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ABSTRACT Biofortification is regarded as a complement to supplementation, industrial fortification and dietary diversification in the fight against micronutrient deficiencies. It is important therefore to first identify areas where biofortification [...]

Background: Micronutrient deficiencies exact an enormous health burden on India. The release of the National Family Health Survey results--showing the relatively wealthy state of Gujarat having deficiency levels exceeding national averages--prompted Gujarat officials to introduce fortified wheat flour in their social safety net programs (SSNPs).Objective: To provide a case study of the introduction of fortified wheat flour in Gujarat's Public Distribution System (PDS), Integrated Child Development Scheme (ICDS), and Mid-Day Meal (MDM) Programme to assess the coverage, costs, impact, and cost-effectiveness of the initiative.Methods: India's 2004/05 National Sample Survey data were used to identify beneficiaries of each of Gujarat's three SSNPs and to estimate usual intake levels of vitamin A, iron, and zinc. Comparing age- and sex-specific usual intakes to Estimated Average Requirements, the proportion of the population with inadequate intakes was estimated. Postfortification intake levels and reductions in inadequate intake were estimated. The incremental cost of fortifying wheat flour and the cost-effectiveness of each program were estimated.Results: When each program was assessed independently, the proportion of the population with inadequate vitamin A intakes was reduced by 34% and 74% among MDM and ICDS beneficiaries, respectively. Both programs effectively eliminated inadequate intakes of both iron and zinc. Among PDS beneficiaries, the proportion with inadequate iron intakes was reduced by 94%. CONCLUSIONS. Gujarat's substitution of fortified wheat flour for wheat grain is dramatically increasing the intake of micronutrients among its SSNP beneficiaries. The incremental cost of introducing fortification in each of the programs is low, and, according to World Health Organization criteria, each program is "highly cost-effective." The introduction of similar reforms throughout India would largely eliminate the inadequate iron intake among persons participating in any of the three SSNPs and would have a significant impact on the global prevalence rate of inadequate iron intake. [ABSTRACT FROM AUTHOR]

Ignorance about the costs, case loads and case mixes of different hospitals within the public health system constitutes an important obstacle to reforming health care spending in many developing countries. National (tertiary) hospitals generally receive significantly larger budgets, per patient, than lower-level (district) hospitals. One reason for these differential allocations is the widely held belief that national hospitals treat persons with more difficult illnesses and persons who are more severely ill than do other, non-national, hospitals. This belief is but a presumption and one that warrants investigation. This paper analyzes expenditures among public hospitals in El Salvador over a 12-year period to address this question. While controlling for patient morbidity, outputs and other characteristics, district hospitals are found to be substantially underfunded relative to national hospitals. Four policy options to redress this situation are examined. [ABSTRACT FROM AUTHOR]

National hospitals in developing countries command a disproportionate share of medical care budgets, justified on the grounds that they have a more difficult patient case mix and higher occupancy rates than decentralized district hospitals or clinics. This paper empirically tests the hypothesis by developing direct measures of the severity of patient illness, hospital case-mix and a resource intensity index for each of El Salvador's public hospitals. Based on an analysis of inpatient care staffing requirements, national hospitals are found to receive funding far in excess of what case-mix and case-load considerations would warrant. The findings suggest that significant system-wide efficiency gains can be realized by allocating hospital budgets on the bases of performance-related criteria which incorporate the case-mix approach developed here. [ABSTRACT FROM PUBLISHER]

Background: The constrained evidence base of food and nutrition policy-making compromises nutrition programs. Nutrition policy-making must do better than relying exclusively on Food and Agriculture Organization Food Balance Sheets. The strategy of relying on observed-weighed food record or 24-hour recall surveys has not proven practical either; they remain few in number, generally not nationally representative, and of dubious external validity. Although Household Consumption and Expenditures Surveys (HCES) have shortcomings, they are increasingly being used to address this information gap. Objective: To promote dialog within the nutrition community, and between it and the greater community of HCES stakeholders, in order to identify their shared agenda and develop a strategy to improve HCES for analyzing food and nutrition issues. Methods: The diverse origins and objectives of HCES are described, the evolution of their use in addressing food and nutrition issues is traced, and their shortcomings are identified. Results: The causes, relative importance, some potential solutions, and the strategic implications of three distinct categories of shortcomings are discussed. Elements of a possible approach and process for strengthening the surveys are outlined, including identifying best practices, developing guidelines and more rigorously analyzing the tradeoffs involved in common, key survey design and implementation decisions. Conclusions: To date, the nutrition community's role in most HCES has been as a passive user of secondary data. The nutrition community must become more involved in the design, implementation, and analysis of HCES by identifying criteria for prioritizing countries, establishing assessment criteria, applying the criteria in retrospective assessments, identifying key shortcomings, and recommending alternatives to ameliorate the shortcomings. Several trends suggest that this is a propitious time for improving the relevance and reliability of HCES. [ABSTRACT FROM AUTHOR]

Background: Globally, there is a scarcity of national food consumption data that could help to assess food patterns and nutrient intakes of population groups. Estimates of food consumption patterns and apparent intakes of energy and nutrients could be obtained from national Household Consumption and Expenditures Surveys (HCES). Objective: To use the HCES conducted in Bangladesh in 2005 (HIES2005) to estimate apparent intakes of vitamin A, iron, and zinc. Methods: Food acquisition data from HIES2005, which surveyed 10,080 households, were transformed into standard measurement units. Intrahousehold food and nutrient distribution was estimated with Adult Male Equivalent (AME) units. Adequacy of intake was assessed by comparing individual nutrient intakes with requirements and was then aggregated by households. Results: The weighted mean energy intake for the population was 2,151 kcal/person/day, with a range among divisions from 1,950 in Barisal to 2,195 in Dhaka division. The apparent intakes of vitamin A and iron were insufficient to satisfy the recommended intakes for more than 80% of the population in Bangladesh, while apparent intakes of zinc, adjusted by bioavailability, satisfied the requirements of approximately 60% of the population. Conclusions: Using the HIES2005, we were able to produce estimates of apparent food consumption and intakes of some key micronutrients for the Bangladeshi population and observed wide differences among divisions. However, the methodological approaches reported here, although feasible and promising, need to be validated with other dietary intake methods. [ABSTRACT FROM AUTHOR]

Background: The dearth of 24-hour recall and observed-weighed food record data--what most nutritionists regard as the gold standard source of food consumption data-has long been an obstacle to evidence-based food and nutrition policy. There have been a steadily growing number of studies using household food acquisition and consumption data from a variety of multipurpose, nationally representative household surveys as a proxy measure to overcome this fundamental information gap. Objective: To describe the key characteristics of these increasingly available Household Consumption and Expenditures Surveys (HCES) in order to help familiarize food and nutrition analysts with the strengths and shortcomings of these data and thus encourage their use in low- and middle-income countries; and to identify common shortcomings that can be readily addressed in the near term in a country-by-country approach, as new HCES are fielded, thereby beginning a process of improving the potential of these surveys as sources of useful data for better understanding food- and nutrition-related issues. Methods: Common characteristics of key food and nutrition information that is available in HCES and some basic common steps in processing HCES data for food and nutrition analyses are described. Results: The common characteristics of these surveys are documented, and their usefulness in addressing major food and nutrition issues, as well as their shortcomings, is demonstrated. Conclusions: Despite their limitations, the use of HCES data constitutes a generally unexploited opportunity to address the food consumption information gap by using survey data that most countries are already routinely collecting. [ABSTRACT FROM AUTHOR]

