Mortality risk in infants receiving therapeutic care for malnutrition: A secondary analysis.

Small and nutritionally at-risk infants aged under 6 months (<6 months) are at high risk of death, but important evidence gaps exist on how to best identify them. We aimed to determine associations between anthropometric deficits and mortality among infants <6 months admitted to inpatient therapeutic care. A secondary analysis of 2002-2008 data included 5034 infants aged <6 months from 12 countries. We estimated the prevalence, concurrence, and severity of wasted, stunted, and underweight, as stand-alone indicators, and using the Composite Index of Anthropometric Failure (CIAF), which combines these indicators into six subgroups of single and multiple anthropometric deficits and into one combined indicator called CIAF. We used logistic regression to examine the association of different anthropometric deficits with in-programme mortality. Among 3692 infants aged <6 months with complete data, 3539 (95.8%) were underweight, 3058 (82.8%) were wasted, 2875 (77.8%) were stunted and 3575 (96.8%) had CIAF. Infants with multiple anthropometric deficits were presented with significantly lower anthropometric indices, that is, they were more severely wasted, stunted and underweight. A total of 141 infants died during inpatient therapeutic care. Among these, severely wasted (116) and severely underweight (138) infants had higher odds of mortality than normal infants (odds ratio [OR] = 2.1, 95% confidence interval [CI]: 1.2-2.7, p = 0.009, and OR = 3.3, 95% CI: 0.8-13.6, p = 0.09, respectively). Boys had higher odds of inpatient mortality than girls (OR = 1.40, 95% CI: 1.02-1.92, p = 0.03). Mortality was only observed in infants <6 months presenting multiple anthropometric deficits, although their odds of mortality were not significant, for example, OR = 2.4, 95% CI: 0.5-10.0, p = 0.21 for stunted, wasted and underweight infants <6 months. In conclusion, multiple anthropometric deficits (CIAF) is common among infants <6 months and may be reported in nutrition care programmes and surveys. Both weight-for-length/height z-score and weight-for-age z-score were found to be useful indicators for programme admission and in-programme prognosis. Future work needs to explore which better accounts for admission bias. Boys appear to be most at-risk of dying while receiving malnutrition therapeutic care. Programmes should ensure that all infants receive timely, evidence-based, effective care.

Mid-upper arm circumference only protocol in Pakistan: missed opportunities for children suffering from severe acute malnutrition? A mixed-methods observational study.

OBJECTIVE: We investigated the missed treatment opportunities affecting programmes using mid-upper arm circumference (MUAC) as the sole anthropometric criterion for identification and monitoring of children suffering from severe acute malnutrition (SAM). DESIGN: Alongside MUAC, we assessed weight-for-height Z-score (WHZ) in children screened and treated according to the national MUAC only protocol in Pakistan. Besides, we collected parents' perceptions regarding the treatment received by their children through qualitative interviews. SETTING: Data were collected from October to December 2021 in Tando Allah Yar District, Sindh. SUBJECTS: All children screened in the health facilities (n 8818) and all those discharged as recovered (n 686), throughout the district, contributed to the study. All children screened in the community in the catchment areas of five selected health facilities also contributed (n 8459). Parents of forty-one children randomly selected from these same facilities participated in the interviews. RESULTS: Overall, 80·3 % of the SAM cases identified during community screening and 64·1 % of those identified in the health facilities presented a 'WHZ-only' diagnosis. These figures reached 93·9 % and 84·5 %, respectively, in children aged over 24 months. Among children treated for SAM and discharged as recovered, 25·3 % were still severely wasted according to WHZ. While parents positively appraised the treatment received by their children, they also recommended to extend eligibility to other malnourished children in their neighbourhood. CONCLUSION: In this context, using MUAC as the sole anthropometric criterion for treatment decisions (referral, admission and discharge) resulted in a large number of missed opportunities for children in need of timely and adequate care.

Clinical and Biochemical Markers of Risk in Uncomplicated Severe Acute Malnutrition.

