Dietary supplementation of cystinotic mice by lysine inhibits the megalin pathway and decreases kidney cystine content.

Megalin/LRP2 is a major receptor supporting apical endocytosis in kidney proximal tubular cells. We have previously reported that kidney-specific perinatal ablation of the megalin gene in cystinotic mice, a model of nephropathic cystinosis, essentially blocks renal cystine accumulation and partially preserves kidney tissue integrity. Here, we examined whether inhibition of the megalin pathway in adult cystinotic mice by dietary supplementation (5x-fold vs control regular diet) with the dibasic amino-acids (dAAs), lysine or arginine, both of which are used to treat patients with other rare metabolic disorders, could also decrease renal cystine accumulation and protect cystinotic kidneys. Using surface plasmon resonance, we first showed that both dAAs compete for protein ligand binding to immobilized megalin in a concentration-dependent manner, with identical inhibition curves by L- and D-stereoisomers. In cystinotic mice, 2-month diets with 5x-L-lysine and 5x-L-arginine were overall well tolerated, while 5x-D-lysine induced strong polyuria but no weight loss. All diets induced a marked increase of dAA urinary excretion, most prominent under 5x-D-lysine, without sign of kidney insufficiency. Renal cystine accumulation was slowed down approx. twofold by L-dAAs, and totally suppressed by D-lysine. We conclude that prolonged dietary manipulation of the megalin pathway in kidneys is feasible, tolerable and can be effective in vivo.

Ephrin-A3 is required for tonotopic map precision and auditory functions in the mouse auditory brainstem.

Tonotopy is a prominent feature of the vertebrate auditory system and forms the basis for sound discrimination, but the molecular mechanism that underlies its formation remains largely elusive. Ephrin/Eph signaling is known to play important roles in axon guidance during topographic mapping in other sensory systems, so we investigated its possible role in the establishment of tonotopy in the mouse cochlear nucleus. We found that ephrin-A3 molecules are differentially expressed along the tonotopic axis in the cochlear nucleus during innervation. Ephrin-A3 forward signaling is sufficient to repel auditory nerve fibers in a developmental stage-dependent manner. In mice lacking ephrin-A3, the tonotopic map is degraded and isofrequency bands of neuronal activation upon pure tone exposure become imprecise in the anteroventral cochlear nucleus. Ephrin-A3 mutant mice also exhibit a delayed second wave in auditory brainstem responses upon sound stimuli and impaired detection of sound frequency changes. Our findings establish an essential role for ephrin-A3 in forming precise tonotopy in the auditory brainstem to ensure accurate sound discrimination.

X-linked hypophosphatemic rickets: an Italian experts' opinion survey.

BACKGROUND: X-linked hypophosphatemic rickets (XLH) is the first cause of inherited hypophosphatemia and is caused by mutation in the PHEX gene, resulting in excessive expression of the phosphaturic factor FGF23. Symptoms are mainly related to rickets in children and osteomalacia in adults and cause several complications that can be highly invalidating. Due to its rarity, XLH is poorly known and diagnosis is frequently delayed. Conventional treatment is based on oral phosphate salts supplementation and activated vitamin D analogs, which however, cannot cure the disease in most cases. OBJECTIVE: Due to the low prevalence of XLH, an experts' opinion survey was conducted across Italian centers to collect data on XLH and on its management. METHODS: A questionnaire was developed by a group of experts to collect data on XLH epidemiology, diagnosis and treatment in Italy. RESULTS: Data from 10 Italian centers (nine of which pediatric) on 175 patients, followed between 1998 and 2017, were included in the survey. Most patients were followed since childhood and 63 children became adults during the investigated period. The diagnosis was made before the age of 1 and between 1 and 5 years in 11 and 50% of cases, respectively. Clinically apparent bone deformities were present in 95% of patients. These were ranked moderate/severe in 75% of subjects and caused growth stunting in 67% of patients. Other frequent complications included bone pain (40%), dental abscesses (33%), and dental malpositions (53%). Treatment protocols varied substantially among centers. Nephrocalcinosis was observed in 34% of patients. Tertiary hyperparathyroidism developed in 6% of patients. CONCLUSIONS: XLH remains a severe condition with significant morbidities.

