multiple links between phenomena which they observed in their own and other women's bodies. The women's ideas about soil-eating and their bodies shows the significance of both social and cultural context on the ways in which women derive knowledge from, and make sense of their bodily states. The cultural associations of soil-eating with blood, fertility and femininity exist alongside knowledge of its links to illness. Our findings show that soil-eating is more than just a physiologically induced behaviour; it is a rich cultural practice. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase and member of the TEC family of kinases, is involved in the regulation, migration, and functional activation of B cells and myeloid cells in the periphery and the central nervous system (CNS), cell types which are deemed central to the pathology contributing to disease progression in MS patients. Herein, we describe the discovery of BIIB129 ( 25 ), a structurally distinct and brain-penetrant targeted covalent inhibitor (TCI) of BTK with an unprecedented binding mode responsible for its high kinome selectivity. BIIB129 ( 25 ) demonstrated efficacy in disease-relevant preclinical in vivo models of B cell proliferation in the CNS, exhibits a favorable safety profile suitable for clinical development as an immunomodulating therapy for MS, and has a low projected total human daily dose.

In this special issue, we bring together anthropological and historical work that considers successive aspirations towards 'health for all': their pasts, their futures, and their diverse meanings and iterations. Across the world, hopes for providing 'health for all' were central to nation building in the long 20th century, and for international relations, particularly after the second world war and the establishment of the WHO. Health became seen as a fundamental good by citizens of North and South and has remained a central force shaping global and national politics until today. But what does 'health for all' actually mean, and how did it come to matter? In this introduction we approach 'health for all as a situated, multi-faceted phenomenon, that - while having a shared aspiration towards universality of access and equality of care - comes into focus in partial, diverse and contentious policies, programmes, projects and practices. Beyond homogenising narratives that frame 'health for all' in terms of either success or failure, the special issue highlights the diverse iterations that 'health for all' has taken on the ground for different subjects and groups of people, exploring exclusions and limitations as well as dreams and aspirations., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The rise of universal health coverage (UHC) as a global policy endorsed in the Sustainable Development Goals (SGDs) appears to signal new directions in global health as it introduces a progressive language of inclusion, solidarity and social justice and advocates the right of 'everyone' to access the healthcare they need 'without financial hardship'. Since 2018 the Kenyan government has attempted to widen access to healthcare by experimenting with free health care services and expanding health insurance coverage. Such progressive moves are, however, layered onto histories of healthcare, citizenship and state responsibility that in Kenya have been dominated by forms of exclusion, differentiation, a politics of patronage, and class inequality, all of which work against universal access. In this paper, we follow recent attempts to increase access to healthcare, paying particular attention to how a language of rights and inclusion circulated among "ordinary citizens" as well as among the health workers and government officials tasked with implementing reforms. Despite being clothed in a language of universalism, solidarity and inclusion, Kenya's UHC reforms feed into an already fragmented and struggling healthcare system, reinforcing differentiated, limited and uneven access to healthcare services and reproducing inequity and exclusions. In this context, reforms for universal health coverage that promise a form of substantial citizenship are in tension with Kenyans' experiences of accessing healthcare. We explore how, amid vocal concerns about healthcare costs and state neglect, the promises and expectations surrounding universal health coverage reforms shaped the claims people made to accessing care. While our informants were cynical about these promises, they were also hopeful. The language of universality and inclusion drew people's attention to entrenched forms of inequality and difference, the limits of solidarity and the gaps between promises and realities, but it also generated expectations and a sense of new possibilities., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aim: To explore what competencies and skills Malawian nurses gained after participating in an institutional health and training programme in Norway and how they viewed these competencies applicable upon return to Malawi. Furthermore, to examine facilitators and challenges experienced on the exchange programme and opportunities and obstacles to make the competencies usable in own local hospital context., Design: Qualitative study with an explorative design., Methods: Fourteen interviews and one focus group discussion were conducted at Queen Elizabeth Central Hospital, Blantyre, Malawi, from August to September 2018., Results: Competencies gained in Norway included clinical skills, teamwork, coordination and strengthened professionalism. The main finding was that the exchange programme was a transformative experience. Upon return to Malawi, the competencies gained on the exchange were helpful. However, the return was characterized by mixed emotions due to the considerable difference between the two clinical settings., (© 2021 The Authors. Nursing Open published by John Wiley & Sons Ltd.)

Child sexual abuse (CSA) is a global, social, and health challenge. Existing literature on post-sexual assault care has focused largely on health providers' skills and capacity to offer quality clinical, medicolegal, and psychosocial care. Services other than medical and psychosocial care provided to survivors of CSA remain poorly studied, particularly in the global south. The study aimed to explore challenges facing service providers supporting children who have experienced sexual abuse and make suitable recommendations. We triangulated different qualitative methods: in-depth interviews with 61 key informants, three focus group discussions with community leaders, and unstructured observations for data collection. Findings indicate that service providers supporting children who had experienced sexual abuse play a vital role in ensuring that survivors receive clinical and medicolegal care, psychosocial support, have access to justice, and are protected from further victimization. However, these service providers face several challenges, including poor infrastructure, the lack of effective coordination and linkage among the service providers in the continuum of care, corruption among officials, and harmful patriarchal norms that hinder reporting of abuse. To effectively support and care for survivors, we recommend government commitment to, and investments in, safe spaces, supervision, and professional development of providers. Working with community leaders and gatekeepers of all genders is critical to address harmful practices that perpetuate CSA and make it difficult to care for and obtain justice for CSA survivors.

Background: Few obesity interventions have been developed for American Indian (AI) families despite the disproportionate risk of obesity experienced within AI communities. The emergence of mobile technologies to enhance intervention delivery could particularly benefit AI communities, many of which are hard to reach and underserved., Objectives: This study aimed to assess the use and perceptions of text messaging and Facebook to support delivery of the Healthy Children, Strong Families 2 (HCSF2) mailed healthy lifestyle/obesity prevention intervention and discuss lessons learned regarding intervention support via these platforms among AI participants., Methods: From among AI families with young children (ages 2-5 y), 450 adult-child dyads were recruited from 5 rural and urban communities for a year-long intervention. Intervention content was delivered by mail and supported by text messaging and optional Facebook groups. Participants provided feedback on text message and Facebook components post-intervention, and Facebook analytic data were tracked., Results: Self-report feedback indicated high satisfaction with both text messaging and Facebook, with tangible content (e.g., recipes, physical activity ideas) cited as most useful. Overall, participants reported higher satisfaction with and perceived efficacy of Facebook content compared with text messaging. Analytic data indicate the optional HCSF2 Facebook groups were joined by 67.8% of adult participants. Among those who joined, 78.4% viewed, 50.8% "liked," and 22.6% commented on ≥1 post. Engagement levels differed by urban-rural status, with more urban participants "liking" ( P  = 0.01) and commenting on posts ( P  = 0.01). Of note, nearly one-third of participants reported changing phone numbers during the intervention., Conclusions: This study demonstrates high satisfaction regarding mobile delivery of HCSF2 intervention support components. Best practices and challenges in utilizing different mobile technologies to promote wellness among AI families are discussed, with particular focus on urban-rural differences. Future mobile-based interventions should consider the context of unstable technology maintenance, especially in low-resource communities.This work is part of the HCSF2 trial, which is registered at clinicaltrials.gov (NCT01776255)., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Child sexual abuse (CSA) is a major global health challenge. Extant literature shows that CSA is prevalent in Kenya. As a signatory of the United Nations Convention on the Rights of the Child and the African Charter on the Rights and Welfare of the Child, the Kenyan government is mandated to ensure that children are protected from sexual abuse through sound laws and policies. This paper reviews existing laws and policies on CSA and highlights their strengths and weaknesses. Our findings indicate that laws on child protection exist and are protective to a large extent, as harsh penalties are outlined for sexual offences. Survivors of CSA are entitled to free legal and medical services. However, there are no reparations offered to survivors in criminal proceedings. Moreover, there is no legislation on age-appropriate comprehensive sexuality education which plays an important role in cultivating positive gender norms and describing what constitutes CSA and reporting procedures. The national standard operating procedures for the management of sexual violence against children lack CSA screening procedures. There is urgent need for review of these laws and policies and development of multisectoral protocols at the national and county level, that outline roles and responsibilities for various service providers, supervisory and accountability measures and referral networks.

