The effect of glutamine-enriched TPN on gut immune cellularity.

Prolonged parenteral feeding with standard nutrient solutions results in significant alteration in the structural, hormonal, and immunological composition of the intestinal tract. The purpose of the following study was to evaluate the effect of glutamine-supplemented parenteral nutrition on the immune cellularity of the gut. Twenty-one Fischer rats were randomized to three groups of seven animals each. Group I was fed rat chow and water ad lib, Group II was fed a standard solution of total parenteral nutrition (TPN) (D25/4.25% amino acids) via a central venous catheter, and Group III was fed the standard solution of TPN with 2% glutamine which was isonitrogenous and isocaloric to Group II. Animals were fed their respective diets for 1 week and bile was collected and assayed for secretory IgA (s-IgA) and IgM. The terminal ileum was stained and assayed for IgA+, IgM+, IgG+, CD4+, and CD8+ plasma cells and lymphocytes. Results indicate that the feeding of a standard parenteral diet results in a significant decrease in biliary s-IgA and IgA+ plasma cells in the gut lamina propria compared to chow-fed animals (S-IgA: chow, 858 +/- 23 micrograms/ml; TPN, 494 +/- 41 micrograms/ml; IgA cells: chow, 35.7 +/- 1.8; TPN, 8.6 +/- 0.9 cells/hpf). In addition a marked depletion of CD4+ and CD8+ lymphocytes was observed with standard solutions of parenteral nutrition compared to chow (CD4+: chow, 36.8 +/- 6.6; TPN, 14.9 +/- 6.0; CD8+: chow, 18.8 +/- 5.6; TPN, 5.7 +/- 2.7 cells/hpf). The addition of glutamine to the standard TPN solution maintained both B and T cell populations at levels similar to chow-fed animals.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of dexamethasone and endotoxin administration on biliary IgA and bacterial adherence.

Adherence of bacteria to the intestinal epithelial cell may be the crucial initiating event for invasion and translocation and is normally prevented by both immune (IgA) and nonimmune (mucus, peristalsis, desquamation) mucosal defense mechanisms. The purpose of the present study was to examine the effect of endotoxin administration on mucosal immunity and to define the role of glucocorticoids, commonly released during endotoxicosis, in this process. Thirty female Fisher rats were randomly assigned to three groups of 10 animals each. Group I (CONT), was fed rat chow and H2O ad lib., Group II (DEX) was administered 0.8 mg/kg subcutaneously of dexamethasone, and Group III (ETX) was given 1 mg/kg of endotoxin. Twenty-four hours later animals were sacrificed and mesenteric lymph nodes and vigorously washed stool-free ceca were collected and cultured. Bile was collected and assayed for IgA from 5 animals in each group. A significant decrease (P < 0.05) in secretory IgA was noted in animals treated with either dexamethasone or endotoxin (CONT = 332 +/- 42, DEX = 78 +/- 24, ETX = 68 +/- 16 micrograms/mg protein +/- SEM). No difference in S-IgA between animals in the dexamethasone-treated group and the endotoxin-treated group was noted (P = NS). A statistically significant increase (P < 0.001) in bacteria adherent to the cecal wall in both the dexamethasone-treated rats and the endotoxin-treated rats over that in = 7.5 +/- 0.8, CONT = 6.4 +/- 0.6 cfu/g(log10) +/- SD). Our results suggest that endotoxin or glucocorticoid administration results in significant bacterial adherence to the cecal mucosa and a decrease in IgA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Biliary secretory IgA levels in rats with protein-calorie malnutrition.

