Fidelity in Animal Modeling: Prerequisite for a Mechanistic Research Front Relevant to the Inflammatory Incompetence of Acute Pediatric Malnutrition.

Inflammatory incompetence is characteristic of acute pediatric protein-energy malnutrition, but its underlying mechanisms remain obscure. Perhaps substantially because the research front lacks the driving force of a scholarly unifying hypothesis, it is adrift and research activity is declining. A body of animal-based research points to a unifying paradigm, the Tolerance Model, with some potential to offer coherence and a mechanistic impetus to the field. However, reasonable skepticism prevails regarding the relevance of animal models of acute pediatric malnutrition; consequently, the fundamental contributions of the animal-based component of this research front are largely overlooked. Design-related modifications to improve the relevance of animal modeling in this research front include, most notably, prioritizing essential features of pediatric malnutrition pathology rather than dietary minutiae specific to infants and children, selecting windows of experimental animal development that correspond to targeted stages of pediatric immunological ontogeny, and controlling for ontogeny-related confounders. In addition, important opportunities are presented by newer tools including the immunologically humanized mouse and outbred stocks exhibiting a magnitude of genetic heterogeneity comparable to that of human populations. Sound animal modeling is within our grasp to stimulate and support a mechanistic research front relevant to the immunological problems that accompany acute pediatric malnutrition.

Midupper Arm Circumference Outperforms Weight-Based Measures of Nutritional Status in Children with Diarrhea.

BACKGROUND: Undernutrition contributes to 45% of all deaths in children <5 y of age worldwide, with a large proportion of those deaths caused by diarrhea. However, no validated tools exist for assessing undernutrition in children with diarrhea and possible dehydration. OBJECTIVE: This study assessed the validity of different measures of undernutrition in children with diarrhea. METHODS: A prospective cohort study was conducted at an urban hospital in Bangladesh. Children <60 mo of age presenting to the hospital rehydration unit with acute diarrhea were eligible for enrollment. Study staff randomly selected 1196 children for screening, of which 1025 were eligible, 850 were enrolled, and 721 had complete data for analysis. Anthropometric measurements, including weight-for-age z score (WAZ), weight-for-length z score (WLZ), midupper arm circumference (MUAC), and midupper arm circumference z score (MUACZ), were calculated pre- and posthydration in all patients. Measurements were evaluated for their ability to correctly identify undernutrition in children with varying degrees of dehydration. RESULTS: Of the 721 patients with full data for analysis, the median percent dehydration was 4%. Of the 4 measures evaluated, MUAC and MUACZ demonstrated 92-94% agreement pre- and posthydration compared with 69-76% for WAZ and WLZ. Although each 1% change in hydration status was found to change weight-for-age by 0.0895 z scores and weight-for-length by 0.1304 z scores, MUAC and MUACZ were not significantly affected by dehydration status. Weight-based measures misclassified 12% of children with severe underweight and 14% with severe acute malnutrition (SAM) compared with only 1-2% for MUAC and MUACZ. CONCLUSIONS: MUAC and MUACZ were the most accurate predictors of undernutrition in children with diarrhea. WAZ and WLZ were significantly affected by dehydration status, leading to the misdiagnosis of many patients on arrival with severe underweight and SAM. This trial was registered at clinicaltrials.gov as NCT02007733.

Fundamental determinants of protein requirements in the ICU.

PURPOSE OF REVIEW: Currently, feeding the ICU patient is highly discussed. Energy feeding has been the topic of randomized studies, but protein feeding has not. Study results are contradictory on early feeding; however, little is known about early protein requirement. What is this protein requirement based on, therefore what are the fundamental determinants? RECENT FINDINGS: Recent studies have addressed the importance of protein feeding and/or muscle (protein) wasting in critically ill patients. Targeted feeding has been shown to improve protein balance in one study, and infection rate in one study. Low muscle mass that is already present during ICU admission has been shown to be related to higher mortality, in two studies. Four studies have related muscle wasting to (protein) feeding strategies with very diverse results: Two small studies have reported no advantage [n = 15, computed tomography] or negative impact (n = 62, ultrasound, 50% sepsis patients) of protein on muscle wasting. Two studies, one small (n = 33, computed tomography) and one very large (n = 1372, Subjective Global Assessment), have reported a positive impact of (early) feeding on muscle wasting. SUMMARY: Fundamental to adequate protein feeding in critically ill patients, at least 1.2 g protein/kg per day, is targeted energy feeding using indirect calorimetry. The level of protein requirement is related to fat free mass or muscle mass, which makes sex and BMI also relevant. Targeted early protein feeding is found to improve short-term outcome, reduction of muscle wasting and hospital mortality. Long-term outcome of protein feeding has not been studied. However, targeted protein feeding may be harmful in sepsis patients. Up to now, we lack biomarkers that provide caregivers with an instrument to increase protein feeding up to the individual protein requirement of the critically ill patient.

