Dehydroepiandrosterone: an inexpensive steroid hormone that decreases the mortality due to sepsis following trauma-induced hemorrhage.

Angele MK, Catania RA, Ayala A, Cioffi WG, Bland KI, Chaudry IH. Center for Surgical Research, Department of Surgery, Brown University School of Medicine, Rhode Island Hospital, Providence 02903, USA.

Arch Surg 1998 Dec;133(12):1281-8

BACKGROUND: Recent studies suggest that male sex steroids play a role in producing immunodepression following trauma-hemorrhage. This notion is supported by studies showing that castration of male mice before trauma-hemorrhage or the administration of the androgen receptor blocker flutamide following trauma-hemorrhage in noncastrated animals prevents immunodepression and improves the survival rate of animals subjected to subsequent sepsis. However, it remains unknown whether the most abundant steroid hormone, dehydroepiandrosterone (DHEA), protects or depresses immune functions following trauma-hemorrhage. In this regard, DHEA has been reported to have estrogenic and androgenic properties, depending on the hormonal milieu.

OBJECTIVE: To determine whether administration of DHEA after trauma-hemorrhage has any salutary or deleterious effects on immune responses, and whether it improves the survival of animals subjected to subsequent sepsis. DESIGN: Male C3H/HeN mice underwent laparotomy (ie, trauma-induced) and hemorrhagic shock (blood pressure, 35+/-5 mm Hg for 90 minutes) followed by fluid resuscitation, or sham operation. The animals then received 100 mg of DHEA (4 mg/kg) or propylene glycol (hereafter referred to as vehicle). At 24 hours after trauma-hemorrhage and resuscitation, the animals were killed and blood, spleens, and peritoneal macrophages were harvested. Splenocyte proliferation and interleukin (IL) 2 release and splenic and peritoneal macrophage IL-1 and IL-6 release were determined. In a separate set of experiments, sepsis was induced by cecal ligation and puncture at 48 hours after trauma-hemorrhage and resuscitation. For those studies, the animals received vehicle, a single 100-microg dose of DHEA, or 100 microg/d DHEA for 3 days following hemorrhage and resuscitation. Survival was monitored for 10 days after the induction of sepsis.

RESULTS: Administration of DHEA restored the depressed splenocyte and macrophage functions at 24 hours after trauma-hemorrhage. Moreover, daily administration of DHEA for 3 days significantly increased the survival of animals subjected to subsequent sepsis (P=.01).

CONCLUSION: The finding that DHEA markedly improves the depressed immune functions and survival of animals subjected to subsequent sepsis suggests that short-term treatment with DHEA after trauma-hemorrhage is a safe and novel approach for preventing immunodepression and for decreasing the mortality rate due to subsequent sepsis.

L-arginine restores the depressed cardiac output and regional perfusion after trauma-hemorrhage.

Angele MK, Smail N, Wang P, Cioffi WG, Bland KI, Chaudry IH. Department of Surgery, Brown University School of Medicine, Providence, RI, USA.

Surgery 1998 Aug;124(2):394-401; discussion 401-2

BACKGROUND: Previous studies indicate that vascular endothelial cell dysfunction occursearly after trauma-hemorrhage and may contribute to further alteration in tissue perfusion and cellular function. Because endothelial cell dysfunction is characterized by the reduced release of nitric oxide (NO) by endothelial constitutive NO synthase (cNOS), we tested the hypothesis that administration of L-arginine (ie, the substrate for cNOS) after trauma and hemorrhage should have beneficial effects on depressed cardiac output and organ blood flow under those conditions.

METHODS: Rats underwent a laparotomy (ie, trauma induced) and were bled to and maintained at a mean arterial pressure of 40 mm Hg until 40% of maximal shed blood volume was returned in the form of Ringer's lactate solution. The animals were than resuscitated with 4 times the volume of the shed blood in the form of Ringer's lactate solution over 1 hour. L-arginine (300 mg/kg body wt) or saline solution was infused intravenously during the first 15 minutes of resuscitation. Cardiac output and organ blood flow were determined by 85Sr-microspheres at 1.5 and 4 hours after the completion of resuscitation. Plasma interleukin-6 (IL-6) was determined by bioassay at 4 hours after resuscitation.

