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A chest wall restrictor to study effects on pulmonary function and exercise. 2. The energetics of restrictive breathing.

Chest wall restriction, whether caused by disease or mechanical constraints such as protective outerwear, can cause decrements in pulmonary function and exercise capacity. However, the study of the oxygen cost associated with mechanical chest restriction has so far been purely qualitative. The previous paper in this series described a device to impose external chest wall restriction, its effects on forced spirometric volumes, and its test-retest reliability. The purpose of this experiment was to measure the oxygen cost associated with varied levels of external chest wall restriction. Oxygen uptake and electromyogram (EMG) of the external intercostals were recorded during chest restriction in 10 healthy males. Subjects rested for 9 min before undergoing volitional isocapnic hyperpnea for 6 min. Subjects breathed at minute ventilations (V.I) of 30, 60, and 90 liters/min with chest wall loads of 0, 25, 50 and 75 mm Hg applied. Frequency of breathing was set at 15, 30, and 45 breaths per minute with a constant tidal volume (VT) of 2 liters. Oxygen uptake was measured continuously at rest and throughout the hyperventilation bouts, while controlling V.I and VT. Integrated EMG (IEMG) from the 3rd intercostal space was recorded during each minute of rest and hyperventilation. Two-way ANOVA with repeated measures revealed that chest wall loading and hyperpnea significantly increased V.O2 values (p < 0.01). External intercostal IEMG levels were significantly increased (p < 0.05) at higher restrictive load (50 and 75 mm Hg) and at the highest minute ventilation (90 liters/min). These data suggest that there is a significant and quantifiable increase in the oxygen cost associated with external chest wall restriction which is directly related to the level of chest wall restriction.

Adult↗

Responses to dietary macronutrient distribution of overweight rats under restricted feeding.

Changes in protein and amino acid balance after energy-restricted feeding have scarcely been studied, although it has been suggested that protein utilization may depend on the macronutrient composition of the restricted diet. The aim of this study is to investigate the influence of dietary fat quality and content, during an energy-restricted regime, on body composition and protein metabolism. Therefore, diet-induced overweight rats were divided into three dietary groups: one group was fed on a control diet ad libitum (control) and the other two groups were fed energy-restricted diets (about 60% of control group), which provided a standard amount (20%) of fat (SFR), based on olive oil, or a high amount (60%) of saturated fat (HFR), based on coconut oil. Measurements of body weight, body composition, serum biochemical parameters and the assessment of the hepatic and muscular protein response were performed. Similar results were found comparing weight losses and serum parameters in both deprived groups, although the high-fat-restricted rats (HFR group) showed a greater reduction in the subcutaneous fat depot and of total body fat. After both energy-restricted treatments, the serum amino acid concentration was reduced while the urinary amino acid excretion increased. Muscle and liver protein metabolism was affected by energy restriction, which produced a decrease in protein synthesis capacity (RNA content) in both tissues and a higher muscle proteolysis (catepsin activity), more marked in the SFR group, while no changes were found in liver protein breakdown. Hepatic glycogen and glycogenic amino acid were also altered, reaching significant differences in the HFR group. Thus, dietary macronutrient composition during energy restriction seems to be involved in the metabolic adaptative response.

Adaptation, Physiological↗

Relationship of air trapping to increased lung recoil pressure induced by chest cage restriction.

Chest cage restriction was produced in 13 normal male subjects. We could not detect trapped air during restriction by comparing lung volumes determined by nitrogen washout with those determined by plethysmography. However, 3 subjects did have definite evidence of trapping because they released small amounts of air (mean, 61 ml) when the restriction was removed. Two subjects had suggestive evidence of trapping. Yet there was no correlation between trapping and the degree of increase in static lung recoil associated with restriction. Seven subjects had chest restriction produced while they were breathing air and again while they were breathing 100 per cent oxygen, in an attempt to reveal the presence of airway closure. In only one subject was oxygen breathing clearly associated with a greater then expected increase in lung recoil after restriction; suggestive changes were seen in 2 other subjects. However, there was no definite correlation between unusual increases in lung recoil induced by restriction while breathing oxygen and the presence of air trapping. We conclude that trapping, hence airway closure, is not required for the increase in static lung recoil that occurs with chest cage restriction.

