Prenatal dietary docosahexaenoic acid supplementation in combination with protein restriction does not affect blood pressure in adult Wistar rats.

Recent findings indicate that prenatal protein restriction, which leads to elevated blood pressure in adult rats, results in decreased levels of docosahexaenoic acid (DHA) in neonatal rat brain. In light of the evidence of a relationship between dietary DHA and adult blood pressure, the purpose of this study was to ascertain whether prenatal dietary supplementation with DHA would prevent the development of hypertension associated with maternal protein restriction. Throughout gestation, female Wistar rats were fed isocaloric diets containing either 18% casein + 10% corn oil (CON; control), 9% casein + 10% corn oil (LP; low-protein) or 9% casein + 8.5% corn oil + 1.5% DHASCO (LP + 0.6% DHA). DHA increased levels of DHA in neonatal forebrain but there were no effects of LP. At 10 weeks there were no dietary effects on blood pressure measured on four consecutive days using tail-cuff plethysmography. There were also no significant effects measured at 30 weeks, using femoral artery catheterisation, despite adequate power to detect a 10 mm Hg difference. Trends in corticosterone measurements suggested higher stress reactivity in the LP group. These results do not provide strong support for the prenatal low protein model of hypertension and a relation with dietary DHA.

Dietary trans fatty acids combined with a marginal essential fatty acid status during the pre- and postnatal periods do not affect growth or brain fatty acids but may alter behavioral development in B6D2F(2) mice.

The objective of this study was to investigate whether dietary trans fatty acids (TFA) during the pre- and postnatal periods would exacerbate the effects of marginal essential fatty acid (EFA) status on growth, brain long-chain polyunsaturated fatty acids (LC-PUFA) and behavioral development in B6D2F(2) mice. Pregnant B6D2F(1) females were randomly assigned to one of the following three diets: marginal EFA plus 22% trans 18:1 (mEFA + TFA); marginal EFA (mEFA); and control (CON). The total 18:1 content in all diets was similar. The offspring were weaned and maintained on the same diets. Both the mEFA and mEFA + TFA groups had reduced growth and brain weight compared with CON, but did not differ from one another. As expected, the mEFA and mEFA + TFA groups had reduced docosahexaenoic acid [DHA; 22:6(n-3)]) and increased 22:5(n-6) concentrations in brain phosphatidylcholine (PC) and phosphatidylethanolamine (PE) compared with the CON group, but again did not differ from one another. Reversal learning in the T-water maze was significantly slower in the mEFA + TFA groups compared with the mEFA group and both were slower than the CON group. These findings illustrate that TFA combined with a marginal EFA status do not exacerbate the effects of marginal EFA status on growth or brain LC-PUFA. However, long-term effects of dietary TFA during the pre- and postnatal period on behavioral development and neural function should be investigated in future studies.

Effect of 17beta-estradiol and voluntary exercise on lymphocyte apoptosis in mice.

During the perimenopause, women may begin estrogen replacement therapy (ERT) and physical activity programs to reduce the symptoms of the climacteric. High-intensity exercise increases lymphocyte apoptosis, and estrogen is also known to have immune modulatory effects. The present study determined whether (1) estrogen exposure in vivo, and (2) low-intensity, voluntary exercise affect thymic and splenic lymphocyte apoptosis in adult female mice. 'Middle-aged' (>1 year), ovarian-intact female B6D2F(1) mice were implanted with 17beta-estradiol (E) pellets (L: 3 microg/day or H: 12 microg/day) or placebo (P: 0 microg/day). Mice were given 1 week to recover from implantation surgery after which they were randomized to wheel-running or no-wheel-running conditions. Twenty one days later, mice were sacrificed and thymus and spleen removed for determination of percent apoptosis and percent necrosis by flow cytometry, serum E levels by RIA, and tissue and body weights. Estrogen-treated, ovarian-intact mice accumulated less cumulative wheel-running activity than mice implanted with placebo (P<.001). E exposure was associated with lighter thymuses (P<.05), higher thymocyte apoptosis (P<.001), and higher serum E levels (P<.001), effects which were not modified by voluntary exercise. In contrast, splenocyte apoptosis and spleen weights did not differ by estrogen treatment or exercise. The results suggest that in vivo exposure to supplemental estrogen is associated with greater spontaneous apoptosis of thymocytes and reduced thymus weights in older ovarian-intact mice. The clinical significance for thymic (cellular) immunity in perimenopausal women given HRT remains to be determined.