Background: Individual dietary intake data are important for informing national nutrition policy but are rarely available. National Household Consumption and Expenditures Surveys (HCES) may be an alternative method, but there is no evidence to assess their relative performance. Objective: To compare HCES-based estimates of the nutrient density of foods consumed by Ugandan women (15 to 49 years of age) and children (24 to 59 months of age) with estimates based on 24-hour recall. Methods: The 52 food items of the Uganda 2006 HCES were matched with nutrient content of foods in a 2008 24-hour recall survey, which were used to refine the HCES-based estimates of nutrient intakes. Two methods were used to match the surveys'food items. Model 1 identified the four or five most commonly consumed foods from the 24-hour recall survey and calculated their unweighted average nutrient contents. Model 2 used the nutrient contents of the single most consumed food from the 24-hour recall. For each model, 14 estimates of nutrient densities of the diet were made and 84 differences were compared. Results: Models 1 and 2 were not significantly different. Of the model 2 HCES-24-hour recall comparisons, 67 (80%) did not find a significant difference. No significant differences were found for protein, fat, fiber, iron, thiamin, riboflavin, and vitamin B6 intakes. HCES overestimated intakes of vitamins C and B12 and underestimated intakes of vitamin A,folate, niacin, calcium, and zinc in at least one of the groups. Conclusions: The HCES-based estimates are a relatively good proxy for 24-hour recall measures of nutrient density of the diet. Further work is needed to ascertain nutrient adequacy using this method in several countries. [ABSTRACT FROM AUTHOR]

Background: Dietary assessment data are essential for designing, monitoring, and evaluating food fortification and other food-based nutrition programs. Planners and managers must understand the validity, usefulness, and cost tradeoffs of employing alternative dietary assessment methods, but little guidance exists.Objective: To identify and apply criteria to assess the tradeoffs of using alternative dietary methods for meeting fortification programming needs.Methods: Twenty-five semistructured expert interviews were conducted and literature was reviewed for information on the validity, usefulness, and cost of using 24-hour recalls, Food Frequency Questionnaires/Fortification Rapid Assessment Tool (FFQ/FRAT), Food Balance Sheets (FBS), and Household Consumption and Expenditures Surveys (HCES) for program stage-specific information needs. Criteria were developed and applied to construct relative rankings of the four methods.Results: Needs assessment: HCES offers the greatest suitability at the lowest cost for estimating the risk of inadequate intakes, but relative to 24-hour recall compromises validity.Design: HCES should be used to identify vehicles and to estimate coverage and likely impact due to its low cost and moderate-to-high validity. Baseline assessment: 24-hour recall should be applied using a representative sample. Monitoring: A simple, low-cost FFQ can be used to monitor coverage. Impact evaluation: 24-hour recall should be used to assess changes in nutrient intakes. FBS have low validity relative to other methods for all programmatic purposes.Conclusions: Each dietary assessment method has strengths and weaknesses that vary by context and purpose. Method selection must be driven by the program's data needs, the suitability of the methods for the purpose, and a clear understanding of the tradeoffs involved. [ABSTRACT FROM AUTHOR]

We explored sex-biased effects of the primary stress glucocorticoid hormone corticosterone on the miRNA expression profile in the rat hippocampus. Adult adrenalectomized (ADX) female and male rats received a single corticosterone (10 mg/kg) or vehicle injection, and after 6 h, hippocampi were collected for miRNA, mRNA, and Western blot analyses. miRNA profiling microarrays showed a basal sex-biased miRNA profile in ADX rat hippocampi. Additionally, acute corticosterone administration triggered a sex-biased differential expression of miRNAs derived from genes located in several chromosomes and clusters on the X and 6 chromosomes. Putative promoter analysis unveiled that most corticosterone-responsive miRNA genes contained motifs for either direct or indirect glucocorticoid actions in both sexes. The evaluation of transcription factors indicated that almost 50% of miRNA genes sensitive to corticosterone in both sexes was under glucocorticoid receptor regulation. Transcription factor-miRNA regulatory network analyses identified several transcription factors that regulate, activate, or repress miRNA expression. Validated target mRNA analysis of corticosterone-responsive miRNAs showed a more complex miRNA-mRNA interaction network in males compared to females. Enrichment analysis revealed that several hippocampal-relevant pathways were affected in both sexes, such as neurogenesis and neurotrophin signaling. The evaluation of selected miRNA targets from these pathways displayed a strong sex difference in the hippocampus of ADX-vehicle rats. Corticosterone treatment did not change the levels of the miRNA targets and their corresponding tested proteins. Our data indicate that corticosterone exerts a sex-biased effect on hippocampal miRNA expression, which may engage in sculpting the basal sex differences observed at higher levels of hippocampal functioning.

Sex differences in the brain have prompted many researchers to investigate the underlying molecular actors, such as the glucocorticoid receptor (GR). This nuclear receptor controls gene expression, including microRNAs (miRNAs), in non-neuronal cells. Here, we investigated sex-biased effects of GR on hippocampal miRNA expression and neuronal morphology by generating a neuron-specific GR knockout mouse ( Emx1-Nr3c1 -/- ). The levels of 578 mature miRNAs were assessed using NanoString technology and, in contrast to males, female Emx1-Nr3c1 -/- mice showed a substantially higher number of differentially expressed miRNAs, confirming a sex-biased effect of GR ablation. Based on bioinformatic analyses we identified several transcription factors potentially involved in miRNA regulation. Functional enrichment analyses of the miRNA-mRNA interactions revealed pathways related to neuronal arborization and both spine morphology and density in both sexes. Two recognized regulators of dendritic morphology, CAMKII-α and GSK-3β, increased their protein levels by GR ablation in female mice hippocampus, without changes in males. Additionally, sex-specific effects of GR deletion were observed on CA1 neuronal arborization and dendritic spine features. For instance, a reduced density of mushroom spines in apical dendrites was evidenced only in females, while a decreased length in basal dendrites was noted only in males. However, length and arborization of apical dendrites were reduced by GR ablation irrespective of the sex. Overall, our study provides new insights into the sex-biased GR actions, especially in terms of miRNAs expression and neuronal morphology in the hippocampus., Competing Interests: The authors declare that no competing interests exist., (© 2021 The Authors.)

Loperamide is a μ-opioid agonist with poor gastrointestinal absorption, mainly because of its modest aqueous solubility and being a P-glycoprotein (Pgp) efflux substrate. Nevertheless, studies associated with therapeutic effects strongly suggest that loperamide holds potential pharmacological advantages over traditional μ-opioid agonists commonly used for analgesia. Thus, in this Communication, we assessed in MDCK-hMDR1 cell lines the effects over loperamide uptake and efflux ratio, when loaded into Eudragit RS (ERS) nanocarriers coated with poloxamer 188 (P188). ERS was chosen for enhancing loperamide aqueous dispersibility and P188 as a potential negative Pgp modulator. In uptake assays, it was observed that Pgp limited the accumulation of loperamide into cells and that preincubation with P188, but not coincubation, led to increasing loperamide uptake at a similar extent of Pgp pharmacological inhibition. On the other hand, the efflux ratio displayed no alterations when Pgp was pharmacologically inhibited, whereas ERS/P188 nanocarriers effectively enhanced loperamide uptake and absorptive transepithelial transport. The latter suggests that loperamide transport across cells is significantly influenced by the presence of the unstirred water layer (UWL), which could hinder the visualization of Pgp-efflux effects during transport assays. Thus, results in this work highlight that formulating loperamide into this nanocarrier enhances its uptake and transport permeability.

Autism spectrum disorder (ASD) is a neurodevelopmental alteration characterized by social/communicative deficits, repetitive/stereotyped movements, and restricted/obsessive interests. However, there is not much information about whether movement alterations in ASD comprise modifications at the basic kinematic level, such as trajectory and velocity, which may contribute to the higher level of processing that allows the perception and interpretation of actions performed by others, and hence, impact social interaction. In order to further explore possible motor alterations in ASD, we analyzed movement parameters in the Valproate (VPA) animal model of autism. We found that VPA-treated rats displayed greater movement acceleration, reduced distance between stops, spent more time in the corner of the open-field arena, and executed a number of particular behaviors; for example, supported rearing and circling, with no major changes in distance and velocity. However, in the social interaction test, we found other alterations in the movement parameters. In addition to increased acceleration, VPA-rats displayed reduced velocity, increased stops, reduced distance/stop and lost the social/non-social area discrimination that is characteristic of control rats in acceleration and stops variables. Hence, even if prenatal VPA-treatment could have a minor effect in motor variables in a non-social context, it has a crucial effect in the capacity of the animals to adjust their kinematic variables when social/non-social context alternation is required., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Quezada, Salas-Ortíz, Peralta, Aguayo, Morgado-Gallardo, Mac-Rae, Fiedler and Aliaga.)

