Tolerogenic dendritic cells generated with dexamethasone and vitamin D3 regulate rheumatoid arthritis CD4+ T cells partly via transforming growth factor-ß1.

Tolerogenic dendritic cells (tolDC) are a new immunotherapeutic tool for the treatment of rheumatoid arthritis (RA) and other autoimmune disorders. We have established a method to generate stable tolDC by pharmacological modulation of human monocyte-derived DC. These tolDC exert potent pro-tolerogenic actions on CD4+ T cells. Lack of interleukin (IL)-12p70 production is a key immunoregulatory attribute of tolDC but does not explain their action fully. Here we show that tolDC express transforming growth factor (TGF)-ß1 at both mRNA and protein levels, and that expression of this immunoregulatory cytokine is significantly higher in tolDC than in mature monocyte-derived DC. By inhibiting TGF-ß1 signalling we demonstrate that tolDC regulate CD4+ T cell responses in a manner that is at least partly dependent upon this cytokine. Crucially, we also show that while there is no significant difference in expression of TGF-ßRII on CD4+ T cells from RA patients and healthy controls, RA patient CD4+ T cells are measurably less responsive to TGF-ß1 than healthy control CD4+ T cells [reduced TGF-ß-induced mothers against decapentaplegic homologue (Smad)2/3 phosphorylation, forkhead box protein 3 (FoxP3) expression and suppression of (IFN)-γ secretion]. However, CD4+ T cells from RA patients can, nonetheless, be regulated efficiently by tolDC in a TGF-ß1-dependent manner. This work is important for the design and development of future studies investigating the potential use of tolDC as a novel immunotherapy for the treatment of RA.

Completeness of West Nile virus testing in patients with meningitis and encephalitis during an outbreak in Arizona, USA.

Accurate data on West Nile virus (WNV) cases help guide public health education and control activities, and impact regional WNV blood product screening procedures. During an outbreak of WNV disease in Arizona, records from patients with meningitis or encephalitis were reviewed to determine the proportion tested for WNV. Of 60 patients identified with meningitis or encephalitis, 24 (40%) were tested for WNV. Only 12 (28%) of 43 patients aged <50 years were tested for WNV compared to 12 (71%) of 17 patients aged ≥50 years (P<0·01). Patients with clinical signs of weakness or paralysis, elevated CSF protein, admitted to an inpatient facility, or discharged to a rehabilitation facility were also more likely to have WNV testing performed. The lack of testing in younger age groups and in those with less severe disease probably resulted in substantial underestimates of WNV neuroinvasive disease burden.

Expression of heparan sulfate proteoglycans in murine models of experimental colitis.

BACKGROUND: Heparan sulfate proteoglycans (HSPGs) are considered important in maintaining physiological homeostasis in many systems. Their expression is altered greatly in several pathophysiological conditions. Herein, we assess the expression and cellular localization of HSPGs in two murine models of human inflammatory bowel disease (IBD). METHODS: Expression and localization of HSPGs, syndecans, and HS epitopes were examined in the colon of 129SvEv interleukin 10 knockout (IL10(-/-)), C3Bir IL10(-/-), and their genetic control (IL10(+/+)) counterparts (129SvEv; C3H/HeJ). mRNA expression of syndecans and heparan sulfate biosynthesis enzymes were evaluated by real-time polymerase chain reaction (PCR). Localization of HSPGs was determined by immunofluorescence. RESULTS: mRNA for all syndecans was detected and expression in colonic tissues altered in IL10(-/-) mice. Syndecan-1 protein was expressed in the intestinal epithelium and on lamina propria cells of IL10(-/-) and control mice but was significantly reduced on the intestinal epithelial cells of IL10(-/-), mice particularly with severe colitis. Syndecan-2 was not detected, whereas syndecan-3 immunoreactivity was localized in the lamina propria but did not differ between control and IL10(-/-) mice. Syndecan-4 was present on epithelial cells of all mice but was significantly reduced in IL10(-/-) mice. Differences in the expression of HS epitopes between control and IL10(-/-) mice were also confirmed. CONCLUSIONS: The study has revealed altered expression of syndecan-1 and -4 and HS epitopes in the gut of mice with an IBD-like gut disorder. The IL10(-/-) mouse is a useful model for further study of the functional role of HSPGs in chronic inflammation and in maintaining healthy gut barrier.

Thymic function in juvenile idiopathic arthritis.

