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Previously, we showed that eating was associated with an increase in lateral hypothalamic area dopamine (LHA-DA) release, which returns to previous level when eating stops. We therefore hypothesize that LHA-DA release may be primarily contributed to by oronasal stimulation. To test our hypothesis, microdialysis was used to compare LHA-DA release during oral and intragastric feeding. A gastrostomy tube was inserted in 12 rats. After recovery from surgery, in vivo microdialysis was performed. Six rats were allowed to drink a liquid diet, whereas in another six rats the same liquid diet was infused at paired doses (volume = 4.8 +/- 0.6 ml; time = 5-10 min) through the gastrostomy tube into the stomach. Oral feeding increased baseline LHA-DA from 10.6 +/- 0.2 to 14.0 +/- 0.8 pg/10 microliters dialysate (P < 0.01) within 20 min. No significant change in measured LHA-DA occurred during intragastric feeding [baseline: 10.5 +/- 0.3 pg/10 microliters; postintragastric: 10.2 +/- 0.3 pg/10 microliters (P < 0.01 vs. oral feeding)], indicating that LHA-DA release occurs with oronasal stimulation.

To examine our hypothesis that dopamine activity in the lateral hypothalamic area (LHA) may play a role in enhancing the process of eating, a fetal cell suspension of predominantly dopaminergic cells was bilaterally transplanted into the LHA of study rats via direct injection; controls had carrier medium injection. Thereafter, mean daily food intake was 1 g per day greater in dopaminergic cell transplanted rats vs. controls for each day of the 10-week observation period. This resulted in a significantly greater cumulative body weight gain in study rats vs. controls (386 +/- 5.1 g vs. 354 +/- 3.8 g, respectively). On sacrifice at the end of the study, transplanted cells in the LHA were viable. Our data suggest that bilateral LHA dopaminergic cell transplant which presumably resulted in chronically and persistently enhanced dopaminergic activity in the LHA is associated with overeating and consequently, an excess weight gain.

During tumor growth, anorexia and reduced food intake markedly contribute to the development of malnutrition, thus worsening overall patients' survival. A better understanding of the pathophysiology of eating behavior may lead to new and more effective therapies, aiming at counteracting the detrimental effects of anorexia and reduced food intake on nutritional status and survival in cancer patients. Brain tryptophan and serotonin concentrations seem to play a pivotal role in the regulation of eating behavior. Increased brain serotonin activity is indeed associated with a reduction of food intake. It has been recently hypothesized that increased availability of tryptophan to the brain and the consequent increased serotonin activity may represent the pathogenic mechanism for cancer-associated anorexia. According to this hypothesis, the modulation of brain serotonin activity may result in an improvement of anorexia. Reducing brain tryptophan availability represents a possible mechanism to restore brain serotonin activity to normal. There is evidence that the oral administration of neutral amino acids competing with tryptophan for brain entry results in a significant improvement of cancer anorexia. The same treatment may also be effective in improving secondary anorexia, which is associated with other chronic illnesses, including renal and liver failure, sepsis, and so forth, sharing a similar pathogenic mechanism.

Our long-term objectives continue to be elucidation of the mechanisms that control spontaneous food intake (SFI), so that we may utilize this information in seeking ways to ameliorate abnormalities of SFI that occur in nutritionally ill humans. To this end, we have developed and used an Automated Computerized Rat Eater Meter (ACREM), which allows detailed determinations of food intake and feeding patterns under a wide variety of experimental conditions. Because food intake is the product of meal number and meal size, these indexes were studied in a variety of experimental situations: normal male Fischer rats, genetically obese Zucker rats, cancer-bearing rats, and an inflammatory bowel rat model. In each model, a reduction in food intake was accomplished; usually by a selective reduction in meal number and, occasionally, meal size; often in both. The independent regulation of meal number and meal size strongly suggests the existence of focal neuronal areas in the hypothalamic food regulatory areas of the brain, which independently control these feeding indexes. To these feeding pattern studies were added in vivo focal hypothalamic microdialysis to correlate changes in meal size and number with changes in the basic neurotransmitters, dopamine and serotonin. To further gain an understanding of anorexia and food intake regulation in these models as it relates to the brain and gut interaction, we used metabolic stimulants, anatomic ablation, and electrophysiological studies, cytokines, selective neurotransmitter agonists, and antagonists peripherally in the gut and centrally in the brain. An integrated view of the gut-brain brain-gut control of food intake has emerged as a working and testable model system. The system includes oronasal pregastric factors, which stimulate an increase in LHA-dopamine facilitating gastric compliance via efferent vagal fibers; postabsorptive factors, including nutrients and hepatoportal receptors via afferent vagal fibers that inhibit further LHA-dopamine, thereby regulating meal size. The same postabsorptive factors simultaneously decrease VMH-dopamine, thereby determining postprandial intermeal duration, because food intake is resumed when VMH-dopamine normalizes--thus regulating meal number. Changes in plasma amino acids, the precursors for neurotransmitters, also affect brain availability for neurotransmitters. This in particular applies to tryptophan, the precursor of serotonin in the VMH, which induces a decrease in meal number and cytokines, which facilitate activity of both dopamine and serotonin.

After more than two decades of nutritional awareness, we designed a prospective study to determine whether malnutrition is still a significant issue in hospitalized patients. Patients admitted to an intensive care unit (ICU) were divided into well-nourished and malnourished groups, according to their nutritional status as assessed by serum albumin level and weight/height ratio. Severity of illness, as assessed by the Therapeutic Intervention Scoring System (TISS), was used to further stratify the study population. All patients were followed clinically until discharge or death and their outcome recorded. Of 129 patients studied, 43% were malnourished. Length of hospital stay (p = n.s.), incidence of complications (p < 0.01), and number of patients not discharged from hospital (p < 0.05) were greater in the malnourished patients than in the well-nourished. In patients with less severe degrees of illness, the existence of malnutrition led to a worse outcome than in sicker patients. To further assess the clinical setting in which hospital-related malnutrition develops or is exacerbated, postoperative patients admitted to the ICU (n = 66) were also studied in a nutritional survey; the results of this survey indicate that: (a) the incidence of malnutrition in the surgical population is similar to that in the whole study population, and (b) hospital-related malnutrition in surgical patients mainly develops during their preoperative stay in general wards. Whereas our conclusion that patients' outcome is adversely affected by a poor nutritional status is not new or startling, malnutrition continues to be a persistent problem in hospitalized patients, which can be readily identified using simple and easily available indices and, furthermore, readily treated.

