The stressful condition as a nutritionally dependent adaptive dichotomy.

The injured body manifests a cascade of cytokine-induced metabolic events aimed at developing defense mechanisms and tissue repair. Rising concentrations of counterregulatory hormones work in concert with cytokines to generate overall insulin and insulin-like growth factor 1 (IGF-1), postreceptor resistance and energy requirements grounded on lipid dependency. Salient features are self-sustained hypercortisolemia persisting as long as cytokines are oversecreted and down-regulation of the hypothalamo-pituitary-thyroid axis stabilized at low basal levels. Inhibition of thyroxine 5'-deiodinating activity (5'-DA) accounts for the depressed T3 values associated with the sparing of both N and energy-consuming processes. Both the liver and damaged territories adapt to stressful signals along up-regulated pathways disconnected from the central and peripheral control systems. Cytokines stimulate liver 5'-DA and suppress the synthesis of transthyretin (TTR), causing the drop of retinol-binding protein (RBP) and the leakage of increased amounts of T4 and retinol in free form. TTR and RBP thus work as prohormonal reservoirs of precursor molecules which need to be converted into bioactive derivatives (T3 and retinoic acids) to reach transcriptional efficiency. The converting steps (5'-DA and cellular retinol-binding protein-I) are activated by T4 and retinol, themselves operating as limiting factors of positive feedback loops. Healthy adults with normal macrophage functioning and liver parenchymal integrity, who submitted to a stress of medium severity, are characterized by TTR-RBP plasma levels reduced by half and an estimated ten-fold increase in free ligand disposal to target cells during the days ensuing injury. This transient hyperthyroid and hyperretinoid climate creates a second defense line strengthening and fine-tuning the effects primarily initiated by cytokines. The suicidal behavior of thyroxine-binding globulin (TBG), corticosteroid-binding globulin (CBG), and IGFBP-3 allows the occurrence of peak endocrine and mitogenic influences at the site of inflammation. The production rate of TTR by the liver is the main determinant of both the hepatic release and blood transport of holoRBP, which explains why poor nutritional status concomitantly impairs thyroid- and retinoid-dependent acute-phase responses, hindering the stressed body to appropriately face the survival crisis. The prognostic significance of low TT4 blood levels may be assigned to the exhaustion of extrathyroidal hormonal pools normally stored in liver and plasma but markedly shrunken in protein-depleted states. These data offer new insights into the mechanisms whereby preexisting malnutrition and stressful complications are interrelated, emphasizing the pivotal role played by TTR in that context.

Usefulness of the prognostic inflammatory and nutritional index (PINI) in hospitalized elderly patients.

The prognostic inflammatory and nutritional index (PINI) is a simple scoring system of overall health which aggregates two blood markers of inflammatory (C-reactive protein and alpha(1)-acid glycoprotein) and of nutritional (albumin and transthyretin) states. This study was undertaken with a view to evaluate, in comparison to currently used predictive approaches, the potential usefulness of PINI to forecast hospital mortality and outcome of patients hospitalized in an acute geriatric unit. 1,066 elderly patients, aged 82.7 +/- 6.6 years and fulfilling inclusion criteria, were enrolled in the study. Logistic regression analysis and calculation of relative risk (RR) were carried out for epidemiological data with a cut-off value of 25 for PINI. Immediate mortality (7.9%) of admissions) was predicted by PINI > or = 25 (RR = 4.34). Only 387 patients (36.3%) could rejoin their residence location (home or family). A sizeable proportion of acute patients (55.8%) failed to recover and/or developed diseased states requiring chronic care management. Incapacity to return home was predicted by PINI > or = 25 (RR = 2.04). Hypoalbuminaemia < or = 30 g/L was not found a predictor of mortality but was associated with total disability (RR = 9.08). The optimal PINI cut-off value to predict mortality was calculated at 8.8 using the ROC analytic approach. We conclude that the PINI formula is helpful to predict both nearest lethality and chronic institutionalization. This scoring system should take a place within the battery of tests used to identify and to follow up acutely ill elderly patients at risk of major complications.

Brassiodol, a new iodised oil for goitrous patients.