Several lines of evidence suggest that antidepressant drugs may act by modulating neuroplasticity pathways in key brain areas like the hippocampus. We have reported that chronic treatment with fasudil, a Rho-associated protein kinase inhibitor, prevents both chronic stress-induced depressive-like behavior and morphological changes in CA1 area. Here, we examined the ability of fasudil to (i) prevent stress-altered behaviors, (ii) influence the levels/phosphorylation of glutamatergic receptors and (iii) modulate signaling pathways relevant to antidepressant actions. 89 adult male Sprague-Dawley rats received intraperitoneal fasudil injections (10 mg/kg/day) or saline vehicle for 18 days. Some of these animals were daily restraint-stressed from day 5-18 (2.5 h/day). 24 hr after treatments, rats were either evaluated for behavioral tests (active avoidance, anxiety-like behavior and object location) or euthanized for western blot analyses of hippocampal whole extract and synaptoneurosome-enriched fractions. We report that fasudil prevents stress-induced impairments in active avoidance, anxiety-like behavior and novel location preference, with no effect in unstressed rats. Chronic stress reduced phosphorylations of ERK-2 and CREB, and decreased levels of GluA1 and GluN2A in whole hippocampus, without any effect of fasudil. However, fasudil decreased synaptic GluA1 Ser831 phosphorylation in stressed animals. Additionally, fasudil prevented stress-decreased phosphorylation of GSK-3β at Ser9, in parallel with an activation of the mTORC1/4E-BP1 axis, both in hippocampal synaptoneurosomes, suggesting the activation of the AKT pathway. Our study provides evidence that chronic fasudil treatment prevents chronic stress-altered behaviors, which correlated with molecular modifications of antidepressant-relevant signaling pathways in hippocampal synaptoneurosomes., Competing Interests: None., (© 2020 The Authors.)

Autism is a neurodevelopmental disorder characterized by a deep deficit in language and social interaction, accompanied by restricted, stereotyped and repetitive behaviors. The use of genetic autism animal models has revealed that the alteration of the mechanisms controlling the formation and maturation of neural circuits are points of convergence for the physiopathological pathways in several types of autism. Brain Derived Neurotrophic Factor (BDNF), a key multifunctional regulator of brain development, has been related to autism in several ways. However, its precise role is still elusive, in part, due to its extremely complex posttranscriptional regulation. In order to contribute to this topic, we treated prenatal rats with Valproate, a well-validated model of autism, to analyze BDNF levels in the hippocampus of juvenile rats. Valproate-treated rats exhibited an autism-like behavioral profile, characterized by a deficit in social interaction, anxiety-like behavior and repetitive behavior. In situ hybridization (ISH) experiments revealed that Valproate reduced BDNF mRNA, especially long-3'UTR-containing transcripts, in specific areas of the dentate gyrus (DG) and CA3 regions. At the same time, Valproate reduced BDNF immunoreactivity in the suprapyramidal and lucidum layers of CA3, but improved hippocampus-dependent spatial learning. The molecular changes reported here may help to explain the cognitive and behavioral signs of autism and reinforce BDNF as a potential molecular target for this neurodevelopmental disorder., (Copyright © 2019 Fuentealba, Fiedler, Peralta, Avalos, Aguayo, Morgado-Gallardo and Aliaga.)

Oral bioavailability of loperamide is restricted by its limited absorption in the gastrointestinal tract due to its poor aqueous solubility and its P-glycoprotein (Pgp) substrate characteristic. In addition, ammonium methacrylate copolymers have shown to have mucoadhesive properties, whereas poloxamer 188, has been suggested as a Pgp inhibitor. Thus, in this work, we evaluate conditions that affect physicochemical parameters of ammonium methacrylate/poloxamer 188-based nanocarriers loaded with loperamide hydrochloride. Nanocarriers were synthesized by nanoprecipitation, enhancing loperamide encapsulation efficiency by modifying the aqueous phase to basic pH. The isolation of the non-encapsulated drug fraction from the nanocarriers-incorporated fraction was conducted by centrifugation, ultrafiltration, vacuum filtration and diafiltration. The last method was effective in providing a deeper understanding of drug-nanocarrier loading and interactions by means of modeling the data obtained by it. Through diafiltration, it was determined an encapsulation efficiency of about 93%, from which a 38% ±6 was shown to be reversibly (thermodynamic interaction) and a 62% ±6 irreversibly (kinetic interaction) bound. Finally, release profiles were assessed through empirical and semi-empirical modeling, showing a biphasic release behavior (burst effect 11.34% and total release at 6 h = 33% ±1). Thus, encapsulation efficiency and release profile were shown to have a strong mathematical modeling-based correlation, providing the mechanistic approach presented in this article a solid support for future translational investigations., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Several studies have shown that a single exposure to stress may improve or impair learning and memory processes, depending on the timing in which the stress event occurs with relation to the acquisition phase. However, to date there is no information about the molecular changes that occur at the synapse during the stress-induced memory modification and after a recovery period. In particular, there are no studies that have evaluated-at the same time-the temporality of stress and stress recovery period in hippocampal short-term memory and the effects on dendritic spine morphology, along with variations in N -methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunits. The aim of our study was to take a multidimensional approach to investigate concomitant behavioral, morphological and molecular changes induced by a single restraint stress exposure (2.5 h) and a recovery period of 6 and 24 h in rats. We found that acute stress elicited a reduced preference to explore an object placed in a novel position (a hippocampal-dependent task). These changes were accompanied by increased activity of LIM kinase I (LIMK; an actin-remodeling protein) and increased levels of NR2A subunits of NMDA receptors. After 6 h of recovery from stress, rats showed similar preference to explore an object placed in a novel or familiar position, but density of immature spines increased in secondary CA1 apical dendrites, along with a transient rise in GluA2 AMPA receptor subunits. After 24 h of recovery from stress, the animals showed a preference to explore an object placed in a novel position, which was accompanied by a normalization of NMDA and AMPA receptor subunits to control values. Our data suggest that acute stress produces reversible molecular and behavioral changes 24 h after stress, allowing a full reestablishment of hippocampal-related memory. Further studies need to be conducted to deepen our understanding of these changes and their reciprocal interactions.Adaptive stress responses are a promising avenue to develop interventions aiming at restoring hippocampal function impaired by repetitive stress exposure.

Studies conducted in rodents subjected to chronic stress and some observations in humans after psychosocial stress, have allowed to establish a link between stress and the susceptibility to many complex diseases, including mood disorders. The studies in rodents have revealed that chronic exposure to stress negatively affects synaptic plasticity by triggering changes in the production of trophic factors, subunit levels of glutamate ionotropic receptors, neuron morphology, and neurogenesis in the adult hippocampus. These modifications may account for the impairment in learning and memory processes observed in chronically stressed animals. It is plausible then, that stress modifies the interplay between signal transduction cascades and gene expression regulation in the hippocampus, therefore leading to altered neuroplasticity and functioning of neural circuits. Considering that miRNAs play an important role in post-transcriptional-regulation of gene expression and participate in several hippocampus-dependent functions; we evaluated the consequences of chronic stress on the expression of miRNAs in dorsal (anterior) portion of the hippocampus, which participates in memory formation in rodents. Here, we show that male rats exposed to daily restraint stress (2.5 h/day) during 7 and 14 days display a differential profile of miRNA levels in dorsal hippocampus and remarkably, we found that some of these miRNAs belong to the miR-379-410 cluster. We confirmed a rise in miR-92a and miR-485 levels after 14 days of stress by qPCR, an effect that was not mimicked by chronic administration of corticosterone (14 days). Our in silico study identified the top-10 biological functions influenced by miR-92a, nine of which were shared with miR-485: Nervous system development and function, Tissue development, Behavior, Embryonic development, Organ development, Organismal development, Organismal survival, Tissue morphology, and Organ morphology. Furthermore, our in silico study provided a landscape of potential miRNA-92a and miR-485 targets, along with relevant canonical pathways related to axonal guidance signaling and cAMP signaling, which may influence the functioning of several neuroplastic substrates in dorsal hippocampus. Additionally, the combined effect of miR-92a and miR-485 on transcription factors, along with histone-modifying enzymes, may have a functional relevance by producing changes in gene regulatory networks that modify the neuroplastic capacity of the adult dorsal hippocampus under stress.