The existence of amino acid sensors sensitive to arginine, alanine, leucine and glycine in the hepato-portal region was previously reported based on recording of the afferent signals from the hepatic branch of the vagus nerve. The present study was carried out to investigate the effects of fifteen different amino acids on the activity of the vagal hepatic afferents. Intraportal administration (10 mM, 0.1 mL) of alanine, arginine, histidine, leucine, lysine, serine, tryptophane and valine increased vagal afferent discharge rate, and that of cysteine, glycine, isoleucine, methionine, phenylalanine, proline and threonine suppressed it. The results indicate the existence of two groups of amino acids sensors which exhibit excitatory or inhibitory effect on the afferent activity of the hepatic branch of the vagus nerve. The change in afferent activity to the hypothalamus may affect reflex regulation of the visceral functions and thereby influence appetite.

gamma-Aminobutyric acidergic (GABA) mechanisms in the ventral hypothalamus may be involved in counterregulatory responses to glucoprivic episodes. Microdialysis probes (1 mm) were placed into the ventromedial hypothalamus (VMH) or lateral hypothalamus (LHA) of male Sprague-Dawley rats 3.5 h before 2-deoxy-D-glucose (2-DG) administration (200 mg/kg i.v.). Probes were perfused (2 ml/min) with Ringer solution, and samples were collected every 10 min from 30 min before to 60 min after 2-DG. By 30 min after 2-DG, GABA concentration in VMH dialysate increased in a bimodal fashion to 204 +/- 36% (P < 0.01) of baseline, and GABA concentration in LHA dialysate decreased to 77 +/- 4% (P < 0.01) of baseline. The changes in dialysate GABA concentrations occurred concurrently with the animals eating and returned to baseline by 60 min. When animals were denied access to food after 2-DG, the decrease in LHA GABA was not apparent and VMH GABA remained approximately 15% above baseline at the end of the sample period. The results of the present study provide evidence that GABAergic systems in the ventral hypothalamus are responsive to alterations in glucose status.

Background: When a subareolar breast abscess (SBA) is incised and drained, an extraordinarily high frequency of recurrence is noted., Methods: To develop a pathogenesis-based treatment plan, 24 women with a total of 84 abscesses were monitored., Results: In nine women SBA was under the left areola, under the right, in 7 and in eight the SBA occurred either simultaneously or sequentially under both areolae. In 11 of 24 patients a chronic lactiferous duct fistula also existed. In four of 24 patients four SBAs were treated with antibiotics; alone; all recurred. In 16 of 24 patients initial treatment was incision and drainage plus antibiotics; all recurred. When the abscess plus the plugged lactiferous duct was excised, there were no recurrences; however, in four patients a new abscess in a different duct occurred, which was treated by en bloc resection of all subareolar ampullae, without further recurrence. Patients with a fistulous tract had the fistula, its feeding abscess, and its plugged lactiferous duct excised, without recurrence. In first time SBA the organism was usually staphylococcus; in recurrences mixed flora was isolated. Pathologic findings ranged from squamous metaplasia with keratinization of lactiferous ducts to chronic abscess., Conclusions: The cause of SBA is plugging of lactiferous duct within the nipple by keratin. To prevent recurrence the abscessed ampulla with its plugged proximal duct needs excision.

Background: We hypothesize that total parenteral nutrition (TPN) induces anorexia by an increase in anorexigenic cytokines (factors with central action via the hypothalamus) and tested this hypothesis by measuring changes in food intake and cytokines in response to TPN., Methods: Fischer rats with an internal jugular catheter and ad libitum food received saline solution for 10 days. On day 11, rats were randomized to TPN (G:F:AA = 50:30:20) for 4 days (days 11 through 14); control rats received on saline solution for 5 days. On day 14, one half of the TPN group was switched back to saline solution for 1 day. Daily food intake was measured. On day 14 in one half of all rats and on day 15 in the remaining, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 alpha were measured in plasma and cerebrospinal fluid (CSF). Spontaneous in vitro TNF-alpha and IL-1 alpha were also measured in peripheral blood mononuclear cells., Results: With TPN, an 80% decrease (p < 0.01) in food intake occurred; plasma TNF-alpha increased (78 +/- 9 pg/ml vs undetectable; p < 0.001), and IL-1 alpha was undetectable. Spontaneous in vitro TNF-alpha and IL-1 alpha production were unchanged. Stoppage of TPN led to return toward normal of food intake and plasma TNF-alpha. TNF-alpha and IL-1 alpha in CSF were undetectable in both groups during and after TPN., Conclusion: Increase in plasma TNF-alpha with no increase in CSF-TNF-alpha during TPN, when food intake decreased, suggests an association between TPN and TNF-alpha but not necessarily cause and effect.

Peripherally infused interleukin-1 reduces food intake. Its temporal and selective effects on meal number and meal size were investigated in seven rats continuously infused for 3 days with recombinant human interleukin-1 alpha (rHu IL-1 alpha; 3 micrograms day-1, i.v.). Food intake decreased significantly during the first two infusion days, and was brought about by first the early reduction of meal number, followed by meal size with a 1 day delay. The primary effect of rHu IL-1 alpha was seen during the dark cycle. After the infusion was stopped, meal number recovered most quickly, followed by a lag in recovery of meal size. We conclude that rHu IL-1 alpha influenced food intake primarily via an effect on meal number, which responds more rapidly than a decrease in meal size, thereby inducing an immediate decrease in food intake.