A Saturated-Fat Diet during Development Alters Dendritic Growth in Mouse Brain.

The objective of this study was to determine whether an essential fatty acid (EFA)-deficient diet (saturated fat) fed during development would alter the pattern of dendritic growth in pyramidal neurons of mouse occipital cortex. Pregnant and lactating mice were fed either a saturated fat or control diet throughout pregnancy and lactation. At weaning, one female was selected randomly from each litter, and these animals were maintained on their respective diets and reared in an enriched environment for eight weeks. Following this, their brains were processed histologically using a modified Golgi-Cox method, and patterns of dendritic growth were analysed in occipital pyramidal cells. A Sholl concentric circle analysis indicated that, for basilar dendrites, starting at a distance of 62.5 µm, animals fed saturated fat had fewer crossings than controls, which is indicative of either shorter dendrites or of less dendritic branching. Although the analysis of branching order was not significant, the trend seen in these data supports less branching in the saturated fat group, particularly of third- and fourth-order dendrites. Similar effects were seen in the apical dendrites, although to a lesser extent. Covariance analysis indicated that these effects could not be accounted for by the smaller brains in the EFA-deficient group. They can therefore be considered preliminary support for an effect of EFA on the pattern of dendritic development.

Arachidonic acid offsets the effects on mouse brain and behavior of a diet with a low (n-6):(n-3) ratio and very high levels of docosahexaenoic acid.

This study investigated the effects of varying dietary levels of very long-chain polyunsaturated fatty acids on growth, brain fatty acid composition and behavior in mice. Five groups of pregnant and lactating B6D2F1 mice were fed diets with either a very high (n-6):(n-3) ratio of 49 [(n-3) deficient)], a normal ratio of 4.0 or a low ratio of 0.32. The (n-6) fatty acids (FA) were provided either entirely as linoleic acid (LA) or as LA in combination with arachidonic acid (ARA), and the (n-6):(n-3) ratios were adjusted by partial replacement of the (n-6) FA with docosahexaenoic acid (DHA). Offspring were maintained on these diets after weaning. The diets with the low (n-6): (n-3) ratio had no effect on the birth weights of the pups, but after 15 d resulted in a significant 12% reduction in body weights. This effect persisted to adulthood and was apparent in both brain and body weights unless ARA was substituted partially for LA as the source of (n-6) FA. There were significant effects of diet on brain fatty acid composition. Increasing levels of DHA in the diet increased brain DHA and decreased ARA, and there was also retroconversion of DHA in EPA in the mice fed high levels of DHA. Addition of ARA to the diet increased brain ARA, and, at high levels only, decreased DHA. There were no effects of this wide variation in dietary (n-6):(n-3) ratio on the ability of the mice to learn the place of the hidden platform in the Morris water maze. However, in both the cued and the place learning, the mice fed the low (n-6):(n-3) diet swam more slowly, unless ARA substituted partially for LA as the source of (n-6) FA. There were no effects of diet on activity in the spatial open field. These findings show that the effects of a diet with a low (n-6):(n-3) ratio and (n-3) FA provided as DHA, can be overcome if LA is partially replaced by ARA as the source of (n-6) FA.

Organizational restructuring in health care: a successful approach.

The process of redesigning the internal organization structure of the Hamilton Civic Hospitals provides a successful example of this type of transformation. Based on a strategic approach to change, this multiphased process used a modified delphi technique to allow maximum participation in a total redesign of the structure during a four-month time frame. Implementation, which followed over the next year, resulted in a 40 percent reduction in management positions and the integration of the two sites of the hospital.

Effects of dietary gamma-linolenic acid and prenatal ethanol on mouse brain and behavior.