A single stress exposure facilitates memory formation through neuroplastic processes that reshape excitatory synapses in the hippocampus, probably requiring changes in extracellular matrix components. We tested the hypothesis that matrix metalloproteinase 9 (MMP-9), an enzyme that degrades components of extracellular matrix and synaptic proteins such as β-dystroglycan (β-DG 43 ), changes their activity and distribution in rat hippocampus during the acute stress response. After 2.5 h of restraint stress, we found (i) increased MMP-9 levels and potential activity in whole hippocampal extracts, accompanied by β-DG 43 cleavage, and (ii) a significant enhancement of MMP-9 immunoreactivity in dendritic fields such as stratum radiatum and the molecular layer of hippocampus. After 24 h of stress, we found that (i) MMP-9 net activity rises at somatic field, i.e., stratum pyramidale and granule cell layers, and also at synaptic field, mainly stratum radiatum and the molecular layer of hippocampus, and (ii) hippocampal synaptoneurosome fractions are enriched with MMP-9, without variation of its potential enzymatic activity, in accordance with the constant level of cleaved β-DG 43 . These findings indicate that stress triggers a peculiar timing response in the MMP-9 levels, net activity, and subcellular distribution in the hippocampus, suggesting its involvement in the processing of substrates during the stress response.

Serotonin acts through its receptors (5-HTRs) to shape brain networks during development and modulates essential functions in mature brain. The 5-HT 1A R is mainly located at soma of hippocampal neurons early during brain development and its expression gradually shifts to dendrites during postnatal development. The 5-HT 7 R expressed early during hippocampus development, shows a progressive reduction in its expression postnatally. Considering these changes during development, we evaluated in cultured hippocampal neurons whether the 5-HT 1A R and 5-HT 7 R change their expression, modulate dendritic growth, and activate signaling pathways such as ERK1/2, AKT/GSK3β and LIMK/cofilin, which may sustain dendrite outgrowth by controlling cytoskeleton dynamics. We show that mRNA levels of both receptors increase between 2 and 7 DIV; however only protein levels of 5-HT 7 R increase significantly at 7 DIV. The 5-HT 1A R is preferentially distributed in the soma, while 5-HT 7 R displays a somato-dendritic localization at 7 DIV. Through stimulation with 5-HT at 7 DIV during 24h and using specific antagonists, we determined that 5-HT 1A R decreases the number of primary and secondary dendrites and restricts the growth of primary dendrites. The activation of 5-HT 1A R and 5-HT 7 R promotes the growth of short secondary dendrites and triggers ERK1/2 and AKT phosphorylation through MEK and PI3K activation respectively; without changes in the phosphorylation of LIMK and cofilin. We conclude that 5-HT 1A R restricts dendritogenesis and outgrowth of primary dendrites, but that both 5-HT 1A R and 5-HT 7 R promote secondary dendrite outgrowth. These data support the role of 5-HT in neuronal outgrowth during development and provide insight into cellular basis of neurodevelopmental disorders., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Despite acknowledged shortcomings, household consumption and expenditure surveys (HCES) are increasingly being used to proxy food consumption because they are relatively more available and affordable than surveys using more precise dietary assessment methods. One of the most common, significant sources of HCES measurement error is their under-estimation of food away from home (FAFH). In 2011, India's National Survey Sample Organization introduced revisions in its HCES questionnaire that included replacing "cooked meals"-the single item in the food consumption module designed to capture FAFH at the household level-with five more detailed and explicitly FAFH sub-categories. The survey also contained a section with seven, household member-specific questions about meal patterns during the reference period and included three sources of meals away from home (MAFH) that overlapped three of the new FAFH categories. By providing a conceptual framework with which to organize and consider each household member's meal pattern throughout the reference period, and breaking down the recalling (or estimating) process into household member-specific responses, we assume the MAFH approach makes the key respondent's task less memory- and arithmetically-demanding, and thus more accurate than the FAFH household level approach. We use the MAFH estimates as a reference point, and approximate one portion of FAFH measurement error as the differences in MAFH and FAFH estimates. The MAFH estimates reveal marked heterogeneity in intra-household meal patterns, reflecting the complexity of the HCES's key informant task of reporting household level data, and underscoring its importance as a source of measurement error. We find the household level-based estimates of FAFH increase from just 60.4% of the individual-based estimates in the round prior to the questionnaire modifications to 96.7% after the changes. We conclude that the MFAH-FAFH linked approach substantially reduced FAFH measurement error in India. The approach has wider applicability in global efforts to improve HCES.

Myelin basic protein (MBP) is a key component of myelin, the specialized lipid membrane that encases the axons of all neurons. Both plasminogen (Pg) and tissue-type plasminogen activator (t-PA) bind to MBP with high affinity. We investigated the kinetics and mechanisms involved in this process using immobilized MBP and found that Pg activation by t-PA is significantly stimulated by MBP. This mechanism involves the binding of t-PA via a lysine-dependent mechanism to the Lys 91 residue of the MBP NH 2 -terminal region Asp 82 -Pro 99 , and the binding of Pg via a lysine-dependent mechanism to the Lys 122 residue of the MBP COOH-terminal region Leu 109 -Gly 126 . In this context, MBP mimics fibrin and because MBP is a plasmin substrate, our results suggest direct participation of the Pg activation system on MBP physiology., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Previous studies in rats have demonstrated that chronic restraint stress triggers anhedonia, depressive-like behaviors, anxiety and a reduction in dendritic spine density in hippocampal neurons. In this study, we compared the effect of repeated stress on the expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) receptor subunits in dorsal and ventral hippocampus (VH). Adult male Sprague-Dawley rats were randomly divided into control and stressed groups, and were daily restrained in their motion (2.5 h/day) during 14 days. We found that chronic stress promotes an increase in c-Fos mRNA levels in both hippocampal areas, although it was observed a reduction in the immunoreactivity at pyramidal cell layer. Furthermore, Arc mRNAs levels were increased in both dorsal and VH, accompanied by an increase in Arc immunoreactivity in dendritic hippocampal layers. Furthermore, stress triggered a reduction in PSD-95 and NR1 protein levels in whole extract of dorsal and VH. Moreover, a reduction in NR2A/NR2B ratio was observed only in dorsal pole. In synaptosomal fractions, we detected a rise in NR1 in dorsal hippocampus (DH). By indirect immunofluorescence we found that NR1 subunits rise, especially in neuropil areas of dorsal, but not VH. In relation to AMPA receptor (AMPAR) subunits, chronic stress did not trigger any change, either in dorsal or ventral hippocampal areas. These data suggest that DH is more sensitive than VH to chronic stress exposure, mainly altering the expression of NMDA receptor (NMDAR) subunits, and probably favors changes in the configuration of this receptor that may influence the function of this area.