RESULTS: Cardiac output and blood flow in the kidneys, small intestine, and lungs decreased significantly after hemorrhage and resuscitation. In addition, portal blood flow and total hepatic perfusion were also significantly reduced. Administration of L-arginine at the onset of fluid resuscitation, however, restored the depressed cardiac output and tissue perfusion. Moreover, the up-regulated plasma levels of IL-6 were also attenuated by L-arginine administration.

CONCLUSIONS: Because the adjuvant use of L-arginine restored the depressed cardiac output and organ blood flow and decreased plasma levels of IL-6, administration of this essential amino acid should be considered as a useful adjunct to fluid resuscitation for improving cardiovascular function in trauma victims.

A prospective, randomized, double-blind, controlled clinical trial of enteral immunonutrition in the critically ill. Guy's Hospital Intensive Care Group.

Atkinson S, Sieffert E, Bihari D. Department of Intensive Care, Guy's Hospital, London, UK.

Crit Care Med. 1998 Jul;26(7):1164-72.

OBJECTIVE: To assess the effects of enteral immunonutrition (IMN) on hospital mortality and length of stay in a heterogeneous group of critically ill patients.

DESIGN: Prospective, randomized, double-blind, controlled clinical trial with an a priori subgroup analysis according to the volume of feed delivered in the first 72 hrs of intensive care unit (ICU) admission.

SETTING: A 13-bed adult general ICU in a London teaching hospital.

PATIENTS: A total of 398 patients were enrolled and data from 390 patients (IMN = 193, control = 197) were used for an intention-to-treat analysis. There were 369 patients (IMN = 184, control = 185) who actually received some enteral nutrition, of whom 101 patients (IMN = 50, control = 51) received >2.5 L within 72 hrs of ICU admission. This latter group was defined as the successful "early enteral nutrition" group.

INTERVENTIONS: Within 48 hrs of ICU admission, patients were randomized to receive either the IMN Impact (Novartis Nutrition), an enteral feed supplemented with arginine, purine nucleotides and omega-3 fatty acids, or an isocaloric, isonitrogenous control enteral feed.

MEASUREMENTS AND RESULTS: There was no significant difference in hospital mortality rate between the two groups on an intention-to-treat analysis (Impact group 48%, control group 44%) nor in any other predefined subgroup analysis. However, patients randomized to receive the IMN had higher Acute Physiology and Chronic Health Evaluation II scores (20.1 +/- 7.1 vs. 18.7 +/- 7.1 [p = .07] intention-to-treat [n = 390]; 20.1 +/- 7.2 vs. 18.5 +/- 7.1 [p = .04] received feed [n = 369]). Of the 101 patients achieving early enteral nutrition, those patients fed with the IMN had a significant reduction in their requirement for mechanical ventilation compared with controls (median duration of ventilation 6.0 and 10.5 days, respectively, p = .007) with an associated reduction in the length of hospital stay (medians 15.5 and 20 days, respectively, p = .03).

CONCLUSION: While the administration of enteral IMN to a general, critically ill population did not affect mortality, those patients in whom it was possible to achieve early enteral nutrition with Impact had a significant reduction in the morbidity of their critical illness.

Influence of large intakes of trace elements on recovery after major burns

Berger M.M.; Cavadini C.; Chiolero R.; Guinchard S.; Krupp S.; Dirren H.; Shenkin A. CHUV,CH-1011 Lausanne Switzerland

Nutrition (United States) 1994, 10/4 (327-334+352)

Because Cu, Se, and Zn are involved in immune and antioxidative defense mechanisms and tissue repair, deficiencies might aggravate complications classically observed with burns. After measuring massive cutaneous trace element losses in 10 burn patients, our aim in this study was to determine whether large intravenous intakes of Cu, Zn, and Sc can modify serum trace element levels and recovery after major burns. Ten patients, aged 34 +/- 6 yr (mean +/- SD), admitted to the burns center of a Swiss university hospital with thermal burns on 41 +/- 9% of their body surface were studied prospectively, with trace element balance studies from day 1 (D1) to D7 postinjury. Urine and blood samples were also collected on D10, D15, D20, and D25. The patients were divided into two groups of five and received either standard (group 1, control) or greatly increased (group 2, treatment: 4.5 mg Cu, 190 mug Se, and 40 mg Zn/day) trace element intakes. Energy and protein intake and wound treatment were similar in both groups. The treatment group was characterized by improved Cu, Se, and Zn status (increase in serum levels and various protein indicators), a much larger leukocyte increase between D4 and D14 (mainly neutrophils), and shorter hospital stay (45 days) compared with the untreated group (57 days). Grafting requirements were more extensive in group 1. Although severity of injury and wound treatment were similar in the groups, the duration of hospitalization was lower in the treated group. Further studies are required to determine whether this is related to trace element supplementation.