We wanted to determine what happens to brain PCr and ATP relative to that in liver during a series of dietary manipulation consisting of a severe fast, during eating (when nutrients are intermittently supplied), and during and after PN-100, when an excess amount of nutrients are continuously supplied, using 31P-NMR spectroscopy, in rats randomized to a Fast or Fed group in which energy was provided either as chow or as PN-100. Liver ATP concentration, and brain and liver 31P-nuclear magnetic resonance (NMR) spectras were measured serially. Brain energy metabolism was not different between groups and among days. In contrast, Fasted group showed increased liver ATP/Pi ratio and decreased ATP concentration and ATP/phosphomonoester ratio, there being no difference between Fed and PN-100 groups. Data suggest that brain energy metabolism is maintained regardless of whether energy is supplied intermittently or continuously, and during a negative caloric intake period, brain energy metabolism is quantitatively preserved, suggesting that ATP production by liver is subservient to brain ATP state.

Anorexia is observed in 50% of cancer patients; however, the pathogenesis for cancer anorexia is unclear. We postulate that centrally acting cytokines play a role in the pathogenesis of cancer anorexia. To test our hypothesis we determined whether central interleukin 1 alpha (IL-1 alpha) was related to anorexia in tumor-bearing (TB) rats. Fischer 344 rats were inoculated with either 1 ml of 1 x 10(6) trypan blue viable methylcholanthrene-induced sarcoma cells (TB rats) or normal saline (non-tumor-bearing [NTB] rats). Rats were placed into individual metabolic cages equipped with an Automated Computerized Rat Eater Meter that continuously measured food intake. When TB rats became anorectic, TB and NTB rats were anesthetized and cerebrospinal fluid (CSF) was collected. IL-1 alpha was measured. Food intake in TB was 7.1 +/- 1.1 g, whereas that in NTB was 12 +/- 1.1 g (p < 0.05). Eight of the 13 TB rats had detectable concentrations of CSF IL-1 alpha; the mean CSF IL-1 alpha concentration for TB rats was 73.2 +/- 17.3 pg/ml. In contrast, none of the NTB rats (n = 11) had detectable concentrations of CSF IL-1 alpha. CSF IL-1 alpha concentrations correlated inversely with food intake. Data suggest a link between CSF IL-1 alpha and food intake in anorectic TB rats.

Interleukin-1 (IL-1) induces anorexia via direct action in the brain, and its participation in the pathogenesis of cancer-associated anorexia has been hypothesized. Because the functional ablation of the ventromedial nucleus of hypothalamus (VMH), where IL-1 receptors have been detected, reverses cancer-associated anorexia in tumor-bearing (TB) rats, we hypothesize that cancer anorexia involves the direct effect of IL-1 on the VMH. To test this hypothesis, we investigated whether the intra-VMH injection of the IL-1 receptor antagonist (IL-1ra) improves food intake in anorectic TB rats. Sixteen Fischer rats (approximately 300 g/BW) were injected s.c. with 10(6) trypan-blue viable methylcholanthrene sarcoma cells, and then individually caged. Chow and water were freely available, and food intake was recorded throughout the study. Normal food intake was measured in 8 more rats, injected s.c. with normal saline. Tumor developed in all rats. When TB rats became anorectic, they were randomly assigned to either treatment or control groups. Using stereotaxic techniques, 25 ng of IL-1ra dissolved in normal saline (TB-IL-1ra; n = 8), or an equal volume of normal saline (TB-NS; n = 8) was injected bilaterally into the VMH. After surgery, rats were caged and changes in food intake recorded. At study's end, rats were sacrificed and brains removed for histological confirmation of injection sites. In the TB-NS group, food intake decreased with the occurrence of anorexia. In contrast, the intra-VMH injection of IL-1ra reduced the severity of cancer anorexia, significantly improving food intake in TB-IL-1ra rats. Data indicate that centrally acting IL-1 plays a significant role in the development of cancer anorexia.

Peripherally infused interleukin-alpha (IL-1 alpha) reduces food intake. Since the innervated liver modulates eating activity via the vagus, we investigated the role of the hepatic vagus in the etiology of IL-1 alpha induced anorexia. Ten male Fischer 344 rats were randomly assigned to hepatic vagotomy (HX-IL-1 group) or sham operation (Sham-IL-1 group), and an internal jugular catheter was inserted in all rats. Another six sham operated rats receiving normal saline i.v. throughout the study period served as general controls. After a 10-day recovery period, HX-IL-1 and Sham-ILI-1 rats were infused with 3 micrograms day-1 of IL-1 alpha for 3 days, followed by a 4 day infusion of saline. During the IL-1 alpha infusion, food intake was reduced at a similar rate and by a similar amount in both vagotomized and sham-operated rats. When IL-1 alpha infusion was stopped, food intake normalized at a similar rate in both HX-ILI-1 and Sham-IL-1 groups. These data indicate that the hepatic vagus is not involved in the etiology of IL-1 alpha induced anorexia.

Whether spontaneous food intake (SFI) is controlled by infused nutrient type or its caloric content, irrespective of nutrient type, was investigated. Rats were infused for 4 days with isocaloric solutions of different nutrient type but sharing the same intermediary metabolic oxidative pathway, providing 25% of daily caloric needs. One parenteral solution was a glucose, fat and amino acid mix (TPN-25%); the other provided ketone bodies (TRI-3.5%). Effects of parenteral infusions on SFI and metabolic concomitants were compared and contrasted to that in a group of orally fed rats. Both infusions reduced SFT by 50%. Rats receiving TRI-3.5% had lower blood glucose and insulin concentrations, but increased hepatic glycogen content compared to TPN-25% or orally fed rats. No differences in hepatic triglycerides occurred between the three groups. However, serum free fatty acids were significantly lower in TRI-3.5% and in TPN-25% groups vs. fed rats. Data indicate food intake suppression is mediated by caloric content rather than nutrient type, suggesting that a mediator of SFI regulation could be at the citric acid cycle level.

