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Ultrasonographic, blinded assessment was made of the extent of hepatic steatosis in 55 children with severe malnutrition: undernutrition (n = 6), marasmus (n = 18), marasmickwashiorkor (n = 17), and kwashiorkor (n = 14). The children were examined on admission, in early recovery (considered as baseline), and again at discharge. Eleven healthy control children and eight of the previously malnourished children were studied as comparison groups. Both oedematous and non-oedematous malnourished children had significantly more steatosis than the comparison groups at each time. Children with oedematous malnutrition had significantly greater steatosis than non-oedematous children at admission. Half of the non-oedematous malnourished children had appreciable hepatic steatosis at both admission and at baseline. Hepatic fat was only slowly mobilised. The rate constant was 1.4 +/- 0.3%/day. One quarter of the children did not change steatosis grades during the period they were in hospital. There was no overall correlation between the extent of steatosis and liver size. Hepatic steatosis in childhood malnutrition is not confined to oedematous children: it is frequently present in marasmic and undernourished children. Its extent is not necessarily related to the degree of hepatomegaly and accumulated lipid is only slowly mobilised. [ABSTRACT FROM AUTHOR]

Recommended Nutrient Intakes (RNIs) are set for healthy individuals living in clean environments. There are no generally accepted RNIs for those with moderate malnutrition, wasting, and stunting, who live in poor environments. Two sets of recommendations are made for the dietary intake of 30 essential nutrients in children with moderate malnutrition who require accelerated growth to regain normality: first, for those moderately malnourished children who will receive specially formulated foods and diets; and second, for those who are to take mixtures of locally available foods over a longer-term to treat or prevent moderate stunting and wasting. Because of the change in definition of severe malnutrition, much of the older literature is pertinent to the moderately wasted or stunted child. A factorial approach has been used in deriving the recommendations for both functional, protective nutrients (type I) and growth nutrients (type II). [ABSTRACT FROM AUTHOR]

The World Health Organization (WHO) has a mandate to promote maternal and child health and welfare through support to governments in the form of technical assistance, standards, epidemiological and statistical services, promoting teaching and training of healthcare professionals and providing direct aid in emergencies. The Strategic and Technical Advisory Group of Experts (STAGE) for maternal, newborn, child and adolescent health and nutrition (MNCAHN) was established in 2020 to advise the Director-General of WHO on issues relating to MNCAHN. STAGE comprises individuals from multiple low-income and middle-income and high-income countries, has representatives from many professional disciplines and with diverse experience and interests.Progress in MNCAHN requires improvements in quality of services, equity of access and the evolution of services as technical guidance, community needs and epidemiology changes. Knowledge translation of WHO guidance and other guidelines is an important part of this. Countries need effective and responsive structures for adaptation and implementation of evidence-based interventions, strategies to improve guideline uptake, education and training and mechanisms to monitor quality and safety. This paper summarises STAGE's recommendations on how to improve knowledge translation in MNCAHN. They include support for national and regional technical advisory groups and subnational committees that coordinate maternal and child health; support for national plans for MNCAHN and their implementation and monitoring; the production of a small number of consolidated MNCAHN guidelines to promote integrated and holistic care; education and quality improvement strategies to support guidelines uptake; monitoring of gaps in knowledge translation and operational research in MNCAHN., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Kwashiorkor and marasmus are two clinical syndromes observed in severe acute malnutrition. In this review, we highlighted the differences between these two syndromes by reviewing the data comparing kwashiorkor and marasmus in literature, combined with recent microbiological findings and meta-analysis. Depletion of antioxidants, vitamins and minerals were more severe in kwashiorkor than marasmus. This was consistent with the severe and uncontrolled oxidative stress associated with the depletion of gut anaerobes and the relative proliferation of aerotolerant gut pathogens. This relative proliferation and invasion of gut microbes belonging to the aerotolerant Proteobacteria phylum and pathogens suggested a specific microbial process critical in the pathogenesis of kwashiorkor. Liver mitochondrial and peroxisomal dysfunction could be secondary to toxic microbial compounds produced in the gut such as ethanol, lipopolysaccharides and endotoxins produced by Proteobacteria, particularly Klebsiella pneumoniae, and aflatoxin produced by Aspergillus species. The gut-liver axis alteration is characterized by oedema and a fatty and enlarged liver and was associated with a dramatic depletion of methionine and glutathione, an excessive level of free circulating iron and frequent lethal bacteraemia by enteric pathogens. This was consistent with the fact that antibiotics improved survival only in children with kwashiorkor but not marasmus. The specific pathogenic characteristics of kwashiorkor identified in this review open new avenues to develop more targeted and effective treatments for both marasmus and/or kwashiorkor. Urgent correction of plasma glutathione depletion, alongside supply of specific essential amino acids, particularly methionine and cysteine, early detection of pathogens and an antibiotic more efficient than amoxicillin in supressing gut Proteobacteria including K. pneumoniae, and probiotics to restore the human gut anaerobic mature microbiota could save many more children with kwashiorkor., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Poor nutrition status is common among hospitalized children and children in low-income countries and may be associated with increased susceptibility to edema and infections. We hypothesized that poor nutrition status, established with a suboptimal composition of parenteral nutrition (PN), predisposes to endotoxemia-induced edema, oxidative stress, and dysregulated immune responses., Methods: Using a 2 × 2 factorial design, 3-day-old piglets (n = 40) were given either optimal or suboptimal composition of PN for 7 days and then infused with either saline or lipopolysaccharide (LPS) for 9 hours to induce an acute-phase reaction. Abdominal tissue edema and blood markers of immunity, inflammation, and oxidative stress were assessed., Results: Piglets receiving suboptimal nutrition showed signs of malnutrition with restricted growth, signs of inflammation (elevated C-reactive protein [CRP], interleukin-6, and serum amyloid A levels), oxidative stress (lower erythrocyte glutathione/hemoglobin and α-tocopherol/cholesterol ratios), and liver dysfunction (increased liver weight and blood bilirubin levels). Perirenal edema was more excessive in malnourished LPS-infused animals, relative to healthy LPS-infused control animals (P < .01). Malnutrition reduced the inflammatory response to LPS (lower CRP, tumor necrosis factor-α, haptoglobin, and neutrophil to lymphocyte ratio) but did not influence LPS-induced oxidative stress markers., Conclusions: We conclude that endotoxemia and malnutrition in combination lead to acute-phase hyporesponsiveness and perirenal edema in piglets. This finding may have implications for pediatric patients that suffer from malnutrition, as their response to bacterial infections may differ substantially from patients of normal nutrition status., (© 2019 American Society for Parenteral and Enteral Nutrition.)