Postnatal protein malnutrition induces neurochemical alterations leading to behavioral deficits in rats: prevention by selenium or zinc supplementation.

BACKGROUND/OBJECTIVES: Protein malnutrition (PM) is a worldwide problem affecting brain development in a large number of children. The present study was aimed at studying the perturbations in antioxidant defense system resulting from protein deficiency and to evaluate the preventive effect of Se and Zn on cortex and cerebellum. METHODS: Well-fed (WF) and PM rats were fed on 16 and 5% protein diet, respectively. After 10 weeks, animals were supplemented with Se and Zn at a concentration of 0.15 and 227 mg/l in drinking water for 3 weeks. RESULTS: PM rats showed significant increase in lipid peroxidation, nitrite, and protein carbonyl levels. Reduction in the activity of antioxidant enzymes, thiol levels, GSH/GSSG ratio, and neurobehavioral deficits were observed in PM groups. Se and Zn supplementation reduced the levels of lipid peroxidation, nitrite, and protein carbonyl and restored the activity of antioxidant enzymes and thiol levels in the cortex and cerebellum of PM rats along with neurobehavioral deficits. DISCUSSION: The study showed that Se and Zn supplementation might be beneficial in preventing biochemical alterations and neurobehavioral deficits in PM children.

A simple protein-energy wasting score predicts survival in maintenance hemodialysis patients.

OBJECTIVE: Nutritional status is a powerful predictor of survival in maintenance hemodialysis patients but remains challenging to assess. We defined a new Protein Energy Wasting (PEW) score based on the nomenclature proposed by the International Society of Renal Nutrition and Metabolism in 2008. DESIGN AND METHODS: This score, graded from 0 (worse) to 4 (best) was derived from 4 body nutrition compartments: serum albumin, body mass index, a normalized serum creatinine value, and protein intake as assessed by nPNA. SUBJECTS: We applied this score to 1443 patients from the ARNOS prospective dialysis cohort and provide survival data from 2005 until 2008. MAIN OUTCOME MEASURE: Patients survival at 3.5 year. RESULTS: Survival ranged from 84%-69% according to the protein-energy wasting score. There was a clear-cut reduction in survival (5%-7%; P < 0.01) for each unit decrement in the score grade. There was a 99% survival at 1 year for patients with the score of 4. In addition, the 6-month variation of this PEW score also strongly predicted patients' survival (P < 0.01). CONCLUSION: A new simple and easy-to-get PEW score predicts survival in maintenance hemodialysis patients. Furthermore, increase of this nutritional score over time also indicates survival improvement, and may help to better identify subgroups of patients with a high mortality rate, in which nutrition support should be enforced.

Probiotics protect the intestinal wall of morphological changes caused by malnutrition.

This study sought to morphometrically analyze the jejunal wall of protein-malnourished rats administered a probiotic supplement. The sample consisted of recently weaned Wistar rats (Rattus norvegicus) distributed among four groups: animals given a commercial diet (G1, n = 4); animals given the same ration as G1 plus a probiotic supplement (G2, n = 4); animals given a 4% protein diet (G3, n = 4); and animals given the same ration as G3 plus a probiotic supplement (G4, n = 4). After 12 weeks, part of the jejunum was harvested and subjected to routine histological processing. Transverse sections with a thickness of 3 µm were stained with HE, and histochemical techniques were used to assay for glycoconjugates, including staining with periodic acid-Schiff (PAS) + diastase, Alcian Blue (AB) solution at pH 2.5, and Alcian Blue solution at pH 1.0. Morphometric analysis of the bowel wall showed that the probiotic culture used in this study induced hypertrophy of several layers of the jejunal wall in well-nourished animals and reduced the bowel wall atrophy usually observed in protein-malnourished animals. Neither malnutrition nor the use of probiotics altered the relationship between the number of goblet cells and the number of enterocytes.