Adult↗

Effects of tyrosine kinase signaling inhibition on survival after cecal ligation and puncture in diet-restricted mice.

BACKGROUND: Malnutrition impairs host immunity, resulting in high mortality and morbidity due to infections. Phosphorylation of protein tyrosine kinase (PTK) is a key step in the signaling of many cellular functions, including immune cell functions. Malnutrition may affect this signaling in response to surgical insults. The aim of this study was to examine the effects of PTK inhibition on mortality in ad libitum and in diet-restricted mice after cecal ligation and puncture (CLP). Moreover, tyrosine phosphorylation of peritoneal cells from these animals was evaluated. METHODS: Survival study: Mice (n = 45) received chow, 146 g/kg per day (ad libitum) or 36.5 g/kg per day (diet-restricted), for 7 days. Two hours before CLP, one-half the mice in each group were given a tyrosine kinase inhibitor, AG 556 (3.0 mg/kg i.p.), and the others received vehicle. Survival was observed up to 7 days after CLP. Effects of AG 556 on survival with a lesser degree of malnutrition (chow 73 g/kg per day) were also examined (n = 41). Measurement of tyrosine phosphorylation: mice (n = 20) were assigned to the ad libitum and diet-restricted (chow 36.5 g/kg per day) groups. Peritoneal cells were harvested either before or 2 hours after glycogen injection. Glycogen treatment elicits polymorphonuclear neutrophil influx into the peritoneal cavity. The cells were incubated with or without N-formyl-methionyl-leucyl-phenylalanine (fMLP). Tyrosine phosphorylation in the cells was examined using flow cytometry, laser scanning cytometry, and Western blotting. RESULTS: Diet restriction significantly reduced survival compared with the ad libitum group. AG 556 treatment decreased the survival of ad libitum, but not in diet-restricted mice in both survival experiments. Stimulation of peritoneal cells with fMLP increased tyrosine phosphorylation in the ad libitum group (23% increase before glycogen and 18% after glycogen), but not in the diet-restricted group (-9% before glycogen and 3% after glycogen). CONCLUSIONS: Inhibition of tyrosine kinase signaling impairs the ability of a well-nourished host to survive CLP-induced sepsis, while having no effects on survival in diet-restricted mice. Peritoneal cells from diet-restricted animals are unable to increase PTK phosphorylation in response to stimulation, which may be the mechanism underlying impaired host defense during malnutrition.

Animals↗

Dietary restriction compromises resistance to gut ischemia-reperfusion, despite reduction in circulating leukocyte activation.

BACKGROUND: Gut ischemia-reperfusion (gut I/R) accompanying severe surgical insults leads to neutrophil-mediated injury and is regarded as a triggering event in early multiple-organ failure. Our previous study demonstrated dietary restriction to down-regulate leukocyte activation. Therefore, we hypothesized dietary restriction might be beneficial in terms of surviving I/R. We also evaluated leukocyte activation and the level of organ glutathione, an antioxidative substance. METHODS: Institute of Cancer Research mice received chow, 170 (ad libitum), 119 (MR: mild restriction) or 68 (SR: severe restriction) g/kg per day for 7 days. Exp. 1: The mice (n = 59) underwent 15 or 45 minutes of gut ischemia and survival was observed. Exp. 2: The mice (n = 73) were killed before or 60 or 120 minutes after 15-minute ischemia. Reactive oxygen intermediate (ROI) production by circulating myeloid cells and CD11b expression was determined. Some mice were assessed for nuclear factor kappa B (NFkappaB) activation. Glutathione levels were measured in some of the small intestine and liver samples from each group. RESULTS: Dietary restriction decreased survival. Circulating myeloid cell priming and activation, in terms of ROI production and CD11b expression, were enhanced in the ad libitum group but not in the restricted groups. NFkappaB was activated only in the ad libitum group. Gut and hepatic glutathione levels were lower in the SR than in the ad libitum group. Dietary restriction caused histologic damages in gut, liver, and lung 120 minutes after reperfusion. CONCLUSIONS: Dietary restriction blunts leukocyte priming and activation after gut ischemic insult but worsens the outcome by, at least in part, decreasing antioxidative activities. Clinically, nutrition replenishment may be required to improve the outcome of gut hypoperfusion.