Food Consumption Patterns of Infants and Toddlers: Findings from the Feeding Infants and Toddlers Study (FITS) 2016.

Background: The prevalence of obesity and type 2 diabetes continues to increase. These conditions disproportionately affect minorities and are associated with poor nutrition early in life. Current food-consumption patterns can inform pending dietary guidelines for infants and toddlers. Objective: The aim of this study was to describe infant feeding, complementary feeding, and food and beverage consumption patterns of 0- to 23.9-mo-olds in the general population. Methods: The Feeding Infants and Toddlers Study 2016 is a cross-sectional survey of caregivers of children aged <4 y. Dietary data were collected from a national random sample by using a 24-h dietary recall (n = 3235). The percentage of children consuming foods from >400 food groups was calculated. Differences in the percentage consuming between Hispanic, non-Hispanic white, and non-Hispanic black children aged 0-23.9 mo were evaluated with the use of ORs and 95% CIs. Results: Eighty-three percent of 0- to 23.9-mo-olds (n = 2635) were ever breastfed, 34% of 0- to 3.9-mo-olds (n = 305) and 15% of 4- to 5.9-mo-olds (n = 295) were exclusively breastfed, and 24% of 12- to 14.9-mo-olds (n = 412) consumed breast milk on the day of the recall. Complementary foods were more likely to be introduced before 4 mo in formula-fed infants (27%) than in infants who did not consume formula (5%). Half of 4- to 5.9-mo-olds consumed iron-fortified infant cereal, but few consumed iron-rich meats. Among toddlers (12-23.9 mo; n = 1133), >20% consumed no servings of fruit or vegetables on the day of the recall, approximately half consumed 100% fruit juice, and one-quarter to one-third consumed a sugar-sweetened beverage (SSB). Conclusions: Breastfeeding initiation and duration have improved, but exclusivity remains low. Low consumption of iron-rich foods, fruit, and vegetables and lack of variety in vegetable consumption are problems. Efforts to reduce the consumption of SSBs and 100% fruit juice are warranted in early childhood.

Total Usual Nutrient Intakes of US Children (Under 48 Months): Findings from the Feeding Infants and Toddlers Study (FITS) 2016.

Background: The US Dietary Guidelines will expand in 2020 to include infants and toddlers. Understanding current dietary intakes is critical to inform policy. Objective: The purpose of this analysis was to examine the usual total nutrient intakes from diet and supplements among US children. Methods: The Feeding Infants and Toddlers Study 2016 is a national cross-sectional study of children aged <48 mo (n = 3235): younger infants (birth to 5.9 mo), older infants (6-11.9 mo), toddlers (12-23.9 mo), younger preschoolers (24-36.9 mo), and older preschoolers (36-47.9 mo) based on the use of a 24-h dietary recall. A second 24-h recall was collected from a representative subsample (n = 799). Energy, total nutrient intake distributions, and compliance with Dietary Reference Intakes were estimated with the use of the National Cancer Institute method. Results: Dietary supplement use was 15-23% among infants and toddlers and 35-45% among preschoolers. Dietary intakes of infants were adequate, with mean intakes exceeding Adequate Intake for all nutrients except vitamins D and E. Iron intakes fell below the Estimated Average Requirement for older infants (18%). We found that 31-33% of children aged 12-47.9 mo had low percentage of energy from total fat, and >60% of children aged 24-47.9 mo exceeded the saturated fat guidelines. The likelihood of nutrient inadequacy for many nutrients was higher for toddlers: 3.2% and 2.5% greater than the Adequate Intake for fiber and potassium and 76% and 52% less than the Estimated Average Requirement for vitamins D and E, respectively. These patterns continued through older ages. Intakes exceeded the Tolerable Upper Intake Level of sodium, retinol, and zinc across most age groups. Conclusions: Dietary intakes of US infants are largely nutritionally adequate; concern exists over iron intakes in those aged 6-11.9 mo. For toddlers and preschoolers, high intake of sodium and low intakes of potassium, fiber, and vitamin D and, for preschoolers, excess saturated fat are of concern. Excess retinol, zinc, and folic acid was noted across most ages, especially among supplement users.