Malnutrition is a recognized cause of failure of host defense mechanisms. In the past 5 years, it has been demonstrated that the gut, long known to have significant morphologic changes with protein calorie malnutrition (PCM), is an immune organ affected by malnutrition. To assess the role of biliary immunoglobulin A (S-IgA), part of the barrier to bacterial invasion from the gastrointestinal tract, the following study was performed. Seventy-eight Fisher female inbred rats weighing 110-130 g were randomly separated into two groups. The control rats were fed standard rat chow. The experimental rats were fed a 2% agar protein depletion (PCM) diet (USP XV). The biliary tract of the rat was cannulated with Silastic tubing and bile flow and rat secretory immunoglobulin A (S-IgA) was sampled at intervals. S-IgA was measured by the Elisa method. Total bile protein was measured by micro-Kjeldahl. Bile was collected from the rats on day 0, 7, 14, 21, 29, 36, 42, and 49. During the study, the weight of rats fed the PCM diet decreased from 127.4 +/- 14.5 g at day 0 to 83 +/- 2.6 g on day 37. Control rats gained weight from 124.4 +/- 14.5 g at day 0 to 153.6 +/- 3.8 g at day 37. Total biliary protein at day 0 was 2.52 +/- .05 mg/ml and at day 36 was 2.51 +/- 11 mg/ml for PCM rats and 2.57 +/- 10 mg/ml for control rats. Normal rats and control rats both had an initial increase of S-IgA from 2.74 +/- 73 mg/ml on day 0 to 5.75 +/- 1.75 mg/ml on day 37. Both PCM and control rats demonstrated an increase in S-IgA levels despite significant loss of weight in the experimental group. Similarly, total biliary protein was not decreased in either group. The results suggest that gut immune system is preserved despite significant protein calorie malnutrition.     

Effect of different enteral nutrients on bacterial translocation in experimental obstructive jaundice

Obstructive jaundice leads to bacterial translocation (BT) by disruption of the gut barrier, intestinal microecology, and impaired host immune defence. The objective of the present study is to investigate the effects of different enteral nutrients on BT that is induced by obstructive jaundice in rats. Eighty male Wistar-Albino rats were randomly assigned into 4 groups. Group 1: 20 rats underwent laparotomy, common bile duct (CBD) was not actually ligated and transected, but sham ligation of CBD was performed. Groups 2-4: 60 rats underwent laparotomy, CBD ligation and transection. Group 1 and 2 rats were given rat chow, group 3 rats were fed a glutamine and arginine supplemented enteral diet, and group 4 rats were fed an arginine, m-RNA and omega-3 supplemented enteral diet, an immunonutrient. Rats in groups 3 and 4 had significantly less BT to mesenteric lymph nodes compared to rats in group 2 (p = 0.001). These findings suggest that oral administration of an arginine and glutamine supplemented diet and immunonutrition reduce BT in rats with obstructive jaundice.     

The effect of early feeding on postburn hypermetabolism

The effect of early enteral feeding upon postburn hypermetabolism was studied on the fourteenth postburn day using five groups of rats. Feeding methods and treatments for the groups were: I) rat chow ad libitum at 2 hours postburn (PB); II) fed early by gastrostomy at 2 hours PB; III) fed late by gastrostomy at 72 hours PB; IV) fed early by gastrostomy--shaved control; V) rat chow ad libitum--shaved control. Gastrostomy feedings delivered 175 kcal/kg.day. The rates of heat production and heat loss did not differ significantly between any of the burn groups, whether fed ad libitum, or early or late by way of gastrostomy. The burned rats fed ad libitum gained significantly more weight than the rats fed late by gastrostomy. Contrary to previous studies using a guinea pig model, method and timing of feeding had no demonstrable effect on the postburn increment in heat loss and the secondary increment in heat production following thermal injury in rats.     

Study on the effects of the hypocholesteremic agents, cholestyramine and compactin on the induction of renal tumors in rats by N-ethyl-N-hydroxyethyl nitrosamine]