Ascorbate treatment prevents accumulation of phagosomes in RPE in light damage

Blanks J.C.; Pickford M.S.; Organisciak D.T. Doheny Eye Institute, 1355 San Pablo Street, Los Angeles, CA 90033 USA

Invest. Ophthalmol. Visual Sci. (USA), 1992, 33/10 (2814-2821)

In dark-reared albino rats, exposure to 2 or 3 hr of intense light interrupted by 2 hr dark periods resulted in extensive degeneration of photoreceptor cells and degeneration of the retinal pigment epithelium (RPE). Ascorbate (ie, Vitamin-C) administration prior to light exposure protected photoreceptors and the RPE from light damage. In the present study, ascorbate-treated and untreated rats were exposed to various cycles of intermittent light. Immediately after this light exposure, phagosome frequency in the RPE was morphologically evaluated in comparable 50 microm sections. In untreated rats, exposure to 2 or 3 hr of intermittent light resulted in a five- to sixfold increase in phagosome density compared to unexposed controls. In contrast, no increase in phagosome density was observed in ascorbate-treated rats. In these animals, under all lighting regimens, phagosome levels remained essentially identical to those in rats not exposed to light. After a single nondamaging light exposure, phagosome density remained at the level of dark controls in ascorbate-treated and untreated rats. These results indicate that phagosome frequency may serve as an index for light damage and that the protective effect of ascorbate may be linked to its capacity to prevent rod outer segment shedding and phagocytosis under intense light conditions. Behavioral effects of chronic melatonin and pregnenolone injections in a myelin mutant rat (taiep).

Bloom CM, Anch AM, Dyche JS. Department of Psychology, Saint Louis University, St Louis, MO 63103, USA.

J Gen Psychol 2002 Jul;129(3):226-37

The taiep (tremor, ataxia, immobility, epilepsy, and paralysis) myelin mutant displays a number of locomotor deficits. Taiep rat gait is characterized by shorter stride and step lengths as well as by larger stride widths. Thirty-day-old taiep mutants were placed under a regimen of daily hormone injections for 60 days. Animals in Condition 1 received melatonin, those in Condition 2 received pregnenolone sulfate, and those in a third control condition received injections of saline. Following the injections, each taiep mutant's gait was analyzed. The animals that received melatonin and pregnenolone displayed significantly larger stride and step lengths than did the controls. In addition, the animals that received hormones displayed shorter stride widths than did the controls. These experimental effects are consistent with a normalization of gait. Possible cellular mechanisms of this behavioral effect are discussed.

Early enteral administration of a formula (Impact) supplemented with arginine, nucleotides, and fish oil in intensive care unit patients: results of a multicenter, prospective, randomized, clinical trial.

Bower RH, Cerra FB, Bershadsky B, Licari JJ, Hoyt DB, Jensen GL, Van Buren CT, Rothkopf MM, Daly JM, Adelsberg BR. Department of Surgery, University of Cincinnati College of Medicine, OH.

Crit Care Med. 1995 Mar;23(3):436-49.

OBJECTIVE: To determine if early enteral feeding, in an intensive care unit (ICU) patient population, using a formula supplemented with arginine, dietary nucleotides, and fish oil (Impact), results in a shorter hospital stay and a reduced frequency of infectious complications, when compared with feeding a common use enteral formula (Osmolite.HN).

DESIGN: A prospective, randomized, double-blind, multicenter trial.

SETTING: ICUs in eight different hospitals.

PATIENTS: Of 326 patients enrolled in the study, 296 patients were eligible for analysis. They were admitted to the ICU after an event such as trauma, surgery, or sepsis, and met a risk assessment screen (Acute Physiology and Chronic Health Evaluation II [APACHE II] score of > or = 10, or a Therapeutic Intervention Scoring System score of > or = 20) and study eligibility requirements. Patients were stratified by age (< 60 or > or = 60 yrs of age) and disease (septic or systemic inflammatory response syndrome).

INTERVENTIONS: Patients were enrolled and full-strength tube feedings were initiated within 48 hrs of the study entry event. Enteral feedings were advanced to a target volume of 60 mL/hr by 96 hrs of the event. One hundred sixty-eight patients were randomized to receive the experimental formula, and 158 patients were randomized to receive the common use control formula.