An operationally simple protocol has been discovered that couples primary or secondary amines with N-aryl-substituted lactams to deliver differentiated diamines in moderate to high yields. The process allows for the partial reduction of a lactam in the presence of Cp 2 ZrHCl (Schwartz's reagent), followed by a reductive amination between the resulting hemiaminal and primary or secondary amine. These reactions can be telescoped in a one-pot fashion to significantly simplify the operation. The scope of amines and substituted lactams of various ring sizes was demonstrated through the formation of a range of differentiated diamine products. Furthermore, this methodology was expanded to include N-aryl pyrrolidinone substrates with an enantiopure ester group at the 5-position, and α-amino piperidinones were prepared with complete retention of stereochemical information. The development of this chemistry has enabled the consideration of lactams as useful synthons.

Child sexual abuse (CSA) is a major global health concern. Although it is prevalent in Kenya, scant literature on factors contributing to CSA vulnerability exists. Using qualitative data from 28 focus groups and ethnographic field notes, we explored and assessed community perceptions of factors contributing to CSA vulnerability in Homa Bay County, Western Kenya. Findings suggest that people living in these communities perceived CSA as being influenced by multiple factors: developmental stage, peer pressure, huge gender disparities exacerbated by negative social norms and cultural practices, the HIV epidemic and social media platforms that circulate sexualised images. From our findings, it was clear that participants also regarded poverty as exacerbating children's vulnerability to CSA. Minors from poor families engaged in transactional sex for survival and social status. Some community members perceived girls dressed in short skirts or tight clothing as warranting unwanted sexual advances. Although poverty and gender roles and relations were viewed as increasing vulnerability to CSA, blame was often placed on survivors' modes of dress or behaviour. There is a need for comprehensive education of the communities on CSA, its consequences and the rights of women and girls.

Background: American Indian (AI) families experience a disproportionate risk of obesity due to a number of complex reasons, including poverty, historic trauma, rural isolation or urban loss of community connections, lack of access to healthy foods and physical activity opportunities, and high stress. Home-based obesity prevention interventions are lacking for these families., Objective: Healthy Children, Strong Families 2 (HCSF2) was a randomized controlled trial of a healthy lifestyle promotion/obesity prevention intervention for AI families., Methods: Four hundred and fifty dyads consisting of an adult primary caregiver and a child ages 2 to 5 y from 5 AI communities were randomly assigned to a monthly mailed healthy lifestyle intervention toolkit ( Wellness Journey ) with social support or to a child safety control toolkit ( Safety Journey ) for 1 y. The Wellness Journey toolkit targeted increased fruit/vegetable (F/V) intake and physical activity, improved sleep, decreased added sugar intake and screen time, and improved stress management (adults only). Anthropometrics were collected, and health behaviors were assessed via survey at baseline and at the end of Year 1. Adults completed surveys for themselves and the participating child. Repeated measures analysis of variance was used to assess change over the intervention period., Results: Significant improvements to adult and child healthy diet patterns, adult F/V intake, adult moderate-to-vigorous physical activity, home nutrition environment, and adult self-efficacy for health behavior change were observed in Wellness Journey compared with Safety Journey families. No changes were observed in adult body mass index (BMI), child BMI z-score, adult stress measures, adult/child sleep and screen time, or child physical activity. Qualitative feedback suggests the intervention was extremely well-received by both the families and our community partners across the 5 participating sites., Conclusions: This multi-site community-engaged intervention addressed key gaps regarding family home-based approaches for early obesity prevention in AI communities and showed several significant improvements in health behaviors. Multiple communities are working to sustain intervention efforts. This trial was registered at clinicaltrials.gov as NCT01776255.

Background: Little is known about factors contributing to physical activity (PA) in American Indian (AI) populations. Addressing this gap is paramount as sedentary activity and obesity continue to increase in this population. The purpose of this study was to determine factors associated with PA among AI families with young children., Methods: Height and weight of both adult (n = 423) and child (n = 390) were measured, and surveys assessed demographics, PA, stress (adult only), sleep, and screen time. Separate multivariate logistic regression models were constructed for adults and children (reported as adjusted odds ratios, aORs)., Results: For adults, age (aOR = 0.952; P ≤ .001), television viewing (aOR = 0.997; P = .01), and computer use (aOR = 0.996; P = .003) decreased the odds of being active. For children, high adult activity (aOR = 1.795; P ≤ .01), longer weekday sleep (aOR = 1.004; P = .01), and family income >$35,000 (aOR = 2.772; P = .01) increased the odds of being active. We found no association between adult PA with stress or adult sleep or between child PA with body mass index and screen time., Conclusions: Given the complexity of the factors contributing to obesity among AI families, multigenerational interventions focused on healthy lifestyle change such as decreasing adult screen time and increasing child sleep time may be needed to increase PA within AI families.

Background: Sleep has emerged as a potentially modifiable risk factor for obesity in children., Objectives: The purpose of this investigation was to evaluate the association between overnight sleep duration and obesity among American Indian (AI) children ages 2-5 years., Methods: Data were examined from the baseline assessment of children enrolling in the Healthy Children, Strong Families study, which is a randomized lifestyle intervention trial in five diverse rural and urban AI communities nationally among children ages 2-5 years. Multivariable models were built to assess the relationship between sleep duration and BMI z-score while controlling for potential sociodemographic and behavioural covariates., Results: Three hundred and ninety-eight children had sufficient data to be included in analysis. In multivariable models controlling for potential covariates, overnight sleep duration was significantly and inversely associated with BMI z-score (B = -0.158, t = -1.774, P = 0.006). Similarly, when controlling for covariates, children who slept 12 or more hours had significantly lower BMI z-scores compared with those who slept 8 to 10 h (P = 0.018) or less than 8 h (P = 0.035); the difference between 12+ hours and 10 to 12-h groups did not reach statistical significance (P = 0.073) but supported a linear relationship between overnight sleep duration and BMI. Weekday-to-weekend variability in overnight sleep duration was not associated with BMI z-score (B = 0.010, t = 0.206, P = 0.837)., Conclusions: Overnight sleep duration is independently and inversely related to BMI z-score among AI children ages 2-5 years, even when controlling for important sociodemographic and obesogenic lifestyle factors. This represents the first report, to our knowledge, of sleep duration as a risk factor for obesity among AI children., (© 2018 World Obesity Federation.)