Pregnant B6D2F mice were treated with ethanol (25% Kcal) from days 5-17 of gestation. The diet was supplemented with either 18 : 2n-6 [linoleic acid (LA)] or 18 : 3n-6 [gamma-linolenic acid (GLA)] throughout the study. Ethanol reduced 20 and 22 carbon n-6 and n-3 fatty acids in the brains of adult offspring. Feeding of GLA, compared with LA, increased levels of 20 : 3n-6 and 22 : 4n-6, but reduced 22 : 6n-3, particularly in the offspring of dams administered ethanol during gestation; adult brain weight was also lower in this group. Ethanol reduced the number of viable litters and adult body weight, and GLA reduced birth weight. Neither prenatal ethanol nor GLA affected open-field activity in adult males, nor did either treatment have an effect on the duration of immobility in the forced swimming test. However, GLA did affect circadian activity by increasing running wheel activity during the dark cycle, and decreasing it slightly during the light cycle. These results do not support a beneficial effect of GLA in preventing the developmental effects of ethanol; we suggest caution in the administration of high doses of GLA with ethanol during pregnancy.

Brain and behavioral effects of dietary n-3 deficiency in mice: a three generational study.

Feeding mice a diet deficient in n-3 fatty acids for three generations resulted in a 53% decrease in docosahexaenoic acid (DHA, 22:6n-3) in the brain. Maternal pup retrieval and social learning of a food preference are both tasks based on olfactory function. All dams made contact more readily with pups of their own dietary group, and animals of both dietary groups demonstrated the ability to learn a food preference through exposure to a conspecific that had previously eaten the food. Both groups showed similar ability to learn the location of the hidden platform in the Morris water maze, while the n-3 deficient animals were marginally faster in locating the platform on the cued trial. They were also more active when tested in the open field. While they did not differ in their duration of immobility in a forced swimming test, the deficient animals did have longer paw-lick latencies on a hot plate. Thus, in this study a significant reduction in brain n-3 fatty acid composition, while associated with some indications of change in emotional reactivity, did not impair olfactory function or learning of either a latent or spatial nature.

The effects of dietary fatty acid composition combined with environmental enrichment on brain and behavior in mice.

In this study we investigated the effects of dietary fatty acid (FA) composition combined with postweaning environmental enrichment on brain fatty acid composition and behavior in mice. There were three dietary conditions: a saturated fat group deficient in essential fatty acids, a group deficient in n-3 fatty acids only, and a control group containing both n-3 and n-6 fatty acids in a ratio of 0.27. Animals were fed these diets during pregnancy and lactation and after weaning. Brain fatty acid composition was determined on days 1, 9, 17 and 25 after birth and in adult animals at 3 months. At weaning two females from each litter were assigned randomly to either an enriched or standard environmental condition. After six weeks in these environments they were tested in the Morris water maze and open field. Adult percentages of 22:6n-3 were present in the brain within the first week after birth. These values were reduced by 50% in the n-3 deficient diet and by 80% in the saturated fat diet; adult animals on the saturated fat diet were also severely retarded in growth. Animals fed the saturated fat diet were initially slightly slower in locating the hidden platform in the Morris maze relative to the control group, but this was not apparent in the reversal learning phase; a cued learning task using a visible platform indicated that these effects did not appear to be related to differences in motor or motivational capacities. The n-3 deficient group did not differ from either the saturated fat group or the controls. All dietary groups showed beneficial effects of environmental enrichment in decreasing their latency to locate the hidden platform, and these effects appeared to be partially independent of the increased swimming speed of the enriched animals. Enriched animals in all groups showed less rearing activity in the open field and spent more time stationary; the animals fed saturated fat reared less and travelled shorter distances more slowly. In all cases the effects of diet and environment were additive, thereby providing little support for the hypothesis that dietary fatty acid composition would affect the animals' capacity to benefit from the functional effects of environmental enrichment.

Growth patterns in the National Library of Medicine's serials collection and in Index Medicus journals, 1966-1985.