Background: Dendritic arbor simplification and dendritic spine loss in the hippocampus, a limbic structure implicated in mood disorders, are assumed to contribute to symptoms of depression. These morphological changes imply modifications in dendritic cytoskeleton. Rho GTPases are regulators of actin dynamics through their effector Rho kinase. We have reported that chronic stress promotes depressive-like behaviors in rats along with dendritic spine loss in apical dendrites of hippocampal pyramidal neurons, changes associated with Rho kinase activation. The present study proposes that the Rho kinase inhibitor Fasudil may prevent the stress-induced behavior and dendritic spine loss., Methods: Adult male Sprague-Dawley rats were injected with saline or Fasudil (i.p., 10 mg/kg) starting 4 days prior to and maintained during the restraint stress procedure (2.5 h/d for 14 days). Nonstressed control animals were injected with saline or Fasudil for 18 days. At 24 hours after treatment, forced swimming test, Golgi-staining, and immuno-western blot were performed., Results: Fasudil prevented stress-induced immobility observed in the forced swimming test. On the other hand, Fasudil-treated control animals showed behavioral patterns similar to those of saline-treated controls. Furthermore, we observed that stress induced an increase in the phosphorylation of MYPT1 in the hippocampus, an exclusive target of Rho kinase. This change was accompanied by dendritic spine loss of apical dendrites of pyramidal hippocampal neurons. Interestingly, increased pMYPT1 levels and spine loss were both prevented by Fasudil administration., Conclusion: Our findings suggest that Fasudil may prevent the development of abnormal behavior and spine loss induced by chronic stress by blocking Rho kinase activity., (© The Author 2016. Published by Oxford University Press on behalf of CINP.)

Serotonin (5-HT) is a neurotransmitter that plays an important role in neuronal plasticity. Variations in the levels of 5-HT at the synaptic cleft, expression or dysfunction of 5-HT receptors may alter brain development and predispose to various mental diseases. Here, we review the transduction pathways described in various cell types transfected with recombinant 5-HT 1A receptor (5-HT 1A R), specially contrasting with those findings obtained in neuronal cells. The 5-HT 1A R is detected in early stages of neural development and is located in the soma, dendrites and spines of hippocampal neurons. The 5-HT 1A R differs from other 5-HT receptors because it is coupled to different pathways, depending on the targeted cell. The signaling pathway associated with this receptor is determined by G α isoforms and some cascades involve βγ signaling. The activity of 5-HT 1A R usually promotes a reduction in neuronal excitability and firing, provokes a variation in cAMP and Ca 2+ , levels which may be linked to specific types of behavior and cognition. Furthermore, evidence indicates that 5-HT 1A R induces neuritogesis and synapse formation, probably by modulation of the neuronal cytoskeleton through MAPK and phosphoinositide-3-kinase (PI3K)-Akt signaling pathways. Advances in understanding the actions of 5-HT 1A R and its association with different signaling pathways in the central nervous system will reveal their pivotal role in health and disease.

Objective: The prevalence of maternal anaemia remains unacceptably high in developing countries. At the same time, the percentage of women who consume one or more Fe+folic acid (IFA) tablets during pregnancy remains persistently low. The objective of the present study was to identify where, within antenatal care (ANC) programmes, pregnant women falter in obtaining and consuming an ideal minimum of 180 IFA tablets., Design: Data from Demographic and Health Surveys were used to develop a schematic which identifies four sequential 'falter points' to consuming 180 IFA tablets: ANC attendance, IFA receipt or purchase, IFA consumption and the number of tablets consumed., Setting: Twenty-two countries with high burdens of undernutrition., Subjects: A sample of 162 958 women, 15 to 49 years of age, with a live birth in the past 5 years., Results: Across all countries, 83 % of all pregnant women had at least one ANC visit, 81 % of whom received IFA tablets. Of those receiving IFA tablets, 95 % consumed at least one. Overall adherence to the ideal supplementation regimen, however, was extremely low: only 8 % consumed 180 or more IFA tablets. There were only two countries in which the percentage of pregnant women consuming 180 or more tablets exceeded 30 %., Conclusions: While most women receive and take some IFA tablets, few receive or take enough. The analysis identifies where ANC-based distribution of IFA falters in each country. It enables policy makers to design and prioritize follow-up activities to more precisely identify barriers, an essential next step to improving IFA distribution through ANC.

Chronic stress promotes cognitive impairment and dendritic spine loss in hippocampal neurons. In this animal model of depression, spine loss probably involves a weakening of the interaction between pre- and postsynaptic cell adhesion molecules, such as N-cadherin, followed by disruption of the cytoskeleton. N-cadherin, in concert with catenin, stabilizes the cytoskeleton through Rho-family GTPases. Via their effector LIM kinase (LIMK), RhoA and ras-related C3 botulinum toxin substrate 1 (RAC) GTPases phosphorylate and inhibit cofilin, an actin-depolymerizing molecule, favoring spine growth. Additionally, RhoA, through Rho kinase (ROCK), inactivates myosin phosphatase through phosphorylation of the myosin-binding subunit (MYPT1), producing actomyosin contraction and probable spine loss. Some micro-RNAs negatively control the translation of specific mRNAs involved in Rho GTPase signaling. For example, miR-138 indirectly activates RhoA, and miR-134 reduces LIMK1 levels, resulting in spine shrinkage; in contrast, miR-132 activates RAC1, promoting spine formation. We evaluated whether N-cadherin/β-catenin and Rho signaling is sensitive to chronic restraint stress. Stressed rats exhibit anhedonia, impaired associative learning, and immobility in the forced swim test and reduction in N-cadherin levels but not β-catenin in the hippocampus. We observed a reduction in spine number in the apical dendrites of CA1 pyramidal neurons, with no effect on the levels of miR-132 or miR-134. Although the stress did not modify the RAC-LIMK-cofilin signaling pathway, we observed increased phospho-MYPT1 levels, probably mediated by RhoA-ROCK activation. Furthermore, chronic stress raises the levels of miR-138 in accordance with the observed activation of the RhoA-ROCK pathway. Our findings suggest that a dysregulation of RhoA-ROCK activity by chronic stress could potentially underlie spine loss in hippocampal neurons., (© 2015 Wiley Periodicals, Inc.)

Background: Micronutrient interventions are contributing to substantial reductions in global morbidity and mortality. As the diversity and coverage of these interventions expand, it is increasingly important to understand their distinct roles and contributions, and the resources they require. To date, comparing program resource use has been hampered by several noncomparabilities in cost studies relating to diverse intervention activities and service delivery pathways, along with differences in methodological approaches., Objective: To promote better understanding of the variations and noncomparabilities in costs and cost structures of micronutrient interventions., Methods: Cost studies on supplementation, fortification and biofortification programs from the published and gray literature were reviewed (n = 130)., Results: Specific areas of noncomparability identified include intervention characteristics and country context, as well as differences in methodological considerations, including data sources and definition of cost centers. Moreover, analyses vary significantly in terms of types of costs included. Implications and practical recommendations for standardizing future costing studies are provided., Conclusions: Methodological variations and non-comparabilities do much more than limit the ability to make direct comparisons of costing studies; they carry important implications for the adoption, design, and implementation of interventions in countries suffering from micronutrient deficiencies. This study synthesizes evidence on the level of support required (both financial and otherwise) for programs to achieve desirable levels of coverage and performance. Having comparable and accurate estimates of costs is a necessary first step in planning for and implementing interventions that are of adequate scale and adequately resourced.

Background: Approximately 1.2 million disability-adjusted life years (DALYs) are lost annually in Bangladesh due to deficiencies of vitamin A, iron, and zinc., Objective: To provide evidence on the coverage, costs, and cost-effectiveness of alternative fortification interventions to inform nutrition policy-making in Bangladesh., Methods: Combining the 2005 Bangladesh Household Income and Expenditure Survey with a Bangladesh food composition table, apparent intakes of energy, vitamin A, iron, and zinc, and the coverage and apparent consumption levels of fortifiable vegetable oil and wheat flour are estimated. Assuming that fortification levels are those established in official regulations, the costs and cost-effectiveness of the two vehicles are assessed independently and as a two-vehicle portfolio., Results: Vegetable oil has a coverage rate of 76% and is estimated to reduce the prevalence of inadequate vitamin A intake from 83% to 64%. The coverage of wheat flour is high (65%), but the small quantities consumed result in small reductions in the prevalence of inadequate intakes: 1.5 percentage points for iron, less than 1 for zinc, and 2 for vitamin A, while reducing average Estimated Average Requirement (EAR) gaps by 8%, 9%, and 15%, respectively. The most cost-effective 10-micronutrient wheat flour formulation costs US $1.91 million annually, saving 129,212 DALYs at a unit cost of US $14.75. Fortifying vegetable oil would cost US $1.27 million annually, saving 406,877 DALYs at an average cost of US $3.25. Sensitivity analyses explore various permutations of the wheat flour formulation. Divisional variations in coverage, cost, and impact are examined., Conclusions: Vegetable oil fortification is the most cost-effective of the three portfolios analyzed, but all three are very cost-effective options for Bangladesh.