Microdialysis was performed to quantitate lateral hypothalamic dopamine (LHA DA) release before, during and after a single meal in food-deprived obese and lean Zucker rats to examine our hypothesis that an abnormally high dopamine activity may exist in the LHA of obese Zucker rats. Food consumption after food deprivation, was significantly greater in obese than in lean rats (4.1 +/- 0.2 and 2.3 +/- 0.4 g, respectively; (p < 0.05). Mean basal dopamine level was significantly higher in obese than in lean rats (12.0 +/- 0.3 and 10.5 +/- 0.3 pg in 10 microliters dialysates, respectively; p < 0.05). Dopamine release during eating was greater in obese than in lean rats (159.1 +/- 6.8% and 135.4 +/- 3.6% of baseline level, respectively; p < 0.05). After eating, the dopamine level returned to that before (105.6 +/- 4.5% in obese rats and 101.9 +/- 4.0% in lean rats) within the first 20 min sample. Data suggest that there may exist an inherently higher LHA DA 'threshold' level in obese Zucker rats and that until it is reached, food intake continues. This higher 'threshold' level may be responsible for their unique feeding behavior and is probably a contributory factor to their development of obesity.

Postulating that total parenteral nutrition (TPN) has a direct metabolic effect in the brain which may be similar to that in the liver, we studied the effects of TPN on brain glycogen and triglyceride in rats. Control rats (n = 24) received normal saline via jugular catheter for 18 days; TPN rats (n = 24) had normal saline for 10 days and then TPN-100 for 4 days, followed by normal saline for 4 more days. TPN-100 (caloric ratio glucose: fat:amino acid = 50:30:20) provided 100% of the rat's daily caloric needs. Chow and water were available ad libitum during the study. Eight rats from each group were sacrificed after 1 and 4 days of TPN-100, and 4 days after stopping TPN-100. Glycogen in brain and liver glycogen, triglyceride, and glycogen synthetase and phosphorylase were measured, as were plasma glucose and insulin. Data were evaluated using Student's t test. With TPN, the following occurred: (a) an 85% decrease (P < 0.05) of spontaneous food intake; (b) an elevated plasma glucose; (c) a three- to fivefold increase (P < 0.01) in plasma insulin; (d) a 23% increase (P < 0.05) in whole brain glycogen but a 22-33% decrease (P < 0.05) in liver glycogen; (e) liver glycogen synthetase and phosphorylase activity were unchanged while whole brain glycogen synthetase activity decreased by 27% (P < 0.05) and phosphorylase activity increased by 10-16%; and (f) whole brain triglyceride content did not change, although there was a 155-241% increase (P < 0.01) in liver triglyceride.(ABSTRACT TRUNCATED AT 250 WORDS)

Postulating that central IL-1 is involved in the pathogenesis of cancer anorexia we measured IL-1 alpha in cerebrospinal fluid (CSF) from anorectic tumor bearing (TB) rats and non-tumor bearing controls, and correlated their CSF IL-1 alpha with food intake and tumor weight. Food intake in controls was significantly higher than that in anorectic TB rats. Eight of the 13 anorectic TB rats had detectable CSF IL-1 alpha; no CSF IL-1 alpha was detected in controls. In anorectic TB rats a negative correlation existed between CSF IL-1 alpha and food intake and a positive correlation between CSF IL-1 alpha and tumor weight. Data suggest a link between CSF IL-1 alpha and the pathogenesis of cancer anorexia.

In order to evaluate whether different solid tumors may specifically influence plasma free amino acid (PFAA) profile, PFAA were analysed in seventy-four patients with lung (41 patients) and breast cancer (33 patients) and 28 healthy subjects. In lung cancer patients a significant reduction of gluconeogenic amino acids, threonine, serine, glycine and a significant increase of free tryptophan and glutamic acid was found. In breast cancer patients a significant increase of ornithine, glutamic acid and free tryptophan was found. The comparison of PFAA profiles between lung and breast cancer suggests that different tumors have a different influence on the host's PFAA pattern.

The relationship between surfeit caloric consumption during intravenous infusion of a parenteral nutrition solution providing 100% daily caloric needs (PN-100; glucose:fat:amino acid = 50:30:20), carcass adiposity, and postinfusion food intake was evaluated. Rats received saline (control) or PN-100 for 4 days via jugular vein. PN-100 rats were either allowed or denied access to chow during the infusion period. When food was available during the 4 days of PN-100, total cumulative caloric intake, eaten and infused, was 40% higher than controls (p < 0.01). Percent carcass adiposity was increased from 8.8% to 11.6% (p = 0.04), and there was a 3-day delay before food intake returned to baseline. When caloric intake was limited to that provided by PN-100, carcass adiposity was not increased and food intake was 86% of baseline during the first 24 h after stopping PN-100. Delayed return of normal food intake following PN-100 is the likely consequence of excess caloric ingestion during the PN-100 infusion period. The surfeit caloric intake resulted in increased carcass adiposity.

In addition to its immunomodulatory action, interleukin-1 (IL-1 alpha) induces anorexia centrally. Whether IL-1-induced anorexia is mediated by dopaminergic activity in the lateral hypothalamic area (LHA) was investigated by using microdialysis in freely moving rats. After recovery from jugular vein catheterization and LHA cannulation, rats had a microdialysis probe inserted into the LHA. Microdialysis samples were continuously collected in control rats not infused, and in IL-1-treated rats during and after a 24 h continuous systemic infusion of 6 micrograms IL-1 alpha. IL-1 alpha significantly suppressed food intake from 13.6 +/- 0.1 g to 4.3 +/- 0.8 g (p < 0.001), but there was no significant difference in dopamine concentration in the LHA dialysates before, during and after IL-1 alpha infusion relative to controls. Although IL-1 alpha has been shown to act centrally, our results suggest that the anorexic effect of IL-1 alpha is not mediated through dopaminergic activity in the LHA.