Male Wistar rats were administered with 0.1% N-ethyl-N-hydroxyethyl nitrosamine (EHEN)-containing diet for 2 weeks, and were then Rept for further 23 weeks on basal diet. At 25 weeks, the rats were divided into three groups. Group I was fed on basal diet to 40 weeks. Group II was fed on 2% cholestyramine-containing diet to 40 weeks. Group III was fed on 0.02% compactin-containing diet to 40 weeks. At 40 weeks after the start of experiment, the rats were sacrificed and examined histologically for the incidence of renal cell tumors (RCT) and dysplastic foci (DF) of the kidney. The serum levels of total cholesterol at 40 weeks were 108.9 +/- 23.4, 78.8 +/- 12.5, 95.6 +/- 43.4 mg/dl in Groups I, II and III, respectively. The levels were significantly lower in Groups II and III (p less than 0.01, 0.05, respectively, Wilcoxon test) than Group I. The average numbers of DF were 4.5 +/- 4.1, 1.3 +/- 0.3, 2.3 +/- 2.0 per cm2 of kidney slices in Groups I, II and III, respectively. DF were significantly less in Group II than Group I (p less than 0.025, Wilcoxon test), and less in Group III than Group I (not statistically significant). There was no statistical difference between Groups II and III. RCT were observed in 9 of 34 kidneys (26%), 2 of 18 (11%), 1 of 20 (5%) in Groups, I, II and III, respectively. The ratios of kidneys with RCT were lower in Group II than Group I (not statistically significant), and lower in Group III than Group I (p less than 0.05, qui-square test). There was no statistical difference between Groups II and III. RCT were classified into gross and microscopic lesions. Four gross RCT were found in 4 rats of Group I; no gross RCT was in Groups II and III. There were 5 microscopic RCT in 5 rats, 3 in 2, 1 in 1 in Groups I, II and III, respectively. In Group I, serum levels of total cholesterol were compared between the following subgroups; the rats with RCT and/or with more than 10 DF per kidney, and the rats without RCT and with less than 10 DF per kidney. The mean level was 120.8 +/- 21.8 mg/dl in the former subgroup, which was significantly higher than that (94.1 +/- 19.6 mg/dl) in the latter subgroup (p less than 0.025, Wilcoxon test). The serum cholesterol was suggested to act as a promoter in the development of DF and RCT.     

The effect of glucocorticoid administration on bacterial translocation. Evidence for an acquired mucosal immunodeficient state.

Adherence of bacteria to intestinal epithelial cells may be the crucial initiating event for translocation and is normally prevented by both specific (secretory IgA) and nonspecific (mucus, bacterial antagonism, desquamation) mucosal defense mechanisms. The purpose of this study was to examine the effect of dexamethasone administration on mucosal immunity; specifically bacterial adherence and IgA. Twenty Fischer rats were randomly assigned to two groups of 10 animals each. Group I received 0.5 mL saline injection intraperitoneally (IP); and group II, 0.8 mg/150 g body weight dexamethasone IP per day for 2 consecutive days. The cecum mesenteric lymph nodes, and bile were aseptically collected, and bacterial adherence, bacterial translocation, and IgA concentration were determined. Results indicate that, compared with saline-treated animals, dexamethasone-treated animals had a fall in IgA (54 +/- 24 versus 232 +/- 41 micrograms/mg protein), an increase in bacterial adherence (8.2 +/- 0.5 versus 3.4 +/- 0.6 cfu (log10)/g cecum), and an increased incidence of bacterial translocation to the mesenteric lymph nodes (60% versus 0%). These data suggest that glucocorticoids may promote bacterial translocation by impairment of mucosal IgA synthesis.     

Tumor growth in experimental animals: nutritional manipulation and chemotherapeutic response in the rat.

The effects of nutritional manipulation on host body weight dynamics, tumor growth patterns and host-tumor responses to chemotherapy were studied in Sprague-Dawley rats with Walker-256 carcinosarcomas. Group I maintained throughout on a regular diet (RD) gained carcass weight steadily. Group II lost carcass weight while fed a protein-free diet (PFD) but rapidly gained weight after switching to RD on day 15. Mean tumor volume increased 105% in Group I from day 15 to 21, 218% in Group II and 77% in Group III (continued on PFD p less than 0.05). From day 21 to day 33 tumor growth patterns were similar in Groups I and II, while mean tumor volume eventually plateaued in Group III. In Study B, Group II animals were given Methotrexate (MTX-20 mg/kg) two days and six days after switching from PFD to RD. The mean change in tumor volume in the MTX-treated rats was 1.31 +/- 0.1 cm3 compared with 8.14 +/- 0.1 cm3 (p less than 0.001) in the saline-treated control rats. MTX did not significantly affect tumor growth patterns in Group III (PFD) rats. In Study A, protein-calorie malnutrition resulted in host carcass weight loss and tumor growth retardation while nutritional repletion restored host carcass weight and stimulated tumor growth. In Study B, MTX was maximally effective in tumor-bearing rats that were switched from PFD to RD demonstrating that nutritional manipulation can improve host nutritional status and increase tumor response to chemotherapy.     