The morphological and developmental changes of the anterior commissure of male Wistar rats submitted to protein malnutrition in the postnatal period.

The aim of this project was to study the effects of protein malnutrition in the anterior commissure of male albino Wistar rats, submitted to diets with different levels of protein to evaluate the possible morphological and developmental changes of the myelinated nervous fibers and glial cells of this important neural structure during the postnatal period until 120 days of age. In this study the animals (dams and pups) were divided into three groups: the control group which received a commercial diet from the laboratory (22% protein); the nourished group which received a diet of 16% of protein (casein); and the malnourished group which received a diet of 6% of protein (casein). Rat pups were fed by lactating females during the lactation period. After weaning the pups received the same diet until 120 days of age. The results obtained showed that the malnourished animals presented less body and brain growth and important morphological changes in the anterior commissure such as the retard in the myelination, damaged myelinic nervous fibers, and the increase of the interstitial space characterizing edema and vacuolization. The current study shows that the effects of protein malnutrition in the anterior commissure cause a bigger alteration in the posterior limb of the referred commissure, indicating that it is more vulnerable to malnutrition and more susceptible to damages of the anterior limb.

Behaviour of postnatally growth-impaired mice during malnutrition and after partial weight recovery.

OBJECTIVES: Early malnutrition is a highly prevalent condition in developing countries. Different rodent models of postnatal early malnutrition have been used to approach the subject experimentally, inducing early malnutrition by maternal malnutrition, temporal maternal separation, manipulation of litter size or the surgical nipple ligation to impair lactation. Studies on the behaviour of (previously) malnourished animals using animal models have produced sometimes contradictory results regarding the effects of early postnatal malnutrition and have been criticized for introducing potential confounding factors. The present paper is a first report on the behavioural effects of early malnutrition induced by an alternative approach: mice nursed by α-casein-deficient knockout dams showed a severe growth delay during early development and substantial catch-up growth after weaning when compared with animals nursed by wild-type females. METHODS: Established behavioural tests were used to study the consequences of early postnatal malnutrition on mouse pups at weaning and after partial weight recovery. RESULTS: Despite the impaired growth, the only behavioural difference between malnourished and normally growing animals was found in exploratory behaviour during acute malnutrition at the time of weaning. After partial catch-up in weight early protein malnourished animals showed no indication of lasting effects on general activity, emotionality and exploration, memory, and pain reactivity. DISCUSSION: These results suggest that the role of early nutrition on behavioural development after recovery in animal models may have been overestimated. Further careful examination of this animal model in terms of maternal care and offspring behaviour will be necessary to confirm if mice nursed by α-casein-deficient dams offer an alternative to existing models while eliminating potential confounding factors.

Effects of early protein malnutrition and environmental stimulation on behavioral and biochemical parameters in rats submitted to the elevated plus-maze test.

The objective of this study was to compare the effects of the tactile/handling stimulation (H) and environmental enrichment (EE) in well-nourished (C - 16% of protein) and malnourished (M - 6% of protein) rats tested in the elevated plus-maze (EPM) at 36 and 37 days of age. The results showed higher exploration of the open arms in the EPM in M as compared with C animals, as well as lower index of risk assessment behaviors, and EE, but not H, reversed the alterations produced by malnutrition in the EPM. Biochemical analysis showed higher levels of corticosterone in M when compared with C rats. The non-stimulated animals presented higher levels of polyamines in the hippocampus when compared with the stimulated ones in both diet conditions. It is suggested that both the lower anxiety levels and the lower risk-assessment behaviors in the EPM, as well as the higher levels of corticosterone, can be due to alterations in the activity of the hypothalamic-pituitary-adrenal axis as the result of early protein malnutrition.