OBJECTIVE: Thymic function declines exponentially with age. Impaired thymic function has been associated with autoimmune disease in adults but has never been formally assessed in childhood autoimmunity. Therefore, thymic function in children with the autoimmune disease juvenile idiopathic arthritis (JIA) was determined. METHODS: Thymic function was measured in 70 children and young adults with JIA (age range 2.1-30.8 (median 10.4)) and 110 healthy age-matched controls using four independent assays. T cell receptor excision circles (WBLogTREC/ml) and the proportion of CD4(+) CD45RA(+)CD31(+) T cells (representing recent thymic emigrants; %RTEs) were quantified and intrathymic proliferation measured by calculating the alphaTREC/SigmabetaTREC ratio. Lastly, regulatory T cells (T(Reg)) of thymic origin (CD4(+)FOXP3(+)) were quantified in peripheral blood to assess the ability of the thymus in JIA to generate this T cell subset. RESULTS: Thymic function was equivalent by all four parameters in JIA when compared with the control population. Furthermore, there was no consistent effect of JIA subtype on thymic function, although intrathymic proliferation was higher in the small rheumatoid factor (RF)(+) polyarticular group. There were no significant effects of disease-modifying antirheumatic drugs (DMARDs) or oral corticosteroids on thymic function, although those with the worst prognostic ILAR (International League of Associations for Rheumatology) subtypes were also those most likely to be on a DMARD. CONCLUSIONS: It is demonstrated that children and young adults with JIA, unlike adults with autoimmune diseases, have thymic function that is comparable with that of healthy controls. The varied pathologies represented by the term "JIA" suggest this observation may not be disease specific and raises interesting questions about the aetiology of thymic impairment in adult autoimmunity.

Determination of thymic function directly from peripheral blood: a validated modification to an established method.

The thymus contributes naïve, self MHC reactive, self tolerant T cells to the peripheral immune system throughout life, albeit with a log-linear decline with age. Quantification of thymic function is clinically relevant in the setting of lymphoablation, but a phenotypic marker distinguishing recent thymic emigrants from long lived naïve T cells remains elusive. T cell receptor excision circles (TREC) are present in thymocytes exiting the thymus and quantification of the most frequent of these, the deltarec-psiJalpha rearrangement has been widely used as a measure of recent thymic function. However, interpretation of results presented as TREC per cell has been criticised on the basis that extra-thymic cellular proliferation impacts on peripherally determined TREC numbers. TREC/ml is now considered to be more representative of thymic function than TREC/cell, especially where significant cellular proliferation occurs (e.g. during reconstitution following stem cell transplantation). Here we describe the validation of a novel variation to the established assay, directly quantifying TREC/ml from 300 microl whole blood. We show the assay to be reproducible, robust and stable longitudinally and we show equivalence of performance when compared with more standard assays. This assay particularly lends itself to the measurement of thymic function in children and where monitoring clinical variables is limited by tissue availability.

Differential expression of syndecans and glypicans in chronically inflamed synovium.

BACKGROUND: Membrane-bound heparan sulphate proteoglycans (HSPGs) act as co-receptors and presenters of cytokines and are involved in cell-matrix and cell-cell adhesion. AIM: To investigate which HSPGs are expressed in knee joint synovia from patients with different forms of arthritis and normal individuals. METHODS: Synovial samples were obtained from patients with early rheumatoid arthritis (n = 8), longstanding rheumatoid arthritis (n = 13), psoriatic arthritis (n = 7), osteoarthritis (n = 6) and normal joints (n = 12). Expression of syndecan-1, -2, -3 and -4 and glypican-1, -3 and -4 was analysed by immunohistochemistry and dual label immunofluorescence. RESULTS: The expression of HSPGs in chronically inflamed synovium exhibited a differential distribution. Syndecan-1 was present in the mononuclear infiltrates of synovia from patients with rheumatoid and psoriatic arthritis where it was expressed by plasma cells. Syndecan-2 was present mainly in blood vessels where it occurred on endothelial cells, pericytes and smooth muscle cells. Syndecan-3 stained intensely in endothelial cells but also occurred in sublining macrophages and the lining layer. Glypican-4 occurred in the lining layer and blood vessels. Increased expression of these HSPGs was apparent in rheumatoid and psoriatic compared to osteoarthritic and normal synovia. Little or no staining for syndecan-4, glypican-1 and glypican-3 was seen in all samples. DISCUSSION: Selected HSPGs, such as syndecan-1, -2 and -3 and glypican-4, could play a part in the pathophysiology of arthritis, such as the migration and retention of leukocytes and angiogenesis in the chronically inflamed synovium.