The effects of an additive small amount of a low residual diet against total parenteral nutrition-induced gut mucosal barrier

BACKGROUND: Total parenteral nutrition (TPN) negatively influences the gut mucosal barrier. It has been suggested that enteral nutrition is effective against the harmful influence. METHODS: Forty-eight male Donryu rats underwent placement of a central venous catheter and tube gastrostomy. They were divided into six groups, receiving isocaloric nutrients in various proportions of PN and a low residual diet (LRD) for 7 days. RESULTS: Intestinal permeability, villous height and crypt depth, and number of secretory IgA-positive cells in the villus were measured.Intestinal permeability was significantly reduced in rats receiving an LRD corresponding to more than 15% of total caloric intake. Gut morphological structure was maintained in rats receiving an LRD corresponding to more than 10%. A higher number of IgA-positive cells was observed in rats receiving an LRD corresponding to more than 15%. CONCLUSIONS: A small amount of LRD could prevent decreases in gut mucosal integrity. There was a stepwise defense mechanism in the gut mucosal barrier.     

Loss of upper respiratory tract immunity with parenteral feeding.

OBJECTIVE: The authors examine the effect of route and type of nutrition on an established upper respiratory tract immunity and investigate potential mechanisms for increased pneumonia rates in critically injured patients fed parenterally. SUMMARY BACKGROUND DATA: The primary immunologic defense against many mucosal infections is IgA. Prior work shows that mice fed total parenteral nutrition (TPN) solutions either intravenously or intragastrically had small intestinal gut-associated lymphoid tissue (GALT) atrophy along with decreased intestinal IgA compared with animals fed complex enteral diets. The small intestine is postulated to be the origin of most mucosal immunity, both intraintestinal and extraintestinal. The impact of diets affecting GALT, small intestine IgA, and upper respiratory tract immunity is studied. METHODS: Male Institute of Cancer Research mice underwent intranasal inoculation with a mouse-specific influenza virus to establish immunity. Three weeks later, the mice were randomized to chow, intragastric Nutren (Clintec, Chicago, IL), intravenous TPN, or intragastric TPN. After 5 days of feeding, mice were challenged with intranasal virus and killed at 40 hours to determine viral shedding from the upper respiratory tract. RESULTS: Despite similar body weights, there was significant atrophy in the Peyer's patch cells from animals fed the TPN solution intravenously or intragastrically. There was no viral shedding in any animal fed via the gastrointestinal tract, whereas 5 of 10 animals fed intravenous TPN had continued viral shedding. CONCLUSIONS: The IgA-dependent upper respiratory tract immunity was preserved with enteral feeding but not with intravenous feeding. Upper respiratory tract immunity is not dependent on intestinal GALT mass but is influenced by route of nutrition. The underlying mechanisms may explain the higher pneumonia rate in critically injured patients fed parenterally.     

The effects of diet on the residual small intestine following massive resection

The midportions of rat small intestines were resected by 90 per cent, and the residual intestines studied for the effects of diet on mucosal morphology, nutrition and gastrointestinal hormones. Groups of rats were fed chow, an elemental diet (ED), or an ED + dietary fiber (EDF) for 1 or 3 weeks. Nonresected rats which were fed chow or ED for 3 weeks were used as controls. Nutritional parameters, such as concentrations of serum total protein, albumin and transferrin were favorable but gain in body weight was not. The parameters indicated that resected rats fed EDF fared better than resected rats fed ED. Mucosal villous height in the residual jejunum, similar in all the resected groups after 1 week, was significantly increased in the resected rats fed chow or EDF after 3 weeks, but did not differ between 1 and 3 weeks in the resected rats fed ED. Changes in the number of villous epithelial cells and villous width were also examined. The level of plasma enteroglucagon was high in the rats fed chow or EDF after both 1 and 3 weeks, and was positively correlated with the increases in villous height. Levels of serum gastrin were not affected by dietary change. Luminal nutrients were significantly associated with the adaptive changes in the mucosa of the residual intestine, and mucosal morphology was also considerably influenced by dietary change.     

The effects of diet on the residual small intestine following massive resection

The midportions of rat small intestines were resected by 90 per cent, and the residual intestines studied for the effects of diet on mucosal morphology, nutrition and gastrointestinal hormones. Groups of rats were fed chow, an elemental diet (ED), or an ED+dietary fiber (EDF) for 1 or 3 weeks. Nonresected rats which were fed chow or ED for 3 weeks were used as controls. Nutritional parameters, such as concentrations of serum total protein, albumin and transferrin were favorable but gain in body weight was not. The parameters indicated that resected rats fed EDF fared better than resected rats fed ED. Mucosal villous height in the residual jejunum, similar in all the resected groups after 1 week, was significantly increased in the resected rats fed chow or EDF after 3 weeks, but did not differ between 1 and 3 weeks in the resected rats fed ED. Changes in the number of villous epithelial cells and villous width were also examined. The level of plasma enteroglucagon was high in the rats fed chow or EDF after both 1 and 3 weeks, and was positively correlated with the increases in villous height. Levels of serum gastrin were not affected by dietary change. Luminal nutrients were significantly associated with the adaptive changes in the mucosa of the residual intestine, and mucosal morphology was also considerably influenced by dietary change.     

