Prenatal factors contribute to the emergence of kwashiorkor or marasmus in severe undernutrition: evidence for the predictive adaptation model

Background

Severe acute malnutrition in childhood manifests as oedematous (kwashiorkor, marasmic kwashiorkor) and non-oedematous (marasmus) syndromes with very different prognoses. Kwashiorkor differs from marasmus in the patterns of protein, amino acid and lipid metabolism when patients are acutely ill as well as after rehabilitation to ideal weight for height. Metabolic patterns among marasmic patients define them as metabolically thrifty, while kwashiorkor patients function as metabolically profligate. Such differences might underlie syndromic presentation and prognosis. However, no fundamental explanation exists for these differences in metabolism, nor clinical pictures, given similar exposures to undernutrition. We hypothesized that different developmental trajectories underlie these clinical-metabolic phenotypes: if so this would be strong evidence in support of predictive adaptation model of developmental plasticity.

Methodology/Principal Findings

We reviewed the records of all children admitted with severe acute malnutrition to the Tropical Metabolism Research Unit Ward of the University Hospital of the West Indies, Kingston, Jamaica during 1962–1992. We used Wellcome criteria to establish the diagnoses of kwashiorkor (n = 391), marasmus (n = 383), and marasmic-kwashiorkor (n = 375). We recorded participants'' birth weights, as determined from maternal recall at the time of admission. Those who developed kwashiorkor had 333 g (95% confidence interval 217 to 449, p<0.001) higher mean birthweight than those who developed marasmus.

Conclusions/Significance

These data are consistent with a model suggesting that plastic mechanisms operative in utero induce potential marasmics to develop with a metabolic physiology more able to adapt to postnatal undernutrition than those of higher birthweight. Given the different mortality risks of these different syndromes, this observation is supportive of the predictive adaptive response hypothesis and is the first empirical demonstration of the advantageous effects of such a response in humans. The study has implications for understanding pathways to obesity and its cardio-metabolic co-morbidities in poor countries and for famine intervention programs.     

Tumour necrosis factor-alpha,interleukin-2 soluble receptor and different inflammatory parameters in patients with rheumatoid arthritis

BACKGROUND AND AIMS: Although the participation of cytokines in the pathogenesis of rheumatoid arthritis (RA) seems to be unequivocal, their relationship with current serum markers of this disease is not clear. The present study analyses whether there is any correlation between the levels of tumour necrosis factor-alpha (TNF-alpha), interleukin-2 soluble receptor (sIL-2R) and the concentrations of C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and beta(2)-microglobulin in a group of 21 patients with RA, all rheumatoid factor positive. METHODS: The levels of TNF-alpha and sIL-2R were analysed in association with other parameters of inflammation (ESR, CRP and beta(2)-microglobulin). RESULTS: In comparison with the control group, RA patients presented high median levels of both cytokines, TNF-alpha (6.4 pg/ml) and sIL-2R (56 pmol/L), as well as of ESR (34 mm/h), CRP (0.9 mg/dl) and beta(2)-microglobulin (1.6 mg/dl) (p < 0.01). However, only ESR levels in the RA group significantly differ from the control group (p < 0.01). No correlation was found between the inflammatory parameters. CONCLUSIONS: These results suggested that TNF-alpha and slL-2R levels are up-regulated in RA patients but did not significantly differ from the control group. Due to the chronic course of this disease, other inflammatory markers must be identified in order to provide early therapeutic strategies to these patients.     

Estrogen reduces pro-inflammatory cytokines in rodent adipose tissue: studies in vivo and in vitro.

Obesity is associated with an increased risk of developing insulin resistance, Type 2 diabetes, and cardiovascular disease. Reports have suggested that adipose tissue-derived cytokines such as tumor necrosis factor-alpha, interleukin-6 and interleukin-8 could be involved in the development of these health complications. Since estrogen has been suggested to attenuate the development of atherosclerosis and cardiovascular disease, we investigated whether ovariectomy affected the production and release of these three adipose tissue-derived cytokines with and without estrogen replacement in vivo and in vitro. Female Wistar rats were submitted to either a) ovariectomy, b) ovariectomy and estrogen replacement, or c) sham operation. After five months, animals were sacrificed and parametrial adipose tissue was removed and incubated for up to 24 hours with either interleukin-1beta (IL-1beta) (5 micro g/l), dexamethasone (50 nM) or estrogen (50 nM). Ovariectomy significantly increased interleukin-6 gene expression (p < 0.05) as well as interleukin-8 protein levels (p < 0.05) and gene expression (p < 0.05) in the adipose tissue, and estrogen replacement significantly reversed this increase (p < 0.05). However, no direct effects of estrogen were found in in vitro adipose tissue incubations. Neither ovariectomy nor estrogen replacement had any effects on tumor necrosis factor-alpha protein levels or gene expression. In conclusion, estrogen-deficient rats were found to have increased production of interleukin-6 and interleukin-8, which could be attenuated by estrogen-replacement. Since estrogen is suggested to be anti-atherosclerotic, this effect might be caused by a reduction in cytokine production from the adipose tissue.     