A new iodised oil, called Brassiodol, is proposed to prevent or eradicate 127I-deficiency disorders. Its original synthesis utilises rapeseed oil as vehicle of iodination, allowing the covalent binding of 127I atoms to all olefin groups of fatty acids (FAs). The final product contains 376 mg 127I/mL, manifests high refractoriness to degradative processes and is well tolerated by goitrous patients. The proposed dosage is 1 mL/year in adults owing to the rapid deiodination and massive 127I leakage of larger amounts in the urinary output. About 300-350 mg 127I may undergo tissue sequestration, insuring appropriate iodine coverage during 9-12 months. Clinical follow-up, hormonal data, and 127I excretory kinetics point to the normalisation of thyroid function within 3 months is stages I and II of the goitrous disease. This iodised oil, characterised by low cost, easy handling and high nutritional efficiency, seems ideally suited to meet public health and economical problems in countries facing severe goitrous areas.

Iodised rapeseed oil for eradication of severe endemic goitre.

Iodised oil is traditionally based on the fatty acids (FAs) of the poppyseed, an expensive commodity. An equipotent but cheaper vehicle would be welcome. Iodination of rapeseed oil yields a product (Brassiodol) with a total iodine content of 376 mg/mL. Brassiodol has been compared with the poppyseed-based Lipiodol in two villages in Chad in the west African goitre belt. A 2 mL dose of Brassiodol is followed by urinary spillover of half the ingested iodine. The other half undergoes tissue sequestration and slow release, allowing protection against iodine deficiency for 9 months and regression of stage I/II goitre for longer than was achieved with Lipiodol. The prolonged protection offered by Brassiodol can be attributed to its unique lipid profile. The urinary output argues that 1 mL should not be exceeded, and at that dose the cost would be only 20 US cents per person per year.

The usefulness of dietary medium-chain triglycerides in body weight control: fact or fancy?

Compared to long-chain triglycerides (LCT), medium-chain triglycerides (MCT) display some specific physico-chemical, and biological characteristics. Thus, MCT are currently used in clinical nutrition as energy-yielding substrates, and have been advocated for three decades as a useful mean for body weight reduction. This review encompasses most aspects of MCT metabolism arguing this slimming hypothesis pro and con. Findings in support of the opinion (lower energy density, control of satiety, rapid intrahepatic delivery and oxidation rates, poor adipose tissue incorporation) may be invalidated by counteracting data (stimulation of insulin secretion and of anabolic-related processes, increased de novo fatty acid synthesis, induced hypertriglyceridemia). The balance between these two opposing influences depends on the composition (energy intake, nature of ingredients, MCT/LCT ratio, octanoate/decanoate ratio) and duration of the regimen. Due to the high energy level (around 50%) of MCT necessary to achieve body weight loss, long-term compliance to such slimming regimens is unlikely in human nutrition.

Flavonoids extracted from fonio millet (Digitaria exilis) reveal potent antithyroid properties.

Digitaria exilis (fonio) is a tiny variety of millet commonly eaten by inhabitants of semiarid regions. A sample of fonio collected right in the middle of a severely iodine-depleted goitrous endemic was submitted to phytochemical investigations in order to assess the potential contributory roles played by vegetable molecules to the goitrogenic processes. The total content of flavonoids amounts to 500 mg/kg of the edible whole cereal grains. Their extraction and identification fail to detect the C-glycosylflavones described in other millet varieties but point out the presence of apigenin (A = 150 mg/kg) and of luteolin (L1 = 350 mg/kg). Ten percent of A and 80% of L1 are present in free form, whereas the remaining 90% of A and 20% of L1 are bound as O-glycosylflavones. Both A and L1 aglycones manifest strong anti-thyroid peroxidase (TPO) activities, resulting in a significant reduction of the hormonogenic capacity of this enzyme. In addition, L1 significantly depresses the cyclic AMP phosphodiesterase, implying a concomitant overproduction of the thyrotropin-dependent nucleotide. These last unreported data are regarded as counteracting to some extent the TPO-mediated goitrogenic properties of L1. Since fonio is devoid of other molecules likely to interfere with the thyroid function, our results are directly and casually attributed to A and L1 found in the customary diet.

Goitrous endemic in Guinea.