MEASUREMENTS AND MAIN RESULTS: Both groups tolerated early enteral feeding well, and the frequency of tube feeding-related complications was low. There were no significant differences in nitrogen balance between groups on study days 4 and 7. Patients receiving the experimental formula had a significant (p = .0001) increase in plasma arginine and ornithine concentrations by study day 7. Plasma fatty acid profiles demonstrated higher concentrations of linoleic acid (p < .01) in the patients receiving the common use formula and higher concentrations of eicosapentaenoic and docosahexaenoic acid (p < .01) in the patients receiving the experimental formula. The mortality rate was not different between the groups and was significantly (p < .001) lower than predicted by the admission severity scores in both feeding groups. In patients who received at least 821 mL/day of the experimental formula, the hospital median length of stay was reduced by 8 days (p < .05). In patients stratified as septic, the median length of hospital stay was reduced by 10 days (p < .05), along with a major reduction in the frequency of acquired infections (p < .01) in the patients who received the experimental formula. In the septic subgroup fed at least 821 mL/day, the median length of stay was reduced by 11.5 days, along with a major reduction in acquired infections (both p < .05) in the patients who received the experimental formula.

CONCLUSIONS: Early enteral feeding of the experimental formula was safe and well tolerated in ICU patients. In patients who received the experimental formula, particularly if they were septic on admission to the study, a substantial reduction in hospital length of stay was observed, along with a significant reduction in the frequency of acquired infections.

Artificial nutrition after major abdominal surgery: impact of route of administration and composition of the diet.

Braga M, Gianotti L, Vignali A, Cestari A, Bisagni P, Di Carlo V. Department of Surgery, Scientific Institute San Raffaele, University of Milan, Italy.

Crit Care Med. 1998 Jan;26(1):24-30.

OBJECTIVE: To evaluate the impact of the route of administration of artificial nutrition and the composition of the diet on outcome.

DESIGN: Prospective, randomized, clinical trial.

SETTING: Department of surgery, university hospital.

PATIENTS: One hundred sixty-six consecutive patients undergoing curative surgery for gastric or pancreatic cancer.

INTERVENTIONS: At operation, the patients were randomized into three groups to receive: a) a standard enteral formula (control group; n = 55); b) the same enteral formula enriched with arginine, RNA, and omega-3 fatty acids (enriched group; n = 55); and c) total parenteral nutrition (TPN group; n = 56). The three regimens were isocaloric and isonitrogenous. Enteral nutrition was started within 12 hrs following surgery. The infusion rate was progressively increased to reach the nutritional goal (25 kcal/kg/day) on postoperative day 4.

MEASUREMENTS AND MAIN RESULTS: Tolerance of enteral feeding, rate and severity of postoperative complications, and length of hospital stay were recorded. Early enteral infusion was well tolerated. Side effects were recorded in 22.7% of the patients, but only 6.3% did not reach the nutritional goal. The enriched group had a lower severity of infection than the parenteral group (4.0 vs. 8.6; p < .05). In subgroups of malnourished (n = 78) and homologous transfused patients (n = 42), the administration of the enriched formula significantly reduced both severity of infection and length of stay compared with the parenteral group (p < .05). Moreover, in transfused patients, the rate of septic complications was 20.0% in the enriched group, 38.4% in the control group, and 42.8% in the TPN group.

CONCLUSIONS: Early enteral feeding is a suitable alternative to TPN after major abdominal surgery. The use of the enriched diet appears to be more beneficial in malnourished and transfused patients.

Dehydroepiandrosterone restores immune function following trauma-haemorrhage by a direct effect on T lymphocytes.

Catania RA, Angele MK, Ayala A, Cioffi WG, Bland KI, Chaudry IH. Center for Surgical Research and Department of Surgery, Brown University School of Medicine and Rhode Island Hospital, Providence, RI 02903, USA.