Objective: Vitamin A deficiency is a serious health problem in Bangladesh. The 2011-12 Bangladesh Micronutrient Survey found 76·8% of children of pre-school age were vitamin A deficient. In the absence of nationally representative, individual dietary assessment data, we use an alternative--household income and expenditure survey data--to estimate the potential impact of the introduction of vitamin A-fortified vegetable oil in Bangladesh., Design: Items in the household income and expenditure survey were matched to food composition tables to estimate households' usual vitamin A intakes. Then, assuming (i) the intra-household distribution of food is in direct proportion to household members' share of the household's total adult male consumption equivalents, (ii) all vegetable oil that is made from other-than mustard seed and that is purchased is fortifiable and (iii) oil fortification standards are implemented, we modelled the additional vitamin A intake due to the new fortification initiative., Setting: Nationwide in Bangladesh., Subjects: A weighted sample of 12,240 households comprised of 55,580 individuals., Results: Ninety-nine per cent of the Bangladesh population consumes vegetable oil. The quantities consumed are sufficiently large and, varying little by socio-economic status, are able to provide an important, large-scale impact. At full implementation, vegetable oil fortification will reduce the number of persons with inadequate vitamin A intake from 115 million to 86 million and decrease the prevalence of inadequate vitamin A intake from 80% to 60%., Conclusions: Vegetable oil is an ideal fortification vehicle in Bangladesh. Its fortification with vitamin A is an important public health intervention.

Background: Systematic collection of national agricultural data has been neglected in many low- and middle-income countries for the past 20 years. Commonly conducted nationally representative household surveys collect substantial quantities of highly underutilized food crop production data., Objective: To demonstrate the potential usefulness of commonly available household survey databases for analyzing the agriculture-nutrition nexus., Methods: Using household data from the 2010 Bangladesh Household Income and Expenditure Survey, the role and significance of crop selection, area planted, yield, nutrient production, and the disposition of 34 food crops in affecting the adequacy of farming households' nutrient availability and nutrient intake status are explored. The adequacy of each farming household's available energy, vitamin A, calcium, iron, and zinc and households' apparent intakes and intake adequacies are estimated. Each household's total apparent nutrient intake adequacies are estimated, taking into account the amount of each crop that households consume from their own production, together with food purchased or obtained from other sources., Results: Even though rice contains relatively small amounts of micronutrients, has relatively low nutrient density, and is a relatively poor source of nutrients compared with what other crops can produce on a given tract of land, because so much rice is produced in Bangladesh, it is the source of 90% of the total available energy, 85% of the zinc, 67% of the calcium, and 55% of the iron produced by the agricultural sector. The domination of agriculture and diet by rice is a major constraint to improving nutrition in Bangladesh. Simple examples of how minor changes in the five most common cropping patterns could improve farming households' nutritional status are provided., Conclusions: Household surveys' agricultural modules can provide a useful tool for better understanding national nutrient production realities and possibilities.

Normal hypothalamic-pituitary-adrenal (HPA) axis activity leading to the rhythmic and episodic release of adrenal glucocorticoids (GCs) is essential for body homeostasis and survival during stress. Acting through specific intracellular receptors in the brain and periphery, GCs regulate behaviour, as well as metabolic, cardiovascular, immune and neuroendocrine activities. By contrast to chronic elevated levels, circadian and acute stress-induced increases in GCs are necessary for hippocampal neuronal survival and memory acquisition and consolidation, as a result of the inhibition of apoptosis, the facilitation of glutamatergic neurotransmission and the formation of excitatory synapses, and the induction of immediate early genes and dendritic spine formation. In addition to metabolic actions leading to increased energy availability, GCs have profound effects on feeding behaviour, mainly via the modulation of orexigenic and anorixegenic neuropeptides. Evidence is also emerging that, in addition to the recognised immune suppressive actions of GCs by counteracting adrenergic pro-inflammatory actions, circadian elevations have priming effects in the immune system, potentiating acute defensive responses. In addition, negative-feedback by GCs involves multiple mechanisms leading to limited HPA axis activation and prevention of the deleterious effects of excessive GC production. Adequate GC secretion to meet body demands is tightly regulated by a complex neural circuitry controlling hypothalamic corticotrophin-releasing hormone (CRH) and vasopressin secretion, which are the main regulators of pituitary adrenocorticotrophic hormone (ACTH). Rapid feedback mechanisms, likely involving nongenomic actions of GCs, mediate the immediate inhibition of hypothalamic CRH and ACTH secretion, whereas intermediate and delayed mechanisms mediated by genomic actions involve the modulation of limbic circuitry and peripheral metabolic messengers. Consistent with their key adaptive roles, HPA axis components are evolutionarily conserved, being present in the earliest vertebrates. An understanding of these basic mechanisms may lead to novel approaches for the development of diagnostic and therapeutic tools for disorders related to stress and alterations of GC secretion., (© 2014 British Society for Neuroendocrinology.)

Background: Increased cortisol levels and genetic polymorphisms have been related to both major depressive disorder and antidepressant treatment outcome. The aim of this study is to evaluate the relationship between circadian salivary cortisol levels, cortisol suppression by dexamethasone and genetic polymorphisms in some HPA axis-related genes to the response to placebo and fluoxetine in depressed patients., Methods: The diagnosis and severity of depression were performed using the Mini International Neuropsychiatric Interview (M.I.N.I.) and Hamilton depression scale (HAM-D17), respectively. Euthyroid patients were treated with placebo (one week) followed by fluoxetine (20 mg) (two months). Severity of depression was re-evaluated after placebo, three weeks and two months of fluoxetine treatments. Placebo response was defined as HAM-D17 score reductions of at least 25% and to < 15. Early response and response were reductions of at least 50% after three weeks and two months, and remission with ≤ 7 after two months. Plasma TSH, free-T4, circadian salivary cortisol levels and cortisol suppression by dexamethasone were evaluated. Seven genetic polymorphisms located in the Corticotrophin-releasing-hormone-receptor-1 (rs242939, rs242941, rs1876828), Corticotrophin-releasing-hormone-receptor-2 (rs2270007), Glucocorticoid-receptor (rs41423247), FK506-binding-protein-5 (rs1360780), and Arginine-vasopressin (rs3729965) genes were determined. Association analyses between response to placebo/fluoxetine and polymorphism were performed by chi-square or Fisher exact test. Cortisol levels were compared by t-test, ANOVA and the general linear model for repeated measures., Results: 208 depressed patients were recruited, 187 of whom were euthyroid. Placebo responders, fluoxetine responders and remitters exhibited significantly lower circadian cortisol levels than those who did not respond (p-values of 0.014, 0.008 and 0.021 respectively). Patients who abandoned treatment before the third week also exhibited a trend to low cortisol levels (p = 0.057). The polymorphisms rs242939 (CRHR1) and rs2270007 (CRHR2) were not in Hardy-Weinberg equilibrium. Only the rs242939 polymorphism (CRHR1) exhibited association with early response (three weeks) to fluoxetine (p-value = 0.043). No other association between outcomes and polymorphisms was observed., Conclusions: These results support the clinical relevance of low salivary cortisol levels as a predictor of antidepressant response, either to placebo or to fluoxetine. Only one polymorphism in the CRHR1 gene was associated with the early response. Other factors may be involved in antidepressant response, although further studies are needed to identify them.