BACKGROUND AND OBJECTIVES: Use of mid-upper arm circumference (MUAC) as a single screening tool for severe acute malnutrition (SAM) assumes that children with a low weight-for-height z score (WHZ) and normal MUAC have lower risks of morbidity and mortality. However, the pathophysiology and functional severity associated with different anthropometric phenotypes of SAM have never been well characterized. We compared clinical characteristics, biochemical features, and health and nutrition histories of nonedematous children with SAM who had (1) low WHZ only, (2) both low WHZ and low MUAC, or (3) low MUAC only. METHODS: In Bangladesh, Burkina Faso, and Liberia, we conducted a multicentric cohort study in uncomplicated, nonedematous children with SAM and low MUAC only (n = 161), low WHZ only (n = 138), or a combination of low MUAC and low WHZ (n = 152). Alongside routine anthropometric measurements, we collected a wide range of critical indicators of clinical and nutritional status and viability; these included serum leptin, an adipocytokine negatively associated with mortality risk in SAM. RESULTS: Median leptin levels at diagnosis were lower in children with low WHZ only (215.8 pg/mL; P < .001) and in those with combined WHZ and MUAC deficits (180.1 pg/mL; P < .001) than in children with low MUAC only (331.50 pg/mL). The same pattern emerged on a wide range of clinical indicators, including signs of severe wasting, dehydration, serum ferritin levels, and caretaker-reported health deterioration, and was replicated across study sites. CONCLUSIONS: Illustrative of the likely heterogeneous functional severity of the different anthropometric phenotypes of SAM, our results confirm the need to retain low WHZ as an independent diagnostic criterion.

Anthropometry at discharge and risk of relapse in children treated for severe acute malnutrition: a prospective cohort study in rural Nepal.

BACKGROUND: There is a dearth of evidence on what should be the optimal criteria for discharging children from severe acute malnutrition (SAM) treatment. Programs discharging children while they are still presenting varying levels of weight-for-height (WHZ) or mid-upper-arm circumference (MUAC) deficits, such as those implemented under the current national protocol in Nepal, are opportunities to fill this evidence gap. METHODS: We followed a cohort of children discharged as cured from SAM treatment in Parasi district, Nepal. Relapse as SAM, defined as the occurrence of WHZ<-3 or MUAC < 115 mm or nutritional edema, was investigated through repeated home visits, during six months after discharge. We assessed the contribution of remaining anthropometric deficits at discharge to relapse risk through Cox regressions. RESULTS: Relapse as SAM during follow-up was observed in 33 % of the cohort (35/108). Being discharged before reaching the internationally recommended criteria was overall associated with a large increase in the risk of relapse (HR = 3.3; p = 0.006). Among all anthropometric indicators at discharge, WHZ<-2 led to a three-fold increase in relapse risk (HR = 3.2; p = 0.003), while MUAC < 125 mm significantly raised it only in the older children. WHZ<-2 at discharge came up as the only significant predictor of relapse in multivariate analysis (HR = 2.8, p = 0.01), even among children with a MUAC ≥ 125 mm. Of note, more than 80 % of the events of relapse as SAM would have been missed if WHZ had not been monitored and used in the definition of relapse. CONCLUSIONS: Our results suggest that the priority for SAM management programs should be to ensure that children reach a high level of WHZ at discharge, at least above or equal to the WHO recommended cut-off. The validity of using a single MUAC cut-off such as 125 mm as a suitable discharge criterion for all age groups is questioned. Further follow-up studies providing a complete assessment of nutritional status at discharge and not based on a restricted MUAC-only definition of relapse as SAM would be urgently needed to set evidence-based discharge criteria. These studies are also required to assess programs currently discounting or omitting WHZ for identification and management of SAM.

"No weight for height" case detection strategies for therapeutic feeding programs: sensitivity to acute malnutrition and target composition based on representative surveys in humanitarian settings.