Effects of enteral and parenteral feeding of malnourished rats on body composition

Many studies have reported similar weight gains and nitrogen balance in groups of well-nourished animals fed either orally or intravenously, but none have investigated the effects on malnourished animals. After protein depleting for 14 days, rats were refed with a D25-4.25% amino acid solution orally ad lib, by gastrostomy, or intravenously. IV animals gained more weight with greater body fat formation than either enteral group but had lower intestinal mass and nitrogen. Route of administration influenced substrate utilization in malnourished animals fed identical diets. We conclude that weight gain cannot be used as a comparative indicator of nitrogen retention between malnourished animals fed enterally and those fed intravenously.     

Effect of Probiotic Supplementation on Bacterial Translocation in Thermal Injury

Purpose To examine the effects of probiotic supplementation and enteral solutions containing glutamine and arginine on bacterial translocation (BT) and intestinal villous atrophy in thermal injury.Methods Forty male Sprague-Dawley rats weighing 200–250 g were divided into four groups of ten. Group 1 served as control group without thermal injury and was fed standard chow. Thermal injury was inflicted as a 30% scald burn in the other three groups. Group 2 was fed standard chow and group 3 was fed standard chow supplemented with a probiotic (Acidophilus plus) containing Bifidobacterium bifidum, Lactobacillus acidophilus, and Lactobacillus bulgaricus (2 × 10⁹ CFU/day) via an orogastric tube. Group 4 was fed only an enteral diet (Stresson multifiber) containing glutamine, arginine, and medium chain triglyceride, at 1 g/kg per day amino acid and 230 kcal/kg, for 7 days before thermal injury. All the animals were killed 24 h after thermal injury, and ileal segments were resected and examined histopathologically. To evaluate BT, samples from blood, mesenteric lymph nodes, and cecal content were cultured under aerobic and anaerobic conditions. Terminal ileum specimens were histologically examined to evaluate mucosal integrity.Results Significantly less BT was seen in groups 3 and 4 than in group 2 (P < 0.001). No significant difference was found between groups 3 and 4. Histological evaluation showed significant reduction in villous atrophy in groups 3 and 4.Conclusion Probiotic supplementation seems to reduce bacterial translocation and decrease intestinal mucosal atrophy in rats with thermal injury, as do enteral solutions with arginine and glutamine.     

The effects of tramadol and fentanyl on gastrointestinal motility in septic rats

In this study, we investigated the effects of tramadol and fentanyl on gastrointestinal transit (GIT) during acute systemic inflammation in an experimental model of cecal ligation and perforation (CLP). One-hundred-twenty male Swiss-Albino rats were divided randomly into 6 groups: Group I = sham-operated + saline; Group II = sham-operated + fentanyl; Group III = sham-operated + tramadol; Group IV = CLP + saline; Group V = CLP + fentanyl; Group VI = CLP + tramadol. Suspension of charcoal was administered as an intragastric meal to measure the GIT. GIT% (mean +/- sd) were 46.1% +/- 9.8%, 43.2% +/- 9.8%, 45.9% +/- 10.2%, 33.2% +/- 9.2%, 24.9% +/- 4.1%, and 31.8% +/- 8.4% in Groups I, II, III, IV, V, and VI, respectively. GIT% was significantly less in Group V than in Groups I, II, III, and IV (P < 0.05). The Group VI mean value was significantly lower than those of Groups I, II, and III (P < 0.05) but not different from those of Groups IV and V (P > 0.05). The antitransit effect of fentanyl was shown to have increased in the experimental sepsis model, but no decrease in GIT was obtained with tramadol. This was thought to be the result of an associated endogenic opioid system activation and receptor upregulation in sepsis.     