Serotonin (5-HT) production and expression of 5-HT receptors (5-HTRs) occur early during prenatal development. Recent evidence suggests that, in addition to its classical role as a neurotransmitter, 5-HT regulates neuronal connectivity during mammalian development by modulating cell migration and neuronal cytoarchitecture. Given the variety of 5-HTRs, researchers have had difficulty clarifying the specific role of each receptor subtype in brain development. Signalling mediated by the G-protein-coupled 5-HT1A R and 5-HT7 R, however, has been associated with neuronal plasticity. Thus, we hypothesized that 5-HT promotes neurite outgrowth through 5-HT1A R and 5-HT7 R. The involvement of 5-HT1A R and 5-HT7 R in the morphology of rat hippocampal neurons was evaluated by treating primary cultures at 2 days in vitro with 5-HT and specific antagonists for 5-HT1A R and 5-HT7 R (WAY-100635 and SB269970, respectively). The stimulation of hippocampal neurons with 100 nM 5-HT for 24 hr produced no effect on either the number or the length of primary neurites. Nonetheless, after 5HT7 R was blocked, the addition of 5-HT increased the number of primary neurites, suggesting that 5HT7 R could inhibit neuritogenesis. In contrast, 5-HT induced secondary neurite outgrowth, an effect inhibited by 1 μM WAY-100635 or SB269970. These results suggest that both serotonergic receptors participate in secondary neurite outgrowth. We conclude that 5-HT1A R and 5-HT7 R regulate neuronal morphology in primary hippocampal cultures by promoting secondary neurite outgrowth., (© 2014 Wiley Periodicals, Inc.)

The economic feasibility of maize flour and maize meal fortification in Kenya, Uganda, and Zambia is assessed using information about the maize milling industry, households' purchases and consumption levels of maize flour, and the incremental cost and estimated price impacts of fortification. Premix costs comprise the overwhelming share of incremental fortification costs and vary by 50% in Kenya and by more than 100% across the three countries. The estimated incremental cost of maize flour fortification per metric ton varies from $3.19 in Zambia to $4.41 in Uganda. Assuming all incremental costs are passed onto the consumer, fortification in Zambia would result in at most a 0.9% increase in the price of maize flour, and would increase annual outlays of the average maize flour-consuming household by 0.2%. The increases for Kenyans and Ugandans would be even less. Although the coverage of maize flour fortification is not likely to be as high as some advocates have predicted, fortification is economically feasible, and would reduce deficiencies of multiple micronutrients, which are significant public health problems in each of these countries., (© 2013 New York Academy of Sciences.)

Background: Twice annually, Uganda implements Child Days Plus (CDP), a month-long outreach activity that distributes vitamin A capsules to preschool children and deworms children 6 months to 14 years old. Introduced initially as a temporary, interim strategy, CDP is now a decade old., Objective: To assess how well CDP is implemented using an activity-based cost analysis., Methods: In the absence of a cost-accounting system for CDP, we defined the six major CDP activities as cost centers and identified five important subactivities required to implement a round of CDP. Based on a purposive sample, we conducted a structured interview survey of 59 Ministry of Health facilities, 9 district offices, and national-level CDP staff., Results: Only one-third of the facilities implemented all 11 CDP core activities. The survey revealed that Ministry of Health staff and volunteers are frequently paid substantially less in allowances than they are entitled to for their CDP outreach activities. Viewing these two practices--nonimplementation and less-than-full-reimbursement--as indicators of CDP's underfinancing, we estimate the program is underfinanced by the equivalent of 37% of its 'full implementation" costs. Two-thirds of underfinancing is manifested in nonimplementation and one-third as less-than full-reimbursement. CDP exploits economies of scale and scope and has an average cost per child served of US$0.22. We estimate that it annually saves 367,000 disability-adjusted life-years (DALYs) at an average cost of US$12.5, making it--despite its underfinancing--highly cost-effective., Conclusions and Recommendations: Increased CDP funding would enable its vitamin A coverage rate of 58% and its deworming coverage rate of 62% to be increased, thereby increasing its effectiveness and efficiency. CDP should be "relaunched," as part of an effort to improve the structure of the program, set expectations about it, and earmark a minimum of resources for CDP. The Ministry of Health should demonstrate its new, greater commitment to CDP by introducing a program-specific budget line item, increasing CDP's budget allocation, and developing and implementing a training program that identifies the minimum uniform activities required to implement CDP.

Background: Micronutrient deficiencies continue to constitute a major burden of disease, particularly in Africa and South Asia. Programs to address micronutrient deficiencies have been increasing in number, type, and scale in recent years, creating an ever-growing need to understand their combined coverage levels, costs, and impacts so as to more effectively combat deficiencies, avoid putting individuals at risk for excess intakes, and ensure the efficient use of public health resources., Objective: To analyze combinations of the two current programs--sugar fortification and Child Health Week (CHW)--together with four prospective programs--vegetable oil fortification, wheat flour fortification, maize meal fortification, and biofortified vitamin A maize--to identify Zambia's optimal vitamin A portfolio., Methods: Combining program cost estimates and 30-year Zambian food demand projections, together with the Zambian 2005 Living Conditions Monitoring Survey, the annual costs, coverage, impact, and cost-effectiveness of 62 Zambian portfolios were modeled for the period from 2013 to 2042., Results: Optimal portfolios are identified for each of five alternative criteria: average cost-effectiveness, incremental cost-effectiveness, coverage maximization, health impact maximization, and affordability. The most likely scenario is identified to be one that starts with the current portfolio and takes into account all five criteria. Starting with CHW and sugar fortification, it phases in vitamin A maize, oil, wheat flour, and maize meal (in that order) to eventually include all six individual interventions., Conclusions: Combining cost and Household Consumption and Expenditure Survey (HCES) data provides a powerful evidence-generating tool with which to understand how individual micronutrient programs interact and to quantify the tradeoffs involved in selecting alternative program portfolios.

Child Health Weeks (CHWs) are semi-annual, campaign-style, facility- and outreach-based events that provide a package of high-impact nutrition and health services to under-five children. Since 1999, 30% of the 85 countries that regularly implement campaign-style vitamin A supplementation programmes have transformed their programmes into CHW. Using data drawn from districts' budget, expenditures and salary documents, UNICEF's CHW planning and budgeting tool and a special purposive survey, an economic analysis of the June 2010 CHW's provision of measles, vitamin A and deworming was conducted using activity-based costing combined with an ingredients approach. Total CHW costs were estimated to be US$5.7 million per round. Measles accounted for 57%, deworming 22% and vitamin A 21% of total costs. The cost per child was US$0.46. The additional supplies and personnel required to include measles increased total costs by 42%, but reduced the average costs of providing vitamin A and deworming alone, manifesting economies of scope. The average costs of covering larger, more urban populations was less than the cost of covering smaller, more dispersed populations. Provincial-level costs per child served were determined primarily by the number of service sites, not the number of children treated. Reliance on volunteers to provide 60% of CHW manpower enables expanding coverage, shortening the duration of CHWs and reduces costs by one-third. With costs of $1093 per life saved and $45 per disability-adjusted life-year saved, WHO criteria classify Zambia's CHWs as 'very cost-effective'. The continued need for CHWs is discussed.

Background. Since fortification of sugar with vitamin A was mandated in 1998, Zambia's fortification program has not changed, while the country remains plagued by high rates ofmicronutrient deficiencies. Objective. To provide evidence-based fortification options with the hope of reinvigorating the Zambian fortification program. Methods. Zambia's 2006 Living Conditions Monitoring Survey is used to estimate the apparent intakes of vitamin A, iron, and zinc, as well as the apparent consumption levels and coverage of four fortification vehicles. Fourteen alternativefoodfortification portfolios are modeled, and their costs, impacts, average cost-effectiveness, and incremental cost-effectiveness are calculated using three alternative impact measures. Results. Alternative impact measures result in different rank orderings of the portfolios. The most cost-effective portfolio is vegetable oil, which has a cost per disability-adjusted life-year (DALY) saved ranging from 12% to 25% of that of sugar, depending on the impact measure used. The public health impact of fortified vegetable oil, however, is relatively modest. Additional criteria beyond cost-effectiveness are introduced and used to rank order the portfolios. The size of the public health impact, the total cost, and the incremental cost-effectiveness of phasing in multiple vehicle portfolios over time are analyzed. Conclusions. Assessing fortification portfolios by measuring changes in the prevalence of inadequate intakes underestimates impact. A more sensitive measure, which also takes into account change in the Estimated Average Requirement (EAR) gap, is provided by a dose-response-based approach to estimating the number ofDALYs saved. There exist highly cost-effective fortification intervention portfolios with substantial public health impacts and variable price tags that could help improve Zambians' nutrition status.