We identified a major goitrous area in the Republic of Guinea, characterised by an overall goitre prevalence of 70% in adults. Thyroid swelling was sometimes present at birth and affected 55% of schoolchildren. A difference between sexes appeared at puberty. Endemic cretinism, mainly in its myxoedematous form, was found in about 2% of goitrous patients. In this region, iodine deficiency is the primary causative factor (median urinary concentrations of 16 micrograms/L, and in 69% of inhabitants below the critical threshold of 20 micrograms/L). The diet contained substantial amounts of thiocyanate anions (median 6 mg/L in urine and in 27%, more than 10 mg/L) likely to further depress iodine bioavailability. Other dietary compounds, notably flavonoids were suspected to contribute. Overall nutritional and general health appeared satisfactory. The affected population is borderline euthyroid with a trend towards hypothyroidism in protracted disease. This area of Guinea may be regarded as the epicentre of the west African endemic and as one of the most severely goitrous regions ever described, requiring urgent public health measures.

Transthyretin (prealbumin) in health and disease: nutritional implications.

The name "transthyretin" reflects the dual physiological roles of this tetrameric unglycosylated plasma protein. TTR is one of three specific carrier proteins involved in the transport of both thyroid hormones and of retinol through the mediation of RBP. TTR is a product of the visceral compartment, and its hepatic synthesis is exquisititely sensitive to both the adequacy and levels of protein and energy intakes--hence the proposal of TTR as a nutritional marker. To date, 38 TTR variants have been described, most of which are associated with variable degrees of cardiac and/or neural tissue amyloid deposits. All known variants arise from a single AA substitution due to single point mutation in the coding region of the TTR gene. Under acute stress conditions, the synthesis of TTR, RBP, and CBG is abruptly depressed by a cytokine-directed orchestration of new metabolic priorities, with a redistribution of organ and tissue protein pools. It is proposed that TTR, RBP, and CBG behave as acute-booster reactants (ABRs), actively participating in the cascade of metabolic events characterizing the stress reaction along pathways best explained by the free hormone/vitamin hypothesis. The latter is governed by the law of mass action--the spontaneous dissociation and instant uptake by hepatocytes of the ligands freed from their specific carrier proteins, which creates a transient hyperthyroid, hyperretinoid, and hypercortisolic climate. This response generally does not exceed four or five days because the initial impact of injury normally subsides, but it may last longer if complications occur. The magnitude and adequacy of the stress responses depend on the preceding nutritional status as assessed by TTR plasma levels and are proportionate to the severity of insult. Clinical, animal, and molecular studies concur to demonstrate the dualistic stimulatory or inhibitory effects triggered by the ligands, whose unmetabolized fractions are excreted in the urinary output. Thyroid hormones and retinoids appear to control the early maturation processes and the synthesis of primary transcripts, whereas cortisol preferentially modulates the secondary responses and confers a protective effect on healthy tissues. During acute stress, the evolutionary patterns of visceral proteins and inflammatory markers exhibit compulsory mirror images. However, they change in independent ways under more chronic circumstances. A relatively simple biochemical micromethod based on the simultaneous measurement of plasma TTR, albumin, CRP, and orosomucoid aggregated into a PINI is proposed for the early recognition and follow-up of both nutritional and inflammatory facets of the disease spectrum.

Soybean oil, blackcurrant seed oil, medium-chain triglycerides, and plasma phospholipid fatty acids of stressed patients.

Thirty-six adult severe head injury and cerebral stroke patients in four intensive-care units were randomized to receive one of three enteral diets for 21 days. These diets, which supplied 45% of calories from fat, differed only in lipid composition. Diet A was comprised of 100% soybean oil, diet B contained a 50:50 (wt/wt) mixture of soybean oil and medium-chain triglycerides (MCTs), and diet C contained 42.5% MCT, 50% soybean oil, and 7.5% blackcurrant seed oils. Plasma phosphatidylcholine and fatty acid composition of plasma total phospholipids were determined before initiating treatment (day 0) and weekly throughout the study. Results indicated that at the start of the study, all patients had low linoleic acid (18:2 omega 6) levels compared with healthy subjects. Emulsion A disturbed the balance between several fatty acids of the omega 6 series, as exemplified by the significant increase in 18:2 omega 6 proportions. In contrast, both emulsions B and C introduced a less-pronounced rise in 18:2 omega 6 associated for emulsion C with a significant increase in dihomo-gamma-linolenic acid (20:3 omega 6) and docosapentaenoic acid (22:5 omega 3) in plasma phospholipids. Furthermore, 18:3 omega 6 change was significantly different between groups A and C and that of 20:3 omega 6 between group A and both groups B and C. Throughout the study, arachidonic acid (20:4 omega 6) exhibited remarkable steady-state levels regardless of the diet. This study shows that providing the injured body with high amounts of 18:2 omega 6 does not lead to high levels of its upper derivatives in plasma phospholipids.(ABSTRACT TRUNCATED AT 250 WORDS)

Composition of phospholipid fatty acids in red blood cell membranes of patients in intensive care units: effects of different intakes of soybean oil, medium-chain triglycerides, and black-currant seed oil.