Animals↗

Oral squamous cell carcinoma in ad libitum-fed and food-restricted Brown-Norway rats.

A high incidence of oral squamous cell carcinoma was present in male and female Brown-Norway rats fed ad libitum or food-restricted dietary formulations. One hundred eight-nine rats were examined from 4 dietary treatment groups: male ad libitum, male food-restricted, female ad libitum, and female food-restricted. The ad libitum treatment groups for both males and females had significantly more cases of oral squamous cell carcinoma than cohort food-restricted groups. In ad libitum rats, 10 of 47 (21%) males and 15 of 47 (32%) females had oral squamous cell carcinoma, whereas only 4 of 47 (9%) males and 5 of 48 (10%) females in the food-restricted groups were similarly affected. The food-restricted rats lived significantly longer than ad libitum cohorts, so the higher incidence of squamous cell carcinoma was not dependent on extended lifespans. In addition to the dietary influence, a significant difference in oral squamous cell carcinoma incidence occurred between various familial lines. Family lines having representatives in both ad libitum and food-restricted groups had lower oral squamous cell carcinoma incidences in the food-restricted group whether comparing affected litters or individuals. Results suggest that the incidence of oral squamous cell carcinoma in our colony of Brown-Norway rats can be influenced by both the dietary treatment group and genetic predilection within certain pedigrees.

Animal Feed↗

Youth tobacco access restrictions: Time to shift resources to other interventions?

There is limited data to guide policy makers as to whether youth tobacco access restriction is an effective strategy. Analysis of the limited data on youth access restriction suggests that (a) scalable models for access restriction are lacking, (b) enforcement of access restriction would be cost prohibitive, (c) the leaky commercial supply of cigarettes combined with the capacity of youth to tap into a "social supply" of cigarettes would hamper all but the most rigorously enforced efforts to restrict access to tobacco, and (d) access restriction may paradoxically increase allure of cigarettes for some youth. Although youth tobacco access restriction does not face strong political or industry opposition, the authors' analysis reveals that youth tobacco access restriction is likely to remain a failed strategy to control tobacco use in the United States.

Adolescent↗

Iron restriction negatively affects bone in female rats and mineralization of hFOB osteoblast cells.

We previously reported that severe iron deficiency negatively affects bone microarchitecture. Here we determined whether marginal iron restriction that reflects some human consumption patterns could have similar consequences. Thirty-two weanling female rats were randomly divided into four groups and fed the following diets for 10 weeks: (i) iron-adequate, calcium-adequate (FeA:CaA), (ii) calcium-restricted (FeA:CaR), (iii) iron-restricted (FeR:CaA), and (iv) both calcium- and iron-restricted (FeR:CaR) diets. DEXA analysis revealed that CaR decreased bone mineral density (BMD), and FeR decreased whole-body bone mineral content (BMC). Iron-restricted and calcium-restricted groups had lower BMD than did their adequate counterparts. All treatment-restricted groups had lower BMD in the fourth lumbar (L-4) vertebrae than the FeA:CaA group. Vertebrae BMD was lower in all treatment groups compared to the control group, and for BMC, the CaR groups were lower than the CaA groups and the FeR groups were lower that the FeA groups, and BMC were lower in iron- and calcium-restricted groups. The microarchitecture of the L-4 vertebrae was compromised in FeA:CaR, FeR:CaA, and FeR:CaR: (i) the connectivity density was reduced by FeR and by CaR; and (ii) trabecular number was decreased and trabecular separation was increased by FeR. Cortical thickness of the femur was reduced by both FeR and CaR. Finite element analysis revealed that L-4 vertebrae from the FeR:CaA group had greater internal stress with an applied force than the FeA:CaA group and, thus, would be more likely to break. Chelation of iron in cultured osteoblast cells impaired mineralization but had no impact upon Type I collagen deposition. Iron depletion, similar to that occurring among some human populations, reduced bone strength and microarchitecture based on the in vivo and in vitro results reported here. Impaired mineralization with iron depletion appears to be a possible mechanism for the observed bone abnormalities.