Aflatoxins and kwashiorkor: a study in Sudanese children.

Blood and urine samples from 252 Sudanese children were investigated for their aflatoxin content by high-performance liquid chromatography. The children comprised 44 with kwashiorkor, 32 with marasmic kwashiorkor, 70 with marasmus, and 106 age-matched, normally nourished controls. Aflatoxins were detected more often and at higher concentrations in sera from children with kwashiorkor than in the other malnourished and control groups. Aflatoxicol, a metabolite of aflatoxins B1 and B2, was detected in the sera of children with kwashiorkor and marasmic kwashiorkor but not in the controls and only once in a marasmic child. The difference between children with kwashiorkor or marasmic kwashiorkor and those in the control or marasmus groups was significant. Urinary aflatoxin was most often detected in children with kwashiorkor but their mean concentration was lower than in the other groups. Aflatoxicol was not detected in urine in any group. These findings suggest either that the children with kwashiorkor have a greater exposure to aflatoxins or that their ability to transport and excrete aflatoxins is impaired by the metabolic derangements associated with kwashiorkor. The presence of aflatoxicol in the sera of children with kwashiorkor but not in the others suggests a difference in metabolism between the two groups. Further studies are needed, and measurement of aflatoxins in the food eaten by these children is already underway.     

Association of serum albumin with markers of nutritional status among HIV-infected and uninfected Rwandan women

Introduction

The objectives of this study are to address if and how albumin can be used as an indication of malnutrition in HIV infected and uninfected Africans.

Methods

In 2005, 710 HIV-infected and 226 HIV-uninfected women enrolled in a cohort study. Clinical/demographic parameters, CD4 count, albumin, liver transaminases; anthropometric measurements and Bioelectrical Impedance Analysis (BIA) were performed. Malnutrition outcomes were defined as body mass index (BMI), Fat-free mass index (FFMI) and Fat mass index (FMI). Separate linear predictive models including albumin were fit to these outcomes in HIV negative and HIV positive women by CD4 strata (CD4>350,200–350 and <200 cells/µl).

Results

In unadjusted models for each outcome in HIV-negative and HIV positive women with CD4>350 cells/µl, serum albumin was not significantly associated with BMI, FFMI or FMI. Albumin was significantly associated with all three outcomes (p<0.05) in HIV+ women with CD4 200–350 cells/µl, and highly significant in HIV+ women with CD4<200 cells/µl (P<0.001). In multivariable linear regression, albumin remained associated with FFMI in women with CD4 count<200 cells/µl (p<0.01) but not in HIV+ women with CD4>200.

Discussion

While serum albumin is widely used to indicate nutritional status it did not consistently predict malnutrition outcomes in HIV- women or HIV+ women with higher CD4. This result suggests that albumin may measure end stage disease as well as malnutrition and should not be used as a proxy for nutritional status without further study of its association with validated measures.     