Dopaminergic function in the lateral hypothalamic area (LHA) is important for processing intrinsic and extrinsic feeding related information. Brain microdialysis was used to examine if dopamine release in the LHA correlates with meal size in normal and bulbectomized rats. Food-deprived bulbectomized rats ate significantly less food (1.7 +/- 0.1 g) than food-deprived sham operated rats (3.1 +/- 0.5 g, p < 0.05), accompanied by a lesser increase in LHA-dopamine release (150.6 +/- 4.9% vs. 195.1 +/- 13.9, p < 0.02). LHA-dopamine release was significantly higher in rats which ate a full meal (2.9 +/- 0.1 g) than in rats which ate half a meal (1.5 +/- 0.1 g, p < 0.05), being 155.9 +/- 7.8% vs. 131.0 +/- 4.9% (p < 0.05) in food-deprived normal rats. Data suggest that dopamine release in the LHA correlates to the quantity of food consumed during a meal.

Effect of arginine-lysine mixture, glucose and ATP on the efferent activities of the vagal thymic branch and splenic nerve were studied in urethane anesthetized rat. In male Wistar rats jugular vein was cannulated for drug administration. In one group the thymus was exposed and a nerve filament of the central cut end of vagal thymus was isolated. In another group a filament was isolated from that of the splenic nerve. The nerve filament was placed on electrodes to record efferent activity before and after administration of argininelysine mixture solution, glucose or ATP solution. Enhancement of efferent activity of vagal thymic nerve was observed after i.v. administration of arginine-lysine mixture, glucose and ATP solution. Suppression in efferent activity of splenic nerve was investigated following i.v. administration of arginine-lysine mixture, glucose and ATP solution. These results suggest that i.v. arginine-lysine, glucose and ATP increase thymic lymphocyte release, and that i.v. arginine-lysine, glucose and ATP enhance NK cell activity.

A patient with acute intermittent porphyria is presented to emphasize the relevance of nutrition in its management. Clinical manifestations, diagnosis of acute intermittent porphyria, simplified heme biosynthetic pathway, the glucose effect, and the rationale for giving nutritional therapy for acute intermittent porphyria are discussed.

To investigate whether there is a synergistic effect of recombinant human tumor necrosis factor-alpha (rhTNF-alpha) and recombinant human interleukin-1 alpha (rhIL-1 alpha) in inducing anorexia, 32 rats with jugular catheters were studied (8 rats/group): controls received normal saline; the IL-1 group received rhIL-1 alpha (10 micrograms/kg); the TNF group received rhTNF-alpha (30 micrograms/kg); and the IL-1 + TNF group received the same concentration of both rhIL-1 alpha+rhTNF-alpha for 3 days; solutions were then switched to normal saline. No significant decrease in light- and dark-phase food intake occurred during infusion of subeffective rhTNF-alpha. Food intake was decreased on the first rhIL-1 alpha infusion day because of a decreased meal number during the dark phase. A significant decrease in food intake occurred with combined infusion of rhIL-1 alpha+rhTNF-alpha because of a reduction in meal number during dark phase and meal size during light phase. Our results show that rhIL-1 alpha and rhTNF-alpha, when administered concurrently, had a synergistic effect in inducing anorexia, suggesting that low concentrations of these cytokines as produced endogenously may have potential effects on other biological functions in vivo.

Background: Parenteral nutrition (PN) suppresses spontaneous food intake in rats by stimulating dopamine in lateral hypothalamic area (LHA), which is attenuated by vagotomy. Sensors for glucose and for some individual amino acids exist in hepatoportal areas sending signals via hepatic vagal afferents to LHA. Hypothesizing that the decrease in spontaneous food intake occurs because a PN amino acid solution is recognized by portal vein sensors, we measured afferent nerve discharges in hepatic vagus in response to PN., Methods: Hepatic vagus was divided in 11 rats, and an isolated nerve filament was placed on recording electrodes. Afferent firing rate was recorded before and after injecting during 1 minute a well-balanced crystalline amino acid mixture into either the portal or peripheral vein. Isotonic glucose was used as standard solution., Results: A significant decrease in hepatic vagal afferent discharge rate was recorded after both intraportal and intravenous injection of the PN amino acid mixture. The mean discharge rate was inversely related to the concentration of the solution. Successive injections produced further decreases in discharge rate, and the effect was more sustained., Conclusions: The observed decrease in discharge rates suggests that the crystalline amino acid PN solution is sensed in hepatoportal areas informing LHA via hepatic afferents. This effect may play a role in regulating food intake during PN.

During parenteral nutrition (PN) there is an incomplete compensatory decrease in oral caloric intake. The effects of two factors influencing nutrient utilization, diurnal timing of PN infusion and composition of available diet, on compensatory feeding were investigated in male rats receiving 100% of daily caloric need as PN (PN-100). Compensation for infused calories increased from 70 to 80% (P < 0.05) when the timing of infused kilocalories more closely matched diurnal pattern of oral kilocalories intake (e.g., 75% kcal daily during the dark phase, 25% during the light phase). There was a similar degree of compensation when the diet and PN-100 had the same caloric distribution (50% kcal from carbohydrate, 30% from fat, and 20% from protein). Adjusting the diurnal timing of infused calories and diet composition concurrently further increased compensation for infused calories from 70 to 90% (P < 0.05). In the rat PN-100 model, compensation for infused calories is improved by adjusting the temporal pattern of infusions and diet composition.