Matrix metalloproteinase 10 promotion of collagenolysis via procollagenase activation: implications for cartilage degradation in arthritis.

OBJECTIVE: We have previously reported the up-regulation of matrix metalloproteinase 10 (MMP-10) following treatment with the procatabolic stimulus of interleukin-1 (IL-1) and oncostatin M (OSM) in chondrocytes. Although MMP-10 is closely related to MMP-3, little is known about the role of MMP-10 in cartilage catabolism. The purpose of this study was to determine whether MMP-10 is expressed in connective tissue cells and to assess how it may contribute to cartilage collagenolysis. METHODS: MMP gene expression was assessed by real-time polymerase chain reaction using RNA from human articular chondrocytes and synovial fibroblasts stimulated with IL-1 plus OSM or tumor necrosis factor alpha (TNFalpha) plus OSM. Synovial fluid levels of MMP-10 were determined by specific immunoassay. Recombinant procollagenases were used in activation studies. Immunohistochemistry assessed MMP-10 expression in diseased joint tissues. RESULTS: MMP-10 expression was confirmed in both chondrocytes and synovial fibroblasts following stimulation with either IL-1 plus OSM or TNFalpha plus OSM, and MMP-10 was detected in synovial fluid samples from patients with various arthropathies. Exogenous MMP-10 significantly enhanced collagenolysis from IL-1 plus OSM-stimulated cartilage, and MMP-10 activated proMMP-1, proMMP-8, and proMMP-13. Immunohistochemistry revealed the presence of MMP-10 in the synovium and cartilage of an IL-1 plus OSM-induced model of arthritis as well as in samples of diseased human tissues. CONCLUSION: We confirm that both synovial fibroblasts and articular chondrocytes express MMP-10 following treatment with procatabolic stimuli. Furthermore, the detectable levels of synovial fluid MMP-10 and the histologic detection of this proteinase in diseased joint tissues strongly implicate MMP-10 in the cartilage degradome during arthritis. The ability of MMP-10 to superactivate procollagenases that are relevant to cartilage degradation suggests that this activation represents an important mechanism by which this MMP contributes to tissue destruction in arthritis.

Regulation of insulin receptor substrate-1 in the liver, skeletal muscle and adipose tissue of rats throughout pregnancy.

The mechanism responsible for insulin resistance during pregnancy remains unclear. Considerable evidence indicates that insulin receptor substrate-1 could play an important role in insulin sensitivity. It seems possible that the gestational hormonal milieu could affect insulin receptor substrate-1. In the present study, measurements of tyrosine phosphorylation and protein content of insulin receptor substrate-1 and gene expression in the liver, skeletal muscle and adipose tissue in the rat indicated that, during pregnancy, significant changes occurred in these parameters. We found in early gestation that muscle and adipose tissue were highly sensitive to insulin action, because the phosphorylation of insulin receptor substrate-1 is greater than in late gestation. However, in late gestation the tissue most sensitive to insulin action, reflecting insulin receptor substrate-1 phosphorylation, was the liver. Our hypothesis was that these results are connected with the changes in concentrations of estradiol and progesterone observed during pregnancy. It was concluded that the present findings demonstrate that different concentrations of gestational hormones play an important role in insulin sensitivity in this period, and that each tissue responds in the most appropriate manner to guarantee the gestation in its entirety, controlling the phosphorylation of insulin receptor substrate-1 in response to insulin receptor activation.

Dose- and time-dependent effects of 17beta-oestradiol on insulin sensitivity in insulin-dependent tissues of rat: implications of IRS-1.

Numerous studies have suggested that ovarian hormones are able to modulate insulin sensitivity, but their exact role remains unclear. We have investigated whether different doses of 17beta-oestradiol mediate changes in insulin sensitivity and if these changes could be related to modifications of insulin receptor substrate-1 (IRS-1). Female rats were ovariectomized and later separated into three groups: untreated; treated with a dose of 17beta-oestradiol sufficient to reproduce gestational plasma concentrations of 17beta-oestradiol (group E); and treated with a dose 100 times greater than that given to group E (group E2). A euglycaemic-hyperinsulinaemic clamp was used to measure insulin sensitivity. Changes in IRS-1 were analysed by Western blotting and RT-PCR assays. In group E we found a decrease in insulin sensitivity between days 11 and 16 of treatment as in late gestation, whereas in the untreated group and group E2, development of insulin resistance was observed throughout the treatment. In contrast, whereas in group E2 insulin resistance throughout the hormonal treatment was related to diminished expression and phosphorylation of IRS-1, in group E the decrease in insulin sensitivity between days 11 and 16 of treatment was not related to a decrease in IRS-1 expression. Our results suggest that the effects of oestradiol on insulin sensitivity were dose-dependent and that the insulin resistance associated with a high dose of 17beta-oestradiol was related to downregulation of IRS-1 expression.

