Liana Schlesinger

Leptin Levels and IgF-Binding Proteins in Malnourished Children: Effect of Weight Gain

OBJECTIVESnAlthough it is well known that leptin reflects body fat content in adults, the regulation of leptin levels during childhood malnutrition is poorly understood. Insulin-like growth factor I (IGF-I) and the IGF-binding proteins (IGFBPs) may play important roles in the regulation of body composition. We investigated the relation between leptin, IGF-I, and IGFBPs in children with protein-energy malnutrition (PEM; before and after recovering 10% of their initial body weights) in comparison with well-nourished children.nnnMETHODSnFifteen PEM and 16 healthy children were studied on admission and after 10% weight gains in the malnourished group. Leptin was measured with radioimmunoassay, IGF-I and IGFBPs were measured with immunoradiometric assay.nnnRESULTSnPatients with PEM had a significantly lower body mass index and percentage of body fat than did the control children. Before weight gain, leptin, IGF-I, and IGFBP-3 were significantly lower and IGFBP-1 was elevated in the malnourished group compared with the control group. Among PEM patients, after 10% weight gains, the levels of leptin, IGF-I, and IGFBP-3 were significantly higher and IGFBP-1 significantly lower compared with the control group. Leptin correlated significantly with IGF-I in the normal children (r(s) = 0.86, P < 0.005). On admission, no correlation was observed between leptin and IGF-I (r(s) = 0.08, P < 0.16) and between leptin and IGFBP-3 (r(s) = 0.02, P < 0.27) in the malnourished group, but those levels improved after 10% recovery of their body weights (r(s) = 0.47, P < 0.002 and r(s) = 0.42, P < 0.005, respectively). In the PEM group, IGF-I correlated significantly with IGFBP-3 when the children gained weight (before: r(s) = 0.006, P < 0.31; after: r(s) = 0.32, P < 0.01). Our study showed results similar to those of anorexia nervosa studies, but the normalization of study variables was obtained in considerable less time for the same weight gain.nnnCONCLUSIONSnThe main finding of this study was that, after refeeding with only a 10% weight gain, the PEM children normalized their leptin, IGF-I, and IGFBP-3 levels. These results provide evidence that leptin can function as link between this hormonal response and improved nutrition status.

Impaired interleukin-1 and tumor necrosis factor production in protein-calorie malnutrition

Abstract The capacity of malnourished infants to produce interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNF-α) was evaluated before and after nutritional rehabilitation. Ten marasmic patients without infectious diseases 2 to 8 months of age with −2.48±0.54 weight for age Z score (mean ± SD) were studied on admission, and after 4 month of nutritional therapy in a Closed Nutritional Recovery Center. Cytokines were induced by in vitro stimulation of blood mononuclear cells with lipopolysaccharide. IL-1β and TNF-α were determined in supernatants and cell lysates using an specific immunoassay. Low levels of released and cell-associated IL-1β were found on admission; mean±SEM values were 2.0±0.5 and 1.3±0.5 ng/ml, respectively. After nutritional rehabilitation, a significant increase of released and cell-associated IL-1β were observed: 5.4±0.8 and 3.7±0.3 ng/ml, (mean±SEM) respectively, p

Phagocytosis and immunoglobulin levels in hypocupremic infants

Abstract Nineteen hypocupremic marasmic infants 5–14 months of age with a normal wt/1gth ratio, were immunologically evaluated during their rehabilitation. The infants were studied 2–3 months after admission to a Closed Nutritional Recovery Center and subsequently after copper supplementation. Two groups were defined: a severely copper deficient group (A), with abnormal copper and ceruloplasmin levels; and a marginal copper deficient group (B), with abnormal plasma copper level and normal serum ceruloplasmin. Immunoglobulin levels were measured by radial immunodiffusion technique and phagocytosis to S. aureus by using autologous and normal homogogous plasma. After copper supplementation plasma copper increased to normal values in both groups of infants. Ceruloplasmin exceeded normal ranges in group A whereas no changes were detected in group B. Serum immunoglobulins were normal and secretory IgA remained low in most of the infants. Phagocytic indices increased in most infants with both types of plasma after copper supplementation in groups A and B (p