Serotoninergic system activity and cytokine production have been both implicated in the pathogenesis of cancer anorexia. To verify the existence of relationships between tryptophan, cytokines and anorexia, twenty cancer and six non-neoplastic patients were studied. Plasma amino acid concentration, including tryptophan, and spontaneous and LPS stimulated tumor necrosis factor and interleukin-1 release from peripheral blood mononuclear cells were determined before and after surgery in both groups of patients. A close relationship between plasma free tryptophan concentration and anorexia was observed, whereas no relationship between cytokine production and either anorexia or plasma tryptophan was found in cancer patients.

Food intake is reduced during parenteral nutrition (PN) proportionally to the amount of calories or composition of the solution infused. The relative importance of infused glucose and lipid, 50 and 30% of PN kilocalories, respectively, in reducing food intake during PN was examined. Glycolysis, fatty acid oxidation, or both were acutely disrupted with 2-deoxy-D-glucose (2-DG) and mercaptoacetate (MA). Rats receiving intravenous infusions of saline or a PN solution providing 100% of total daily calories (PN-100) received a single intraperitoneal injection of saline, 2-DG, and/or MA during the early light phase. 2-DG (1.4 or 2.2 mmol/kg) did not initiate feeding in PN-100 rats, although hyperglycemia was evident in all rats 1 h after 2-DG. Food intake of PN-100 rats after MA (0.4 mmol/kg) was approximately 50% that of control rats. When 2-DG (1.4 mmol/kg) and MA (0.4 mmol/kg) were administered concomitantly, PN-100 and control rats consumed the same amount of food. During PN-100, rats appeared to be more sensitive to losing metabolic energy derived from lipid than from glucose.

During parenteral nutrition (PN) glucoprivic-induced feeding appeared to be neutralized by the oxidation of infused fatty acids. With the use of a latin-square design, the feeding response to 2-deoxy-D-glucose (2-DG) and/or 2-mercaptoacetate (MA) was evaluated in male Sprague-Dawley rats with hepatic branch vagotomy (HV) or sham operations (SO). Rats received continuous infusions of 0.9% saline or PN providing 100% of daily caloric needs (PN-100) for four consecutive days. During PN-100, food intake was stimulated by 2-DG in HV rats and when fatty acid oxidation was simultaneously inhibited by MA. 2-DG-induced hyperglycemia was apparent under all conditions. Lipoprivic-induced feeding and increased plasma free fatty acid concentrations were absent in HV rats, whether MA was administered alone or with 2-DG. The feeding response to glucoprivic challenges is influenced by the relative availability of alternate energy sources. The lack of feeding response to 2-DG during PN-100 is mediated by vagal input of hepatic fatty acid oxidation status.

The status of plasma taurine and whether its concentration can be influenced by total parenteral nutrition (TPN) was determined in 51 malnourished fasting cancer patients after surgery and 7-14 days after starting TPN providing 41 +/- 2 kcal, 0.30 +/- 0.02 g N kg-1.day-1 and 40 mg pyridoxine. Plasma taurine was 50% lower in patients than in control subjects. Plasma taurine was significantly greater than baseline only after 14 days of TPN. We also studied the effects of surgery and taurine supplementation (8.6 mg.kg-1.day-1) on plasma and urine taurine concentrations in 12 malnourished patients. Preoperatively, all patients had normal plasma taurine concentrations; postoperatively, it was in the deficient range in 4 patients. Taurine-supplemented patients initially had higher than baseline concentrations; by day 10, none had subnormal levels. Subnormal taurine concentrations commonly occur in malnourished postoperative cancer patients; surgery further precipitates their fall. Plasma concentrations were maintained only with taurine-supplemented TPN.

To determine whether brain glycogen concentrations change during parenteral nutrition, Fischer 344 rats with jugular vein catheters received 0.9 N saline or parenteral nutrition providing 100% of daily calories (PN-100). Rats were killed after 4 days of PN-100 and serially after PN-100 was stopped. Food intake decreased during PN-100 to approximately 15% of control, but total kilocalories eaten and infused over the 4-day PN-100 period was approximately 130% of control. Food intake of PN-100 rats remained low for 3-4 days post-PN-100. At the end of the 4-day PN-100 period, plasma glucose and insulin (P = 0.01) and whole brain glycogen (P < 0.005) were higher than but similar to control within 24 h of PN-100 being stopped. When PN-100 rats were not allowed to eat during the infusion period, plasma glucose was lower, plasma insulin higher, and brain glycogen content the same as in control rats after 4 days of PN-100. The increased brain glycogen was the likely consequence of the hyperglycemia and hyperinsulinemia during PN-100 and was not causally associated with the reduced food intake either during or immediately after PN-100.

Male Fischer rats are widely used to evaluate the effects of nutritional repletion or deprivation on the rat's nutritional status. Practical methods are needed to evaluate changes in body composition. Chemical analysis is expensive, time consuming, and often not available; bioelectrical impedance analysis in laboratory animals lacks standardization. Postulating that the measurement of densitometry would allow reliable estimation of body composition in the male Fischer rat, we studied 27 male Fischer rats. Densitometric measurements of the carcasses and their chemical analysis were performed to obtain reference values. Initial estimation of the fraction of body fat based on densitometry was attempted with the Siri equation intended for use in humans. We found that this equation was not suitable for use in the male Fischer rat because it underestimated fat mass at high carcass weights and overestimated fat mass at low carcass weights. Therefore, the Siri equation was modified to more accurately predict carcass composition in the male Fischer rat. Three different predictive equations based on simple densitometric measurements were developed that allow separate estimation of carcass fat, carcass water, and carcass protein in the male Fischer rat. These equations were found to be accurate to within 2-5-3% of carcass weight.

The role of olfactory input in the regulation of food intake and feeding patterns in rats was investigated by performing bilateral olfactory bulbectomy. Compared to control rats, bulbectomized rats ate the same amounts of food, but did so via a decrease in meal size, and a doubling in meal number. Although no increase in meal duration occurred, the exploratory behavior of sniffing during meals and between meals also increased significantly. While it is not yet clear how the olfactory bulbs participate in regulating food intake configuration resulting in changed feeding patterns, their clinical role can be appreciated by observing the acute changes in feeding pattern that occur when their input to the lateral hypothalamic area is damaged experimentally.

