Eli Seifter

Intrajejunal administration of an elemental diet at neutral pH avoids pancreatic stimulation: Studies in dog and man*

Summary o 1. An elemental diet (Vivonex 100) stimulates pancreatic secretion when instilled into the stomach of dogs. 2. When Vivonex 100 at near neutral pH is perfused through a Thirty-Vella loop, pancreatic secretion is not stimulated significantly. 3. A mixture of essential and nonessential amino acids and a mixture of phenylalanine, leucine, and tryptophan (which are the strongest stimulators of pancreatic secretion in the dog), when perfused through a Thirty-Vella loop at neutral pH and in the concentration present in Vivonex 100, cause minimal stimulation of pancreatic secretion. 4. When the same amino acid mixtures acidified to a pH of 3.5 are perfused through a Thirty-Vella loop, strong pancreatic stimulation occurs. 5. Perfusion of hypertonic glucose solution (22.6 per cent) in a Thirty-Vella loop inhibits protein and bicarbonate output from the pancreas. 6. When 22.6 per cent glucose solution is introduced into the stomach, pancreatic secretion is stimulated. 7. When amino acid mixtures in the concentration present in Vivonex 100 are instilled into the stomach, strong stimulation of pancreatic secretion results. 8. The foregoing information emphasizes the importance of bypassing the stomach and minimizing acid secretion to keep the pancreas at rest. 9. Measurements of net absorption from the Thirty-Vella loop suggest that sodium chloride enhances glucose absorption. 10. Hypertonic glucose appears to inhibit amino acid absorption from a jejunal loop. 11. Separation of the amino acids and the glucose for intrajejunal feedings may improve the absorption of amino acids. This may be of particular importance in feeding elemental diets to patients with the short bowel syndrome.

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.

Immunostimulatory effects of arginine in normal and injured rats

Abstract We have shown in the present experiments that femoral fractures, particularly bilateral fractures, lead to impaired thymic function in rats as assessed by thymic size, numbers of thymic lymphocytes, and ability of thymic lymphocytes to respond to mitogenic stimulation. The in vitro depression in T-cell function appears to be a primary one since it is also observed in serum-free microculture systems. We have also shown that 1% dietary arginine supplementation largely prevents or minimizes the thymolysis and T-cell dysfunction that appear post-trauma. In addition, dietary supplemental arginine significantly increases thymic weight, cellularity, and T-cell blastogenic responsiveness in uninjured rats. This suggests that arginine may be a safe nutritional means of correcting immune depression in injured and/or stressed patients.

Supplemental vitamin A prevents the acute radiation-induced defect in wound healing.

Acute radiation injury leads to thymic involution, adrenal enlargement, leukopenia, thrombocytopenia, gastrointestinal ulceration, and impaired wound healing. The authors hypothesized that supplemental vitamin A would mitigate these adverse effects in rats exposed to acute whole-body radiation. This hypothesis was based on previous experiments in their laboratory that showed that supplemental vitamin A is thy-motropic for normal rodents and lessens the thymic involution, lymphopenia, and adrenal enlargement that follows stress, trauma, and neoplasia, largely obviates the impaired wound healing induced by the radlomimetic drugs streptozotocin and cyclophosphamide, lessens the systemic response (thymic involution, adrenal enlargement, leukopenia, lymphocytopenia) to local radiation, and shifts the median lethal dose (LD50/30) following whole-body radiation to the right. To test their hypothesis, dorsal skin incisions and subcutaneous implantation of polyvinyl alcohol sponges were performed in anesthetized Sprague-Dawley rats at varying times following sham radiation or varying doses of whole-body radiation (175–850 rad). In each experiment, the control diet [which contains about 18,000 IU vit. A/kg chow (3 X the NRC RDA for normal rats)] was supplemented with 150,000 IU vit. A/kg diet beginning at, before, or after sham radiation and wounding or radiation and wounding. The supplemental vitamin A prevented the impaired wound healing and lessened the weight loss, leukopenia, thrombocytopenia, thymic involution, adrenal enlargement, decrease in splenic weight, and gastric ulceration of the radiated (750–850 rad) wounded rats. This was true whether the supplemental vitamin A was begun before (2 or 4 days) or after (1–2 hours to 4 days) radiation and wounding; the supplemental vitamin A was more effective when started before or up to 2 days after radiation and wounding. The authors believe that prevention of the impaired wound healing following radiation by supplemental vitamin A is due to its 1) enhancing the early inflammatory reaction to wounding, including increasing the number of monocytes and macrophages at the wound site; 2) possible

Thymic stimulatory actions of arginine.