Physical activity is a critical component of obesity prevention, but few interventions targeting early childhood have been described. The Active Early guide was designed to increase physical activity in early care and education (ECE) settings. The purpose of Active Early 2.0 was to evaluate the effectiveness of Active Early along with provider training, microgrant support, and technical assistance over 2 years (2012-2014) to increase physical activity and related behaviors (e.g., nutrition) in settings serving a high proportion of children from underserved groups in recognition of significant disparities in obesity and challenges meeting physical activity recommendations in low-resource settings. The physical activity and nutrition environment were assessed before and after the intervention in 15 ECE settings in Wisconsin using the Environment and Policy Observation Assessment tool, and interviews were conducted with providers and technical consultants. There was no significant change in Total Physical Activity Score or any EPAO subscale over the intervention period; however, significant improvements in the Total Nutrition Score and the several Nutrition subscales were observed. Additionally, the percentage of sites with written activity policies significantly increased. Overall minutes of teacher-led physical activity increased to 61.5 ± 29.0 min (p < 0.05). Interviews identified key benefits to children (i.e., more energy, better rest, improved behavior) and significant barriers, most notably care provider and child turnover and low parent engagement. Moderate policy and environmental improvements in physical activity and nutrition were achieved with this intervention, but more work is needed to understand and address barriers and to support sustained changes in lower-resource ECE settings.

Introduction: Pelvic examination training and competency-based assessment are expensive and time consuming. Our goal was to use the results of skill evaluation early in residency to identify residents who required training., Methods: Incoming residents performed pelvic examinations with gynecological teaching assistants. Faculty observed residents performing examinations with clinic patients to assess for competency. Written assessment of residents by teaching assistants and faculty were completed. A regression-based software tool was used to determine items in early resident performance to best predict subsequent competency., Results: Sixty-eight residents were evaluated. Thirty-eight (56%) residents were not able to demonstrate competency in three clinical exams and therefore received more observation. One third of evaluations were completed by faculty performing ≤1 evaluation per year. Two items were found most likely to identify a resident who required further training ("identifies cervix" and "properly assembles equipment"). The model based on these items had a sensitivity of 100% (95% confidence interval [CI]=86-100%) and specificity of 36.8% (95% CI=22-54%)., Conclusions: A model using early skills assessments was not sufficiently specific to identify residents who needed more training. Next steps include limiting the number of faculty assessors, faculty development to improve discriminatory capacity, and creating separate processes for (1) providing feedback and identifying learning needs in new residents, and (2) documenting competency in performance of pelvic exams., (© 2017 by the Society of Teachers of Family Medicine.)

Background/Aims Few obesity prevention trials have focused on young children and their families in the home environment, particularly in underserved communities. Healthy Children, Strong Families 2 is a randomized controlled trial of a healthy lifestyle intervention for American Indian children and their families, a group at very high risk of obesity. The study design resulted from our long-standing engagement with American Indian communities, and few collaborations of this type resulting in the development and implementation of a randomized clinical trial have been described. Methods Healthy Children, Strong Families 2 is a lifestyle intervention targeting increased fruit and vegetable intake, decreased sugar intake, increased physical activity, decreased TV/screen time, and two less-studied risk factors: stress and sleep. Families with young children from five American Indian communities nationwide were randomly assigned to a healthy lifestyle intervention ( Wellness Journey) augmented with social support (Facebook and text messaging) or a child safety control group ( Safety Journey) for 1 year. After Year 1, families in the Safety Journey receive the Wellness Journey, and families in the Wellness Journey start the Safety Journey with continued wellness-focused social support based on communities' request that all families receive the intervention. Primary (adult body mass index and child body mass index z-score) and secondary (health behaviors) outcomes are assessed after Year 1 with additional analyses planned after Year 2. Results To date, 450 adult/child dyads have been enrolled (100% target enrollment). Statistical analyses await trial completion in 2017. Lessons learned Conducting a community-partnered randomized controlled trial requires significant formative work, relationship building, and ongoing flexibility. At the communities' request, the study involved minimal exclusion criteria, focused on wellness rather than obesity, and included an active control group and a design allowing all families to receive the intervention. This collective effort took additional time but was critical to secure community engagement. Hiring and retaining qualified local site coordinators was a challenge but was strongly related to successful recruitment and retention of study families. Local infrastructure has also been critical to project success. Other challenges included geographic dispersion of study communities and providing appropriate incentives to retain families in a 2-year study. Conclusion This multisite intervention addresses key gaps regarding family/home-based approaches for obesity prevention in American Indian communities. Healthy Children, Strong Families 2's innovative aspects include substantial community input, inclusion of both traditional (diet/activity) and less-studied obesity risk factors (stress/sleep), measurement of both adult and child outcomes, social networking support for geographically dispersed households, and a community selected active control group. Our data will address a literature gap regarding multiple risk factors and their relationship to health outcomes in American Indian families.

American Indian (AI) children are disproportionately affected by unintentional injuries, with injury mortality rates approximately 2.3 times higher than the combined rates for all children in the United States. Although multiple risk factors are known to contribute to these increased rates, a comprehensive, culturally informed curriculum that emphasizes child safety is lacking for this population. In response to this need, academic and tribal researchers, tribal community members, tribal wellness staff, and national child safety experts collaborated to develop a novel child safety curriculum. This paper describes its development and community delivery. We developed the safety curriculum as part of a larger randomized controlled trial known as Healthy Children, Strong Families 2 (HCSF2), a family-based intervention targeting obesity prevention in early childhood (2-5 years). During the development of the HCSF2 intervention, participating tribal communities expressed concern about randomizing enrolled families to a control group who would not receive an intervention. To address this concern and the significant disparities in injuries and unintentional death rates among AI children, we added an active control group (Safety Journey) that would utilize our safety curriculum. Satisfaction surveys administered at the 12-month time point of the intervention indicate 94% of participants (N = 196) were either satisfied or very satisfied with the child safety curriculum. The majority of participants (69%) reported spending more than 15 min with the curriculum materials each month, and 83% thought the child safety newsletters were either helpful or very helpful in making changes to improve their family's safety. These findings indicate these child safety materials have been well received by HCSF2 participants. The use of community-engaged approaches to develop this curriculum represents a model that could be adapted for other at-risk populations and serves as an initial step toward the creation of a multi-level child safety intervention strategy.