Diet score is associated with plasma homocysteine in a healthy institutionalised elderly population.

BACKGROUND AND AIM: Total plasma homocysteine (tHcy) is an independent risk factor for cardiovascular diseases. Among other dietary and non-dietary factors, B vitamins, such as folate, riboflavin and cobalamin, are primary determinants of tHcy in the general population. However, research has concentrated on the relationship of these nutrients with tHcy, and little is known about overall eating patterns and tHcy. METHODS AND RESULTS: In this study, we analysed whether a diet score based on the consumption of folate-, riboflavin- and cobalamin-rich food groups was associated with tHcy in a sample of 140 institutionalised elderly subjects (59 men and 81 women aged 60-80 years) from Northern Spain. The food groups identified as the major contributors to the intake of the three vitamins were vegetables, fruit, fish, meat and milk and dairy products. The mean tHcy level was 13.3+/-5.1 micromol/L (range: 3.9-30.7 micromol/L). None of the food groups predicted tHcy levels individually, but the overall diet score was inversely associated with tHcy in a multiple linear regression analysis. High tHcy levels (>16 micromol/L) were almost twice as prevalent in the groups scoring less than 7 than in those scoring 7 or more (37.5 vs 19.6%, p=0.021). CONCLUSIONS: These data suggest that a dietary pattern characterised by high intakes of B vitamin-rich foods is associated with a lower tHcy concentration and a reduced percentage of high tHcy levels in elderly subjects. They also support the use of dietary pattern approaches to evaluate the relationships between diet and health outcomes that go beyond single nutrient analyses.

Physiological differences and rating of perceived exertion (RPE) in professional, amateur and young cyclists.

BACKGROUND: The aim of this study is to measure and compare the physiological characteristics and the rating of perceived exertion (RPE) in 72 high level road cyclists of 3 different categories. METHODS: These cyclists were divided in 3 groups according to their age (24 professionals, mean age 26 years, 22 amateurs, 22 years and 26 juniors, 18 years). MEASURES: they carried out a progressive test to exhaustion in a specific cycloergometer, starting with a power output of 100 watts and increasing 50 watts each 4 min. VO2 was measured continuously. At the end of each one of the 4 min steps the subject was asked about his RPE using the 6-20 Borg's scale. RESULTS: Professional cyclists showed a VO2max, VO2 x kg(-1) and a maximum power output significant higher than other groups, while there were no significant differences between amateurs and juniors. VO2 and RPE were significantly different, in all the categories, during high work loads. No significant differences were found between RPE and %VO2max. RPE and heart rate (HR) were significantly different between professionals and juniors. RPE and %HR max were significantly different with low loads, but no with high loads. In the same way, RPE/w and RPE/(w x kg(-1) were significantly different in all categories. CONCLUSIONS: We conclude that professional road cyclists reached a VO2max, VO2max x kg(-1) and a maximum power higher than the other categories; so, therefore, these parameters are good as performance indicators, and RPE is of practical value to prescribe exercise training intensities in each category.

Effects of pregnancy on insulin receptor in liver, skeletal muscle and adipose tissue of rats.

The mechanism responsible for insulin resistance during pregnancy remains unclear. Considerable evidence indicates that the insulin receptor plays an important role in insulin sensitivity. It seems possible that the hormonal milieu during gestation could have an effect on the insulin receptor. In the present study, measurements of tyrosine phosphorylation and protein content of the insulin receptor and expression of its gene in liver, skeletal muscle and adipose tissue indicate that during pregnancy significant changes occur in these parameters. We found that at the end of early gestation (day 10), muscle and adipose tissue are very sensitive to insulin action because the amount, phosphorylation and gene expression of insulin receptor is higher than in late gestation (days 15-20), while the tissue which is most sensitive to insulin action in late gestation is the liver. Our hypothesis is that these results are connected with changes in the concentrations of estradiol and progesterone observed during pregnancy. In conclusion, our previous and present findings seem to demonstrate that the different concentrations of gestational hormones play an important role in insulin sensitivity in this period and that each tissue responds in the most appropriate manner to guarantee the gestation in its entirety.