Animals↗

Induction of insulin-like growth factor binding protein-1 gene expression in liver of protein-restricted rats and in rat hepatoma cells limited for a single amino acid.

Restriction of the dietary protein intake of young growing animals results in a rapid cessation of growth. In order to gain further insight into the molecular mechanisms for metabolic adaptation to protein restriction, the expression of the insulin-like growth factor binding protein-1 (IGFBP-1) gene was examined in 4-week-old male rats fed isocaloric diets containing 20%, 8%, or 4% protein over a 10-day period. Expression of the IGFBP-1 gene was strongly induced in the protein-restricted animals. Animals on the 8% protein diet exhibited a 14-fold increase, and animals on the 4% protein diet exhibited a 33-fold increase in hepatic IGFBP-1 messenger RNA (mRNA) abundance relative to the abundance of IGFBP-1 mRNA in animals on the 20% protein diet. Expression of the IGFBP-1 gene was also strongly increased by severe energy restriction: IGFBP-1 mRNA abundance was increased 15-fold in animals maintained for 10 days on a diet with energy restricted to 50% of the ad libitum intake rate. In animals fasted for 24 h there was a 6-fold increase in IGFBP-1 mRNA abundance, a lower induction than was observed in either of the two chronic nutritional restriction models. To determine whether limitation for substrate (i.e. amino acids) might have a direct effect on IGFBP-1 gene expression, we examined the effect on IGFBP-1 gene expression of limitation of H4-II-E rat hepatoma cells for a single essential amino acid (phenylalanine, methionine, leucine, or tryptophan) for a period of 24 h. The abundance of IGFBP-1 mRNA was increased by approximately 4- to 5-fold in cultures limited for any of these four amino acids as compared with its abundance in cells incubated in medium containing all essential amino acids. To study further the molecular mechanism for induction of IGFBP-1 gene expression by nutritional restriction, probes specific for intron 3 or intron 1 of the rat IGFBP-1 gene were used to quantify levels of the IGFBP-1 primary nuclear transcript in protein-restricted rats and amino acid-limited cultured cells. The level of the IGFBP-1 primary transcript was increased by 8-fold in animals on the 8% protein diet and 14-fold in animals on the 4% protein diet, suggesting that the induction of IGFBP-1 mRNA was caused largely by an increase in transcription.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗

Regional differences in the distribution of gonadotropin-releasing hormone cells between rapidly growing and growth-restricted prepubertal female sheep.