Objective: American Indian children of pre-school age have disproportionally high obesity rates and consequent risk for related diseases. Healthy Children, Strong Families was a family-based randomized trial assessing the efficacy of an obesity prevention toolkit delivered by a mentor v. mailed delivery that was designed and administered using community-based participatory research approaches., Design: During Year 1, twelve healthy behaviour toolkit lessons were delivered by either a community-based home mentor or monthly mailings. Primary outcomes were child BMI percentile, child BMI Z-score and adult BMI. Secondary outcomes included fruit/vegetable consumption, sugar consumption, television watching, physical activity, adult health-related self-efficacy and perceived health status. During a maintenance year, home-mentored families had access to monthly support groups and all families received monthly newsletters., Setting: Family homes in four tribal communities, Wisconsin, USA., Subjects: Adult and child (2-5-year-olds) dyads (n 150)., Results: No significant effect of the mentored v. mailed intervention delivery was found; however, significant improvements were noted in both groups exposed to the toolkit. Obese child participants showed a reduction in BMI percentile at Year 1 that continued through Year 2 (P<0·05); no change in adult BMI was observed. Child fruit/vegetable consumption increased (P=0·006) and mean television watching decreased for children (P=0·05) and adults (P=0·002). Reported adult self-efficacy for health-related behaviour changes (P=0·006) and quality of life increased (P=0·02)., Conclusions: Although no effect of delivery method was demonstrated, toolkit exposure positively affected adult and child health. The intervention was well received by community partners; a more comprehensive intervention is currently underway based on these findings.

Introduction: Since the 1950s, sexual health education in medical schools has been evaluated and reported upon, but there has never been an assessment published about sexual health curricula in U.S. physician assistant (PA) programs., Aim: The aim of this study was to gain better understanding of how PA programs cover sexual health topics., Methods: Between January and March 2014, 181 accredited PA programs received a mailed survey inquiring about their sexual health curriculum., Main Outcome Measures: The survey assessed general sexual health topics; lesbian, gay, bisexual, transgender (LGBT) topics; teaching methods; and the amount of time spent on sexual health education., Results: A total of 106 programs responded (59%). Ten programs offered a required, discrete course on human sexuality. The majority incorporated training into other coursework, which is consistent with most medical schools. LGBT topics were covered less thoroughly than the general sexual health topics. Total amount of time spent on sexual health topics varied widely among programs, from a minimum of 2-4 hours to a maximum of 60 hours, with a median of 12 hours., Conclusions: PA programs in the United States appear to compare favorably with the training offered to medical students in regard to time spent on sexual health education. Transgender issues were least well-covered of all the topics queried., (© 2015 International Society for Sexual Medicine.)

During the past decade, donor funding for health interventions in Kenya and other African countries has risen sharply. Focused on high-profile diseases such as HIV/AIDS, these funds create islands of intervention in a sea of under-resourced public health services. This paper draws on ethnographic research conducted in HIV clinics and in a public hospital to examine how health workers experience and reflect upon the juxtaposition of 'global' medicine with 'local' medicine. We show that health workers face an uneven playing field. High-prestige jobs are available in HIV research and treatment, funded by donors, while other diseases and health issues receive less attention. Outside HIV clinics, patient's access to medicines and laboratory tests is expensive, and diagnostic equipment is unreliable. Clinicians must tailor their decisions about treatment to the available medical technologies, medicines and resources. How do health workers reflect on working in these environments and how do their experiences influence professional ambitions and commitments?

This article explores the orientations of lay people in Kenya to science-specifically to biomedical knowledge about HIV--and their struggles to convert this knowledge into meaningful futures. In Kenya, the global response to the HIV-AIDS epidemic has resulted in a highly stratified landscape of intervention. Globally-funded treatment programs and clinical trials, focusing on HIV, channel transnational resources, expertise, and knowledge into specific sites--HIV clinics, NGOs, and research stations--inscribing these spaces as 'global' while leaving others decidedly 'local.' Rolled out in the form of 'projects,' these interventions offer resources and opportunities for a limited time only. Based on ethnographic fieldwork in the city of Kisumu, this article follows the circulation of biomedical knowledge through such projects and its conversion in ways beyond those imagined by policy-makers, as it meets the aspirations of city-dwellers and enters into local livelihoods. Mediated by nongovernmental organizations through workshops and certificates, this knowledge is both fragmentary and ephemeral. I explore the temporal and spatial implications of such knowledge for those who seek to attach themselves to it and shape their identities and futures in relation to it.

How are publics of protection and care defined in African cities today? The effects of globalization and neo-liberal policies on urban space are well documented. From London to São Paulo, denationalization, privatization, offshoring and cuts in state expenditure are creating enclaves and exclusions, resulting in fragmented, stratified social geographies (see Caldeira 2000; Ong 2006; Harvey 2006; Murray 2011). 'Networked archipelagoes', islands connected by transnational circulations of capital, displace other spatial relations and imaginaries. Spaces of encompassment, especially, such as 'the nation' or simply 'society' as defined by inclusion within a whole, lose practical value and intellectual purchase as referents of citizenship (Gupta and Ferguson 2002; Ferguson 2005). In African cities, where humanitarian, experimental or market logics dominate the distribution of sanitation and healthcare, this fragmentation is particularly stark (see, for example, Redfield 2006, 2012; Fassin 2007; Bredeloup et al . 2008; Nguyen 2012). Privilege and crisis interrupt older contiguities, delineating spaces and times of exception. The 'public' of health is defined by survival or consumption, obscuring the human as bearer of civic rights and responsibilities, as inhabitants of 'objective' material worlds 'common to all of us' (Arendt 1958: 52). Is it possible, under these conditions, to enact and imagine public health as a project of citizens, animated in civic space?

Over the past fifteen years, the city of Kisumu in western Kenya has emerged as an epicentre of 'global health' interventions, organized by non-governmental and transnational groups. These interventions involve concrete, practical engagements with the city's populations, but also imaginations and desires, as they intersect with residents' expectations of development. This article follows the hopes, aspirations and trajectories of people who attach themselves as volunteers to these interventions, or who hope to do so through a process they describe as 'tarmacking'. In exploring how volunteers orient themselves to ideas of 'empowerment' that are promoted by NGOs and also have influence outside institutional settings, it examines the relations between the landscapes of intervention, the spatial-temporal horizons, and the geographies of responsibility emergent in the city. Through its association with 'moving ahead' and with development, empowerment implies movement towards some kind of future. While there is a widely shared sense among volunteers that they are going somewhere, just where that might be is not clearly articulated. Rather than attempt to pinpoint this destination, this article follows their trajectories in an attempt to grasp why and how it remains obscure.

Background: Physician quality of work life is a key factor in career choice, satisfaction, and retention. The majority of physicians are currently employed by large health care organizations where physician loss of autonomy is common, yet some physicians have opened micropractices. There have been no previous studies comparing physician satisfaction between employed physicians and micropractice physicians., Methods: A previously validated survey of physician satisfaction was sent to 72 physicians practicing in a residency setting, 111 physicians in community, nonresidency setting, and 42 physicians in a micropractice setting., Results: Physicians in micropractices had the lowest satisfaction with income, but the highest satisfaction with family time and the ability to provide continuity of care. Micropractice physicians rated the overall quality of medical care they provide higher than employed physicians. Micropractice physicians reported a much smaller scope of practice., Conclusions: Overall, physicians in micropractices found more satisfaction in their work at the cost of decreased income and a narrower scope of practice.