Fatty acid composition of phospholipids in red blood cell membranes was studied in 32 severely head-injured or cerebral stroke patients receiving enteral nutrition for 3 weeks. During this study the effects of three diets differing only by their lipid composition were investigated. The daily energy intake of each patient amounted to 2950 kilocalories, of which the lipid fraction represented 45.7%. Diet A contained only soybean oil, diet B consisted of a 50% soybean oil and 50% medium-chain triglycerides mixture, and diet C was an emulsion of 50% soybean oil, 42.5% medium-chain triglycerides, and 7.5% black-currant seed oil. Our results showed no biochemical signs of fatty acid deficiency in red blood cell membranes for the patients at the beginning of the study, after a comparison with a control group of 20 healthy adults. Inhibition of delta 6-desaturase activity on linoleic acid (C18:2 omega 6) after diet A was suggested by an increase of linoleic acid without a corresponding increase of dihomo-gamma-linolenic acid (C20:3 omega 6). Replacing 50% of soybean oil by with medium-chain triglycerides (diet B) prevented this enzyme inhibition. Supply of black-currant seed oil rich in gamma-linolenic (C18:3 omega 6) and stearidonic (C18:4 omega 3) acids (diet C) induced significant increases of dihomo-gamma-linolenic and eicosapentaenoic (C20:5 omega 3) acids, without influencing arachidonic acid (C20:4 omega 6) levels. This balance was evaluated through the ratio (C20:3 omega 6 + C20:5 omega 3)/C20:4 omega 6.

Usefulness of a prognostic inflammatory and nutritional index in pediatric clinical practice.

The clinical usefulness of a prognostic inflammatory and nutritional index (PINI) was evaluated in 47 hospitalized infants and 72 age-matched controls from 1 mth to 14 yr of age. The PINI formula is a combination of two markers each of infection (C-reactive protein and orosomucoid) and of malnutrition (albumin and transthyretin). Healthy children are identified by a PINI value less than 1 whereas sick patients are characterized by a progressive rise above 1 as the conditions worsens. The PINI scoring system provides the clinician with a sensitive and universal tool, allowing the correct follow-up of both inflammatory and nutritional poles of the disease spectrum. The formula is of particular help in pediatric practice in recognising early subclinical complications and efficacy of specific therapeutic strategies. The micromethod is simple, rapid and may be regularly repeated since it requires only 46 microliters of serum.

Nutritional significance of alterations in serum amino acid patterns in goitrous patients.

Twenty-nine amino acids were analyzed in the sera of 105 adult Senegambian goitrous patients classified as stages I, II, and III according to World Health Organization recommendations. Mean serum concentration of all essential amino acids revealed highly significant drops (p less than 0.001) as goiter stage increased, except for methionine (Met). Most nonessential amino acids (NEAA) and intermediary metabolites were similarly characterized by a general decrease to the subnormal range, although some resisted depression in stages II and III. Homocystine (Hcy) demonstrated a unique pattern in that it was the only NEAA distinguished by regularly rising serum levels. These data are consistent with the view that endemic goiter is associated with overall stepwise downregulation in protein metabolism. In addition to iodine restriction, generalized malnutrition may aggravate the goitrogenic processes. Serum levels of Met and Hcy strongly suggest that the first step of the transsulfuration pathway is impaired in protein-depleted states due to cystathionine beta-synthase (EC 4.2.1.22) deficiency.

A prognostic inflammatory and nutritional index scoring critically ill patients.

A new prognostic inflammatory and nutritional index is described allowing the correct follow-up of most pathological conditions. Discriminant analysis of eleven currently utilized blood markers of the phlogistic reaction and of the nutritional status has afforded the selection of the two most reliable acute-phase reactants (orosomucoid and C-reactive protein) and visceral proteins (albumin and prealbumin). These parameters are combined in a simple formula which consistently and accurately stratifies critically ill patients by risk of complications or death. The grading system is determined by a rapid and inexpensive micromethod encompassing both infectious and nutritional poles of the disease spectrum within a self-explanatory scale. The scoring system provides a more sensitive tool for the diagnosis and prognosis of stressed patients than any other method available to date.