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., Competing Interests: The authors have declared that no competing interests exist.

Background: The WHO recommended criteria for diagnosis of sever acute malnutrition (SAM) are weight-for-height/length Z-score (WHZ) of <- 3Z of the WHO 2006 standards, a mid-upper-arm circumference (MUAC) of < 115 mm, nutritional oedema or any combination of these parameters. A move to eliminate WHZ as a diagnostic criterion has been made on the assertion that children with a low WHZ are healthy, that MUAC is a "superior" prognostic indicator of mortality and that adding WHZ to the assessment does not improve the prediction of death. Our objective was to examine the literature comparing the risk of death of SAM children admitted by WHZ or MUAC criteria., Methods: We conducted a systematic search for reports which examined the relationship of WHZ and MUAC to mortality for children less than 60 months. The WHZ, MUAC, outcome and programmatic variables were abstracted from the reports and examined. Individual study's case fatality rates were compared by chi-squared analysis and random effects meta-analyses for combined data., Results: Twenty-one datasets were reviewed. All the patient studies had an ascertainment bias. Most were inadequate because they had insufficient deaths, used obsolete standards, combined oedematous and non-oedematous subjects, did not report the proportion of children with both deficits or the deaths occurred remotely after anthropometry. The meta-analyses showed that the mortality risks for children who have SAM by MUAC < 115 mm only and those with SAM by WHZ < -3Z only are not different., Conclusions: As the diagnostic criteria identify different children, this analysis does not support the abandonment of WHZ as an important independent diagnostic criterion for the diagnosis of SAM. Failure to identify such children will result in their being denied treatment and unnecessary deaths from SAM.

Background: Severe acute malnutrition (SAM) is diagnosed when the weight-for-height Z-score (WHZ) is <-3Z of the WHO 2006 standards, or a mid-upper-arm circumference (MUAC) of < 115 mm or there is nutritional oedema. Although there has been a move to eliminate WHZ as a diagnostic criterion we have shown that children with a low WHZ have at least as high a mortality risk as those with a low MUAC. Here we take the estimated case fatality rates and published case-loads to estimate the proportion of total SAM related deaths occurring in children that would be excluded from treatment with a MUAC-only policy., Methods: The effect of varying case-load and mortality rates on the proportion of all deaths that would occur in admitted children was examined. We used the same calculations to estimate the proportion of all SAM-related deaths that would be excluded with a MUAC-only policy in 48 countries with very different relative case loads for SAM by only MUAC, only WHZ and children with both deficits. The case fatality rates (CFR) are taken from simulations, empirical data and the literature., Results: The relative number of cases of SAM by MUAC alone, WHZ alone and those with both criteria have a dominant effect on the proportion of all SAM-related deaths that would occur in children excluded from treatment by a MUAC-only program. Many countries, particularly in the Sahel, West Africa and South East Asia would fail to identify the majority of SAM-related deaths if a MUAC only program were to be implemented. Globally, the estimated minimum number of deaths that would occur among children excluded from treatment in our analyses is 300,000 annually., Conclusions: The number, proportion or attributable fraction of children excluded from treatment with any change of current policy are the correct indicators to guide policy change. CRFs alone should not be used to guide policy in choosing whether or not to drop WHZ as a diagnostic for SAM. All the criteria for diagnosis of malnutrition need to be retained. It is critical that methods are found to identify those children with a low WHZ, but not a low MUAC, in the community so that they will not remain undetected.

Background: According to WHO childhood severe acute malnutrition (SAM) is diagnosed when the weight-for-height Z-score (WHZ) is <-3Z of the WHO 2006 standards, the mid-upper-arm circumference (MUAC) is < 115 mm, there is nutritional oedema or any combination of these parameters. Recently there has been a move to eliminate WHZ as a diagnostic criterion on the assertion that children meeting the WHZ criterion are healthy, that MUAC is universally a superior prognostic indicator of mortality and that adding WHZ to the assessment does not improve the prediction; these assertions have lead to a controversy concerning the role of WHZ in the diagnosis of SAM., Methods: We examined the mortality experience of 76,887 6-60 month old severely malnourished children admitted for treatment to in-patient, out-patient or supplementary feeding facilities in 18 African countries, of whom 3588 died. They were divided into 7 different diagnostic categories for analysis of mortality rates by comparison of case fatality rates, relative risk of death and meta-analysis of the difference between children admitted using MUAC and WHZ criteria., Results: The mortality rate was higher in those children fulfilling the WHO 2006 WHZ criterion than the MUAC criterion. This was the case for younger as well as older children and in all regions except for marasmic children in East Africa. Those fulfilling both criteria had a higher mortality. Nutritional oedema increased the risk of death. Having oedema and a low WHZ dramatically increased the mortality rate whereas addition of the MUAC criterion to either oedema-alone or oedema plus a low WHZ did not further increase the mortality rate. The data were subject to extreme confounding giving Simpson's paradox, which reversed the apparent mortality rates when children fulfilling both WHZ and MUAC criteria were included in the estimation of the risk of death of those fulfilling either the WHZ or MUAC criteria alone., Conclusions: Children with a low WHZ, but a MUAC above the SAM cut-off point are at high risk of death. Simpson's paradox due to confounding from oedema and mathematical coupling may make previous statistical analyses which failed to distinguish the diagnostic groups an unreliable guide to policy. WHZ needs to be retained as an independent criterion for diagnosis of SAM and methods found to identify those children with a low WHZ, but not a low MUAC, in the community.