Changes in lower esophageal sphincter pressure (LES) after Stamm gastrostomy

Previous clinical and experimental reports have implicated placement of a Stamm gastrostomy (SG) as a cause of gastroesophageal reflux (GER) in children. This study evaluates this problem by measuring alterations in the lower esophageal sphincter pressure (LES) after SG with and without maintenance of the esophagogastric angle of Hiss. In 20 cats (2.8-3.2 kg) general anesthesia was induced using 20 mg/kg ketamine im. Esophageal manometrics were measured using a continuous perfusion catheter and recording system, evaluating three measurements for each animal. Eight cats (Group I) underwent SG placement in the anterior stomach wall two-thirds of the way down from the fundus. This was tacked to the anterior abdominal wall 3 cm lateral to the midline at the appropriate level. Six cats (Group II) had standard SG tube placement and in addition, two interrupted sutures were placed between the fundus and the esophagus maintaining the gastroesophageal angle of Hiss. Six cats (Group III) had sham laparotomy. After awakening, the animals were fed cat chow and water ad libitum. At 7 and 14 days, the animals were reanesthetized with ketamine and manometrics were repeated. Preoperative LES pressure measured 11.3 +/- 4.7 Torr. LES pressure in Group I decreased to 6.61 +/- 1.6 Torr at 7 days (P less than 0.01) and 4.8 +/- 1.6 Torr at 14 days postoperatively (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Total parenteral nutrition solution increases bile lithogenicity in rat

The effect of parenteral and enteral nutrition on bile composition was studied in rats. Bile flow, bile fractional composition, bile component output, and lithogenic index were determined in five groups of rats: (A) preoperative control, (B) freely feeding rats infused with normal saline, (C) parenterally fed rats with balanced total parenteral nutrition (TPN) formula (4% amino acids, 22.5% dextrose, 1% Intralipid), (D) constantly intragastrically fed rats with the same TPN formula, and (E) rats fed intragastrically with the same TPN formula but only during 10 hr at night. After 12 days of infusion, bile and blood were collected. There were no differences between the two parenterally and enterally continuously fed groups. Both Groups C and D showed decreased bile flow, decreased bile components output, increased molar percentage concentrations of biliary cholesterol (2.2 ± 0.3 and 1.8 ± 0.1 in Groups C and D, respectively, control, 1.4 ± 0.1), and increased lithogenic index. The cyclically enterally fed group had a normal lithogenic index in the postabsorptive period. Plasma cholesterol and triglycerides were higher in the formula fed groups. There were no changes in plasma liver function tests between the groups. We conclude, therefore, that continuous administration of TPN solution induces an increase in lithogenicity of the bile, independent of the route of administration.     

Immunomodulation of intradermal mammary carcinoma using staphage lysate in a rat model

Staphage lysate (SPL), a preparation of Staphylococcus aureus obtained by bacteriophage lysis, is an interferon-inducer and stimulator of T and B lymphocytes. Does SPL, as an immunopotentiator, have an effect on the growth and metastases of an intradermal mammary carcinoma? To answer this question, a study using SPL in female Fischer rats injected with 7 x 10(6) viable 13762 mammary tumor cells on the midback were used. Four groups were created with 10 animals in each group. Group I was the control group. They received no treatment. Group II received 0.3 ml of medium in which SPL was carried on alternate days. Group III received 0.3 ml SPL on alternate days. Group IV were sensitized with dead staphylococcal organisms prior to SPL treatment as in Group III. Tumor diameters were recorded on days 10, 13, 17, and 21, and autopsies were performed to determine the extent of metastases. Histologic examination and serum antibody measurements were performed. The mean tumor diameters on day 21 were: Group I: 4.1 +/- 0.2 cm; Group II: 3.80 +/- 0.19 cm; Group III: 3.04 +/- 0.13 cm; and Group IV: 2.97 +/- 0.14 cm. Rats receiving SPL treatment in Groups III and IV had significantly smaller tumors (P less than .001). The incidence of axillary lymph node involvement was: Group I: 100%; Group II: 87.5%; Group III: 62.5%; and Group IV: 40%. Lung metastases were seen in all groups. Groups I and II had 100% incidence of grossly visible nodules, whereas Groups III and IV had 75% and 70% involvement. Gross findings were confirmed by microscopic examination.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of acute and chronic glucocorticoid excess on leucine kinetics and protein turnover in vivo