Identities ascribed to research staff in face-to-face encounters with participants have been raised as key ethical challenge in transnational health research. 'Misattributed' identities that do not just deviate from researchers' self-image, but obscure unequivocal aspects of researcher identity - e.g. that they are researchers - are a case of such ethical problem. Yet, the reasonable expectation of unconcealed identity can conflict with another ethical premise: confidentiality; this poses challenges to staff visiting participants at home. We explore these around a case study of 'follow-up' staff, observed during an ethnographic study of a Kenyan HIV 'trial community', which included participant observation, conversations, and interviews with staff (n = 79) and participants (n = 89). We found that because of the need to maintain confidentiality and because of some suspicions towards researchers, research staff drew upon alternative identities - presenting themselves to non-participants as relatives or friends, rather than as researchers. Several staff experienced this as necessary but uncomfortable. Simultaneously, staff and participants forged close relations in line with their fictional identities, which however also posed challenges because they entailed personal responsibilities that were difficult to live up to, due to limited resources, and the trial's limited duration. Similar challenges may arise in transnational HIV treatment programmes and should be explored further in that context., (© 2013 Blackwell Publishing Ltd.)

American Indian (AI) children have the highest rates of obesity among ethnic groups in the United States, and rates continue to increase. This study was designed to examine the effects of prenatal and early postnatal factors on AI children's body mass index (BMI) trajectories, adiposity, and cardiovascular risk markers during early childhood. We screened 471 AI children (ages 5-8) from three Wisconsin tribes. Screenings included anthropometric and body fat measures and non-fasting lipid and glucose via fingerstick blood samples. Tribal records from Women Infants and Children (WIC) programs and clinic charts provided data on children's BMI trajectories, maternal prenatal factors, and the early postnatal feeding environment. Forty-seven percent of children were overweight or obese. Analysis of growth trajectories showed that children's BMI category was largely determined within the 1 year of life. Significant predictors of children's BMI category at age 1 included macrosomia (OR 4.38), excess gestational weight gain (OR 1.64) and early termination of breastfeeding (OR 1.66). Children who were overweight/obese at age 1 had greater odds of being overweight (OR 3.42) or obese (OR 3.36), and having unhealthy levels of body fat (OR 2.95) and LDL cholesterol (OR 1.64) at ages 5-8. Children's BMI category is determined in the early post-natal environment, within the 1 year of life, by factors including excess gestational weight gain and early termination of breastfeeding. In turn, children's BMI category at age 1 predicts the emergence of cardiovascular risk markers in early childhood.

Healthy Children, Strong Families (HCSF) is a 2-year, community-driven, family-based randomized controlled trial of a healthy lifestyles intervention conducted in partnership with four Wisconsin American Indian tribes. HCSF is composed of 1 year of targeted home visits to deliver nutritional and physical activity curricula. During Year 1, trained community mentors work with 2-5-year-old American Indian children and their primary caregivers to promote goal-based behavior change. During Year 2, intervention families receive monthly newsletters and attend monthly group meetings to participate in activities designed to reinforce and sustain changes made in Year 1. Control families receive only curricula materials during Year 1 and monthly newsletters during Year 2. Each of the two arms of the study comprises 60 families. Primary outcomes are decreased child body mass index (BMI) z-score and decreased primary caregiver BMI. Secondary outcomes include: increased fruit/vegetable consumption, decreased TV viewing, increased physical activity, decreased soda/sweetened drink consumption, improved primary caregiver biochemical indices, and increased primary caregiver self-efficacy to adopt healthy behaviors. Using community-based participatory research and our history of university-tribal partnerships, the community and academic researchers jointly designed this randomized trial. This article describes the study design and data collection strategies, including outcome measures, with emphasis on the communities' input in all aspects of the research.

Objective: To report dietary intake and physical activity among preschool-aged children living in rural American Indian communities before participation in a family-based healthy lifestyle intervention and to compare data to current age-specific recommendations., Subjects/design: One hundred thirty-five preschool-aged children, living in rural American Indian communities, provided diet and physical activity data before participating in a 2-year randomized healthy lifestyle intervention. Three 24-hour dietary recalls assessed nutrient and food and added sugar intake, which were compared to the National Academy of Science's Dietary Reference Intakes, the US Department of Agriculture's MyPyramid, and American Heart Association recommendations. Time watching television and moderate plus vigorous activity was compared to MyPyramid and American Academy of Pediatrics recommendations., Statistical Analysis: Nutrient, food group, added sugar intake, and time watching television and in moderate or vigorous activity were compared to recommendations by computing the percent of recommendations met. Nonparametric tests identified differences in diet and physical activity among age groups and normal and overweight children (body mass index <85th and > or = 85th percentile)., Results: Average nutrient intakes met recommendations whereas food group intakes did not. Mean fruit and vegetable intakes for 2- to 3-year-olds were 0.36 c/day fruit and 0.45 c/day vegetables and, for 4- to 5-year-olds, 0.33 c/day fruit and 0.48 c/day vegetables. Both age groups reported consuming more than 50 g added sugar, exceeding the recommendation of 16 g. Overweight vs normal weight children reported significantly more sweetened beverage intake (8.0+/-0.10 vs 5.28+/-0.08 oz/day, P<0.01). On average, all children reported watching television 2.0 hours/day and significant differences were observed for total television viewing and nonviewing time between overweight and normal weight children (8.52+/-0.6 vs 6.54+/-0.6 hours/day, P<0.01). All children engaged in <20 minutes/day of moderate or vigorous activity., Conclusions: Overall, children in this sample did not meet MyPyramid recommendations for fruits or vegetables and exceed added sugar intake recommendations. Television viewing time and time when the television was on in the home was highly prevalent along with low levels of moderate or vigorous activity. The Healthy Children Strong Families intervention we studied has potential for improving nutrition and physical activity among preschool-aged children living in rural American Indian communities., (Copyright 2010 American Dietetic Association. Published by Elsevier Inc. All rights reserved.)

This paper examines a sequence of investigations in parasitology, botany, pharmacology, psychometrics and ethnopsychology focused on Kenyan village children's knowledge of medicinal herbs. We follow this work of making and ordering of knowledge, showing that the different disciplinary perspectives on bodies, medicines, knowledges, children and cultures produced by this research all sought the foundation of knowledge in reference to objective reality, and that they aimed to make the world known in the specific form of distinct and comparable entities with individual properties and capacities. Based on subsequent ethnographic observations of healing in the same village, we outline a different, contrasting modality of knowing, which places ontology above epistemology. Medicinal knowledge and its transformational capacity are here not located within entities but between them; not in objective reality but in effects; 'to know' means 'to come together' with the implication of having an effect on one another. We use this ethnographic sketch of a different form of knowing as a foil against which to contrast the imaginary that had shaped our previous research. Beyond the stark contrast between herbal village healing and pharmacological laboratory analysis, we expand our argument by moving from natural science to social science, from studies of plants and substances to those of humans, minds and cultures; from laboratories to ethno-psychological tests, cultural models, and eventually econometrics. We suggest that by reiterating a particular scientific imaginary, remaking humans (and non-human beings) as known things, a specific notion of man and a related political economy of knowledge is naturalized. Looking back at our involvement with this sequence of research, we realize that, contrary to our intentions, our inclusion as 'social scientists' into a multidisciplinary scientific project may have exacerbated rather than mitigated its potentially problematic effects.