Age-related differentiations of Th1/Th2 cytokines in newborn infants

OBJECTIVE: To evaluate age-related differentiation of immune response in newborns by measuring serum concentrations of interleukin-2 (IL-2), interleukin-4 (IL-4) and interferon-gamma (IFN-gamma) during the perinatal period. SUBJECTS AND METHODS: Fifty-seven healthy term neonates, their mothers and 25 healthy adults (controls) age-matched to the mothers were included in the study. Cytokine concentrations were measured in the umbilical cord (UC), and in first-day (1N) and fifth-day (5N) neonatal samples, compared with those in maternal serum (MS) and control serum samples. RESULTS: Serum IL-2 concentrations in the UC were markedly elevated compared with those in MS and controls (p < 0.0001), decreasing significantly thereafter up to 5N (p < 0.001). IL-4 serum concentrations did not differ significantly between the UC, 1N and 5N samples; they were, however, markedly elevated compared with those in MS (p < 0.001, p < 0.0007 and p < 0.0001, respectively) and controls (p < 0.05, p < 0.01 and p < 0.006, respectively). IFN-gamma serum concentrations were significantly lower in the UC compared with those in controls (p < 0.04), increasing significantly up to 5N (p < 0.03). Both IFN-gamma/IL-2 and IFN-gamma/IL-4 ratios increased significantly in 5N, compared with those in the UC (p < 0.001 and p < 0.03). CONCLUSION: Our findings indicate a differential cytokine balance at birth with enhanced expression of IL-2 and IL-4 against IFN-gamma. However, a regularization of immune response seems to proceed quickly during the early neonatal life.     

Cytokine soluble receptors in perinatal and early neonatal life

BACKGROUND: In contrast to cellular receptors, soluble receptors do not enhance the cellular activation because they do not have transmembranic and cytoplasmic parts, acting thereby as endogenous regulatory mechanisms against systemic functions of cytokines. AIM: To measure serum concentrations of the soluble interleukin-2 receptor (sIL2R), soluble interleukin-4 receptor (sIL4R), soluble interleukin-6 receptor (sIL6R), and soluble tumor necrosis factor-alpha receptor I and soluble tumor necrosis factor-alpha receptor II, during the perinatal and early neonatal period, in order to evaluate their role in activation of immune response in labor and the first days postpartum. METHODS: Soluble receptor serum concentrations were determined by enzyme-linked immunosorbent assay, in 45 healthy, full-termed neonates during the first and fifth days after birth, in 25 of their mothers (MS), in 25 samples of umbilical cords (UC) and in 25 healthy adult donors age-matched with the mothers (controls). RESULTS: Soluble receptor serum concentrations showed considerable changes during labor and early neonatal life, being significantly higher both in MS (except sIL6R) and in neonatal sample UC, first and fifth days after birth, compared with controls (p<0.0001). Neonatal serum sIL2R and sIL6R increased significantly from birth to the fifth day, while the remaining receptors showed a rapid increase in the first day (p<0.0001), declining significantly thereafter (p<0.0001). CONCLUSION: Our findings suggest that the elevated concentrations of all studied soluble cytokine receptors reflect the activation of immune response, and represent also regulatory protective mechanisms for mother and fetus-neonate against the systemic function of cytokines during labor and early neonatal life.     

Pepsins in protein-energy malnutrition

This study reports on basal gastric pepsins in 40 normal, kwashiorkor and marasmic children admitted to the paediatric wards of the University of Benin Teaching Hospital, Nigeria. The activity of total pepsin was significantly depressed in the diseased states. The various fractions of pepsin separated on ion-exchange chromatography also showed dramatic reductions for both kwashiorkor and marasmus. This adaptive reduction of pepsin and its fractions was more drastic in marasmus than kwashiorkor. On disc-gel electrophoresis, four of the pepsin bands found in normal gastric aspirate were missing in children with the syndromes. Gastric electrolytes and acidity recorded for the diseased states were not conducive for maximal peptic activity. It is suggested that due to the reduced proteolytic capability of the malnourished infants, rehabilitation with intact protein should be cautious and gradual.     

Serum bone alkaline phosphatase in assessing illness severity of infected neonates in the neonatal intensive care unit

Background: Infections can influence bone metabolism of neonates, which may lead to changes in some bone metabolism biomarkers. The purpose of this study was to determine whether serum bone alkaline phosphatase (BALP), osteocalcin (OC) and beta carboxy-terminal peptide of type I collagen (CTX), as specific biomarkers of bone metabolism, can be used to assess the severity of neonatal infections.Methods: Sixty-three neonates in the NICU were enrolled in this study. The neonates were divided into infected group (n=33) and non-infected group (n=30). The scores for neonatal acute physiology-perinatal extension II (SNAPPE-II) were calculated and interleukin-6 (IL-6), procalcitonin (PCT), BALP, OC and CTX were measured among the neonates with or without infections, and among the infected neonates before and after treatment.Results: The serum BALP levels were lower in the infected group than that in the non-infected group (p<0.01). The serum BALP levels increased markedly in the infected neonates after treatment (p<0.01). The serum BALP levels were also inversely correlated with SNAPPE-II of infected neonates before and after treatment (r=-0.56, p<0.05; r=-0.37, p<0.05, respectively). In infected neonates, the differences between serum BALP levels before and after treatment were inversely correlated with those of IL-6 levels (p<0.05). There were no significant changes in the OC, CTX and PCT levels in the infected or non-infected group before and after treatment.Conclusion: Our data suggest that serum BALP level might be used as a marker for assessing the severity of illness in infected neonates.     