A Qualitative Analysis of Stress and Relaxation Themes Contributing to Burnout in First-Year Psychiatry and Medicine Residents.

OBJECTIVE: Qualitative research on trainee well-being can add nuance to the understanding of propagators of burnout, and the role for interventions aimed at supporting well-being. This qualitative study was conducted to identify (i) situations and environments that cause stress for trainees, (ii) stress-reducing activities that trainees utilize, and (iii) whether trainees who report distress (high burnout and depression scores) describe different stressors and relaxation factors than those who do not. METHODS: The study was conducted with a convenience sample of first-year medicine and psychiatry residents at a large urban teaching hospital. Participants were asked to complete electronic stress and relaxation diaries daily for 1 week. Diary entries were coded for recurrent themes. Participants were screened for burnout and depression. Codes were compared by subgroup based on baseline burnout and depression status to elucidate if specific themes emerged in these subgroups. RESULTS: Study sample included 51 interns. Sixteen (16/50, 32%) screened positive for burnout and three (3/50, 14%) had a positive depression screen. The most common stressors related to aspects of the learning environment, compounded by feeling under-equipped, overwhelmed, or out of time. The majority of relaxation activities involved social connection, food, other comforts, and occurred outside of the hospital environment. CONCLUSIONS: This study reveals that interns (regardless of burnout or depression screen) identify stressors that derive primarily from organizational, interpersonal, and cultural experiences of the learning environment; whereas relaxation themes are diversely represented across realms (home, leisure, social, health), though emphasize activities that occur outside of the work place.

High-content drug screening for rare diseases.

Per definition, rare diseases affect only a small number of subjects within a given population. Taken together however, they represent a considerable medical burden, which remains poorly addressed in terms of treatment. Compared to other diseases, obstacles to the development of therapies for rare diseases include less extensive physiopathology knowledge, limited number of patients to test treatments, and poor commercial interest from the industry. Recently, advances in high-throughput and high-content screening (HTS and HCS) have been fostered by the development of specific routines that use robot- and computer-assisted technologies to automatize tasks, allowing screening of a large number of compounds in a short period of time, using experimental model of diseases. These approaches are particularly relevant for drug repositioning in rare disease, which restricts the search to compounds that have already been tested in humans, thereby reducing the need for extensive preclinical tests. In the future, these same tools, combined with computational modeling and artificial neural network analyses, may also be used to predict individual clinical responses to drugs in a personalized medicine approach.

Early Initiation of Breastfeeding Among Maya Mothers in the Western Highlands of Guatemala: Practices and Beliefs.

BACKGROUND: Guatemala exhibits the sixth highest rate of child stunting worldwide, and stunting disproportionately affects Guatemala indigenous communities. In a country struggling to combat this result of malnutrition, early child nutrition is especially critical. Specifically, early initiation of breastfeeding is important for the development of newborn infants. Understanding beliefs and practices related to early initiation of breastfeeding in Maya Guatemala may provide an avenue to guide nutrition interventions in indigenous communities. Research aim: This study aimed to determine major beliefs and practices associated with early initiation of breastfeeding among Maya mothers in Lake Atitlán, Guatemala. METHODS: As part of a larger study to assess child nutrition in the Lake Atitlán region, we created a series of semistructured interview questions to document breastfeeding practices and beliefs among mothers. We conducted and audio-recorded in-person interviews that were translated from Kaqchikel, the local language, to Spanish by a community assistant. RESULTS: We conducted 178 interviews with mothers; 76% practiced early initiation. Early initiation was associated with the village and complementary feeding practices. Mothers held a variety of beliefs about the value of colostrum, and these beliefs were associated with the village. Mothers who held negative beliefs toward colostrum were more likely to delay breastfeeding initiation. CONCLUSION: Although most Maya mothers practice early initiation, the intervillage disparity in breastfeeding practices demonstrates a need to geographically focus breastfeeding interventions. Our novel insights into the breastfeeding beliefs among Maya mothers will serve as a guide to structure culturally competent breastfeeding education interventions in indigenous communities.