Growth retardation induced by dietary restriction in the lamb results in a low GnRH pulse frequency, and thus, puberty is delayed. In our experimental model, in which ovariectomized lambs are maintained at weaning weight (approximately 20 kg BW), hypothalamic GnRH is present and releasable, suggesting that central mechanisms limit the release of GnRH during chronic growth restriction. Our study compared the number and distribution of GnRH-containing neurons in growth-restricted (n = 5) and rapidly growing (n = 5) ovariectomized prepubertal female lambs at 24 weeks of age (normal age of puberty is about 30 weeks). Immunoreactive cells were labeled using LR-1 antiserum (R. Benoit) and an avidin-biotin-immunoperoxidase procedure. GnRH neurons were localized in 60-micron coronal sections from the level of the diagonal band of Broca to the mammillary bodies. The estimated total number of GnRH neurons in the growth-restricted and rapidly growing lambs was similar (3364.8 +/- 513.8 vs. 3151.2 +/- 279.8, respectively). In addition, the percent distributions of GnRH neurons in the diagonal band of Broca, the anterior hypothalamus, the lateral hypothalamus, and the posterior hypothalamus were not different. A trend (P = 0.07) toward a smaller percent distribution in the preoptic area was noted in growth-restricted lambs (30.6 +/- 3.6) compared to rapidly growing lambs (44.0 +/- 5.2). By contrast, the percent distribution of GnRH neurons in the medial basal hypothalamus was significantly greater in the growth-restricted lambs compared with the rapidly growing lambs (17.7 +/- 2.2 vs. 6.7 +/- 1.4, respectively; P < 0.005). It is of interest that the percent distribution of GnRH-containing neurons in the medial basal hypothalamus of the hypogonadotropic growth-restricted lamb is similar to that observed in the fetal lamb, whereas the eugonadotropic rapidly growing lamb is more similar to the adult female. In this context, decreased GnRH secretion and delayed puberty during diet-induced growth restriction may arise from alterations in the GnRH neurosecretory system.

Animals↗

Central inhibition of gonadotropin-releasing hormone secretion in the growth-restricted hypogonadotropic female sheep.

Growth retardation induced by dietary restriction results in hypogonadotropism, and thus, puberty is delayed. The present studies determined 1) whether reduced LH secretion in the growth-retarded condition is due to a reduction in the frequency and/or in the amplitude of GnRH secretion, and 2) whether the mechanism regulating LH secretion is being actively inhibited via central mechanisms. To determine whether GnRH pulse frequency and/or amplitude are reduced during growth restriction, blood samples were simultaneously collected from pituitary portal blood for GnRH and from jugular blood for LH determinations over a 4-h period in ovariectomized lambs (52 wk of age) that were either growth restricted (28 kg; n = 8) or growing normally (60 kg; n = 7). As expected, the growth-restricted females were hypogonadotropic and exhibited a long LH interpulse interval compared with the normally growing females. However, although the GnRH interpulse interval was longer in the growth-restricted lambs compared with that in the normally growing lambs, the pattern of GnRH secretion did not directly correspond with that of LH secretion in the growth-restricted group. In addition, high amplitude GnRH pulses that coincided with LH pulses and small, low amplitude GnRH pulses without a concomitant LH pulse occurred. The second study tested the hypothesis that diet-induced hypogonadotropism is the result of actively inhibited central mechanisms by investigating the effects of the nonspecific central nervous system inhibitor, sodium pentobarbital, on pulsatile LH secretion in the growth-restricted lamb. Serial blood samples were collected from 11 ovariectomized lambs that were maintained at weaning weight (approximately 20 kg) by reduced diet. After a 4-h pretreatment period, six of the lambs were anesthetized with sodium pentobarbital for 4 h; the other five lambs were untreated and served as controls. Pentobarbital anesthesia reduced the LH interpulse interval (increased the frequency) and increased mean LH levels. These findings suggest that during growth restriction hypogonadotropism arises from a central inhibition of GnRH neurons and is manifest as a decrease in both frequency and amplitude of GnRH pulses.

Activity Cycles↗

Relative effects of calorie restriction and weight loss in noninsulin-dependent diabetes mellitus.