Data from the National Library of Medicine (NLM) automated Master Serials System and its MEDLINE database were used to chart the growth of NLM's serials collection and of the journals indexed in Index Medicus from 1966 to 1985. The number of live serial titles in the subset of NLM's collection examined increased 30% in the twenty years. The average number of articles per Index Medicus journal increased 56%. The average number of articles in U.S. Index Medicus journals grew more rapidly than the average number in journals published elsewhere. The NLM data provide clear evidence that the years from 1966 to 1985 saw a substantial increase in the percentage of the biomedical serial literature published in English. The period from 1966 to 1985 saw substantial but uneven growth in the number of serial titles in the NLM collection and in the average number of articles in Index Medicus journals. Although data on the number of articles published in Index Medicus journals is unlikely to reflect the number of articles in other journals, the pattern of growth in the number of serials held by NLM probably reflects trends in the universe of all biomedical serials.

Effects of environmental enrichment on cortical depth and Morris-maze performance in B6D2F2 mice exposed prenatally to ethanol.

Pregnant mice were fed a liquid diet with 25% of the calories as ethanol from day 5 to 17 of gestation; controls received equivalent amounts of diet with maltose-dextrin substituted isocalorically for the ethanol. Two male weanlings from each litter were assigned randomly to an enriched or isolated environmental condition. After 6 weeks in these environments measures of brain growth were obtained, including thickness of frontal, parietal, and occipital cortex (study 1), or their behavioral capabilities were assessed in a Morris water maze (study 2). Ethanol decreased birth weight (both studies), postweaning body weight (study 2), and brain weight (study 1), while the enriched animals in both studies were heavier. Ethanol decreased the thickness of the occipital cortex only. All groups demonstrated learning by showing a decrease in latency to locate the hidden platform over the 5 days of testing; this was supported by their spending most time in the target quadrant during the probe trial. The latencies of the enriched animals were shorter than the isolated; covariance analysis indicated that this was not due solely to their faster swimming speed.

Attenuation of cyclosporine-induced hypertension by dietary fatty acids in the borderline hypertensive rat.

The effects of dietary (10% calories) safflower (SAF), evening primrose (EPO), and fish oil (F) as sources of linoleic acid (control), gamma-linolenic acid, and long-chain n-3 fatty acids, respectively, on cardiovascular and renal responses to chronic (5 weeks) cyclosporine administration were studied in male borderline hypertensive rats. In one experiment (n = 9/group), oral administration of CsA at 0.1 mg/kg.day significantly increased awake systolic blood pressure vs. placebo in SAF-fed rats (P less than 0.01). This increase was prevented by both EPO (P less than 0.001) and F (P less than 0.01), in the absence of group differences in body weight gain or plasma electrolyte levels. In a second experiment, CsA also increased blood pressure vs. placebo in SAF-fed rats (P less than 0.001). While this increase was prevented by EPO (P less than 0.001), F had no significant effect. Differences in group blood pressure responses were not explained by group differences in body weight gain or trough levels of blood CsA. Renal function, assessed in anesthetized rats after week 5, demonstrated a CsA-related (10 mg/kg.day) decrease in whole-kidney GFR in SAF-fed animals vs. placebo (P less than 0.05) that was prevented by EPO and attenuated by F. EPO and F also tended to reduce the CsA-induced elevation in renovascular resistance, but this difference did not reach statistical significance. These findings suggest the potential of dietary EPO and F to offset nephrotoxic effects of CsA administration, and suggest that EPO may also be useful in countering CsA-induced hypertension.

The effects of dietary n-3/n-6 ratio on brain development in the mouse: a dose response study with long-chain n-3 fatty acids.

This study examines the effects of the ratio of n-3/n-6 fatty acids (FA) on brain development in mice when long-chain n-3 FA are supplied in the diet. From conception until 12 days after birth, B6D2F1 mice were fed liquid diets, each providing 10% of energy from olive oil, and a further 10% from different combinations of free FA concentrates derived from safflower oil (18:2n-6), and fish oil (20:5n-3 and 22:6n-3). The range of dietary n-3/n-6 ratios was 0, 0.25, 0.5, 1.0, 2.0 and 4.0, with an n-6 content of greater than 1.5% of energy in all diets, and similar levels of total polyunsaturated fatty acids (PUFA). In an additional group of ratio 0.5, 18:2n-6 was partially replaced by its delta 6 desaturation product, 18:3n-6. Biochemical analyses were conducted on 12-day-old pup brains, as well as on samples of maternal milk. No obvious effects on overall pup growth and development were observed, apart from a smaller litter size at ratio 1. Co-variance analysis indicated that increasing the n-3/n-6 ratio was associated with slightly smaller brains, relative to body weight. We found that 18:2n-6 and 20:5n-3 were the predominant n-6 and n-3 FA in the milk; in the brain these were 20:4n-6 and 22:6n-3, respectively. Increasing dietary n-3/n-6 ratios generally resulted in an increase in n-3 FA, with a corresponding decrease in n-6 FA.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of treadmill exercise on weight cycling in female mice.