Background: Representative surveys collecting weight, height and MUAC are used to estimate the prevalence of acute malnutrition. The results are then used to assess the scale of malnutrition in a population and type of nutritional intervention required. There have been changes in methodology over recent decades; the objective of this study was to determine if these have resulted in higher quality surveys., Methods: In order to examine the change in reliability of such surveys we have analysed the statistical distributions of the derived anthropometric parameters from 1843 surveys conducted by 19 agencies between 1986 and 2015., Results: With the introduction of standardised guidelines and software by 2003 and their more general application from 2007 the mean standard deviation, kurtosis and skewness of the parameters used to assess nutritional status have each moved to now approximate the distribution of the WHO standards when the exclusion of outliers from analysis is based upon SMART flagging procedure. Where WHO flags, that only exclude data incompatible with life, are used the quality of anthropometric surveys has improved and the results now approach those seen with SMART flags and the WHO standards distribution. Agencies vary in their uptake and adherence to standard guidelines. Those agencies that fully implement the guidelines achieve the most consistently reliable results., Conclusions: Standard methods should be universally used to produce reliable data and tests of data quality and SMART type flagging procedures should be applied and reported to ensure that the data are credible and therefore inform appropriate intervention. Use of SMART guidelines has coincided with reliable anthropometric data since 2007.

Background: It is often thought that random measurement error has a minor effect upon the results of an epidemiological survey. Theoretically, errors of measurement should always increase the spread of a distribution. Defining an illness by having a measurement outside an established healthy range will lead to an inflated prevalence of that condition if there are measurement errors., Methods and Results: A Monte Carlo simulation was conducted of anthropometric assessment of children with malnutrition. Random errors of increasing magnitude were imposed upon the populations and showed that there was an increase in the standard deviation with each of the errors that became exponentially greater with the magnitude of the error. The potential magnitude of the resulting error of reported prevalence of malnutrition were compared with published international data and found to be of sufficient magnitude to make a number of surveys and the numerous reports and analyses that used these data unreliable., Conclusions: The effect of random error in public health surveys and the data upon which diagnostic cut-off points are derived to define "health" has been underestimated. Even quite modest random errors can more than double the reported prevalence of conditions such as malnutrition. Increasing sample size does not address this problem, and may even result in less accurate estimates. More attention needs to be paid to the selection, calibration and maintenance of instruments, measurer selection, training & supervision, routine estimation of the likely magnitude of errors using standardization tests, use of statistical likelihood of error to exclude data from analysis and full reporting of these procedures in order to judge the reliability of survey reports., Competing Interests: The studentship does not alter our adherence to PLOS ONE policies on sharing data and materials. MG received no support and has no competing interests.

The various types of oedema in man are considered in relation to Starling's hypothesis of fluid movement from capillaries, with the main emphasis on nutritional oedema and the nephrotic syndrome in children. It is concluded that each condition has sufficient anomalous findings to render Starling's hypothesis untenable. The finding that the endothelial glycocalyx is key to control of fluid movement from and into the capillaries calls for complete revision of our understanding of oedema formation. The factors so far known to affect the function of the glycocalyx are reviewed. As these depend upon sulphated proteoglycans and other glycosaminoglycans, the argument is advanced that the same abnormalities will extend to the interstitial space and that kwashiorkor is fundamentally related to a defect in sulphur metabolism which can explain all the clinical features of the condition, including the formation of oedema.

Ready-to-use therapeutic foods (RUTFs) are solid foods that were developed by changing the formulation of the existing liquid diet, F-100, recommended by the World Health Organization (WHO) for the rapid catch-up phase of the treatment of children suffering from severe acute malnutrition (SAM). The resulting products proved highly effective in promoting weight gain in both severely and moderately wasted children and adults, including those infected with HIV. The formulation of the existing RUTFs, however, has never been optimized to maximize linear growth, vitamin and mineral status, and functional outcomes. The high milk content of RUTFs makes it an expensive product, and using lower quantities of milk seems desirable. However, the formulation of alternative, less expensive but more effective versions of RUTF faces difficult challenges, as there are uncertainties regarding the effect in terms of protein quality, antinutrient content, and flatulence factors that will result from the replacement of current dairy ingredients by less expensive protein-rich ingredients. The formulation of alternative RUTFs will require further research on these aspects, followed by efficacy studies comparing the future RUTFs to the existing formulations.

Wasting, kwashiorkor and stunting are not usually due to either protein or energy deficiency. Treatment based upon this concept results in high mortality rates, and failure of treated children to return physiologically to normal. They become relatively obese with insufficient lean tissue. Preventive strategies have also failed. Wasting and stunting are primarily due to deficiency of type II nutrients and kwashiorkor probably due to deficiency of several type I nutrients that confer resistance to oxidative stress. Modern dietary treatments are based upon the F75 formula whilst the child is sick without an appetite, followed by F100 for rapid gain of weight. Derivative, ready-to-use therapeutic foods (RUTF) allow treatment of large numbers of children at home, are preferred by mothers and dramatically improve coverage. Children are indentified by screening in the community and treated before complications arise, using simple protocols. Successful treatment of the sick children with severe malnutrition not only depends upon these products, but appropriate management of complications. The physiology of the malnourished child is completely different from the normal child and many drugs and treatments that are safe in children with normal physiology are fatal for the malnourished child. In particular, the diagnosis and management of diarrhea and dehydration is different in the malnourished child. Giving standard treatment frequently leads to circulatory overload and death from heart failure. The challenge now is to find successful local ways to prevent malnutrition and achieve nutritional security. Until prevention works, we have to rely on fortified foods for treatment and convalescence from illness.