Effect of treatment with different doses of 17-beta-estradiol on the insulin receptor.

The mechanism for the development of insulin resistance in normal pregnancy is complex and is associated with serum levels of sex hormones. However, the influence of these hormones on the early steps of insulin action has not been extensively studied, although the potentially beneficial effect of estradiol on glucose homeostasis has been reported. In this paper, we attempted to determine the effect of 17-beta-estradiol on the insulin receptor of ovariectomized rats treated with different doses of hormones. Our results showed a tissue-dependent response to estradiol. We found that low doses of estradiol increased the amount of insulin receptors in liver and muscle on days 6 and 11 of treatment but not in adipose tissue, and after 16 days only the muscle responsed in this way. On the other hand, high doses of estradiol significantly decreased the amount of insulin receptors, at least in muscle and adipose tissue. We believe that the low concentrations of 17-beta-estradiol (similar to early pregnancy) could be responsible for the increase in insulin sensitivity by increasing the amount of insulin receptors in peripheral tissues. When the hormone levels were high (similar to late pregnancy) the amount of insulin receptors decreased in peripheral tissues, and insulin sensitivity is diminished just as in late pregnancy. The specific molecular mechanism for this action is as yet unknown.

Effects of education on the quality of life, diet, and cardiovascular risk factors in an elderly Spanish community population.

An inverse relation between education and health has been reported, suggesting the importance of examining the underlying mechanism of this association. We examined whether cardiovascular risk factors, diet, and indicators of quality of life (mood, self-perceived health, social relationships, self-rated sensory, and dental adequacy) vary according to educational level among 352 old people (65-95 years old) in the city of Oviedo (Northern Spain). Lower educational level (LE) was associated with unhappiness, poor social relationships, poor self-assessed health, and sensory, and masticatory problems. LE elderly consumed less vegetables and meat products and more carbohydrates. LE women had a lower contribution of proteins and lipids to their total energy intake as well as a lower vitamin A intake. Except for hypercholesterolemia, no differences were found for the cardiovascular risk factors studied. The educational level of old people has a strong influence on their quality of life, nutrient intake and food consumption. These findings may provide part of the explanation for the social gradient in mortality.

Effect of treatment with different doses of 17-beta-estradiol on insulin receptor substrate-1.

CONTEXT: Ovarian hormones modulate insulin sensitivity, but their exact role remains unclear. OBJECTIVE: We tried to determine whether different doses of 17-beta-estradiol cause changes in the regulation of insulin receptor substrate (IRS-1) levels, and if so, the possible implications in insulin sensitivity. DESIGN: Ovariectomized rats were treated with different doses of 17-beta-estradiol at 6, 11 and 16 days. MAIN OUTCOME MEASURES: Immunoprecipitation and Western blotting for IRS-1 were performed in different tissues. RESULTS: We found that estradiol treatment has an influence on the amount of IRS-1 but that it acts in different ways depending on the tissue studied, on the length of treatment, and on the doses employed. CONCLUSIONS: Our results suggest that low concentrations of 17-beta-estradiol could be responsible for the upregulation of insulin receptor substrate 1, increasing insulin sensitivity in muscle and adipose tissue. However, insulin receptor substrate 1 is downregulated with high concentrations of 17-beta-estradiol, thus these high hormone plasma levels could favour insulin resistance in peripheral tissues. The role of 17-beta-estradiol seems to modulate insulin receptor substrate 1 levels in insulin dependent tissues, but in a different manner in each tissue. These novel findings are important for improving knowledge about the possible risk for insulin resistance in women taking oral contraceptives or receiving hormone replacement therapy at menopause.

Comparison of dietary intake and eating behavior of professional road cyclists during training and competition.

The dietary intake and eating behavior of a group of professional elite road cyclists during high intensity training and competition was compared. Their eating pattern consisted of several snacks throughout the race or training, a meal eaten no later than 1 hr postexercise, supper, and breakfast. Protein intake showed a significant difference between evaluation times expressed in three ways: per total amount intake, by kg body weight, and percentage of energy supplied. Due to the high energy intake of these cyclists during training and competition (22.9 +/- 1.5, 22.4 +/- 1.7 MJ, respectively) they presented a high consumption of each macronutrient both in competition and in training. The eating behavior of these athletes was similar during breakfast (possibility to choose from among approximately 25 foods) and supper (set menu), with variation in the energy intake and a similar relative contribution of the different macronutrients. In general, it is possible to consider the professional road cyclists as a homogeneous group with a similar nutrition intake, eating habits, and nutritional needs throughout the more demanding periods of the season. Furthermore, differences found in protein intake between periods could not be explained by differences in the food available in competition and training periods.