Weight cycling increases food efficiency and rate of weight regain. This study induced weight loss in adult female B6D2F1 mice via dietary energy restriction and exercise to determine whether the weight loss regimen influenced rate of weight regain. Four groups of animals were studied: RES, restricted (food restricted); EX, exercised (treadmill exercised); SC, sham control (treadmill exposure, not exercised); LC, lab chow control (appropriately aged control). Both EX and SC voluntarily reduced food intake to the level of the RES animals. The RES group showed increased food efficiency and rate of weight regain relative to the LC group; this effect was attenuated in both the EX and SC groups. These findings demonstrate that a) the cycling phenomenon occurs in mice, and b) stressors such as forced exercise or exposure to a novel environment can modify the pattern of food efficiency and rate of weight regain engendered by dietary restriction.

The role of n-3 essential fatty acids in brain and behavioral development: a cross-fostering study in the mouse.

A cross-fostering design was used to examine the effects on brain and behavioral development in mice of pre- and/or postnatal dietary supplementation with n-3 fatty acids. Pregnant mice were fed either of two liquid diets, control (con) or experimental (exp). Each diet provided 3% of the calories in the form of n-6 fatty acids; the experimental diet was supplemented with an additional 1.5% from long chain n-3 fatty acids derived from fish oil. There were four treatment groups, with all pups fostered at birth. These groups were (prenatal diet/postnatal diet): Group 1. exp/exp; Group 2, exp/con; Group 3, con/exp; Group 4, con/con; a fifth control group (unfostered) was fed lab chow (LC) throughout the study. Animals from the exp/exp and con/con groups were weaned onto lab chow for later behavioral assessment. Prenatal n-3 supplementation resulted in a small acceleration of behavioral development. The adult animals did not differ on visual discrimination learning nor did they differ in visual acuity. During development the fatty acid composition of the brain membrane phospholipids reflected closely that of the pre- and postnatal dietary conditions. Levels of 22:5n-3 and 22:6n-3 increased in the n-3 supplemented groups, accompanied by a decrease in levels of 22:4n-6 and 22:5n-6; the net effect of these changes was to increase the total levels of C22 fatty acids. While these results support considerable plasticity of the fatty acid composition of the developing brain with respect to the immediate dietary availability of n-3 compounds, they do not support long term effects on learning capacity of n-3 supplementation during the developmental period.

Effects of prenatal ethanol and long-chain n-3 fatty acid supplementation on development in mice. 1. Body and brain growth, sensorimotor development, and water T-maze reversal learning.

Pregnant mice were fed equivalent daily amounts of a liquid diet containing 25% (kcal) ethanol, or with maltose dextrin substituted isocalorically for ethanol. In addition, the diet contained 20% oil; this was either of two mixtures, one comprised of predominantly n-6 (18:2n-6) fatty acids, and the other containing an equivalent amount of n-6, but supplemented with a source of long chain n-3 (20:5n-3, 22:6n-3) fatty acids. An additional control group was fed lab chow ad libitum. The treatment was implemented from day 7 to 17 of gestation, whereafter all groups were fed lab chow. Ethanol decreased maternal weight gain and pup body and brain weight; it also retarded both sensory and motor development in the pups and impeded reversal learning in a water maze. The n-3 supplementation lowered maternal blood alcohol concentration, but counteracted only some of the effects of ethanol, by increasing maternal weight gain and pup body weight, and also by enhancing sensory development in the pups. Such effects were additive, in that they were also present in the maltose-dextrin control group. These findings suggest that n-3 supplementation may ameliorate some of the effects of ethanol on neurobehavioral development, but the magnitude of the effect appears to be small.