Background: Observed-Weighed Food Record Surveys (OWFR) are regarded as the most precise dietary assessment methodology, despite their recognized shortcomings, which include limited availability, high cost, small samples with uncertain external validity that rarely include all household members, Hawthorne effects, and using only 1 or 2 days to identify "usual intake." Although Household Consumption and Expenditures Surveys (HCES) also have significant limitations, they are increasingly being used to inform nutrition policy, Objective: To investigate differences in fortification simulations based on OWFR and HCES from Bangladesh., Methods: The pre- and postfortification nutrient intake levels from the two surveys were compared., Results: The total population-based rank orderings of oil, wheat flour, and sugar coverage were identical for the two surveys. OWFR found differences in women's and children's coverage rates and average quantities consumed for all three foods that were not detected by HCES. Guided by the Food Fortification Formulator, we found that these differences did not result in differences in recommended fortification levels. Differences were found, however, in estimated impacts: although both surveys found that oil would be effective in reducing the prevalence of inadequate vitamin A intake among both subpopulations, only OWFR also found that sugar and wheat flour fortification would significantly reduce inadequate vitamin A intake among children., Conclusions: Despite the less precise measure of food consumption from HCES, the two surveys provide similar guidance for designing a fortification program. The external validity of these findings is limited. With relatively minor modifications, the precision of HCES in dietary assessment and the use ofHCES in fortification programming could be strengthened.

Background: Zambia was a pioneer when it started fortifying sugar with vitamin A in 1998. Micronutrient deficiencies-especially among young children-have changed little over the past decade. In 2008 an initiative to introduce fortified flours was halted when last-hour questions about the program could not be answered., Objective: To provide information about the need, coverage, and impact of alternative fortification portfolio options to help Zambia overcome its fortification impasse., Methods: Using household data from the 2006 Living Conditions Monitoring Survey, apparent micronutrient intake levels and apparent consumption levels of sugar, vegetable oil, wheat flour and maize meal were estimated. The household level data were used to estimate individual intakes by assuming that food was distributed among household members in direct proportion to their share of the household's total adult consumption equivalent. Intake adequacy was measured relative to age- and gender-specific Estimated Average Requirements. Combining information on the industrial structure and estimated fortifiable quantities consumed of each food, and assuming the nutrient content is that specified in official regulations, simulations were conducted of the coverage and impact of 14 fortification portfolios., Results: Maize, the most commonly consumed food, is consumed in a fortifiable form by only 23% of the population. Sugar fortification is estimated to have reduced inadequate intake of vitamin A from 87% to 79%. Introducing oil fortification could reduce the prevalence of inadequate vitamin A intake to 61%, and fortifying roller and breakfast maize meal would further reduce it to 57%, and reduce inadequate iron and zinc intakes by 2.2% and 5.5%, respectively. Implementing WHO flour guidelines would triple the potential iron and zinc impacts., Conclusion: Analysis of LCMS apparent consumption data have helped address important information gaps and provide better understanding of the coverage and impacts of alternative fortification portfolios.

Background: The technical and resource demands of the most precise dietary assessment methods, 24-hour recall and observed-weighed food records, have proven impractical for most low- and middle-income countries, leaving nutrition policymakers with a woefully inadequate evidence base and compromising nutrition program effectiveness., Objective: To better understand the relative costs of informing food and nutrition policy-making using two different data sources: 24-hour recall survey data and Household Consumption and Expenditures Survey (HCES) data., Methods: A comparative analysis of the costs of designing, implementing, and analyzing a 24-hour recall survey and the cost of secondary analysis of HCES data., Results: The cost of conducting a 24-hour recall survey with a sample of the size typical of HCES would be roughly 75 times higher than the cost of analyzing the HCES data., Conclusions: Although the 24-hour recall method is undoubtedly more precise, it has become self-evident that the practical choice for most countries is not between these two surveys, but between having data from less precise, but much more readily available and affordable HCES or having no nationally representative data. In the light of growing concerns about inappropriate fortification policies developed without data, there is an urgent need to begin working to strengthen HCES to provide more precise food and nutrition data. The best way forward is not likely to rest with one data source or another, but with the development of an eclectic approach that exploits the strengths and weaknesses of alternative surveys and uses them to complement one another.

This study assessed the cost-effectiveness of adding the community-based management of severe acute malnutrition (CMAM) to a community-based health and nutrition programme delivered by community health workers (CHWs) in southern Bangladesh. The cost-effectiveness of this model of treatment for severe acute malnutrition (SAM) was compared with the cost-effectiveness of the 'standard of care' for SAM (i.e. inpatient treatment), augmented with community surveillance by CHWs to detect cases, in a neighbouring area. An activity-based cost model was used, and a societal perspective taken, to include all costs incurred in the programme by providers and participants for the management of SAM in both areas. Cost data were coupled with programme effectiveness data. The community-based strategy cost US$26 per disability-adjusted life year (DALY) averted, compared with US$1344 per DALY averted for inpatient treatment. The average cost to participant households for their child to recover from SAM in community treatment was one-sixth that of inpatient treatment. These results suggest that this model of treatment for SAM is highly cost-effective and that CHWs, given adequate supervision and training, can be employed effectively to expand access to treatment for SAM in Bangladesh.

The risk for neuropsychiatric illnesses has a strong sex bias, and for major depressive disorder (MDD), females show a more than 2-fold greater risk compared to males. Such mood disorders are commonly associated with a dysregulation of the hypothalamo-pituitary-adrenal (HPA) axis. Thus, sex differences in the incidence of MDD may be related with the levels of gonadal steroid hormone in adulthood or during early development as well as with the sex differences in HPA axis function. In rodents, organizational and activational effects of gonadal steroid hormones have been described for the regulation of HPA axis function and, if consistent with humans, this may underlie the increased risk of mood disorders in women. Other developmental factors, such as prenatal stress and prenatal overexposure to glucocorticoids can also impact behaviors and neuroendocrine responses to stress in adulthood and these effects are also reported to occur with sex differences. Similarly, in humans, the clinical benefits of antidepressants are associated with the normalization of the dysregulated HPA axis, and genetic polymorphisms have been found in some genes involved in controlling the stress response. This review examines some potential factors contributing to the sex difference in the risk of affective disorders with a focus on adrenal and gonadal hormones as potential modulators. Genetic and environmental factors that contribute to individual risk for affective disorders are also described. Ultimately, future treatment strategies for depression should consider all of these biological elements in their design., (© Georg Thieme Verlag KG Stuttgart · New York.)

Depressive patients often have altered cortisol secretion, an effect that likely derives from impaired activity of the glucocorticoid receptor (GR), the main regulator of the hypothalamus-pituitary-adrenal (HPA) axis. Glucocorticoids reduce the levels of brain-derived neurotrophic factor (BDNF), a downstream target of antidepressants. Antidepressants promote the transcriptional activity of cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), a regulator of BDNF expression. To identify potential biomarkers for the onset of antidepressant action in depressive patients, GR and phospho-CREB (pCREB) levels in lymphocytes and serum BDNF levels were repeatedly measured during the course of antidepressant treatment. Thirty-four depressed outpatients (10 male and 24 female) were treated with venlafaxine (75mg/day), and individuals exhibiting a 50% reduction in their baseline 17-Item Hamilton Depression Rating Scale score by the 6th week of treatment were considered responders. Responders showed an early improvement in parallel with a rise in BDNF levels during the first two weeks of treatment. Non-responders showed increased GR levels by the third week and reduced serum BDNF by the sixth week of treatment. In contrast, venlafaxine did not affect levels of pCREB. We conclude that levels of BDNF in serum and GR levels in lymphocytes may represent biomarkers that could be used to predict responses to venlafaxine treatment., (Copyright © 2011 Elsevier Ltd. All rights reserved.)