In obese patients with noninsulin-dependent diabetes mellitus (NIDDM), reducing calorie intake improves glycemic control, often more rapidly than weight loss. Conversely, after weight loss has been achieved, metabolic control can deteriorate once calorie intake is increased, even if there is no regaining of weight. The current study, therefore, tested the hypothesis that restricting calorie consumption has an important role, independent of weight loss, in metabolic regulation of NIDDM patients. Isotopic determinations of hepatic glucose production (HGP), post-absorptively and after ingestion of 75 g glucose (dual glucose isotope method), were made in conjunction with measurement of insulin secretion and insulin sensitivity in seven obese NIDDM volunteers after four periods of controlled calorie intake: 1) 7 days of a baseline weight maintenance diet, 2) followed immediately by 7 days of calorie restriction (800 Cal/day); 3) followed by a weight loss program that consisted of 2 months of a very low calorie diet (400 Cal/day) and then 4 weeks of gradual refeeding and 7 days on a weight maintenance diet; and 4) a final week of calorie restriction (800 Cal/day). The initial brief interval of calorie restriction produced substantial decreases in fasting plasma glucose, HGP, and fasting plasma triglyceride and increases in insulin sensitivity and secretion. After a substantial weight loss (12.7 +/- 2 kg), each parameter improved further, with the effect of weight loss approximately equal to that obtained with initial calorie restriction. Reimposing calorie restriction after weight loss had little effect, except that fasting plasma glucose and HGP improved slightly further. In obese NIDDM subjects, a 7-day period of calorie restriction produces approximately half of the overall improvement in HGP, insulin sensitivity, and insulin secretion that is obtained after a substantial loss of weight. These findings indicate that calorie restriction has an important regulatory effect on the metabolism of obese patients with NIDDM that is independent of weight loss.

Adult↗

Diaphragm levels as determinants of P axis in restrictive vs obstructive pulmonary disease.

BACKGROUND AND OBJECTIVE: Verticalized P axes in adults with obstructive lung disease have long been appreciated as characteristic of emphysema. After demonstrating P axes in restrictive lung disease to have a significantly different orientation (intermediate to horizontal), it was hypothesized that opposite effects on diaphragm level by obstructive disease (low diaphragm) and by restrictive disease (high diaphragm) could explain the axis differences, because the right atrium is attached via the inferior vena cava and adjacent pericardium to the right leaf of the diaphragm. METHODS: Electrocardiograms and chest radiographs were analyzed independently in a new series of 20 consecutive patients with purely obstructive and 19 consecutive patients with purely restrictive pulmonary disease. P axes were calculated to the nearest 5 degrees and grouped as vertical (+65 degrees to +90 degrees), intermediate (+40 degrees to +60 degrees), and horizontal (< +50 degrees). Chest radiographs established the right diaphragmatic level by posterior rib number or interspace with interspaces designated as "0.5" plus the number of the rib above. RESULTS: P axes for obstructive vs restrictive disease were different (p < 0.001) as in our previous investigation. In the present series, 19 of 20 electrocardiograms in patients with obstructive disease had vertical P axes between +70 degrees and +90 degrees; in 11 of 19 patients with restrictive disease, P axes were less than +40 degrees (horizontal); 6 were between +40 degrees and +60 degrees (intermediate); and only 2 were vertical. Diaphragm levels were between rib/interspace numbers 10.5 and 12.5 in all patients with obstructive disease. Diaphragm levels among patients with restrictive disease were higher and, like their P axes, more widely distributed: 10 of 19 between rib levels 8.0 and 9.5; only 4 at 10.5 or lower. Thus, vertical P axes corresponded to low (rib/interspace 10.5 to 12.5) and intermediate to horizontal P axes with higher (8.0 to 11.0 rib) diaphragm levels (p < 0.001). CONCLUSION: Because the separate P-axis distributions in restrictive and obstructive lung disease parallel the separate diaphragm levels and because the right atrium is necessarily carried by attachments to the right diaphragmatic leaf, it is likely that the consequent positional effects on the right atrium contribute to or cause the significantly different P-axis orientations in restrictive and obstructive pulmonary disease.

Atrial Function↗

Effect of a liberal versus restrictive transfusion strategy on mortality in patients with moderate to severe head injury.