Background: Kwashiorkor, a form of severe malnutrition with high mortality, is characterized by edema and systemic abnormalities. Although extremely common, its pathophysiology remains poorly understood, and its characteristic physical signs are unexplained., Objective: Because kwashiorkor can develop in protein-losing enteropathy, which is caused by a loss of enterocyte heparan sulfate proteoglycan (HSPG), and previous observations suggest abnormal sulfated glycosaminoglycan (GAG) metabolism, we examined whether intestinal GAG and HSPG are abnormal in children with kwashiorkor., Design: Duodenal biopsy samples collected from Zambian children with marasmus (n = 18), marasmic kwashiorkor (n = 8), and kwashiorkor (n = 15) were examined for expression of HSPG, GAGs, and immunologic markers and compared against reference samples from healthy UK control children. GAG and HSPG expression density and inflammatory cell populations were quantitated by computerized analysis., Results: The kwashiorkor group was less wasted and had a lower HIV incidence than did the other groups. All duodenal biopsy samples showed inflammation compared with the histologically uninflamed control samples. Biopsy samples from marasmic children had greater inflammation and greater CD3+ and HLA-DR (human leukocyte antigen DR)-positive cell densities than did samples from children with kwashiorkor. Expression of both HSPG and GAGs was similar between marasmic and well-nourished UK children but was markedly lower in children with kwashiorkor in both the epithelium and lamina propria. Although underglycosylated and undersulfated, epithelial syndecan-1 protein was normally expressed in kwashiorkor, which confirmed that abnormalities arise after core protein synthesis., Conclusions: Intestinal HSPG loss occurs in kwashiorkor, which may precipitate protein-losing enteropathy to cause edema. If occurring systemically, impaired HSPG expression could cause several previously unexplained features of kwashiorkor. We speculate that a genetic predisposition to reduced HSPG biosynthesis may offer a contrasting selective advantage, by both diminishing protein catabolism during transient undernutrition and protecting against specific infectious diseases.

Background: The menopausal transition is characterized by rapid bone loss. Few data exist on the role of nutrition., Objective: The objective of the study was to ascertain which dietary factors influence perimenopausal skeletal loss., Design: A longitudinal study was conducted of 891 women aged 45-55 y at baseline and 50-59 y at follow-up 5-7 y later. Bone mineral density (BMD) was measured by using dual-energy X-ray absorptiometry at the lumbar spine and femoral neck (FN). Nutrient intakes were assessed after the baseline visit and 5 y later, by using the same food-frequency questionnaire., Results: After adjustment for energy intake and other confounders, higher intakes of calcium were correlated with change in FN BMD (ie, reduced loss) (r = 0.073, P < 0.05), and the intake of modest amounts of alcohol was associated with less lumbar spine bone loss (P < 0.01 for quartile of alcohol intake). Greater FN BMD loss was associated with increased intake of polyunsaturated fatty acids (r = -0.110, P < 0.01), monounsaturated fatty acids (r = -0.069, P < 0.05), retinol (r = -0.067; P < 0.05), and vitamin E (r = -0.110; P < 0.01). The latter 2 nutrients were highly correlated with polyunsaturated fatty acids. For premenopausal women, calcium and nutrients found in fruit and vegetables (vitamin C, magnesium, and potassium) were associated with FN BMD, and calcium, vitamin C, and magnesium were associated with change in FN BMD., Conclusions: Although menopausal status and hormone replacement therapy use dominate women's bone health, diet may influence early postmenopausal bone loss. Fruit and vegetable intake may protect against premenopausal bone loss.

Study Design: The lumbar vertebral canal was measured in two cohorts of 10-year-old children (n = 161) using magnetic resonance imaging (MRI) and compared with obstetric records., Objective: To investigate whether there are identifiable obstetric factors that determine the size of the lumbar vertebral canal., Summary of Background Data: The most rapid period growth for the lumbar vertebral canal is between 12 and 32 weeks in utero, with the midsagittal diameter of L1-L4 already 70% of adult dimension at birth. Therefore, adverse antenatal factors during this critical growth period may be expected to affect the size of the canal., Methods: The canal size was measured from axial MRI sections taken through each lumbar vertebra (L1-L5) at the pedicular level of 84 children. Relations with obstetric data, prospectively collected in a neonatal database, were sought. The relation of low birthweight and canal size was further investigated in a second cohort of children (n = 77)., Results: The canal size, particularly the midsagittal diameter and the cross-sectional area, was found to be significantly reduced by low birthweight (with growth retardation in utero being a more important factor than length of gestation), low placenta weight, and lower socioeconomic class. Smoking during pregnancy significantly reduced the perimeter at L3 (P = 0.032) and L5 (P = 0.031), and also the cross-sectional area at L3 (P = 0.030) and L5 (P = 0.016)., Conclusions: This study showed that, for this group of children, the size of the lumbar vertebral canal was reduced by low birthweight, with maternal smoking as an added adverse factor. Therefore, good antenatal care and maternal education may help to reduce the risk of spinal stenosis in adult life.

The protection of children may be enhanced if ill treatment is classified by motive and degree rather than by type of injury. Four categories are proposed: A, abuse: premeditated ill treatment undertaken for gain by disturbed, dangerous, and manipulative individuals; B, active ill treatment: impulsively undertaken because of socioeconomic pressures, lack of education, resources, and support, or mental illnesses; C, universal mild ill treatment: behaviour undertaken by all normal caring parents in all societies; and D, neglect: defined here as an unintentional failure to supply the child's needs. Such a classification could clarify the procedures for investigation and protection, and support the creation of a Special Interagency Taskforce on Criminal Abuse (SITCA) for those suspected of abuse (category A).