BACKGROUND: One newly proposed approach to determining eligibility of children aged 6-59 months for therapeutic feeding programs (TFPs) is to use mid-upper arm circumference (MUAC) < 115 mm, bilateral oedema or Weight-for-Age Z-score (WAZ) < - 3 as admission criteria (MUAC+SWAZ). We explored potential consequences of this approach on the eligibility for treatment, as compared with the existing WHO normative guidance. We also compared sensitivity and specificity parameters of this approach for detecting wasted children to the previously described "Expanded MUAC" approach. METHODS: We analyzed data from 558 population representative cross-sectional cluster surveys conducted since 2007. We retrieved all children classified as severe acute malnutrition (SAM), moderate acute malnutrition (MAM), and those who are both wasted and stunted (WA + ST), and calculated proportions of previously eligible children who would now be excluded from treatment, as well as proportions of non-malnourished children among those who would become eligible. We also analyzed the expected changes in the number and demographics (sex, age) of the selected populations of children according to the different admission approaches. RESULTS: Both MUAC+SWAZ and Expanded MUAC case detection approaches substantially increase the sensitivity in detecting SAM, as compared to an approach which restricts detection of SAM cases to MUAC< 115 mm and oedema. Improved sensitivity however is attained at the expense of specificity and would require a very large increase of the size of TFPs, while still missing a non-negligible proportion (20-25%) of the SAM caseload. While our results confirm the sensitivity of the MUAC+SWAZ case detection approach in detecting WA + ST (over 80%), they show, on the other hand, that about half of the additional target detected by using SWAZ criterion will be neither SAM nor WA + ST. CONCLUSIONS: These results suggest that recently promoted approaches to case detection inflate TFPs' targets through the allocation of treatment to large numbers of children who have not been shown to require this type of support, including a significant proportion of non-acutely malnourished children in the MUAC+SWAZ approach. Considering the scarcity of resources for the implementation of TFPs, the rationale of abandoning the use of WHZ and of these alternative case detection strategies need to be critically reviewed.

Potential consequences of expanded MUAC-only programs on targeting of acutely malnourished children and ready-to-use-therapeutic-food allocation: lessons from cross-sectional surveys.

BACKGROUND: Some of the recently piloted innovative approaches for the management of acute malnutrition in children use the "expanded MUAC-only" approach, with Mid Upper Arm Circumference (MUAC) < 125 mm as the sole anthropometric criterion for screening and admission, classification of cases as severe using the 115 mm cut-off, and use Ready-to-Use-Therapeutic-Food (RUTF) for the management of both moderate (MAM) and severe (SAM) cases of acute malnutrition. Our study aimed at exploring the potential consequences of this "expanded MUAC-only" program scenario on the eligibility for treatment and RUTF allocation, as compared with the existing WHO normative guidance. METHODS: We analyzed data from 550 population representative cross-sectional cluster surveys conducted since 2007. We retrieved all children classified as SAM and MAM according to currently used case definitions, and calculated the proportions of SAM children who would be excluded from treatment, misclassified as MAM, or whose specific risks (because of having both MUAC and weight-for height deficits) would be ignored. We also analyzed the expected changes in the number and demographics (sex, age) of children meant to receive RUTF according to the new approach. RESULTS: We found that approximately one quarter of SAM children would not be detected and eligible for treatment under the "expanded MUAC-only" scenario, and another 20% would be classified as MAM. A further 17% of the total SAM children would be admitted and followed only according to their MUAC or oedema status, while they also present with a severe weight-for height deficit on admission. Considering MAM targeting, about half of the MAM children would be left undetected. This scenario also shows a 2.5 time increase in the number of children targeted with RUTF, with approximately 70% of MAM and 30% of SAM cases among this new RUTF target. CONCLUSIONS: This empirical evidence suggests that adoption of "expanded MUAC-only" programs would likely lead to a priori exclusion from treatment or misclassifying as MAM a large proportion of SAM cases, while redirecting programmatic costs in favor of those less in need. It underscores the need to explore other options for improving the impact of programs addressing the needs of acutely malnourished children.

Weaning and stunting affect nitrogen and carbon stable isotope natural abundances in the hair of young children.