Cytokine 1999 Jun;11(6):443-50

Although a profound depression in immune function occurs following injury, the mechanism responsible for this is not fully understood. Furthermore, steroid hormones are known to be important mediators in the regulation of immune function. Although dehydroepiandrosterone (DHEA), the most plentiful steroid hormone, has been shown to stimulate immune function in normal animals, it is unknown whether DHEA has any salutary or detrimental effects on immune responses after trauma and haemorrhage. To study this, male mice were subjected to trauma, haemorrhage and resuscitation, following which they received either DHEA or vehicle subcutaneously. DHEA administration restored the normally depressed splenocyte proliferation as well as interleukin 2, interleukin 3, and interferon gamma elaboration following trauma and haemorrhage. In an attempt to determine the mechanisms mediating this effect, T cells were stimulated in vitro in the presence of DHEA and a variety of hormone antagonists. The stimulatory effect of DHEA on splenocyte proliferation was unaltered by the testosterone receptor antagonist flutamide, while the oestrogen antagonist tamoxifen completely abrogated its effect. In addition, DHEA administration normalized the elevated serum corticosterone level typically seen following injury. These results indicate, therefore, that DHEA improves splenocyte function after trauma and haemorrhage by directly stimulating T cells and also by preventing a rise in serum corticosterone. Copyright 1999 Academic Press.

Hepatocytic ultrastructure in splenectomized rats treated with pregnenolone-16alpha-carbonitrile, a microsomal enzyme inducer.

Cathala L, Garg BD.

Acta Anat (Basel) 1975;93(1):51-9

Pregnenolone-16alpha-carbonitrile (PCN), given orally at the dose of 6.8 mg/100 g body wt, twice daily for 3 or 6 days, increased liver weight in intact rats, and reduced zoxazolamine paralysis in both unoperated and splenectomized animals. The steroid induced smooth endoplasmic reticulum proliferation in the hepatocytes of intact and splenectomized rats, while splenectomy alone caused rough endoplasmic reticulum fragmentation and vesiculation. It appears that the spleen does not influence the hepatic action of PCN.

Metabolic and immune effects of dietary arginine, glutamine and omega-3 fatty acids supplementation in immunocompromised patients.

Chuntrasakul C; Siltharm S; Sarasombath S; Sittapairochana C; Leowattana W; Chockvivatanavanit S; Bunnak A Research Center for Nutritional Support, Siriraj Hospital.

J Med Assoc Thai (Thailand) May 1998, 81 (5) p334-43

To evaluate the nutritional, metabolic and immune effects of dietary arginine, glutamine and omega-3 fatty acids (fish oil) supplementation in immunocompromised patients, we performed a prospective study on the effect of immune formula administered to 11 severe trauma patients (average ISS = 24), 10 burn patients (average % TBSA = 48) and 5 cancer patients. Daily calorie and protein administration were based on the patient's severity (Stress factor with the range of 35-50 kcal/kg/day and 1.5-2.5 g/kg/day, respectively) Starting with half concentration liquid immune formula through nasogastric tube by continuous drip at 30 ml/h and increasing to maximum level within 4 days. The additional energy and protein requirement will be given either by parenteral or oral nutritional support. Various nutritional, metabolic, immunologic and clinical parameters were observed on day 0 (baseline), day 3, 7, and 14. Analysis was performed by paired student-t test. Initial mean serum albumin and transferrin showed mild (trauma ) to moderate (burn and cancer) degree of malnutrition. Significant improvement of nutritional parameters was seen at day 7 and 14 in trauma and burn patients. Significant increase of total lymphocyte count (day 7, P < 0.01), CD4 + count (day 7, p < 0.01), CD8 + count (day 7, p < 0.0005 < day 14, p < 0.05), complement C3 (day 7, p < 0.005 day 14, p < 0.01), IgG (day 7, and 14, p < 0.0005), IgA (day 7, p < 0.0005 & day 14, p < 0.05), in all patients. C-reactive protein decreased significantly on day 7 (p < 0.0005) and day 14 (p < 0.005). 3 cases of burn wound infection, one case of UTI and one case of sepsis were observed. Two cases of hyperglycemia in burn, 3 cases of hyperbilirubinemia in trauma, 10 cases of elevated LFT (5 trauma /5 burn), and one case of hyponatremia in cancer patients were observed. Two cases of nausea, 4 cases of vomiting, 5 cases of diarrhea (< 3 times/day), 2 cases of abdominal cramp, 1 case of distension were observed. The feeding of IMMUNE FORMULA was well tolerated and significant improvement was observed in nutritional and immunologic parameters as in other immunoenhancing diets. Further clinical trials of prospective double-blind randomized design are necessary to address the so that the necessity of using immunonutrition in critically ill patients will be clarified.

Use of piracetam in treatment of head injuries. Observations in 903 cases.