In this article an overview of the historical development of light water reactor health physics programs is presented. Operational health physics programs have developed and matured as experience in operating and maintaining light water reactors has been gained. Initial programs grew quickly in both size and complexity with the number and size of nuclear units under construction and in operation. Operational health physics programs evolved to face various challenges confronted by the nuclear industry, increasing the effectiveness of radiological safety measures. Industry improvements in radiological safety performance have resulted in significant decreases in annual collective exposures from a high value of 790 person-rem in 1980 to 117 person-rem per reactor in 2002. Though significant gains have been made, the continued viability of the nuclear power industry is confronted with an aging workforce, as well as the challenges posed by deregulation and the need to maintain operational excellence.

The agonist binding sites of the fetal muscle nicotinic acetylcholine receptor are formed at the interfaces of alpha-subunits and neighboring gamma- and delta-subunits. When the receptor is in the nonconducting desensitized state, the alpha-gamma site binds the agonist epibatidine 200-fold more tightly than does the alpha-delta site. To determine the structural basis for this selectivity, we constructed gamma/delta-subunit chimeras, coexpressed them with complementary wild-type subunits in HEK 293 cells, and determined epibatidine affinity of the resulting complexes. The results reveal three determinants of epibatidine selectivity: gamma104-117/delta106-delta119, gamma164-171/delta166-177, and gammaPro190/deltaAla196. Point mutations reveal that three sequence differences within the gamma104-117/delta106-delta119 region are determinants of epibatidine selectivity: gammaLys104/deltaTyr106, gammaSer111/deltaTyr113, and gammaTyr117/deltaTyr119. In the delta-subunit, simultaneous mutation of these residues to their gamma equivalent produces high affinity, gamma-like epibatidine binding. However, converting gamma to delta affinity requires replacement of the gamma104-117 segment with delta sequence, suggesting interplay of residues in this region. The structural basis for epibatidine selectivity is explained by computational docking of epibatidine to a homology model of the alpha-gamma binding site.

Objectives: Pediatric obesity is a significant and increasing problem in Native-American communities. The aim of this study was to determine whether parents and other caregivers from three Wisconsin tribes recognized overweight children. We also assessed caregiver attributes associated with levels of concern for risk of future overweight and chronic disease., Research Methods and Procedures: Data were obtained from child health screenings and caregiver surveys. Participants included 366 kindergarten-through-second grade child-caregiver dyads. Children's BMI percentiles were calculated and compared with caregiver responses. We assessed the relationships between predictors of caregiver concern for health risk factors and recognition of overweight., Results: Twenty-six percent of children were overweight (>or=95th percentile), and 19% were at risk for being overweight (>or=85th to <95th percentile) using Centers for Disease Control standards. Caregivers recognized only 15.1% of overweight children. Factors predictive of child overweight recognition included a child BMI >99th percentile and grandmother as caregiver. Overall, caregivers were more concerned about diabetes and cardiovascular disease than obesity. Parents with diabetes and heart disease were more concerned than others about risk for these diseases; however, only diabetic parents made a connection between child weight status and future risk of obesity-related disease. Child sex, child age, and parental education level were not significant predictors for caregiver recognition of an overweight child., Discussion: Most caregivers did not recognize overweight children or associate excess weight with increased risk of disease. When designing community interventions, it is crucial to incorporate caregivers' attitudes and beliefs regarding childhood overweight and risk of future disease.

In this article an overview of the historical development of light water reactor health physics programs is presented. Operational health physics programs have developed and matured as experience in operating and maintaining light water reactors has been gained. Initial programs grew quickly in both size and complexity with the number and size of nuclear units under construction and in operation. Operational health physics programs evolved to face various challenges confronted by the nuclear industry, increasing the effectiveness of radiological safety measures. Industry improvements in radiological safety performance have resulted in significant decreases in annual collective exposures from a high value of 790 person-rem in 1980 to 117 person-rem per reactor in 2002. Though significant gains have been made, the continued viability of the nuclear power industry is confronted with an aging workforce, as well as the challenges posed by deregulation and the need to maintain operational excellence.

Background: Alcohol abuse and alcoholism are leading causes of death among Native Americans. Little is known about the impact of negative childhood exposures, including parental alcoholism, childhood maltreatment, and out-of-home placement, on risk of lifetime DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) diagnosis of alcohol dependence in this population., Methods: Face-to-face interviews were conducted with 1660 individuals from seven Native American tribes from 1998 to 2001. Logistic regression was used to estimate the impact of specific types and number of different adverse childhood experiences on alcohol dependence. Relationships between tribe-specific cultural characteristics and alcohol dependence were also examined., Results: There were significant tribal differences in rates of alcohol dependence and several adverse childhood exposures. Lifetime prevalence of alcohol dependence was high among all tribes (men: 21%-56%, women: 17%-30%), but one (men: 1%, women: 2%). High prevalence rates were documented for one or more types of adverse childhood experiences (men: 74%-100%; women: 83%-93%). For men, combined physical and sexual abuse significantly increased the likelihood of subsequent alcohol dependence (odds ratio [OR]=1.58; 95% confidence interval [CI], 1.10-2.27). For women, sexual abuse (OR=1.79; 95% CI, 1.21-2.66) and boarding school attendance increased the odds of alcohol dependence (OR=1.57; 95% CI, 1.03-2.40). Two separate patterns of dose-response relationships were observed for men and women. Significant inter-tribal differences in rates of alcohol dependence remained after accounting for tribe-specific cultural factors and geographic region., Conclusions: Effects of childhood exposures on high-risk behaviors emphasize screening for violence in medical settings and development of social and educational programs for parents and children living on and near tribal reservations.

In a follow-up to studies of school-children's medical knowledge among the rural Luo of western Kenya, seven mothers were asked for their knowledge of plant medicine, and the 91 plant remedies mentioned by them were collected, 74 of these remedies were identified as 69 different species (in 13 cases, the material did not allow identification of the species, in two cases, only the family could be identified, and in two, not even this was possible). The results of this survey and some comments on Luo illness concepts are presented below and briefly discussed in relation to the earlier work on school-children and to another survey of Luo plant medicine in the same district. The article concludes that the consensual core of Luo plant medicine is known by ordinary mothers and their children as well as by recognised healers. It is a shared resource, that is used by women, mainly in the care for their children, and it is not an expert domain of knowledge, as is often, in studies of herbal or 'traditional' medicine are studied. The medicinal plants, upon which many mothers as well as healers agree should be examined further pharmacologically in order to assess their efficacy against the common infectious and parasitic diseases found in this area of western Kenya.

We used single-channel kinetic analysis to study the inhibitory effects of tacrine on human adult nicotinic receptors (nAChRs) transiently expressed in HEK 293 cells. Single channel recording from cell-attached patches revealed concentration- and voltage-dependent decreases in mean channel open probability produced by tacrine (IC(50) 4.6 microM at -70 mV, 1.6 microM at -150 mV). Two main effects of tacrine were apparent in the open- and closed-time distributions. First, the mean channel open time decreased with increasing tacrine concentration in a voltage-dependent manner, strongly suggesting that tacrine acts as an open-channel blocker. Second, tacrine produced a new class of closings whose duration increased with increasing tacrine concentration. Concentration dependence of closed-times is not predicted by sequential models of channel block, suggesting that tacrine blocks the nAChR by an unusual mechanism. To probe tacrine's mechanism of action we fitted a series of kinetic models to our data using maximum likelihood techniques. Models incorporating two tacrine binding sites in the open receptor channel gave dramatically improved fits to our data compared with the classic sequential model, which contains one site. Improved fits relative to the sequential model were also obtained with schemes incorporating a binding site in the closed channel, but only if it is assumed that the channel cannot gate with tacrine bound. Overall, the best description of our data was obtained with a model that combined two binding sites in the open channel with a single site in the closed state of the receptor.