Natural abundances of stable nitrogen and carbon isotopes (δ15N and δ13C) can vary with both dietary intake and metabolic (specifically catabolic) state. In low-income countries, weaning is a period of dietary transition from milk to plant-based foods and a high-risk period for malnutrition. We explored how diet and malnutrition impact hair δ15N and δ13C in young children by an observational, cross-sectional study in Cox's Bazar District, Bangladesh [255 children, 6-59 months with 19.6% wasted (7.1% severely) and 36% stunted (9.8% severely)]. Hair δ15N and δ13C exhibited exponential decreases with age, with the loss of one trophic level (3.3‰ and 0.8‰, respectively) from 6 to 48 months, which we associate with the shift from exclusive breastfeeding to complete weaning. After adjustment for age and breastfeeding status, hair isotopic values were unaffected by wasting but lower in severe stunting (-0.45‰ to -0.6‰, P < 0.01). In this population of young children, whose isotopic values in hair primarily depended on age, we failed to observe any effect of wasting, likely due to opposite, compensating effects between dietary and metabolic changes involved. In contrast, we evidenced low δ15N and δ13C values in severely stunted children that likely indicate chronic exposure to diets low in animal products.

Severe acute malnutrition and mortality in children in the community: Comparison of indicators in a multi-country pooled analysis.

OBJECTIVES: This study aims to describe the mortality risk of children in the community who had severe acute malnutrition (SAM) defined by either a mid-upper arm circumference (MUAC) <115mm, a low weight-for-height Z-score (WHZ) <-3 or both criteria. METHODS: We pooled individual-level data from children aged 6-59 months enrolled in 3 community-based studies in the Democratic Republic of the Congo (DRC), Senegal and Nepal. We estimate the mortality hazard using Cox proportional hazard models in groups defined by either anthropometric indicator. RESULTS: In total, we had 49,001 time points provided by 15,060 children available for analysis, summing to a total of 143,512 person-months. We found an increasing death rate with a deteriorating nutritional status for all anthropometrical indicators. Children identified as SAM only by a low MUAC (<115mm) and those identified only by a low WHZ (Z-score <-3) had a similar mortality hazard which was about 4 times higher than those without an anthropometric deficit. Having both a low MUAC and a low WHZ was associated with an 8 times higher hazard of dying compared to children within the normal range. The 2 indicators identified a different set of children; the proportion of children identified by both indicators independently ranged from 7% in the DRC cohort, to 35% and 37% in the Senegal and the Nepal cohort respectively. CONCLUSION: In the light of an increasing popularity of using MUAC as the sole indicator to identify SAM children, we show that children who have a low WHZ, but a MUAC above the cut-off would be omitted from diagnosis and treatment despite having a similar risk of death.

Comparison of Clinical Characteristics and Treatment Outcomes of Children Selected for Treatment of Severe Acute Malnutrition Using Mid Upper Arm Circumference and/or Weight-for-Height Z-Score.

OBJECTIVES: Debate for a greater role of mid-upper arm circumference (MUAC) measures in nutritional programming continues, but a shift from therapeutic feeding programs admitting children using MUAC and/or weight-for-height Z (WHZ) to a new model admitting children using MUAC only remains complicated by limited information regarding the clinical profile and response to treatment of children selected by MUAC vs. WHZ. To broaden our understanding of how children identified for therapeutic feeding by MUAC and/or WHZ may differ, we aimed to investigate differences between children identified for therapeutic feeding by MUAC and/or WHZ in terms of demographic, anthropometric, clinical, and laboratory and treatment response characteristics. METHODS: Using secondary data from a randomized trial in rural Niger among children with uncomplicated severe acute malnutrition, we compared children that would be admitted to a therapeutic feeding program that used a single anthropometric criterion of MUAC< 115 mm vs. children that are admitted under current admission criteria (WHZ< -3 and/or MUAC< 115 mm) but would be excluded from a program that used a single MUAC< 115 mm admission criterion. We assessed differences between groups using multivariate regression, employing linear regression for continuous outcomes and log-binomial regression for dichotomous outcomes. RESULTS: We found no difference in terms of clinical and laboratory characteristics and discharge outcomes evaluated between children that would be included in a MUAC< 115 mm therapeutic feeding program vs. children that are currently eligible for therapeutic feeding but would be excluded from a MUAC-only program. CONCLUSIONS: A single anthropometric admission criterion of MUAC < 115 mm did not differentiate well between children in terms of clinical or laboratory measures or program outcomes in this context. If nutritional programming is to use a single MUAC-based criterion for admission to treatment, further research and program experience can help to identify the most appropriate criterion in a broad range of contexts to target children in most urgent need of treatment.