Neglect is a major cause of inadequate childcare in all societies and should be differentiated from abuse. "Neglect" is defined here, as the "neglectful" failure to supply the needs of the child, including emotional needs. It does not include the deliberate and malicious withholding of needs, which is a form of abuse. Neglect has its roots in ignorance of a child's needs and competing priorities; it is passive and usually sustained. The carer is without motive and unaware of the damage being caused. Malnutrition is a prime example of neglect; the stigma associated with the term abuse should never be applied to the poor struggling or uneducated mother whose child, that she loves dearly, becomes malnourished. Education of the mother and society and relief from the vicissitudes of poverty are required to alleviate most neglect of the world's children.

To estimate the potential outcomes of food processing on the fate of foodborne pathogens. variations in microbial parameters such as growth rate, survival time, thermal inactivation time, and toxin production must be known. Previous microbial studies using single strains or cocktails provide error estimates for the uncertainty of the experimental and statistical procedures, but not for variations among strains. In this study, the behavior of 17 strains of Escherichia coli O157:H7 were followed when placed in synthetic media that permitted growth, survival, or thermal inactivation. The parameter values were not rejected as being normal, lognormal, gamma, or Weibull distributions. The ratio of the standard deviation to mean (normal distribution) for the exponential growth rate was 0.16 and for the lag phase duration, it was 0.38. The ratios of times to achieve a 4-log10 reduction at two survival conditions were 0.39 and 0.46; ratios of thermal D values at 55 and 60 degrees C were 0.42 and 0.33, respectively. The ratio of the negative log10 of toxin production was 0.24. These distributions are larger than the coefficient of variations observed for experimental errors in single strain and cocktail experiments. This indicates the limitations in precision that predictions of future population numbers can have when the potential presence of all strains needs to be considered. This variation among strains is applicable whether predictions are made by traditional subjective and point estimates or by using models and risk assessments.

An immunoassay based on immunomagnetic separation and time-resolved fluorometry was developed for the detection of E. coli O157:H7 in apple cider. The time-resolved fluorescent immunoassay (TRFIA) uses a polyclonal antibody bound to immunomagnetic beads as the capture antibody and the same antibody labeled with europium as the detection antibody. Cell suspensions of 10(1) to 10(8) E. coli O157:H7 and K-12 organisms per ml were used to test the sensitivity and specificity of the assay. The sensitivity of the assay was 10(3) E. coli O157:H7 cells with no cross-reaction with K-12. Pure cultures of E. coli O157:H7 (10(1) to 10(5) CFU/ml) in apple cider could be detected within 6 h, including 4 h for incubation in modified EC broth with novobiocin and 2 h for the immunoassay. When apple cider was spiked with 1 to 10(3) CFU/ml of E. coli O157:H7 and 10(6) CFU/ml of K-12, our data show that the high level of K-12 in apple cider did not impede the detection of low levels of O157:H7. The minimum detectable numbers of cells present in the initial inoculum were 10(2) and 10(1) CFU/ml after 4- and 6-h enrichment. The TRFIA provides a rapid and sensitive means of detecting E. coli O157:H7 in apple cider.

Background: Increased plasma homocysteine is associated with coronary artery disease, peripheral vascular disease and venous thrombosis. Folic acid is the most effective therapy for reducing homocysteine levels. The lowest effective supplement of folic acid is not known, particularly for the elderly who have the highest prevalence of these conditions., Aim: To explore the effects of daily supplements of 0, 50, 100, 200, 400 and 600 microg folic acid on plasma homocysteine in an elderly population., Design: Randomized double-blind placebo-controlled trial., Methods: Participants (n=368) aged 65-75 years were randomly allocated to receive one of the treatments for 6 weeks. Plasma homocysteine was recorded after 3 weeks and 6 weeks of supplementation., Results: Only the 400 microg and 600 microg groups had significantly lower homocysteine levels compared to placebo (p=0.038 and p<0.001, respectively). Using multiple linear regression and each individual's total folic acid intake (diet plus supplement), a total daily folic acid intake of 926 microg per day would be required to ensure that 95% of the elderly population would be without cardiovascular risk from folate deficiency., Discussion: A daily folic acid intake of 926 microg is unlikely to be achieved by diet alone. Individual supplementation or fortification of food with folic acid will be required to reach this target.

Aim: To investigate the validity of urinary pyridinium cross-links (pyridinoline and deoxypyridinoline) as markers of growth in healthy children., Methods: Three pilot studies (P1-P3) were conducted to investigate the time of day, the minimal duration within a day, and how many times per week urine samples needed to be collected to obtain representative values of cross-link excretion in normal children 3-5 years of age. The results were used to design a 4-month longitudinal protocol to evaluate whether pyridinium cross-links could be used as markers of growth velocity., Results: Mean differences from 24-hour values were only between 1 and 4% for urinary cross-links (nmol/h) in overnight 12-hour collections. Three consecutive collections were required for weekly output estimates with a maximum error of 10% in >90% of the children. During the 4-month longitudinal study, the regression equation of height velocity on pyridinoline and deoxypyridinoline excretion explained approximately 60% of the variance in the subgroup of subjects who provided three complete urinary collections per observation period. No relationship was observed when the cases with fewer or incomplete collections were included in the analysis. Cross-link values collected at baseline were of no use to predict height velocity at 4 months., Conclusions: Urinary pyridinium cross-links correlate with the growth velocity in healthy children when using an appropriate urinary collection protocol. However, their predictive value in this population is negligible., (Copyright 2002 S. Karger AG, Basel)