Various arginine HCl supplements (0.5-3%), half added to a basal commercial rodent chow (1.8% arginine) and half to the drinking water, were given to 8- to 9-week-old male CBA/J mice for 6 days. Control animals were fed the basal chow and drank tap water. All mice ate and drank ad libitum. Weight gain and food intake were similar in all groups. All arginine supplements increased significantly: thymic weight (average 22%), thymic lymphocyte content (average 45%), and the in vitro reactivity of thymic lymphocytes judged by the incorporation of 3H-leucine into the TCA-precipitable protein fraction in response to stimulation by phytohemagglutinin and concanavalin A. All these thymic effects resulted from the 0.5% arginine hydrochloride supplement; further increases in arginine supplementation did not increase these effects. These data suggest that supplemental arginine may improve host defence mechanisms and thereby may play an important role in the care of severely injured or ill patients, since it is well established that their defense mechanisms are reduced.

Influence of vitamin A on wound healing in rats with femoral fracture.

Groups of healthy wounded rats with and without comminuted femoral fractures, and maintained on nutritionally complete commercial rat chow with and without supplemental vitamin A, were studied. The test wounds were standard dorsal skin incisions and s.c. polyvinyl alcohol sponge implants. In some experiments the rats were pair-fed; the rats with femoral fracture not receiving supplemental vitamin A were the lead group for determining food allowanced. In other experiments, the rats were allowed food ad libitum. We found that wound healing of rats with femoral fracture was increased when supplemental vitamin A was given, but the supplemental vitamin A did not completely obviate the adverse effects of fracture. The ratio of the breaking strengths of the skin incisions after formalin fixation to the breaking strengths of the incisions in the fresh state was higher in the unsupplemented rats, supporting the results of our earlier experiments that vitamin A increases the rate of collagen cross-linking.

Effect of supplemental vitamin A on colon anastomotic healing in rats given preoperative irradiation

We studied the effect of dietary supplementation with vitamin A on the healing of colon anastomoses in irradiated bowel. Rats were divided into two groups. Those in the first group were fed a standard chow diet and those in the second group were fed the same diet supplemented with 150 IU vitamin A/g of chow. The rats were maintained on their respective diets throughout the experiment. After 7 days, half the rats in each group underwent abdominal irradiation (200 rads). Seven days later, all of the rats underwent distal colon division and anastomosis under pentobarbital anesthesia. All rats were killed 7 days postoperatively, the colons excised, and bursting strength and hydroxyproline determinations performed on both the anastomotic segment and a normal proximal segment of adjacent colon. There was a significant decrease in the bursting strength at the colon anastomosis (p less than 0.02) and in the collagen content (p less than 0.02) after preoperative irradiation. This effect was mitigated by dietary vitamin A supplementation.

Time-dependent effect of glutaraldehyde on the tendency to calcify of both autografts and xenografts**

To determine mechanisms responsible for the reduced calcification in short-term glutaraldehyde (Glu)-treated autologous pericardial bioprostheses, we studied the time effect of Glu on subsequent calcification and differences in calcification of autograft and xenograft implants in a rat subcutaneous implantation model. In experiment 1, four groups of bovine pericardial pieces (1 cm2) were prepared: (A) fresh bovine pericardium without Glu, (B) with 15-minute Glu, (C) with 60-minute Glu, and (D) with 120-minute Glu. Seven young male Sprague-Dawley rats were used; each received four bovine pericardial pieces from group A, B, C, or D for subcutaneous implantation. Calcium content of the implants (microgram/mg dry weight) 45 days later was 4.8 +/- 2.9, 29.8 +/- 13.6, 106.3 +/- 13.7, and 176.3 +/- 85.5 in groups A, B, C, and D, respectively (p < 0.05 between any two groups). Experiment 2 used 8 young male Sprague-Dawley rats from different mothers. Each received five subcutaneous skin implants. The five skin implants were prepared as follows: (1) fresh self skin, (2) self skin with 30-minute Glu, (3) self skin with 48-hour Glu, (4) fresh skin of others, and (5) skin of others with 48-hour Glu. After 45 days of implantation, the calcium content of the implants was 1.4 +/- 1.1, 57.9 +/- 35.4, 142.7 +/- 61.4, 1.5 +/- 1.1, and 94.9 +/- 24.1 micrograms/mg dry weight in groups 1, 2, 3, 4, and 5, respectively (p < 0.05 for 1 versus 2, 3, or 5; 2 versus 3, 4, or 5; 3 versus 4; and 4 versus 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Inhibitory action of vitamin A on a murine sarcoma.

Abstract High doses of vitamin A decrease the incidence and severity of tumor development in mice inoculated with a murine sarcoma virus.

Role of vitamin A and β carotene in radiation protection: relation to antioxidant properties

ELI SEIFTER * t , JOZEF MENDECKI + , SEYMOUR HOLTZMAN §, JACOB D. KANOFSKY¶, ESTHER FRIEDENTHAL + , LAWRENCE DAVIS ~: and JEFFREY WEINZWEIG* Denartments of *Surgery, t Biochemistry, and ¶Psychiatry, Albert Einstein College of Medicine, New York, U.S.A. (c Department of Radiation Oncology, Montefiore Medical Center, New York, U.S.A. §Department of Physiology, New York College of Osteopathic Medicine, Old Westbury, New York, U.S.A.