Inconsistent diagnosis of acute malnutrition by weight-for-height and mid-upper arm circumference: contributors in 16 cross-sectional surveys from South Sudan, the Philippines, Chad, and Bangladesh.

BACKGROUND: The two anthropometric indicators of acute malnutrition in children under 5 years, i.e. a Mid-Upper Arm Circumference < 125 mm (MUAC125) or a Weight-for-Height Z-score<-2 (WHZ-2), correlate poorly. We aimed at assessing the contribution of age, sex, stunting (Height-for-Age HAZ<-2), and low sitting-standing height ratio Z-score (SSRZ in the 1st tertile of the study population, called hereafter 'longer legs') to this diagnosis discrepancy. METHODS: Data from 16 cross-sectional nutritional surveys carried out by Action Against Hunger International in South Sudan, the Philippines, Chad, and Bangladesh fed multilevel, multivariate regression models, with either WHZ-2 or MUAC125 as the dependent variable and age, sex, stunting, and 'longer legs' as the independent ones. We also compared how the performance of MUAC125 and WHZ-2 to detect slim children, i.e. children with a low Weight-for-Age (WAZ<-2) but no linear growth retardation (HAZ≥-2), was modified by the contributors. RESULTS: Overall 23.1% of the 14,409 children were identified as acutely malnourished by either WHZ-2 or MUAC125, but only 28.5% of those (949/3,328) were identified by both indicators. Being stunted (+17.8%; 95 % CI: 14.8%; 22.8%), being a female (+16.5%; 95 % CI: 13.5%; 19.5%) and being younger than 24 months (+33.6%; 95 % CI: 30.4%; 36.7%) were factors strongly associated with being detected as malnourished by MUAC125 and not by WHZ-2, whereas having 'longer legs' moderately increased the diagnosis by WHZ-2 (+4.2%; 95 % CI: 0.7%; 7.6%). The sensitivity to detect slim children by MUAC125 was 31.0% (95 % CI: 26.8%; 35.2%) whereas it was 70.6% (95 % CI: 65.4%; 75.9%) for WHZ-2. The sensitivity of MUAC125 was particularly affected by age (57.4% vs. 18.1% in children aged < 24 months vs. ≥ 24 months). Specificity was high for both indicators. CONCLUSIONS: MUAC125 should not be used as a stand-alone criterion of acute malnutrition given its strong association with age, sex and stunting, and its low sensitivity to detect slim children. Having 'longer legs' moderately increases the diagnosis of acute malnutrition by WHZ-2. Prospective studies are urgently needed to elucidate the clinical and physiological outcomes of the various anthropometric indicators of malnutrition.

Involvement of the opioid system in the orexigenic and hedonic effects of melanin-concentrating hormone.

Melanin-concentrating hormone (MCH) exerts an orexigenic effect that resembles that of opioids, suggesting that the MCH and opioid systems could interact in controlling the food intake behavior. Three series of experiments were conducted in male Wistar rats: 1) to test the ability of the κ-, µ-, and δ-opioid receptor antagonists binaltorphimine (nor-BNI-κ), ß-funaltrexamine (ß-FNA-µ), and naltrindole (NTI-δ), respectively, to block the stimulating effects of MCH on food intake; 2) to verify the ability of MCH to induce a positive hedonic response to a sweet stimulus when injected into the nucleus accumbens shell (NAcSh) or right lateral ventricle (LV) of the brain; and 3) to assess the ability of nor-BNI, ß-FNA, and NTI to block the effects of MCH on the hedonic response to a sweet stimulus. Nor-BNI, NTI (0, 10 and 40 nmol), and ß-FNA (0, 10 and 50 nmol) were administered into the LV prior to injecting MCH (2.0 nmol). To assess the hedonic response, rats were implanted with an intraoral cannula allowing for the infusion of a sweet solution into the oral cavity. Food intake was assessed in sated rats during the first 3 h following the MCH or vehicle (i.e., artificial cerebrospinal fluid) injection. The hedonic response to a sweet stimulus was assessed by examining facial mimics, following the intraoral administration of a sucrose solution. Blockade of each of the three opioid receptors by selective antagonists prevented MCH-induced feeding. Furthermore, MCH-injections into the NAcSh and right LV resulted in enhanced hedonic responses. Finally, antagonism of the three opioid receptors blunted the LV-injected, MCH-induced, facial-liking expressions in response to an intraoral sweet stimulus. Overall, the present study provides evidence to link the MCH and opioid systems in the food intake behavior.