Impact of protein malnutrition on histological parameters of experimentally infected animals with Giardia lamblia.

Giardiasis is one of the most common parasitic diseases worldwide, and the disease is an important cause of diarrhoea and malabsorption in children and immunosuppressed individuals. However, there is no evidence that characterises malnutrition as an aggravating factor for this disease. We evaluated changes in villi structures to examine the association between malnutrition and Giardia lamblia infection. We used 32 gerbils, divided into 4 groups: Control (CT) and Control Infected (CTIn), which each received a 20% protein diet, Malnourished (MN) and Malnourished Infected (MNIn), which each received a 5% protein diet. Groups CTIn and MNIn were inoculated with 1×10(6) trophozoites of G. lamblia, while the remaining groups were mock infected. Seven days post-infection, all groups were sacrificed, and the proximal portions of the small intestines were collected for the analysis of villus height, mucus area and extent of Giardia infection. Gerbils fed with a low-protein diet had significantly lower body weights. Malnourished infected animals presented significantly increased production of mucus, suggesting a synergism occurs between malnutrition and Giardiasis, potentially to control the adhesion of Giardia in the mucosa. Villus height was significantly lower in group MNIn compared to CTIn. This work suggests that malnutrition contributes to severity of Giardiasis by decreasing the intestinal absorption capacity via shortening of the villi.

[Protein-energy malnutrition in patients with connective tissue dysplasia].

In the conditions of the specialized Center of a dysplasia of a connecting tissue the assessment of an protein--energy malnutrition at 121 patients with signs of a dysplasia of a connecting tissue is carried out. High frequency of an oligotrophy at patients with a dysplasia of a connecting tissue is registered. The I degree of a gipotorofiya is taped at 26.21% of the patients, II degree--at 18.44%, the III degree--at 3.88% of patients.

[Functional diseases of the digestive organs in patients with the connective tissue dysplasia].

Research objective was studying of features of functional diseases of digestive organs at patients with a dysplasia of a connecting tissue. In the conditions of the specialized Center of a dysplasia of a connecting tissue the assessment of a functional condition of digestive organs at 121 patients with signs of a dysplasia of a connecting tissue is carried out. High frequency of functional disorders of digestive organs at patients with a dysplasia of a connecting tissue (74-75%) is registered. Overlapping of syndromes of functional diseases (functional dyspepsia and syndrome of the angry intestine) it is registered at 73 +/- 3.9% of patients with DST, in group of comparison - at 9 +/- 2.3% (p &It; 0.001). Syndromes demonstrated against a wide range of changes of the digestive organs associated with a dysplasia of a connecting tissue. Existence of a dysplasia of a connecting tissue defines variety and features of a course of functional diseases of digestive organs, development of a syndrome of a maldigestiya and advance of an protein-energy malnutrition at this category of patients.

Characterization of the myenteric neuronal population and subpopulation of the duodenum of adult wistar rat fed with hypoproteic chow.

The effects of severe protein malnutrition (4%) on myenteric neurons of Wistar rat duodenum, in relation to a standard 22%-protein diet for rodents, were assessed in this study. Segments of the duodenum from 10 rats from each nutritional group were submitted to the elaboration of whole mounts - 5 stained with Giemsa to determine the total population of myenteric neurons and the others stained by a histochemical method to detect nervous cells through the NADPH-diaphorase enzyme activity for studying the subpopulation of nitrergic neurons. The area of 100 neurons per animal, totalizing 2,000 neurons, were randomly measured by using the Image Pro-Plus(®)software. Malnourished rats presented 34.38% lower body weight and 10.60% duodenum length reduction when compared to the control group. Quantitative analysis demonstrated no significant differences between control and malnourished group by using Giemsa; however, as the organ reduction was not followed by an increase inversely proportional to the density of neurons, the condition imposed suggests the loss of neurons from the total population. Nevertheless, through NADPH-d histochemistry, there was a neuronal density increase for the malnourished group. There was no significant difference between the groups for both techniques with respect to the morphometric analysis of the body cell.

Quantitative histologic evaluation reveals different degree of liver atrophy in cachectic and starved dogs.