Four nested, theoretically specified, increasingly complex models were tested representing cognitive mediation of rape's effects on mental, physical, and social health. Data were cross-sectional (N = 253 rape survivors). Outcomes were standardized assessments of social maladjustment, physical, and psychological symptoms, including posttraumatic stress disorder (PTSD). The best-fitting model was not fully cognitively mediated. Personological and rape characteristics influenced the level of self-blame experienced and the intensity of maladaptive beliefs about self and others. Self-blame and maladaptive beliefs predicted psychological distress, which strongly influenced all health outcomes. Self-ratings of rape memory characteristics contributed little to predicting postrape distress. The model accounted for 56% of the variance in general distress, including 91% of psychological symptom severity; 54% of PTSD symptoms; 65% of social maladjustment; and 17% of physical symptoms. Longitudinal replication is planned.

In a rural area of western Kenya, primary schoolchildren's health seeking behaviour in response to common illnesses was investigated. 57 primary schoolchildren (age 11-17 years, median 13 years) were interviewed weekly about their health status and health seeking activities for 30 weeks. The children each experienced on average 25 illness episodes during this period. Most episodes could be categorised into 4 groups: 'cold', 'headache', 'abdominal complaints' and 'injuries'. One fifth (21%) of the illness episodes were serious enough to keep the children from school. In 28% of them, an adult was consulted, while 72% were not reported to an adult caretaker. Of the episodes without adult involvement, 81% remained untreated, while 19% were treated by the children themselves with either herbal or Western medicines. Of all the medicines taken by the children, two thirds were provided or facilitated by adults (assisted treatment) and one third taken by the children themselves without adult involvement (self-treatment). Among boys, the proportion of illnesses, which were self-treated increased with age from 12% in the youngest age group (< 13 years) to 34% in the oldest (> 14 years). In girls, the proportion of illnesses which were self-treated was consistently lower than among boys and remained constant around 9% for all age groups. The proportion of Western pharmaceuticals used for self-treatment increased with age from 44% in the youngest age group to 63% in the oldest (average 52% Western pharmaceuticals). Again, there were differences between boys and girls: among the youngest age group, boys were twice as likely to use pharmaceuticals than girls (62 versus 32% of the self-treatments, respectively) and in the oldest age group they were nearly three times more likely (75 versus 25%, respectively). These differences in self-treatment practices and choice of medicines between girls and boys may reflect the higher income potential of boys, who can earn money by fishing. Pharmaceuticals were generally preferred for the treatment of headache and fevers, or colds, while herbal remedies were the preferred choice for the treatment of abdominal complaints and wounds. The most commonly used pharmaceuticals were antimalarials (mainly chloroquine), painkillers and antipyretics (mainly aspirin and paracetamol), which were stocked in most small shops in the village at low prices and readily sold to children. Throughout primary school age Kenyan children are growing into a pluralistic medical practice, integrating Western pharmaceuticals into the local herbal medical system, and gradually become autonomous agents in their health care.

The muscle acetylcholine receptor (AChR) has served as a prototype for understanding allosteric mechanisms of neurotransmitter-gated ion channels. The phenomenon of cooperative agonist binding is described by the model of Monod et al. (Monod, J., Wyman, J., and Changeux, J. P. (1965) J. Mol. Biol. 12, 88-118; MWC model), which requires concerted switching of the two binding sites between low and high affinity states. The present study examines binding of acetylcholine (ACh) and epibatidine, agonists with opposite selectivity for the two binding sites of mouse muscle AChRs. We expressed either fetal or adult AChRs in 293 HEK cells and measured agonist binding by competition against the initial rate of 125I-alpha-bungarotoxin binding. We fit predictions of the MWC model to epibatidine and ACh binding data simultaneously, taking as constants previously determined parameters for agonist binding and channel gating steps, and varying the agonist-independent parameters. We find that the MWC model describes the apparent dissociation constants for both agonists but predicts Hill coefficients that are far too steep. An Uncoupled model, which relaxes the requirement of concerted state transitions, accurately describes binding of both ACh and epibatidine and provides parameters for agonist-independent steps consistent with known aspects of AChR function.

We recently showed that at desensitized muscle nicotinic receptors, epibatidine selects by 300-fold between the two agonist binding sites. To determine whether receptors in the resting, activatible state show similar site selectivity, we studied epibatidine-induced activation of mouse fetal and adult receptors expressed in 293 HEK cells. Kinetic analysis of single-channel currents reveals that (-)-epibatidine binds with 15-fold selectivity to sites of adult receptors and 75-fold selectivity to sites of fetal receptors. For each receptor subtype, site selectivity arises solely from different rates of epibatidine dissociation from the two sites. To determine the structural basis for epibatidine selectivity, we introduced mutations into either the gamma or the delta subunit and measured epibatidine binding and epibatidine-induced single-channel currents. Complexes formed by alpha and mutant gamma(K34S+F172I) subunits bind epibatidine with increased affinity compared to alphagamma complexes, whereas the kinetics of alpha2betadeltagamma(K34S+F172I) receptors reveal no change in affinity of the low-affinity site, but increased affinity of the high-affinity site. Conversely, complexes formed by alpha and mutant delta(S36K+I178F) subunits bind epibatidine with decreased affinity compared to alphadelta complexes, whereas the kinetics of alpha2betagammadelta(S36K+I178F) and alpha2betaepsilondelta(S36K+I178F) receptors show markedly reduced sensitivity to epibatidine. The overall data show that epibatidine activates muscle receptors by binding with high affinity to alphagamma and alphaepsilon sites, but with low affinity to the alphadelta site.

In a cross sectional survey based in an antenatal clinic at Kilifi District Hospital, Coast Province, Kenya, 154 of 275 pregnant women (56%) reported eating soil regularly. Geophagous women had lower haemoglobin and serum ferritin concentrations than non-geophagous women (mean haemoglobin level 9.1 vs. 10.0 g/dL, P < 0.001; median ferritin level 4.5 vs. 9.0 micrograms/L, P < 0.001). In multiple linear regression analyses, geophagy was a significant predictor of haemoglobin (beta = -6.4, P = 0.01) and serum ferritin concentrations (beta = -6.6, P = 0.002), while controlling for gestational age and malaria and hookworm infection. Another 38 pregnant women, who reported eating soil regularly, participated in focus group discussions and were interviewed on geophagy. The most commonly eaten soil was from the walls of houses. The median estimated daily intake was 41.5 g (range 2.5-219.0 g). Twenty-seven of these women assisted in the collection of soil samples which were then analysed for their content of iron, zinc and aluminium after extraction with 0.1 M HC1. The average daily soil intake supplied the geophagous women with 4.3 mg of iron, corresponding to 14% of the recommended dietary allowance of iron for pregnant women. The study revealed a strong negative association between geophagy and both haemoglobin and ferritin status. At the same time it demonstrated the potential of soil as a source of dietary iron for geophagous women. These seemingly contradictory results might be due to other components in the soil interfering with iron uptake or metabolism. Alternatively, it may be that the geophagous women had extremely depleted iron stores before starting to eat soil. From these cross-sectional data, no inference about causality could be made.