The aim of this study was to evaluate the effect of growth hormone (GH) treatment on bone resorption in children with GH deficiency and those with idiopathic short stature. The study population included seven children with subnormal spontaneous GH secretion and 13 children with idiopathic short stature, all of them pre-pubertal. Anthropometric measurements, free, protein-bound and total urinary pyridinoline (Pyd) and deoxypyridinoline (Dpd), serum GH, and serum immunoreactive PTH were measured at baseline and months 1, 3, 6 and 12 of GH treatment. The urinary excretion of total Pyd and Dpd, standardized by the cube of height (m3) in overnight, 24-hour urine collections was not different from age-matched healthy controls at baseline in either group of patients. During treatment with human recombinant GH, both pyridinium crosslinks increased above normal values, reaching a peak after one month in children with GH deficiency and later (after 3-6 months) in children with short stature. Free and total crosslink forms were correlated, and GH treatment did not affect the proportion of free to bound crosslinks. Serum concentrations of iPTH showed a moderate but not statistically significant increase. This study provides no evidence of reduced bone resorption in untreated GH deficiency or in idiopathic short stature. GH treatment induced a marked, but temporary, increase of bone resorption in both groups of patients.

Genetic factors play an important role in the pathogenesis of osteoporosis but the genes that determine susceptibility to poor bone health are defined incompletely. Previous work has shown that a polymorphism that affects an Spl binding site in the COLIA1 gene is associated with reduced bone mineral density (BMD) and an increased risk of osteoporotic fracture in several populations. Data from cross-sectional studies have indicated that COLIA1 Sp1 alleles also may be associated with increased rates of bone loss with age, but longitudinal studies, which have examined bone loss in relation to COLIA1 genotype, have yielded conflicting results. In this study, we examined the relationship between COLIA1 Sp1 alleles and early postmenopausal bone loss measured by dual-energy X-ray absorptiometry (DXA) in a population-based cohort of 734 Scottish women who were followed up over a 5- to 7-year period. The distribution of genotypes was as expected in a white population with 484 "SS" homozygotes (65.9%); 225 "Ss" heterozygotes (30.7%), and 25 "ss" homozygotes (3.4%). Women taking hormone-replacement therapy (HRT; n = 239) had considerably reduced rates of bone loss at the spine (-0.40 +/- 0.06%/year) and hip (-0.56 +/- 0.06%/year) when compared with non-HRT users (n = 352; spine, -1.36 +/- 0.06%/year; hip, -1.21 +/- 0.05%/year; p < 0.001 for both sites). There was no significant difference in baseline BMD values at the lumbar spine (LS) or femoral neck (FN) between genotypes or in the rates of bone loss between genotypes in HRT users. However, in non-HRT users (n = 352), we found that ss homozygotes (n = 12) lost significantly more bone at the lumbar site than the other genotype groups in which ss = -2.26 +/- 0.31%/year compared with SS = -1.38 +/- 0.07%/year and Ss = -1.22 +/- 0.10%/year (p = 0.004; analysis of variance [ANOVA]) and a similar trend was observed at the FN in which ss = -1.78 +/- 0.19%/year compared with SS = -1.21 +/- 0.06%/year and Ss = -1.16 +/- 0.08%/year (p = 0.06; ANOVA). The differences in spine BMD loss remained significant after correcting for confounding factors. Stepwise multiple regression analysis showed that COLIA1 genotype independently accounted for a further 3.0% of the variation in spine BMD change after age (4.0%), weight (5.0%), and baseline BMD (2.8%). We conclude that women homozygous for the Sp1 polymorphism are at significantly increased risk of excess rates of bone loss at the spine, but this effect may be nullified by the use of HRT.

Severe malnutrition is uncommon but often fatal, particularly in very young infants or when oedema is present. Another major contributor to mortality is undiagnosed infection. Three pilot studies have recently been performed in severely malnourished patients in therapeutic feeding centres in sub-Saharan Africa. In each, a practical management problem was addressed and a potential solution tested. Three conclusions were reached: young breastfeeding infants were best managed using a supplemented suckling technique; routine antibiotics from admission reduced mortality; and in adults with oedematous malnutrition, therapeutic diets with a lower-than-usual protein:energy ratio were effective in reducing mortality and permitting catch-up weight gain.

Background: The reason why elderly human hips tend to break in one of two anatomical regions is uncertain. Nutritional factors may affect the site of fracture., Objective: To assess possible nutritional differences in patients with proximal femoral fractures., Design: Prospective observational cohort study., Setting: University teaching hospital., Subjects: 119 consecutive patients over the age of 65 with a hip fracture admitted to the trauma wards in a single centre., Methods: One researcher measured triceps, biceps and supra-iliac skinfold thickness, and mid upper arm circumference on admission and on the fifth post-operative day. Body mass index was calculated for each patient, and used to classify patients as severely, moderately or mildly malnourished, normal, overweight or obese. Logistic regression was used to determine the influence of various factors on fracture site., Results: According to their body mass index, 31% of patients were classified as malnourished and 11% as severely malnourished. Patients with intracapsular fractures were significantly more malnourished than patients with trochanteric fractures (P < 0.008). Nutritional status was not related to post-operative complications. Ability to weigh a patient on the fifth post-operative day was the single most important prognostic indicator for complications., Conclusions: Patients with intracapsular fractures are more malnourished. Those with trochanteric fractures tend to be overweight.