Role of 17beta-estradiol and/or progesterone on insulin sensitivity in the rat: implications during pregnancy.

The mechanism for the development of insulin resistance in normal pregnancy is complex and is associated with serum levels of both progesterone and 17beta-estradiol. However, it remains unclear whether estrogens alone or progestins alone can cause insulin resistance, or whether it is a combination of both which produces this effect. We attempted to determine the role played by progesterone and/or 17beta-estradiol on the phenomena of sensitivity to insulin action that take place during pregnancy in the rat. Ovariectomized rats were treated with different doses of progesterone and/or 17beta-estradiol in order to simulate the plasma levels in normal pregnant rats. A euglycemic/hyperinsulinemic clamp was used to measure insulin sensitivity. At days 6 and 11, vehicle (V)- and progesterone (P)-treated groups were more insulin resistant than 17beta-estradiol (E)- and 17beta-estradiol+progesterone (EP)-treated groups. Nevertheless, at day 16, the V, EP and E groups were more resistant to insulin action than the P group. On the other hand, the V, EP and E groups were more insulin resistant at day 16 than at day 6, whereas the P group was more insulin resistant at day 6 than at day 16. Our results seem to suggest that the absence of female steroid hormones gives rise to a decreased insulin sensitivity. The rise in insulin sensitivity during early pregnancy, when the plasma concentrations of 17beta-estradiol and progesterone are low, could be due to 17beta-estradiol. However, during late pregnancy when the plasma concentrations of 17beta-estradiol and progesterone are high, the role of 17beta-estradiol could be to antagonize the effect of progesterone, diminishing insulin sensitivity.

Mediterranean diet and age with respect to overall survival in institutionalized, nonsmoking elderly people.

BACKGROUND: In studies from Italy and Greece, a Mediterranean dietary pattern was shown to favorably affect life expectancy in the elderly population. This pattern is thought to reduce the risk of cancer in addition to being cardioprotective. OBJECTIVE: The objective of this study was to evaluate the interactive effects of the Mediterranean diet and age with respect to survival after controlling for several other variables that could be considered as confounders: age, sex, body mass index, albumin concentration, physical activity, self-assessment of health, and dieting in response to chronic conditions. DESIGN: This was a cohort study involving 161 nonsmoking elderly subjects (74 subjects aged <80 y and 87 subjects aged > or =80 y) living in Spain. The subjects were followed up for > or =9 y. Diet was assessed with a semiquantitative food-frequency questionnaire. RESULTS: A diet score based on 8 characteristics of the traditional diet in the Mediterranean region was associated with a significant reduction in overall mortality in elderly subjects aged <80 y but not in subjects aged > or =80 y. A unit increase in the diet score predicted a 31% reduction in mortality in subjects aged <80 y (95% CI: 7%, 57%). CONCLUSION: Efforts to promote adherence to the Mediterranean dietary pattern appear to be worthwhile in persons aged <80 y, in whom the diet predicts survival, but we do not have any available evidence that such a diet benefits subjects aged > or =80 y.

The effects of food restriction on maternal endocrine adaptations in pregnant rats.

The aim of this study was to characterize hemodynamic, electrolytic and endocrine alterations produced by food restriction (50%) in pregnant rats for the purpose of evaluating the importance of these parameters on the plasma volume expansion and fetal growth. One hundred seventy six pregnant rats were divided into two groups, a control group (C) with an ad libitum diet and another with a restricted diet (U) (50% by weight of the diet of the control group). On days 5, 10, 15 and 20 of pregnancy, the weight of the mother, water intake, urine output, urine and plasma sodium concentration, plasma potassium concentration, blood pressure and heart rate, osmolality, plasma renin activity (PRA) and vasopressin were recorded. The number and weight of the fetuses were determined on days 15 and 20 of gestation. Food restriction results in inadequate weight gain in the mother and retardation of fetal growth. Water and sodium balance (p< or =0.001) were decreased in U group and basal PRA (p< or =0.001) was increased in U group. Food restriction did not significantly alter urine sodium excretion, plasma osmolality, plasma sodium and potassium values, blood pressure and basal vasopressin values. We conclude that the higher values of PRA, described in food restriction situations during pregnancy, seem to be caused by the adaptation to low sodium intake.