Cases of neglect in dogs are among the forensic cases submitted most commonly for postmortem examination. Starvation is a form of primary protein-energy malnutrition in which the availability of food is severely restricted or absent; cachexia is a form of protein-energy malnutrition secondary to progressive metabolic derangement during chronic diseases. Despite both conditions leading to an emaciated appearance of the cadaver, discrimination between the two is crucial in forensic cases. We hypothesized that among emaciated dogs, the degree of liver atrophy in starved animals is higher than in cachectic ones, and that this can be investigated microscopically, regardless of the degree of cadaver decomposition. We studied 46 animals: 23 starved, 11 cachectic, and 12 control dogs. Portal tracts were identified by the presence of a bile duct and associated vascular structures recognizable by a thin rim of collagen still visible regardless of the degree of cadaver decomposition. The number of portal tracts per lpf (10×) was used as an indirect measure of atrophy. The number of portal tracts in starved dogs was significantly higher (p < 0.01) compared to both cachectic and control dogs, indicating a higher degree of liver atrophy in starvation. Measuring the density of portal tracts offers a reliable additional tool for discrimination between starvation and cachexia.

[Underweight in elderly persons. A retrospective analysis of 3821 forensic autopsies in Hamburg]. / Untergewicht älterer Menschen zum Sterbezeitpunkt. Eine retrospektive Analyse 3821 rechtsmedizinischer Sektionen in Hamburg.

AIM AND METHOD: Based on the systematic analyses of a 10-year period at the Institute of Forensic Medicine at the University Clinic Hamburg-Eppendorf, the frequency of underweight in elderly persons at their time of death was retrospectively calculated. Body mass index (BMI) values <20 kg/m(2) were taken as indicative of underweight and the data of 1,551 women and 2,270 men, mean age 69 years (51-101 years) were analyzed. RESULTS: The prevalence of underweight was 15.4%. Low BMI values were more frequent in women than men (18.8 vs. 13.1%) and more frequent in persons needing professional nursing care at the time of death (28.9%). Underweight increased for the age range 70-79 from about 15% to over 38% for those 90 years and older at the time of death. Pressure sores were documented in 1.8% of cases. Persons in need of professional nursing care more often had pressure sores at their time of death. Furthermore, pressure sores were observed more often in underweight elderly in need of professional nursing care. CONCLUSION: Underweight at the time of death is observed more often in the very old. This is associated with the need for professional nursing care and also the occurrence of pressure sores. Less than 5% of persons with tumors were included. The results underscore the need of early detection of people at risk of malnutrition when growing older.

[Nitrogenous metabolism vitamin provision and anthrometric indices by Uzbek young with a different nutrition status].

Nitrogenous metabolism, vitamin provision and anthroponietric indices were inventigated in 1560 Uzbek youths (18-21 years old) with diverse alimentary status. Changes cheatinine in urine, insufficient vitamines content and violations of authropometric indices were revald in patients with protein-calorie deficiency.

Adult characteristics of survivors of early life malnutrition in an impoverished population.

BACKGROUND & AIMS: To determine the characteristics of adults who survived early life malnutrition (ELM) and the possible associated factors. The setting is an impoverished community in Kenya. The coastal region of Kenya has a high prevalence of acute protein-energy-malnutrition and stunting. METHODS: Observational cross-sectional survey where 872 skeletally mature adults of African origin, were surveyed in a period of three months. A discrimination tool to detect ELM survivors was created. Personal, historical and family data were collected in a semi-structured questionnaire. Various observations and body measurements were done. The subjects were grouped into two, those with ELM (Group1), and those without (Group2). RESULTS: Group1 had 242 participants, 49.8% males, mean age of 49.1 ± 8.7 years. Group2 had 630 participants, 48.3% males, mean age 41.0 ± 9.7 years. The phenotypic characteristics included height, BMI, and head circumference (P < 0.05). Developmental characteristics were duration of schooling, occupation and income (P < 0.001). Factors associated with malnutrition were County of origin, parental education, parental occupation, and family size (P < 0.001). CONCLUSIONS: There are discernible phenotypic and developmental characteristics associated with adult survivors of ELM. The predisposing factors for ELM are location of birth, parental education and occupation, and family size.