Additive effects of olanzapine and melanin-concentrating hormone agonism on energy balance.

Atypical antipsychotic drugs (AAPDs) induce hyperphagia and body weight gain as a deleterious side effect. However, the mechanism whereby these drugs affect the neuronal pathways regulating energy balance has yet to be fully elucidated. The present study was conducted to investigate the respective and interaction effects of olanzapine and agonism of the melanin-concentrating hormone (MCH) receptor (MCHR1) on body weight, food intake, adiposity and expressions of genes liable of being involved in the anabolic action of AAPDs and MCH agonism. MCH is a hypothalamic neuropeptide, which exerts stimulating effects on food intake and body weight gain. Male Wistar rats received olanzapine (1 mg/kg of rat/day per os) and/or an intracerebroventricular (ICV) infusion of a MCHR1 agonist (30 microg/rat/day) during 13 days. Food intake and body weight were recorded daily, whereas adipose tissue depots were weighed at day 13. At the end of the experiment, we also measured brain levels of the messengers RNAs (mRNAs) encoding for MCH, MCHR1, neuropeptides-Y (NPY) and agouti-related peptide (AgRP) using in situ hybridization. The 13-day treatments combining olanzapine and the MCHR1 agonist exerted additive effects in enhancing food intake and adiposity. Consistently, each treatment differently affected brain expression of genes influencing energy balance. While the MCHR1 agonist treatment increased NPY mRNA expression in the hypothalamic arcuate nucleus, olanzapine treatment specifically increased MCHR1 mRNA expression in the nucleus accumbens shell (NAcSh). AAPDs and MCH agonism exert additive effects on energy balance and selective effects on the brain expression of energy balance-related genes.

The brain endocannabinoid system in the regulation of energy balance.

The role played by the endocannabinoid system in the regulation of energy balance is currently generating a great amount of interest among several groups of investigators. This interest in large part comes from the urgent need to develop anti-obesity and anti-cachexia drugs around target systems (such as the endocannabinoid system), which appears to be genuinely involved in energy balance regulation. When activated, the endocannabinoid system favors energy deposition through increasing energy intake and reducing energy expenditure. This system is activated in obesity and following food deprivation, which further supports its authentic function in energy balance regulation. The cannabinoid receptor type 1 (CB1), one of the two identified cannabinoid receptors, is expressed in energy-balance brain structures that are also able to readily produce or inactivate N-arachidonoyl ethanolamine (anandamide) and 2-arachidonoylglycerol (2AG), the most abundantly formed and released endocannabinoids. The brain action of endocannabinoid system on energy balance seems crucial and needs to be delineated in the context of the homeostatic and hedonic controls of food intake and energy expenditure. These controls require the coordinated interaction of the hypothalamus, brainstem and limbic system and it appears imperative to unravel those interplays. It is also critical to investigate the metabolic endocannabinoid system while considering the panoply of functions that the endocannabinoid system fulfills in the brain and other tissues. This article aims at reviewing the potential mechanisms whereby the brain endocannabinoid system influences the regulation energy balance.

Effects of intracerebroventricular and intra-accumbens melanin-concentrating hormone agonism on food intake and energy expenditure.

The brain melanin-concentrating hormone (MCH) system represents an anabolic system involved in energy balance regulation through influences exerted on the homeostatic and nonhomeostatic controls of food intake and energy expenditure. The present study was designed to further delineate the effect of the MCH system on energy balance regulation by assessing the actions of the MCH receptor 1 (MCHR1) agonism on both food intake and energy expenditure after intracerebroventricular (third ventricle) and intra-nucleus-accumbens-shell (intraNAcSH) injections of a MCHR1 agonist. Total energy expenditure and substrate oxidation were assessed following injections in male Wistar rats using indirect calorimetry. Food intake was also measured. Pair-fed groups were added to evaluate changes in thermogenesis that would occur regardless of the meal size and its thermogenic response. Using such experimental conditions, we were able to demonstrate that acute MCH agonism in the brain, besides its orexigenic effect, induced a noticeable change in the utilization of the main metabolic fuels. In pair-fed animals, MCH significantly reduced lipid oxidation when it was injected in the third ventricle. Such an effect was not observed following the injection of MCH in the NAcSH, where MCH nonetheless strongly stimulated appetite. The present results further delineate the influence of MCH on energy expenditure and substrate oxidation while confirming the key role of the NAcSH in the effects of the MCH system on food intake.