Plasma fibronectin levels in acute and recovering malnourished children

58 malnourished children (mean age 18 months) with a clinical diagnosis of marasmus or kwashiorkor were studied with respect to plasma fibronectin levels, plasma total solids, spun hematocrits, heights, weights, mid-arm circumferences, and head circumferences. Bimodal distributions were demonstrated for plasma fibronectin versus weight deficits, total solids, hematocrits, and mid-arm circumference in children 12 months of age and older (p less than 0.003 for all). The mean plasma fibronectin level for controls was 253 micrograms/ml. The mean level for the malnourished group was 96 micrograms/ml (p less than 0.0001). Malnourished children with initial plasma fibronectin levels above 100 micrograms/ml had a higher survival rate than those with levels less than 100 (92 versus 69%). With successful therapy, plasma fibronectin levels rose quickly in most children often before detectable changes were noted in clinical and other laboratory parameters. An overshoot of the mean normal levels was observed with successful treatment wherein the mean levels rose to 315 micrograms/ml (p less than 0.05). Plasma fibronectin determinations on malnourished children can serve as an important prognostic marker as well as a reliable indicator of successful therapy and recovery.     

Production of biologically active recombinant human soluble CD23 and its effect on PBMCs isolated from hyper-IgE blood

A recombinant form of human soluble CD23 (sCD23), the low affinity receptor for IgE (FcepsilonRII), was produced by PCR cloning the lectin-binding domain sequence into a bacterial expression vector. After renaturation and purification, the sCD23 bound IgE and divalent metal ions, indicating its activity. The recombinant human sCD23 exhibited similar proinflammatory properties as the native protein. Although interleukin-1beta, tumour necrosis factor-alpha, and nuclear factor-kappaB appeared not to be enhanced significantly in unstimulated RPMI 8866 B-lymphoblastoid and U937 promonocytic cell lines with 24 h incubation of recombinant sCD23, they were produced in both healthy and hyper-IgE-derived peripheral blood mononuclear cells, especially tumour necrosis factor-alpha. This study concludes that while recombinant and chimeric sCD23 may be useful in blocking IgE binding to immune cells and decreasing IgE synthesis by B-lymphocytes, the production of proinflammatory cytokines, particularly tumour necrosis factor-alpha will enhance immune responses in cases of asthma, allergy, and hyper-IgE syndrome.     

Effects of aliskiren on stroke in rats expressing human renin and angiotensinogen genes

Objective

Pre-treatment with angiotensin receptor blockers is known to improve neurological outcome after stroke. This study investigated for the first time, whether the renin inhibitor aliskiren has similar neuroprotective effects.

Methods

Since aliskiren specifically blocks human renin, double transgenic rats expressing human renin and angiotensinogen genes were used. To achieve a systolic blood pressure of 150 or 130 mmHg animals were treated with aliskiren (7.5 or 12.5 mg/kg*d) or candesartan (1.5 or 10 mg/kg*d) via osmotic minipump starting five days before middle cerebral artery occlusion with reperfusion. Infarct size was determined by magnetic resonance imaging. mRNA of inflammatory marker genes was studied in different brain regions.

Results

The mortality of 33.3% (7 of 21 animals) in the vehicle group was reduced to below 10% by treatment with candesartan or aliskiren (p<0.05). Aliskiren-treated animals had a better neurological outcome 7 days post-ischemia, compared to candesartan (Garcia scale: 9.9±0.7 vs. 7.3±0.7; p<0.05). The reduction of infarct size in the aliskiren group did not reach statistical significance compared to candesartan and vehicle (24 h post-ischemia: 314±81 vs. 377±70 and 403±70 mm³ respectively). Only aliskiren was able to significantly reduce stroke-induced gene expression of CXC chemokine ligand 1, interleukin-6 and tumor necrosis factor-alpha in the ischemic core.

Conclusions

Head-to-head comparison suggests that treatment with aliskiren before and during cerebral ischemia is at least as effective as candesartan in double transgenic rats. The improved neurological outcome in the aliskiren group was blood pressure independent. Whether this effect is due to primary anti-inflammatory mechanisms has to be investigated further.     