The effects of a continuous intragastric (via a gastrostomy) and intravenous (via an indwelling jugular catheter) infusion of 3% ethanol at 3 ml/h on food intake was examined in rats randomly assigned to a two period crossover study. The 3% ethanol solution provided 19 kcal/day, which was equivalent to about 50% of the daily caloric intake of the rats. Ethanol significantly decreased food intake irrespective of the route administered. But, reduction in food intake did not result in a calorie-to-calorie compensation. Instead, providing 50% of calories as 3% ethanol via the intragastric route led to a 16% reduction in food intake, while only a 9% reduction in food intake occurred when the 3% ethanol solution was given intravenously.

Background: The lateral hypothalamic dopaminergic neurons dominate modulation of food intake. Changes in lateral hypothalamic synaptic dopaminergic release before and during total parenteral nutrition (TPN) and its components were measured in vivo with microdialysis probes., Methods: Rats had an intracerebral guide cannula and an internal jugular catheter placed. Ten days after recovery, rats were fasted for 24 hours. A 2 mm microdialysis probe was inserted into the lateral hypothalamus neurons via the guide cannula. Dopamine level was measured by high-performance liquid chromatography in three 60-minute baseline dialysis samples. TPN, glucose, fat, or amino acid was then infused via the internal jugular catheter, and dopamine level was measured in three more 60-minute dialysate samples. Single nutrients were infused for 24 hours, and dopamine was measured during the 3 hours after the infusions were stopped. Data were analyzed by paired t test (mean +/- standard error) and represented percentage change from baseline., Results: Dopamine levels rose significantly (p < 0.05) and remained so during infusions in TPN (26% +/- 3%), glucose (26.5% +/- 4.6%), fat (36.2% +/- 6.7%), and amino acids (9.6% +/- 4.2%). After infusions were stopped, dopamine levels decreased to -35.4% +/- 1.5% in glucose but remained unchanged with fat and amino acids., Conclusions: Increase in lateral hypothalamic dopamine level occurs with TPN and its components, and changes persist temporarily after stopping the infusions, explaining in part the slow recovery of food intake after TPN is stopped.

Diabetic patients unable to ingest nutrients orally but who have functioning gastrointestinal tracts should be nutritionally supported via enteral feeding. Provision of enteral nutrition can be problematic in terms of glycemic control. Diabetes compounded with kidney failure further complicates calorie delivery and distribution. Enteral-nutrition formulas should be carefully selected with attention to macronutrient profile, specific carbohydrate constituents, and presence or absence of dietary fiber. Modular components can be added to standard enteral feedings to alter calorie distribution while enhancing calorie provision. Selecting the method of insulin infusion (i.e., intermittent subcutaneous insulin therapy versus continuous intravenous or continuous subcutaneous infusion) for maximizing glucose control is an important step in the acute nutrition management of insulin-dependent diabetic patients. Attention to nutrition indices, fingersticks, and parameters of enteral-feeding intolerance is of utmost importance. The transition from enteral to oral nutrition will depend on adequacy of oral intake as determined by calorie counts.

To determine when catheter-related sepsis clears after removal of an infected central venous catheter (CVC) and when a new sterile CVC can be inserted without risk of recolonization, a catheter infected with 10(5) CFU of Staphylococcus epidermidis per ml was inserted into 40 Fischer 344 rats. Five control rats had sterile catheters. Insertion of an infected CVC was followed by a significant rise in leukocytes after 4 days and the presence of S. epidermidis in lungs, livers, spleens, kidneys, and the catheter tip, as examined by bacteriological assay. After the infected catheter was removed, the rat recovered from the induced catheter-related sepsis within 12 h. When a new sterile CVC was inserted into the femoral vein, the leukocyte count remained normal, and all catheter tips and tissue cultures were sterile 4 days later.

Total parenteral nutrition has become a well-established intervention for the following indications: to sustain life in patients with short-bowel syndrome; for perioperative use in nutritionally deprived patients; to improve quality of life for patients with inflammatory bowel diseases; to assist the healing of enterocutaneous and pancreatic fistulas; for supportive care in patients with acute pancreatitis; as an adjunct to therapy in patients with acute renal or hepatic failure; for hypermetabolic states such as sepsis, trauma, burns and acquired immunodeficiency syndrome; in neonatal and pediatric patients; in transplantation recipients, including bone marrow, renal, cardiac and liver transplants; for precoronary artery bypass graft myocardial glycogen loading; in the field of obstetrics; to enhance survival in patients with closed head injuries; to treat life-threatening anorexia nervosa; in patients with cystic fibrosis and for nutritional support in home use.

A case report is presented in which a man developed acute renal failure after a surgical misadventure. The initial management, postoperative course with the manifestation of acute tubular necrosis with oliguria and its physiological sequelae, nutrition management in the context of the overall treatment, hospital course, and patient's disease are discussed in detail. The rationale for giving nutrition support, the general considerations for providing nutrients, and the specific nutrition considerations as they pertain to the patient under discussion are outlined to provide a comprehensive guide and overview of the nutrition management of a patient with acute renal failure.