INTERACTION BETWEEN CYTOKINES, NUTRITION AND INFECTION

Present evidence suggests that cytokines, as intercellular mediators, play a key role in the nutrition-infection complex. Protein-calorie malnutrition, deficiency of fatty acids, vitamins, trace elements, impair cytokine production. By the other hand, infections increase pro-inflammatory cytokine production interfering with nutritional status by impairing metabolic activity and by inducing anorexia. Elevated cytokine levels in human milk represent a physiological phenomenon and is not necessarily associated to infectious processes. Research on the kinetical behaviour of pro-inflammatory cytokine in each of the above mentioned conditions should be performed as a goal for future investigations. The development of comprehensive studies on the influence of dietary supplementation on cytokine production could be of clinical interest. However, the results obtained should be considered with caution because cytokines are highly interdependent and changes in some of them could affect target tissue. For instance dietary supplementation with (n-3) polyunsaturated fatty acids (PUFA), generally recommended in elderly subjects for reducing or preventing inflammatory diseases, down-regulate cytokine production, but secondarily suppress cell-mediated immune response, effect that may not be desirable. When evaluating cytokine production during dietary supplementation programs is important to consider food consumption, age, presence of infection and/or stress. Future clinical trials are needed to define the diet composition that will have an anti-inflammatory effect maintaining a normal immune response. Finally, the better understanding of nutrition-cytokine interaction may also be important as this information could be relevant for treatment of patients with cancer or other diseases in which malnutrition is present.

Immune depression induced by protein calorie malnutrition can be suppressed by lesioning central noradrenaline systems

Depressed immune function is well documented in protein calorie malnutrition (PCM). Also, central noradrenergic hyperactivity has recently been reported in malnourished animals. Increase in central noradrenaline activity could be responsible for cell-mediated immune depression. The present study is designed to address this hypothesis by testing whether neurotoxic lesion of central noradrenergic systems by 6-hydroxydopamine (6-OHDA) could improve lymphoproliferative response to mitogens and interleukin (IL)-1 production in PCM rats. A significant enhancement of lymphoproliferative response to concanavalin A (ConA) and in IL-1 production was observed in spleen mononuclear cells of PCM rats injected intracerebroventricularly with 120 micrograms of 6-OHDA, as compared with solvent injected and untreated PCM animals. A significant decrease in brain noradrenaline levels was produced in the drug-injected animals. These results suggest that central noradrenergic hyperactivity is one of the mechanisms involved in the immunodepression produced by malnutrition.

Interleukin-6 production and deregulation of the hypothalamic-pituitary-adrenal axis in patients with major depressive disorders.

The present study was designed to determine whether an association exists between HPA activity and cytokine production in major depression (MD). In 9 patients with MD and 11 control subjects of both sexes, all drug-free, activity of the HPA axis was evaluated by circadian rhythm of plasma cortisol, 24-h free urinary cortisol, an overnight 1 mg dexamethasone suppression test, and an oCRF stimulation test. Spontaneous and LPS-stimulated production of IL-1β, IL-6, and TNFα by peripheral blood mononuclear cells were also determined. We found a significantly elevated spontaneous production of IL-6 in patients with MD (3541.2 ± 726.8 vs 380.4 ± 77.5 pg/mL in controls, p<0.05), while LPS-stimulated production was significantly lower in patients than in control subjects (19,867.7 ± 3649.2 vs 33,142.2 ± 15,47.2 pg/mL, p<0.05). The adrenocorticotropic hormone response to oCRF, evaluated as the area under the curve (AUCACTH) was significantly lower in patients than in control subjects (p=0.02). A positive correlation between AUCACTH and LPS-stimulated IL-6 secretion was observed in patients with MD (r=0.75, p<0.05) but not in controls. These findings suggest that the activation of the inflammatory response described in depression might be associated with long-term hyperactivity of the HPA axis.

Functional Capacity of Colostral Leukocytes from Women Delivering Prematurely

The phagocytic, bactericidal, and metabolic activity of colostral leukocytes from mothers delivering preterm infants was compared with that of colostral leukocytes from mothers of term infants. In addition, the proliferative capacity of colostral lymphocytes was compared. Preterm adherent colostral leukocytes had a significantly higher phagocytic index than term colostral adherent leukocytes. Mean ± SEM values were 5.4 ± 0.5 versus 2.7 ± 0.2, respectively (p < 0.001). Bactericidal capacity against Escherichia coli and nitroblue tetrazolium reduction of preterm and term colostral leukocytes were comparable. Lymphocyte proliferative response was equivalent in preterm and term milk. We conclude that colostral leukocytes from preterm mothers are at least as functional in their antimicrobial activity and possibly phagocytose even better than the colostral cells of mothers of term infants.