The present studies were undertaken to assess the effects of excess cortisol on amino acid exchange in the conscious dog. Three groups of 18-hr fasted dogs with catheters chronically implanted in the femoral artery were studied: Group I (n = 6) received saline; Groups II and III (n = 5, each) received ACTH intravenously (1 U/min) for 7 hr; in addition, Group III received ACTH, 500 U/day intramuscularly for 4 days. Leucine rates of appearance (Ra) and clearance were measured using a constant infusion of L-4,5-[3H]leucine. ACTH treatment resulted in a 9-fold increase in plasma cortisol in Groups II and III (from 2 +/- 1 to 18 +/- 1 and 17 +/- 2 micrograms/dl, in II and III, respectively P less than 0.001), with no effect on either plasma insulin or glucagon. Plasma leucine (mmole/liter) increased from 118 +/- 6 (I) to 153 +/- 6 (II, P less than 0.005) to 275 +/- 35 (III, P less than 0.001). Leucine Ra (micromoles/kilogram/minute) did not change in II, but rose by 39% (P less than 0.005) in III. Clearance (milliliters/kilogram/minute) dropped from 25 +/- 2 (I) to 18 +/- 2 (II, P less than 0.005), to 15 +/- 2 (III, P less than 0.001). It is concluded that acute elevations of cortisol increased plasma leucine only by inhibiting its rate of disposal, whereas chronic elevations had a dual effect; they inhibited leucine disposal and increased its entry into the plasma compartment, suggesting an inhibition of protein synthesis and stimulation of protein breakdown.     

Impaired wound healing in streptozotocin diabetes. Prevention by supplemental vitamin A.

Goodson and Hunt showed that wound healing is impaired in streptozotocin (Sz) diabetic rats; we speculated that this impairment results from defective early inflammatory responses to wounding. Because we had shown that supplemental vitamin A stimulates the early inflammatory response to wounding in nondiabetic rats, we studied the effect of supplemental vitamin A on wound healing in rats with Sz-induced diabetes. Male Sprague-Dawley rats were fed a commercial rat chow containing twice the amount of vitamin A recommended by the NRC for healthy rats. The rats ate and drank (tap water) ad libitum. Two-thirds of the rats were injected (intravenously) with Sz 60 mg/kg body weight. All of these rats became diabetic (hyperglycemia greater than 350 mg/dl, hyperphagic, polydipsic, polyuric, glycosuric greater than 2%). Seven days later, half of the Sz-injected rats were continued on the chow (Group 2) while the other half (Group 3) were switched to the chow supplemented with 150,000 units of vitamin A/kg chow. The next day, all were wounded (7 cm skin incisions and s.c. polyvinyl alcohol sponge implants). Similarly wounded saline injected nondiabetic rats ingesting the unsupplemented chow served as controls (Group 1). The wounds of Group 2 rats healed poorly compared to Group 1 (breaking strength of skin incisions, 308 +/- 19 g vs 584 +/- 23 g, p less than 0.001; hydroxyproline of the sponge reparative tissue, 0.87 mg vs 2.40 mg/100 mg sponge p less than 0.001). Supplemental vitamin A (Group 3) did not affect the hyperglycemia, hyperphagia, polydipsia or glycosuria, but increased the breaking strengths of the incisions of the diabetic rats (468 +/- 40 g, p less than 0.001), and the sponge hydroxyproline (2.38 mg/100 mg sponge, p less than 0.001). In another experiment, in which the wounding and start of supplemental vitamin A were delayed until 28 days after streptozotocin administration (50 mg/kg body weight), similar results were obtained. Streptozotocin diabetes also caused a decrease in the cross-linking of reparative collagen as judged by the ratio of breaking strengths of skin incisions before and after formalin fixation. Supplemental vitamin A did not influence this defect. Sz also caused peripheral lymphocytopenia, adrenal hypertrophy and thymic involution which responded to the supplemental vitamin A. Based upon experimental data and theoretical considerations we conclude Sz diabetes causes two defects in wound healing: a) quantitatively (reduction in reparative collagen accumulation) and b) qualitative reduction in the degree of cross-linking of reparative wound collagen. The action of supplemental vitamin A in correcting the impaired wound healing, adrenal enlargement, thymic involution and lymphocytopenia of Sz-diabetic rats is independent of an effect on their disturbed carbohydrate metabolism.