Serum albumin concentration,arm circumference,and oedema and subsequent risk of dying in children in central Africa.

OBJECTIVE--To measure the prognostic value of clinical, anthropometric, and biological indicators of protein energy malnutrition in hospitalised children. DESIGN--Hospital based follow up study from admission to discharge or death of a cohort of children. SETTING-Paediatric hospital in Zaire. SUBJECTS--1129 children consecutively admitted between August 1986 and October 1988. MAIN OUTCOME MEASURES--Height, weight, arm circumference, skinfold thicknesses, serum albumin concentration, and mortality. RESULTS--Mortality was higher in wasted children and in those with a mid-upper arm circumference < 125 mm, a serum albumin concentration < 16 g/l, and oedema. After multivariate analysis, serum albumin concentration was the best predictor of subsequent risk of dying. Mid-upper arm circumference and oedema, however, still contributed considerably to evaluation of mortality. CONCLUSIONS--In this specific environment of central Africa an isolated clinical sign such as oedema is not enough to detect children with a high risk of dying among those admitted to paediatric wards with severe protein energy malnutrition. Measurement of additional indicators such as arm circumference and serum albumin concentration seems to be of crucial importance.     

Nociceptive neurons detect cytokines in arthritis

Proinflammatory cytokines are major mediators in the pathogenesis of diseases of joints such as rheumatoid arthritis and osteoarthritis. This review emphasizes that proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1beta, interleukin-6 and interleukin-17 are also mediators of pain by directly acting on the nociceptive system. Proportions of nociceptive sensory neurons express receptors for these cytokines, and the application of cytokines rapidly changes the excitability, ion currents and second messenger systems of these neurons. By inducing persistent sensitization of nociceptive sensory neurons (C- and a proportion of Aδ-fibers) for mechanical stimuli in the joint (a process called peripheral sensitization), these cytokines significantly contribute to the persistent hyperalgesia typical for many disease states of the joint. In addition, the disease-associated release of cytokines in the spinal cord supports the generation of central sensitization. The therapeutic neutralization of proinflammatory cytokines thus not only reduces the process of inflammation but may directly reduce hyperalgesia and pain by reversing the neuronal effects of cytokines. It is emerging that different cytokines have different actions on neurons. The neutralization of tumor necrosis factor-alpha reduces both mechanical and thermal hyperalgesia of the joint. The neutralization of interleukin-1beta attenuates thermal hyperalgesia whereas the neutralization of interleukin-6 and interleukin-17 mainly reduces mechanical hyperalgesia. These different effects are partly explained by influencing different target molecules in sensory neurons. For example, in cultured sensory neurons tumor necrosis factor-alpha and interleukin-1beta upregulate the TRPV1 ion channel, which is involved in the transduction of heat stimuli, consistent with an effect of these cytokines in thermal hyperalgesia. By contrast, interleukin-17 upregulates the TRPV4 ion channel, which has a role in the transduction of mechanical stimuli. Thus, the analgesic potential of neutralizing cytokines seems to depend on which cytokine is mainly involved in the particular pain state.     

IL-10 in antilipopolysaccharide immunity against systemic Klebsiella infections

AIM: This study was undertaken in order to determine whether anti-inflammatory cytokine interleukin-10 is responsible for a previously described protection against Klebsiella infection mediated by antilipopolysaccharide antibodies. METHODS: BALB/c mice were infected intraperitoneally with a lethal challenge of Klebsiella pneumoniae Caroli. One group was protected with monoclonal antibodies prior to infection and the second was not. We measured plasma levels of interleukin-10 at different time points by enzyme immunoassay and analyzed the relation between interleukin-10 and proinflammatory cytokines interleukin-6 and tumor necrosis factor-alpha in order to determine the association of these ratios with the outcome of infection. MAJOR FINDINGS AND CONCLUSIONS: We found different pattern of interleukin-10 production in protected mice compared with unprotected ones. The difference is greatest 24 hours postinfection. The ratios between IL-10 and proinflammatory cytokines confirmed the suppressed proinflammatory response in protected animals, especially 24 hours postinfection. Hence the mortality in unprotected mice begins immediately after we conclude that such cytokine relation and IL-10 production are, at least partially, responsible for the destiny of infected animals and the outcome of infection.