Effects of prenatal ethanol and long-chain n-3 fatty acid supplementation on development in mice. 2. Fatty acid composition of brain membrane phospholipids.

Pregnant mice were fed equivalent daily amounts of a liquid diet containing 25% (kcal) ethanol, or with maltose dextrin substituted isocalorically for ethanol. The diet also contained 20% oil; this was either of two mixtures, one comprised of predominantly n-6 (18:2n-6) fatty acids, and the other containing an equivalent amount of n-6, but supplemented with a source of long chain n-3 (20:5n-3, 22:6n-3) fatty acids. An additional control group was fed lab chow ad libitum. The treatment was implemented from day 7 to 17 of gestation, whereafter all groups were fed lab chow. Birth occurred on day 19, and the fatty acid composition of the brain membrane phospholipids was determined in the pups 3 days after birth (day 22 postconception) and again, 10 days later (day 32 postconception). On day 22 the polyunsaturated fatty acid (PUFA) composition of the brain phospholipids reflected dietary availability, with the n-3/n-6 ratio higher in the n-3 groups; this was decreased by ethanol in the phosphatidylcholine (PC) fraction. The dietary effect was still apparent on day 32; again ethanol reduced this in both the PC and phosphatidylethanolamine (PE) fractions. The n-3 oil, but not ethanol, increased the 20:3n-6/20:4n-6 ratio, indicative of an inhibition of the activity of delta-5 desaturase. With respect to the 22:C compounds, the n-3 oil decreased the levels of 22:5n-6, while increasing those of 22:6n-3, but generally the sum of these two fatty acids remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Interactive effects of prenatal ethanol and N-3 fatty acid supplementation on brain development in mice.

This study assesses the combined effects on brain and behavioral development of ethanol administration and supplementation of the maternal diet with long chain n-3 polyunsaturated fatty acids. From day 7 to 17 of gestation, pregnant mice were fed equivalent daily amounts of isocaloric liquid diets; 20% of the energy was provided by either ethanol or maltose-dextrin, and a further 20% by either safflower oil (rich in linoleic acid, 18:2 n-6), or a combination of safflower oil with a fish oil concentrate (rich in eicosapentaenoic acid, 20:5 n-3, and docosahexaenoic acid, 22:6 n-3). On day 18 the liquid diets were replaced by lab chow; a fifth group was maintained on lab chow throughout the experiment. Measures on the pups included brain weight and the fatty acid composition of the brain phospholipids on days 22 and 32 post-conception (birth = day 19), as well as behavioral development. Maternal weight gain during gestation was decreased by ethanol relative to maltose-dextrin, and increased by fish relative to safflower oil. On day 32, the brain weight of ethanol-treated animals fed fish oil was greater than their safflower oil controls, whereas the reverse was true in the two maltose-dextrin groups; a similar trend was apparent on day 22. The brain phospholipid content of the longer chain fatty acids (20:4 n-6, 22:4 n-6, 22:5 n-6, 20:5 n-3, 22:5 n-3, 22:6 n-3) on day 22 reflected that of the prenatal diet, with the proportion of n-3 compounds being higher and that of n-6 lower in the fish oil than safflower oil groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of early rearing experience on feeding behavior in B6D2F2 mice.

This work investigated putative factors contributing to the hyperphagia previously observed in mice which had been overfed during the preweaning period by rearing in small litters. In the first study, B6D2F2 mice, reared in small (Sm = 4), medium (Md = 8) and large (Lg = 12) litters, were subjected to a series of diets adulterated with varying concentrations of sucrose octa-acetate (1, 2, 4, and 8%). All animals reduced their food intake in response to the dietary adulteration, with evidence of a dose-response effect, but this response did not differ as a function of litter size. The second study addressed the involvement of the opioid system in the feeding response through the administration of a series of doses of naloxone (0.1, 0.25, 0.5, 1.0, 2.5, and 5.0 mg/kg, or 5, 7.5 and 10.0 mg/kg). Although naloxone treatment did reduce food intake, there was not a clear dose-response relationship. Again, there was no interaction with litter size. These results do not support effects of early rearing on the feeding response to dietary adulteration or to the effects of naloxone administration.