A tryptic hydrolysate from bovine milk alphaS1-casein improves sleep in rats subjected to chronic mild stress.

The putative effects of a tryptic bovine alphaS1-casein hydrolysate on stress-induced sleep disorders were investigated and their possible link with typical blood stress parameters such as plasma corticosterone concentrations and glycaemia was assessed. Rats were subjected to chronic stress in the form of environmental disturbances, while receiving an oral administration of the alphaS1-casein hydrolysate (CH). Chronic stress significantly reduced sleep duration in control rats during the first 2 days of the stress period, but stress-induced sleep disturbance was prevented in CH-treated rats. Indeed, CH administration allowed the maintenance of slow wave sleep (SWS) duration and even a slight increase in paradoxical sleep (PS) duration in treated rats. Results on plasma corticosterone concentrations and on glycemia values were inconclusive with respect to the implication of the HPA axis in this study. However, the protective effect of the alphaS1-casein hydrolysate on sleep during exposure to our chronic mild stress conditions may be mediated by modulation of the central adrenergic response.

Restriction-refeeding of calories and protein induces changes to slow wave and paradoxical sleep that parallel changes in body lipid and protein levels in rats.

Recent data have suggested that the activity of various brain nuclei is modulated during sleep. In this context, we developed the idea that sleep may participate in adapting brain responsiveness to feeding, so as to tune the control of peripheral energy metabolism. In order to characterize the nature of a possible link between sleep and peripheral energy metabolism, we have investigated the relationship between sleep parameters [wakefulness (W), slow wave sleep (SWS), paradoxical sleep (PS)] and the intensity of peripheral lipid and protein deposition processes. To achieve this, by manipulating the amount and quality of food available to rats, we induced states of energy or protein depletion/repletion which would specifically affect lean or fat body mass, which was quantified by an analysis of body composition. In parallel, using a permanently implanted cortical electrode, we measured electroencephalogram signals (EEG) to quantify the time spent in W, SWS and PS. Analysis of EEG changes in relation to the changes induced in body composition, showed that (1) the amount of sleep (PS and SWS) followed the evolution of energy supply levels, and (2) the time spent in PS relative to SWS varied to a considerable degree (14-23.5%) and followed the same trend as the ratio of lean body mass to fat mass. These results suggest the possible existence of quantitative and qualitative interactions between sleep quality and the anabolic and catabolic processes of peripheral fat and protein deposition.

Effects of chronic neuroleptic treatments on nutrient selection, body weight, and body composition in the male rat under dietary self-selection.

New antipsychotic drugs often increase weight and produce metabolic disturbances in treated patients. However, the mechanisms by which neuroleptics induce these undesirable side effects in humans are not known. Studies have shown that antipsychotics can increase body weight in female but not in male rats. However, no studies investigated changes in macronutrient selection during chronic treatments with antipsychotics in male rats, and no studies investigated precisely body composition after such treatments. In the present work, we studied in male rats the effects of long-term administration of two neuroleptics: haloperidol, a classical neuroleptic which has a moderate effect on weight gain in humans, and olanzapine, an atypical neuroleptic which has a more important effect on weight gain. Treatments (both 1 mg/kg) were given orally for 6 weeks, and the animals were allowed to self-select food among carbohydrates, lipids and proteins. Food selection was measured throughout the study, and body composition was measured by dissection and weighing of the main organs and tissues. Circulating leptin, insulin and glucose were also assayed at the end of the study on blood collected at the time of carcass analysis. The results show that none of the neuroleptic treatments modified caloric intake, food selection, body weight, and body composition. Olanzapine produced a statistically non-significant increase in subcutaneous fat tissue. It is concluded that a 6-week olanzapine or haloperidol treatment in male rats under dietary macronutrient selection does not significantly affect energy regulation.