Ligand binding sites in fetal (alpha2betagammadelta) and adult (alpha2betadeltaepsilon) muscle acetylcholine receptors are formed by alphadelta, alphagamma, or alphaepsilon subunit pairs. Each type of binding site shows unique ligand selectivity due to different contributions by the delta, gamma, or epsilon subunits. The present study compares epibatidine and carbamylcholine binding in terms of their site and state selectivities for muscle receptors expressed in human embryonic kidney 293 cells. Measurements of binding to alphagamma, alphadelta, and alphaepsilon intracellular complexes reveal opposite site selectivities between epibatidine and carbamylcholine; for epibatidine the rank order of affinities is alphaepsilon > alphagamma > alphadelta, whereas for carbamylcholine the rank order is alphadelta congruent with alphaepsilon > alphagamma. Because the relative affinities of intracellular complexes resemble those of receptors in the closed activable state, the results suggest that epibatidine binds with unique site selectivity in activating the muscle receptor. Measurements of binding at equilibrium show that both enantiomers of epibatidine bind to adult and fetal receptors with shallow but monophasic binding curves. However, when receptors are fully desensitized, epibatidine binds in a biphasic manner, with dissociation constants of the two components differing by more than 170-fold. Studies of subunit-omitted receptors (alpha2betadelta2, alpha2betagamma2, and alpha2betaepsilon2) reveal that in the desensitized state, the alphadelta interface forms the low affinity epibatidine site, whereas the alphagamma and alphaepsilon interfaces form high affinity sites. In contrast to epibatidine, carbamylcholine shows little site selectivity for desensitized fetal or adult receptors. Thus epibatidine is a potentially valuable probe of acetylcholine receptor binding site structure and of elements that confer state-dependent selectivities of the binding sites.

Agonists and antagonists select between the alphagamma and ns31744adelta binding sites of the fetal muscle acetylcholine receptor owing to different contributions by the gamma and delta subunits. To identify determinants of selectivity for agonists, we constructed a panel of gamma-delta subunit chimeras, co-expressed them with the alpha subunit in 293 HEK cells, and measured carbamylcholine binding affinity of intracellular complexes. Wild-type alphadelta complexes bind carbamylcholine about 30-fold more tightly than alphagamma complexes. This degree of selectivity is similar to that of the resting state of the receptor determined by kinetic analysis of single-channel events. We identify a primary set of determinants of selectivity, Lysgamma34/Serdelta36 and Phegamma172/Iledelta178, and a secondary set, Glugamma57/Aspdelta59 and Cysgamma115/Tyrdelta117. The contributions of all four determinants are subunit-dependent and are modified by interaction with one another. Coexpression of point mutant subunits with complementary wild-type subunits to form cell surface pentamers shows that Lysgamma34/Serdelta36 and Phegamma172/Iledelta178 contribute in a manner consistent with affecting selectivity of the resting state of the receptor, while Glugamma57 appears to contribute to the affinity of the desensitized state. The four determinants either coincide with or are close to residues known to contribute to the acetylcholine binding site. These results suggest that a minimum of four loops in the gamma and delta subunits contribute to the agonist binding site.

The calcium channel subtypes mediating nicotine-evoked [3H]dopamine release from rat striatal synaptosomes were probed with L-, N-, and P-type calcium channel ligands. Responses to nicotine were blocked by the peptides omega-conotoxin GVIA and omega-agatoxin IVA. The affinity constants for these compounds were consistent with their actions at N- and P-type channels, respectively. Together, these channels mediate at least 90% of the calcium-dependent response to nicotine. The L-type antagonists nifedipine, verapamil, and nicardipine were also effective blockers of nicotine-evoked release with maximal effects of 80-100% inhibition. However, these effects occurred at concentrations 2-3 orders of magnitude higher than those necessary to block L-type channels. Moreover, Bay K8644, an L-type agonist, also blocked nicotine-evoked release. Together, these findings argue strongly against the involvement of L-type channels.

[3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester] (TMB-8) has seen wide use as an "intracellular Ca2+ antagonist." However, this study shows that TMB-8 acts as a noncompetitive, functional antagonist at diverse nicotinic acetylcholine receptor (nAChR) subtypes with potencies that exceed those for other reported effects of TMB-8, including inhibition of intracellular Ca2+ mobilization. TMB-8 is a potent inhibitor (IC50 approximately 400 nM) of agonist-stimulated ion flux mediated by functional human muscle nAChR or ganglionic alpha 3 beta 4-nAChR subtypes expressed by TE671/RD or SH-SY5Y cells. TMB-8 is also a potent inhibitor (IC50 approximately 500 nM) of a functional, central nervous system nAChR subtype that mediates nicotinic agonist-stimulated [3H]dopamine release from rat brain synaptosomes. TMB-8 is much less potent (IC50 approximately 30-200 microM) as an inhibitor of high-affinity 3H-labeled acetylcholine or 125I-labeled alpha-bungarotoxin binding to human muscle nAChR, ganglionic alpha 3 beta 4-nAChR, or ganglionic alpha 7-nAChR subtypes. Moreover, functional inhibition by TMB-8 of muscle-type nAChR is due to a reduction in agonist efficacy, but not potency, and is proportionately stronger with increasing agonist concentration, thereby suggesting that TMB-8 acts as a noncompetitive inhibitor. Similar effects are observed for local anesthetics such as tetracaine and procaine (functional IC50 values of approximately 5 and approximately 50 microM, respectively), although TMB-8 is the most potent of these agents. Studies with TMB-8 or BAPTA [1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid] analogues indicate that the amino group of TMB-8 is essential and that Ca2+ chelation is not required for inhibition of nAChR function.(ABSTRACT TRUNCATED AT 250 WORDS)

The behavior and event-related potentials (ERPs) of high functioning subjects with autism (Autism group) were contrasted with the results of normal controls (Control group) during a focused visual attention, a focused auditory attention and a visual/auditory divided attention task. Detecting targets by the Autism group in the cross-modal divided attention condition was more difficult (longer RTs, lower % of correct detections) than attending to one modality. However, both the Autism and Control groups performed all tasks above chance level. The slow negative wave (SNW) was the only negative component which reflected Focused vs Divided task effect in Controls, being largest to stimuli in single channel-focused attention, intermediate when attention was divided between targets of two modalities and smallest to unattended stimuli. Task effects were more evident in the positive peaks for the Autism group. No significant divided attention task effect was noted for P3b, although it was larger for attended than ignored stimuli, of normal morphology and only slightly decreased in size in the Autism group as compared to the Control group. The failure of the Autism group to modulate the slow negative wave in response to Focused/Divided/Ignored conditions in a normal manner, the presence of relatively normal morphology despite the reduced amplitude of the P3b and other positive components, together with the high level of correct target detections are discussed in the context of a selective inhibition deficit and an alternative mechanism of selective attention in autism.