Tumor growth is accompanied by an anorexia mediated by humoral factors that appear to influence appetitive mechanisms in the brain. Because tumor resection is followed by resumption of normal food intake, the circulating anorexigenic substance(s) are produced either by the neoplastic tissue or by the host in response to the tumor. Increased levels of plasma free tryptophan and plasma ammonia have been proposed to mediate cancer anorexia. With animal models, it is often difficult to ascertain whether changes in food intake depend upon metabolic changes or the progressively increasing tumor mass per se. The feeding patterns and biochemical changes that occur during tumor growth were evaluated in 96 male Fischer rats that were inoculated with 10(6) methylcholanthrene sarcoma cells or saline (controls). Rats were placed into metabolic cages equipped with an Automated Computerized Rat Eater Meter to continuously determine meal size and meal number. Plasma free tryptophan and ammonia were evaluated 6, 10, 16, 18, 22, and 26 days after tumor inoculation. Anorexia developed by day 17-18, when food intake started to decrease via a decrease in meal size but not meal number and reached 60% of control by day 26. However, long before anorexia developed, free tryptophan was significantly higher 6 days after tumor inoculation, and the greatest increase occurred after 18 days. Ammonia did not differ from control at any time. Data confirm tumor-associated increases in plasma free tryptophan that occurred before the manifestation of anorexia and support a possible role of brain serotonin in cancer anorexia.

The reduction in DNA, RNA, amino acid, and total protein in muscle tissue of tumor-bearing rats may influence muscle function. The effects of MCA-sarcoma tumor burden on muscle performance and adenine nucleotides was evaluated in three fiber types of skeletal muscle. Twenty-one days after MCA-sarcoma tumor inoculation, the gastrocnemius-soleus muscle group of Fischer 344 rats was stimulated using an in situ preparation; tetanic stimulation for 10 min at 7.5, 15, or 30 tetani per min (TPM) or 60 TPM for 5 min (n = 6 control and six tumor-bearing rats/group). ATP, ADP, AMP, IMP, phosphocreatine, and creatine content in white and red gastrocnemius muscle and soleus muscle was measured. There were no differences among controls and tumor-bearing rats in force output; however, ATP content in the soleus muscle of tumor-bearing rats was significantly reduced after 30 TPM for 10 min or 60 TPM for 5 min. The performance of skeletal muscle, over a wide range of stimulation frequency, in tumor-bearing rats does not appear to be influenced by changes in adenine nucleotide content.

Background: Estimates of daily postoperative fluid balance usually rely on properly recorded inputs, outputs, and daily weights or clinical signs. These may be imprecise (when poorly done) and are often considered tedious to perform., Methods: We used bioelectric impedance analysis (BIA) to assess changes in body water shifts in cardiac patients after surgery. Nine consecutively admitted patients undergoing coronary artery bypass (seven men and two women; age range, 43 to 67 years) were studied. Body weight, fluid intake and output, and BIA variables (resistance and reactance) were measured daily. Relationships between body weight and changes in resistance and reactance and net change in fluid balance (in liters per day) were evaluated statistically by regression analysis., Results: Mean body weights changed significantly, reflecting early operative fluid accumulation and later postoperative diuresis; net fluid balance correlated poorly (r = 0.48; p less than 0.05) with body weight, whereas both resistance (r = -0.82; p less than 0.001) and reactance (r = -0.92; p less than 0.0001) correlated highly with net fluid balance., Conclusions: BIA is useful as an accurate, rapid bedside method for assessing changes in hydration status sequentially after surgery in cardiac patients with complicated fluid shifts.

The comparative effects of discontinuing total parenteral nutrition (TPN: caloric ratio of glucose:fat:amino acid = 50:30:20) abruptly or in a stepwise manner on spontaneous food intake were investigated in two studies. Study 1: In 16 rats, TPN was given for 4 days, then stopped abruptly in eight rats. In the other eight rats, TPN was tapered; they received TPN at 75%, 50%, and 25% of their mean daily energy requirements per day for 3 consecutive days, and then switched to normal saline. Total parenteral nutrition induced a significant 60% reduction in spontaneous food intake (SFI) in both groups during the first TPN day. After 4 days of TPN, an 80% decrease in SFI had occurred in both groups. Resumption of SFI was significantly sooner in the abruptly-stopping group than in the stepwise-stopping group. But, in the latter group, there was a significantly greater cumulative caloric intake during the entire study. Study 2: In 32 rats, TPN providing either 100%, 50%, or 25% of their mean daily caloric requirements was given to three groups each of eight rats, for 3 days, then abruptly changed to normal saline; control rats received normal saline throughout. The TPN-induced decrease in SFI was proportional to the caloric density of the solution infused. Three days of 100%, 50%, or 25% TPN infusion led to an approximate 85%, 60%, or 35% decrease in SFI, respectively. Spontaneous food intake recovery was independent of the caloric density of TPN.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of general anesthesia and operation on dynamics of postoperative food intake resumption was investigated in eight rats. A laparotomy was performed on each rat under anesthesia induced by intraperitoneally injected chloral hydrate. Spontaneous food intake and feeding indexes were continuously measured using an Automated Computerized Rat Eater Meter (ACREM) before and after operation. Although spontaneous food intake and all feeding indexes were depressed immediately following anesthesia and operation, each feeding index was depressed to a greater degree during the dark vs. the light cycle. Initially, rats fully capable of eating ate fewer, smaller, and shorter meals. The return to normal of each feeding index differed temporally. Thus, although meal number normalized by the third postoperative day, meal size by the sixth postoperative day, and meal duration by the fourth postoperative day, normalization of meal number during the light cycle occurred sooner than during the dark cycle, while the converse occurred with meal size and meal duration.

The hypothesis that tumors arising in a particular organ site impose a characteristic plasma free amino acid (PFAA) pattern was tested by analyzing PFAA in fasting venous blood of preoperative patients with breast cancer, gastrointestinal tract cancer, and head and neck cancer. Healthy volunteers served as control subjects. Levels of 28 PFAA were determined in blood samples using an amino acid analyzer, and the data were compared using discriminant analysis and chi-square testing. Compared with control subjects, the concentrations of seven amino acids (glutamine, threonine, histidine, cysteine, alanine, arginine, and ornithine) in patients with tumors correlated closely with the known diagnoses. By means of discriminant analysis, these seven amino acids had the highest correlation with the specific diagnoses, indicating that PFAA profiles correlate diagnostically with the organ-site origin of three different kinds of malignant tumors.