OBJECTIVE: To compare a restrictive versus a liberal transfusion strategy in patients with moderate to severe closed head injury following multiple trauma in 13 Canadian intensive care units (ICUs). METHODS: This is a subgroup analysis of a multicenter randomized controlled clinical trial involving sixty-seven critically ill patients from the Transfusion Requirements in the Critical Care trial who sustained a closed head injury. Patients had a hemoglobin concentration less than 9.0 g/dL within 72 hours of admission to the ICU. Patients were randomized to a restrictive allogeneic red blood cell transfusion strategy (hemoglobin 7.0 g/dL and maintained between 7.0 and 9.0 g/dL) or a liberal strategy (hemoglobin 10.0 g/dL and maintained between 10.0 and 12.0 g/dL). RESULTS: Baseline characteristics in the restrictive ( n = 29) and the liberal ( n = 38) transfusion groups were comparable. Average hemoglobin concentrations and red blood cell units transfused per patient were significantly lower in the restrictive compared to the liberal group. The 30-day all-cause mortality rates in the restrictive group were 17% as compared to 13% in the liberal group (risk difference 4.1 with 95% confidence interval [CI], 13.4 to 21.5, p = 0.64). Presence of multiple organ dysfunction (12.1 +/- 6.4 versus 10.6 +/- 6.3, p = 0.35) and changes in multiple organ dysfunction from baseline scores adjusted for death (4.5 +/- 6.2 versus 3.4 +/- 6.2, p = 0.49) were similar between the restrictive and liberal transfusion groups, respectively. Median length of stay in ICU (10 days, interquartile range 5 to 21 days versus 8 days, interquartile range 5 to 11 days, p = 0.26) and hospital (27 days, interquartile range 14 to 39 days versus 30.5 days, interquartile range 17 to 47 days, p = 0.72) were similar between the restrictive and liberal transfusion groups. CONCLUSIONS: We were unable to detect significant improvements in mortality with a liberal as compared to restrictive transfusion strategy in critically ill trauma victims with moderate to severe head injury.

Adult↗

Influence of placentally mediated fetal growth restriction on the onset of puberty in male and female lambs.

The onset of puberty in prenatally growth-restricted versus normally grown lambs of both sexes, born in April and housed under natural photoperiod, was examined. Singleton pregnancies were established and adolescent ewes were offered a high or moderate nutrient intake throughout gestation. Placental mass was reduced (P < 0.001) in high compared with moderate intake dams and resulted in the birth of growth-restricted and normal birth weight offspring, respectively. At birth, female lambs weighed 3.43 kg versus 5.03 kg (P < 0.001; n = 14 per group) and male lambs weighed 2.75 kg versus 5.18 kg (P < 0.001; n = 7 per group) in growth-restricted and normal birth weight groups, respectively. Lambs suckled for 12 weeks and thereafter were fed ad libitum until week 43 of age. Growth-restricted lambs had lower preweaning live weight gains and this difference was more pronounced in male (P < 0.05) than in female lambs (P = 0.07). Thereafter, live weight remained lower (P < 0.05) in growth-restricted than in normally grown lambs of both sexes until week 25 of age. In females, the time of onset of puberty was similar in the two groups. All females ovulated and there were no differences in the number of ovarian cycles recorded or in the incidence of aberrant ovarian function. In males, testosterone concentrations and testicular volume were lower in growth-restricted compared with normally developed lambs from birth until weeks 28 and 35 of age, respectively (P < 0.05). The seasonal increase in plasma testosterone concentrations occurred later in growth-restricted than in normally developed lambs (P < 0.01) but the timing of maximum peak concentrations was similar. Peak testosterone concentrations were lower (P < 0.05) in growth-restricted than in normal male lambs.

Aging↗

Immunological function of food-restricted germfree and specific pathogen-free mice.

The effects of food restriction on immune function was investigated in germfree (GF) and specific pathogen-free (SPF) mice. They were maintained from five weeks of age under either full-fed or food-restricted conditions to 4.5 grams per day (equivalent to approximately 80% of full-fed intake) of a commercial diet. Longest survival rate was attained in food-restricted SPF mice followed by food-restricted GF, full-fed GF, and full-fed SPF animals. Food-restricted GF mice showed shorter survival rate than their SPF counterparts. This result suggests that food restriction may be just as effective as GF status for extending life span. Immune function declined significantly with age in full-fed groups of GF and SPF mice. In both food-restricted GF and SPF mice, mitogenic response to concanavalin A or lipopolysaccharide and antibody response to sheep red blood cells were lower early in life and became higher later in life as compared with full-fed mice. Hence, the maintenance of effective immunological function until old age may be the reason for food-restricted groups to live slightly longer than full-fed groups.