Maternal Spirulina supplementation during pregnancy and lactation partially prevents oxidative stress, glial activation and neuronal damage in protein malnourished F1 progeny.

Protein malnutrition (PMN) is a global health issue but most prevalent in Africa and Asia. It exerts detrimental effect on structural and physiological aspects of hippocampal circuitry. Despite accumulating evidence for PMN induced changes in nervous system, relatively very little is known about how maternal nutritional supplementation during malnutrition affects glial cells and neurons. Herein, we aimed to investigate the effects of maternal Spirulina supplementation against PMN induced oxidative stress, reactive gliosis and neuronal damage in hippocampus of F1 progeny. Three months old healthy Sprague Dawley females (n = 24) were shifted to normoprotein (NC; 20% protein) and low protein (LP; 8% protein) diets 15 days before conception. The NC and LP group females were subdivided into two groups according to Spirulina supplementation (400 mg/kg/b.wt. orally throughout gestation and lactation period): normal control with Spirulina (NC SPI) and low protein with Spirulina supplemented group (LP SPI). F1 progeny born were used in present study. Thus, building on earlier results of ameliorated neurobehavioral and cognitive abilities in Spirulina supplemented protein deprived rats, the present study incorporates neurochemical and morphometric analysis of glial cells and neurons and revealed that maternal Spirulina consumption partially prevented the PMN associated neuropathological alterations in terms of attenuated oxidative brain damage, reduced reactive gliosis and apoptotic cell population, improved dendritic branch complexity with few damaged neurons and enhanced mushroom shaped spine density. The results suggest that cellular changes in hippocampus after PMN are partially restored after maternal Spirulina supplementation and one could envision intervention approaches using Spirulina against malnutrition.

Elevated blood interleukin-10 levels and undiminished systemic interleukin-10 production rate prevail throughout acute protein-energy malnutrition in the weanling mouse.

The objectives were to determine if blood IL-10 levels rise during the early stages of acute (wasting) pre-pubescent malnutrition in metabolically distinct murine models known to depress inflammatory immune competence and whether systemic IL-10 production is affected in these pathologies. Weanling C57BL/6J mice were assigned to dietary protocols that elicited wasting pathologies mimicking the human diseases of marasmus (restricted-intake group) or incipient kwashiorkor (low-protein group). An age-matched control group also was included. Serum IL-10 bioactivities were assessed in the early (day 3) and advanced (day 14) stages of weight loss, and net systemic IL-10 production was assessed at the same stages of pathology by in vivo cytokine capture. Blood IL-10 levels were elevated in both malnourished groups relative to controls at days 3 and 14 (range of P values: 0.03-0.0001). Further, despite a limited supply of energy and nitrogenous substrates, the systemic IL-10 production rate was at least sustained in the malnourished groups and, in fact, was elevated in the marasmic group (P=0.05) throughout the progression of weight loss. IL-10 emerges as an anti-inflammatory mediator positioned to participate in initiating and upholding the depressed immune competence that accompanies acute pre-pubescent deficits of protein and energy.

Could intervention by clinics such as Primeros Pasos affect the prevalence of childhood malnutrition in the developing world?

OBJECTIVE: Guatemala is a country severely affected by malnutrition, particularly in its child population. The present study aimed to assess the impact of recognised aetiological factors on the prevalence of malnutrition and to establish the efficacy of a Guatemalan malnutrition clinic by examining the changes in the prevalence of malnutrition in the ten surrounding communities served by the clinic. DESIGN: Records of children (n 7681) aged 5-16 years seen by the clinic between 2004 and 2006 were examined. Anthropometric data for each child were taken from these records and used as an indicator for their nutritional status to estimate the change in rates of malnutrition during this period. RESULTS: An overall reduction was seen in all forms of malnutrition over the 3-year period, although over 50 % of the study population remained malnourished in 2006. A consistent reduction was also seen in rates of moderate and severe malnutrition, but not in rates of mild malnutrition. CONCLUSIONS: The results demonstrate that clinics such as Primeros Pasos can have a beneficial effect on schoolchildren, particularly those who are severely malnourished. A need has been highlighted for more research in this area, particularly how clinics such as Primeros Pasos can be best used in the fight against malnutrition.