What parents say about disclosing the end of their pregnancy due to fetal abnormality.

OBJECTIVE: to describe men's and women's experiences of deciding whether to tell people in their social network, including their children, about their pregnancy loss following a termination for fetal abnormality. DESIGN: secondary analysis of qualitative narrative interview data informed by a critical realist approach. SETTING: respondents were recruited throughout the United Kingdom and interviewed at home between 2004 and 2005. PARTICIPANTS: twenty-eight women and nine men who had ended a pregnancy diagnosed with a fetal abnormality and who talked about disclosing or not disclosing the termination to others. FINDINGS: few respondents reported having any advice or information about whether or how to disclose their termination. None said they completely concealed their decision from adults in their social network; most said they disclosed selectively, telling close friends and family they had terminated and acquaintances they had miscarried. Most respondents reported telling their young children that the baby had died but did not reveal that they had chosen to end the pregnancy. A minority had not told their existing offspring about the pregnancy loss. Common reasons given for (partially) concealing a termination were: guilt over the decision; to avoid being judged; and to protect other people's feelings. Common reasons for disclosure were: others knew of the pregnancy; needing time off work; needing practical help and/or emotional support during diagnosis and termination; and wanting recognition of their loss. Positive consequences of disclosure were said to be getting more support and less criticism than expected; negative consequences included not getting the anticipated support and empathy; and encountering disapproval. Some respondents felt that concealing their pregnancy loss from their children had resulted in their confusion over the cause of their parents' distress. Some men said they found it hard to access emotional support from their social networks because of expectations about how men 'should' deal with emotions. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: midwives have to make difficult judgements about what, how and when to provide information when trying to support and advise parents who have ended a pregnancy due to fetal abnormality. Further education and training in this area could be of benefit. Midwives could signpost parents to existing sources of advice around disclosure, taking into account parents' individual preferences, help parents to consider the potential implications of disclosure and concealment and different ways of disclosing. They could also recommend alternative sources of emotional support, bearing in mind that men in particular may find it harder to access support from their social networks.

Fibroblast growth factor receptor 2 phosphorylation on serine 779 couples to 14-3-3 and regulates cell survival and proliferation.

The fibroblast growth factors (FGFs) exert their diverse (or pleiotropic) biological responses through the binding and activation of specific cell surface receptors (FGFRs). While FGFRs are known to initiate intracellular signaling through receptor tyrosine phosphorylation, the precise mechanisms by which the FGFRs regulate pleiotropic biological responses remain unclear. We now identify a new mechanism by which FGFR2 is able to regulate intracellular signaling and cellular responses. We show that FGFR2 is phosphorylated on serine 779 (S779) in response to FGF2. S779, which lies adjacent to the phospholipase Cgamma binding site at Y766, provides a docking site for the 14-3-3 phosphoserine-binding proteins and is essential for the full activation of the phosphatidylinositol 3-kinase and Ras/mitogen-activated protein kinase pathways. Furthermore, S779 signaling is essential for promoting cell survival and proliferation in both Ba/F3 cells and BALB/c 3T3 fibroblasts. This new mode of FGFR2 phosphoserine signaling via the 14-3-3 proteins may provide an increased repertoire of signaling outputs to allow the regulation of pleiotropic biological responses. In this regard, we have identified conserved putative phosphotyrosine/phosphoserine motifs in the cytoplasmic domains of diverse cell surface receptors, suggesting that they may perform important functional roles beyond the FGFRs.