Aging↗

Randomized trial of liberal versus restrictive guidelines for red blood cell transfusion in preterm infants.

OBJECTIVE: Although many centers have introduced more restrictive transfusion policies for preterm infants in recent years, the benefits and adverse consequences of allowing lower hematocrit levels have not been systematically evaluated. The objective of this study was to determine if restrictive guidelines for red blood cell (RBC) transfusions for preterm infants can reduce the number of transfusions without adverse consequences. DESIGN, SETTING, AND PATIENTS: We enrolled 100 hospitalized preterm infants with birth weights of 500 to 1300 g into a randomized clinical trial comparing 2 levels of hematocrit threshold for RBC transfusion. INTERVENTION: The infants were assigned randomly to either the liberal- or the restrictive-transfusion group. For each group, transfusions were given only when the hematocrit level fell below the assigned value. In each group, the transfusion threshold levels decreased with improving clinical status. MAIN OUTCOME MEASURES: We recorded the number of transfusions, the number of donor exposures, and various clinical and physiologic outcomes. RESULTS: Infants in the liberal-transfusion group received more RBC transfusions (5.2 +/- 4.5 [mean +/- SD] vs 3.3 +/- 2.9 in the restrictive-transfusion group). However, the number of donors to whom the infants were exposed was not significantly different (2.8 +/- 2.5 vs 2.2 +/- 2.0). There was no difference between the groups in the percentage of infants who avoided transfusions altogether (12% in the liberal-transfusion group versus 10% in the restrictive-transfusion group). Infants in the restrictive-transfusion group were more likely to have intraparenchymal brain hemorrhage or periventricular leukomalacia, and they had more frequent episodes of apnea, including both mild and severe episodes. CONCLUSIONS: Although both transfusion programs were well tolerated, our finding of more frequent major adverse neurologic events in the restrictive RBC-transfusion group suggests that the practice of restrictive transfusions may be harmful to preterm infants.

Anemia↗

Seminiferous epithelium of rats with food restriction and carbon tetrachloride-induced cirrhosis.

OBJECTIVE: Analyze the changes in the seminiferous epithelium in rats with carbon tetrachloride-induced cirrhosis (CCl4). MATERIALS AND METHODS: Forty-eight male Wistar rats aged 45-50 days, weighing 150-180 grams were used. Twenty-two rats underwent CCl4-induced cirrhosis with CCl4 0.25 mL/Kg weekly intragastrically once a week, during 10 weeks. Additionally, they had a 44% food restriction diet (Group 1). The control group was divided in two subgroups: 13 rats had a 44% food restriction diet and no CCl4 (Group 2) and 10 rats were not submitted to CCl4 or food restriction (Group 3). After 10 weeks, the rats were sacrificed and liver sections were collected for histological analysis. The testicular analysis was carried out to evaluate the frequency of tubules in stages VIII and XIV. RESULTS: The mean rates of stage VIII in animals with food restriction plus CCl4-induced cirrhosis and food restriction without CCl4 were significantly different from animals without either food restriction or CCl4 (18.1 +/- 5.5%, 20.5 +/- 2.5% and 13.4 +/- 3.5%, respectively, p = 0.002). The mean rate of stage VIII in rats with cirrhosis was not significantly different from rats without cirrhosis (18.1 +/- 5.5% and 17.4 +/- 4.6% respectively). The mean frequency of stage XIV in rats with cirrhosis was significantly greater than rats without cirrhosis (4.7 +/- 2.3% and 6.8 +/- 1.9% respectively, p = 0.027). CONCLUSION: Animals with CCl4-induced cirrhosis and food restriction have shown alterations in spermatogenic cycle that were not seen in rats without CCl4-induced cirrhosis and food restriction.

Animals↗