The aim of this study was to investigate the incidence and epidemiology in 1994 of hip fracture in Shenyang, a large city in the northeast of The People's Republic of China, using register information and medical records collected from the 36 hospitals in Shenyang. The hip fracture data were restricted to cervical or trochanteric types. A subset (59% of total) of medical records of hip fracture was used to investigate the causes of hip fracture. The causes were classified as simple fall, fall from a bicycle during cycling, bicycle accident, car accident, and fall from a height. There was a total of 453 hip fractures (206 in women and 247 in men) in the population over 50 years of age. The age-adjusted 1 year cumulative incidence rate was 67/100,000 (95% confidence interval [CI] = 58-76/100,000) for women and 81/100,000 (95% CI = 71-91/100,000) for men. The standardized incidence rate against the 1985 U.S. population was 87/100,000 (95% CI = 77-97/100,000) for women and 100/100,000 (95% CI = 89-111/100,000) for men. The mean (+/-standard deviation) age of patients with a hip fracture was 67.5+/-9.8 years for men and 66.9+/-9.0 years for women. The overall male-to-female ratio of hip fracture was 1.21:1 for age-adjusted hip fracture incidence and 1.15:1 for standardized incidence. Simple fall accounted for 70% hip fractures in women but caused only 49% in men (chi2 = 11.2, degrees of freedom [df] = 1,p = 0.0008). The frequency of hip fractures caused by a fall from a bicycle was higher in men (28%) than women (10%) (chi2 = 13.0, df = 1,p = 0.0003). The results of this study indicate (1) a low incidence of hip fracture in a Chinese population compared with more affluent countries, and (b) a higher incidence in men than women that is related in part to a higher incidence of accidents, especially bicycle-related ones.

Nowadays, median case fatality rate of severely malnourished children treated in hospitals is 23.5%, a rate which has not changed for the last 50 years. This is probably related to the use of inappropriate or even unsafe treatment protocols. This work aimed at reducing case fatality rates of severe malnutrition by developing a treatment protocol and assessing its effectiveness during humanitarian crises. A therapeutic food was designed from pathophysiologic studies and its use adapted to therapeutic feeding centres. This food (F100) contains 100 Kcal/100 ml, with 10% of its energy derived from proteins; it has a low sodium and iron content but is fortified with vitamins and minerals. It can be prepared either at the treatment centre or at an industrial level. Industrial production, which started in 1993 reached 1,500 MT in 1997. In refugee camps, F100 was used according to a strict protocol adapted to local conditions. Intakes started at 100 Kcal/kg/day and reached 200 kcal/kg/day once appetite was restored. A model to assess the risk of death according to weight, height and oedema was developed. First results show that mortality was often below 5%. Hence, it is possible to standardise and evaluate a nutritional treatment in such unfavourable conditions as a refugee camp. Standardised use of F100 can markedly reduce mortality of severely malnourished children.

Oedematous malnutrition in the child or adult is not caused by protein deficiency; such a concept can lead to fatal therapeutic error in oedematous malnutrition treatment. On the other hand, deficiency of protein, or the other type II nutrients, is common and causes stunting and wasting. In kwashiorkor, the deficiency is more likely to be due to one or several type I nutrients, particularly those involved with anti-oxidant protection.

Objective: To determine a simple model to calculate the number of deaths which could be expected in a therapeutic feeding centre from the height, weight and oedema of children on admission., Design: Admission weight, height, presence of oedema of the children and outcome were prospectively recorded., Setting: Data were recorded in 18 feeding centres set-up during emergency operations in Africa. Ten of the feeding centres were selected, a priori, as reference centres and eight centres as test centres., Subjects: Data for 3858 children were recorded. 837 children absconded from the centres and were excluded from the analysis. Analysis was performed on data from 2753 children who left the centre after recovery and 268 children who died during treatment., Interventions: The relation between the risk of death and, anthropometric measurements and presence of oedema has been determined in a previous paper. The maximum likelihood estimate of the constant of the model was determined from global analysis of the data of the reference centres. The model was applied to the data of the reference and test centres., Results: The model to predict the individual probability of death was: P(death) = 1/(1 + exp[-(20.63 - 9.99 1n(weight/height1.74) + 1.36 oedema)]) The predicted number of deaths was close to the recorded number of deaths for each reference centre. For three of the eight test centres there was a significant excess of observed deaths over predicted., Conclusion: This model can be easily used by the supervisor of a centre to assess the expected number of deaths during treatment of malnutrition from simple measurements on children that are routinely taken on admission and thus help to determine the nature of variation in observed mortality rates.

Previously developed four-variable response surface models for describing the effects of temperature, pH/lactic acid, sodium chloride and sodium nitrite on the time to achieve a 4-log, non-thermal inactivation (t4D) of Listeria monocytogenes in aerobic, acidic environments were expanded to five-variable models that distinguish the effects of pH and acidulant concentration. A total of 18 new variable combinations were evaluated and the inactivation kinetics data appended onto a consolidation of two data sets from earlier studies. The consolidated data set, which included 315 inactivation curves representing 209 unique combinations of the five variables, was analysed by response surface analysis. The quadratic model without backward elimination regression was selected for further evaluation. Three additional quadratic models were generated using the concentrations of undissociated lactic and/or nitrous acids as variables in place of percentage lactic acid and sodium nitrite concentration. Comparison of predicted t4D values against literature values for various food systems indicated that the models provide reasonable initial estimates of the inactivation of L. monocytogenes. The models based on the concentration of undissociated lactic and nitrous acids support the hypothesis that antimicrobial activity is associated with this form of the compounds. Evaluation of several examples suggests that these models may be useful for predicting the equivalent of the compounds' "minimal inhibitory concentrations' for accelerating inactivation under various conditions.

The three syndromes of childhood malnutrition are contrasted with respect to protein. It is concluded that stunting and wasting are the outcomes of protein deficiency, and that kwashiorkor is not due to protein deficiency, rather it is related to unopposed oxidant stress. Formula for the energy and protein requirements are derived and contour plots of the amounts needed to sustain high rates of weight gain at different body compositions generated. It is suggested that all nutrients be expressed with energy as the denominator. No more than 12.5% of protein energy is required to sustain maximum likely rates of weight gain. Using this approach to design a diet, high rates of weight gain are achieved under field conditions in refugee camps.