Impaired lymphoproliferative response to alloantigens and phytohaemagglutinin in marasmic infants.

Abstract The lymphoproliferative response using a whole blood microtechnique was studied in marasmic infants. The blastic transformation to alloantigens was measured in one way mixed leukocyte cultures (MLC) and phytohaemagglutinin (PHA) by 3 H-thymidine incorporation. The results were expressed as cpm in stimulated cultures and stimulation indices. The mean cpm of leukocyte cultures from marasmic and control infants stimulated with irradiated leukocytes from 3 unrelated donors were 2813, 3083, 1816 and 6243, 8216, 6767 respectively (p

Transferrin and iron salts modulate differently tumor necrosis factor-α secretion by cultured human mononuclear cells1–3

Abstract Iron is an essential element for the normal function of many biological processes, including the immune response and hematopoiesis. Since iron deficiency results in impaired cytokine production (TNF-α), we investigated if iron, bound to its transport protein transferrin or by itself, modulates the secretion of tumor necrosis factor-α (TNF-α) by circulating monocytes. In particular, we examined the effect of Tf-bound iron or ferric chloride (FeCl 3 ) in the secretion of TNF-α by cultured blood mononuclear cells (BMNC) obtained from women with either normal Fe status (n=10) or with iron deficiency (n=10). The addition of 30 μM Tf, either in its apo or holo form, to BMNC cultures derived from both normal and iron deficient subjects, induced a marked increase in TNF-α secretion by cells, to about 1.2–1.4 ng/mL. Similarly, the addition of μM amounts of FeCl 3 to normal BMNC resulted in a dose-dependent increase of TNF-α secretion. By contrast, BMNC from iron deficient subjects were unable to secrete TNF-α under similar conditions. Lipopolysaccharide (LPS) induced a maximal secretion of TNF-α (3.9 ± 0.6 ng/mL, mean ± SEM) in BMNC derived from both normal and iron deficient women, an indication that ID cells had the capacity to secrete TNF-α in response to a bacteriologic insult. However, the combined addition of LPS and iron-salt did not induce a further increase in TNF-α secretion. These findings indicate that iron modulates the in vitro secretion of TNF-α by human mononuclear cells through a process that depends both on the iron status of the subject and on the form in which iron is supplied. Moreover, transferrin also induces the secretion of TNF-α in a way apparently independent of its iron-donating capacity.

Increased cytokine production is associated with acute inflammation in cirrhotic alcoholic patients

Abstract The role of cytokines in the etiology of liver injury and their contribution to the systemic manifestations that occur in patients with liver disease, are not clearly understood. Aim: To study if serum levels and in vitro blood mononuclear cell (BMC) production of IL-Iβ and TNFα are related to the severity of alcoholic liver cirrhosis, and identify potential factors that can modify cytokine production in these patients. Serum levels, spontaneous and in vitro LPS stimulated BMC production of Interleukin-Iβ (IL-Iβ) and Tumor Necrosis Factor α (TNFα), were measured in 38 patients with alcoholic cirrhosis Child B or C, and nine normal volunteers. Serum levels and spontaneous in vitro production of IL-Iβ and TNFα were below detection limits. There were no differences between normal controls and Child B or C patients in LPS-stimulated production of IL-Iβ or TNFα. However eight patients with alcoholic hepatitis or infections superimposed on cirrhosis, had higher levels on LPS-stimulated BMC production of IL-Iβ (12.9 ± 5.8 ng/ml) and TNFα (4.9 ± 2.3 ng/ml) than the rest of cirrhotic patients (5.3 ± 3.5 and 1.8 ± 0.9 ng/ml). There was no association between IL-Iβ and TNFα BMC production and parameters of liver function or recent alcohol ingestion. Increased levels of IL-Iβ and TNFα production by stimulated BMC are associated with acute inflammatory events in cirrhotic alcoholic patients and not with the severity of liver disease.