To compare the effectiveness of treating malnourished children in different centers, the authors believe there is a need to have a simple method of adjusting mortality rates so that differences in the nutritional status of the children are taken into account. The authors compared different anthropometric indices based on weight and height to predict the risk of death among severely malnourished children. Anthropometric data from 1,047 children who survived were compared with those of 147 children who died during treatment in therapeutic feeding centers set up in African countries in 1993. The optimal ratio of weight to height determined by logistic regression was weight (kg)/height (m)1.74 (95% confidence interval of beta estimate 1.65-1.84). The receiver operating curves (sensitivity vs. specificity) showed that the body mass index (weight (kg)/height (m)2), optimal ratio of weight to height, and weight/height index expressed as the percentage of the median of the National Center for Health Statistics' standard were equivalent and superior to the weight/height index expressed as the z score of the National Center for Health Statistics' standard to predict death. As the optimal ratio of weight to height is easier to calculate than the weight/height index expressed as the percentage of the median or z score and does not depend upon either standards or tables, the optimal ratio of weight to height could be conveniently used to adjust mortality rates for nutritional status in therapeutic feeding centers.

A matrixed approach to long-term stability testing of pharmaceutical products is presented. The basic matrix design, suitable for testing three lots at one storage condition, may be extended to multiple product presentations or storage conditions. The design has full testing at the endpoints (0 and 36 months) and partial testing at the interim time points (3, 6, 9, 12, 18, and 24 months). The test points were selected with the assistance of a statistical search algorithm. The proposed matrix design provides a 37.5% reduction in analytical testing, while still permitting a reliable interim expiry estimate based on 12-month stability data. The expiration dating periods estimated using the matrixed approach are typically more conservative than estimates derived from a full-testing approach. A comparison of expiration dating period estimates for a metered-dose inhaler and capsule drug product using the matrixed and full-testing approaches is presented.

Brain function in 10 severely malnourished children and matched controls was assessed using spectral analysis of electroencephalographic responses to photic driving during slow-wave sleep. The percentage power in the classical EEG broad-band domains was derived from temporo-occipital records. The malnourished group (5-23 months old; z-score height-for-age -3.2 +/- 0.3, weight-for-height -2.5 +/- 0.3) were tested on admission and on discharge from hospital. No significant differences were found between admission and discharge. Significant differences were found between malnourished and control groups, in the alpha 1 band in the undriven EEG, and in the alpha/beta 1 power ratio while driving at 8 Hz. These electrophysiological abnormalities, persisting despite somatic rehabilitation, must be associated with the chronic rather than the acute aspects of malnutrition, and can index the deviation of brain function from normality.

Objective: To assess micronutrient status indices in blood and plasma of subjects subjected to siege conditions., Design: Whole blood and serum samples were taken from subjects, sampled from 30 clusters in four Municipal Areas of Sarajevo. The blood samples were flown, under appropriate refrigeration, to the UK for analysis., Setting: The study was conducted in besieged Sarajevo and laboratory analyses were carried out at Department of Clinical Chemistry, Aberdeen Royal Infirmary and at Rowett Research Institute, Aberdeen, Scotland., Subjects: 202 subjects, aged from 1 to 82 years were included in the sample., Interventions: Serum folate, ferritin, transferrin, retinol, retinol-binding protein, beta-carotene, alpha-tocopherol, 25-hydroxycholecalciferol, C-reactive protein, haemoglobin and mean corpuscular volume of blood were determined. Micronutrient status was assessed by comparison with a range of values derived from multinational data sets from both pathologically malnourished and normal subjects., Results: Haemoglobin, ferritin, folate, retinol and 25-hydroxycholecalciferol levels were lower in the Sarajevan sample than in normal reference populations. Serum alpha-tocopherol was low in children and adolescents while a low beta-carotene level probably reflected the scarcity of green vegetables. No consistent evidence of protein/energy deficits were detected., Conclusions: Data for retinol binding protein and transferrin, when considered in association with BMI and Z-score data, provided no significant evidence of protein-energy undernutrition. However, the prevailing food aid rations failed to maintain adequate reserves of several micronutrients, particularly iron, folate and vitamin D. The significance of low values for serum retinol and beta-carotene and of low serum alpha-tocopherol in children must be investigated further.

The enzyme glyoxalase I (Glyox I) is involved in metabolic detoxification, and requires glutathione (GSH) as a cofactor. Given the low concentration of whole blood GSH in children with oedematous malnutrition, it is possible that the function of this pathway may be compromised in these children. Glyox I activity was therefore assayed in erythrocytes taken from 133 severely malnourished children and 21 age-matched controls. The mean values (+/- SEM) for the marasmic group (Marasmus: 105 +/- 4/u/gm Hb) and the group with kwashiorkor (Kwash: 103 +/- 4/u/gm Hb) were not significantly different from controls (Cont: 104 +/- 2 u/gm Hb). In the group with marasmic-kwashiorkor (M-K: 88 +/- 4 u/g Hb) Glyox I activity was significantly lower than in controls (p < 0.005), as well as in children with Marasmus (p < 0.005), and kwashiorkor (p < 0.05). Enzyme activity was lower than normal in 45% of the MK group. Seven children died subsequent to admission; in five cases Glyox I activities were exceedingly low. There was a weak positive correlation between Glyox I activity and whole blood levels of GSH (r = 0.215). We conclude that Glyox I activity is relatively unaffected in malnutrition, except in those with M-K and especially those who do not survive the acutely malnourished state.

In three experiments [amide-15N]glutamine was infused intravenously in male volunteers. After 4-8 h of infusion acidosis was achieved by an oral dose of CaCl2 (1 mmol/kg). In one subject acidosis was maintained for 5 d. The acid load produced an approximately 3-fold increase in urinary NH3 excretion, with a small (approximately 20%) and transient increase in the isotope abundance of urinary NH3. Estimates of glutamine production rate (flux) were obtained in two experiments. There was no evidence that it was increased in acidosis. The extra NH3 production by the kidney represented only a very small part, about 3%, of the total glutamine production rate.