Cicerchia G.; Santucci R.; Palmieri M. Ospedale della Misericordia, Servizio di Pronto Soccorso, Area di Degenza per l'Emergenza, Grosseto Italy

Clin. Ter. (Italy), 1985, 114/6 (481-487)

The authors report on 903 patients with head concussion of varying degrees of severity who were treated with anti-oedema drugs associated with an activator of cerebral metabolism. This treatment resulted in a swift disappearance of symptoms and in a quick recovery of normal cerebral activity, and moreover in a noticeable decrease of the time of hospitalisation.

Effects of dietary arginine supplementation on protein turnover and tissue protein synthesis in scald-burn rats.

Cui XL, Iwasa M, Iwasa Y, Ohmori Y, Yamamoto A, Maeda H, Kume M, Ogoshi S, Yokoyama A, Sugawara T, Funada T. Department of Surgery II, Kochi Medical School, Japan.

Nutrition 1999 Jul-Aug;15(7-8):563-9

We assessed the effects of dietary arginine supplementation on protein turnover and organ protein synthesis in burned rats. Male Wistar rats weighing about 200 g underwent catheter jejunostomy and received scald burns covering 30% of the whole-body surface area. Animals were divided into a control group (n = 9) and an arginine group (n = 9) and continuously received total enteral nutrition for 7 d (250 kcal.kg-1.d-1, 1.72 gN.kg-1.d-1). Changes in body weight, plasma total protein, plasma albumin, urinary excretion of polyamines, nitrogen balance, whole-body protein kinetics, and tissue protein synthesis rates were determined. Whole-body protein kinetics and tissue fractional protein synthetic rates (Ks, percent/d) were estimated using a 24-h constant enteral infusion of 15N glycine on the last day. The changes in body weight were not different between the control and arginine groups. The urinary excretion of polyamines was higher in the arginine group than in the control group (P < 0.01). Burned rats enterally fed arginine-supplemented diet yielded significantly greater cumulative and daily nitrogen balance on days 3 and 5 than those fed a control diet (cumulative, P < 0.05; day 3, P < 0.01; day 5, P < 0.01). Whole-body protein turnover rate was significantly elevated in the arginine group as compared to that in the control group (P < 0.05). The Ks of rectus abdominis muscles were significantly increased in the arginine group in comparison to the control group (P < 0.01). We have shown that dietary arginine supplementation improved protein anabolism and attenuated muscle protein catabolism after thermal injury.

Arginine-supplemented diet decreases expression of inflammatory cytokines and improves survival in burned rats.

Cui XL, Iwasa M, Iwasa Y, Ogoshi S. Department of Surgery II, Kochi Medical School, Nankoku, Japan.

JPEN J Parenter Enteral Nutr 2000 Mar-Apr;24(2):89-96

BACKGROUND: We examined whether the expression of inflammatory cytokines in organs was influenced by the enteral diet supplemented with arginine in burned rats.

METHODS: Male Wistar rats weighing about 200 g underwent catheter jejunostomy and received scald burns covering 30% of the whole-body surface area. Animals were divided into two groups: a control group (no supplemental arginine, n = 12) and an arginine group (supplemental arginine: 7.7 g/L, n = 10), which continuously received total enteral nutrition for 7 days (250 kcal/kg/d, 1.72 gN/kg/d). The following were measured after the experiment: (1) messenger RNA (mRNA) expression of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin-1beta (IL-1beta), and IL-6 in the spleen, thymus, lung, and liver by a semiquantitative reverse transcription-polymerase chain reaction method, (2) inflammatory cytokines in the plasma and supernatant of cultured splenic lymphocytes by enzyme-linked immunosorbant assay, (3) nitric oxide (NO) product, NO2-/NO3-, in the plasma and supernatant of cultured splenic lymphocytes by the Griess method, and (4) survival rate by the Kaplan-Meier method.

RESULTS: The mRNA expression of TNF-alpha was significantly decreased in the spleen and lung (p < .01, p < .05), IFN-gamma in the lung (p < .05), IL-1beta in the spleen (p < .05), and IL-6 in the thymus and liver (p < .05, p < .05) in the arginine group when compared with the control group. The production of TNF-alpha by splenic lymphocytes was suppressed in the arginine group in both concanavalin A (Con A)-treated and -untreated cultures (p < .01, p < .05). The production of IFN-gamma by splenic lymphocytes treated with Con A was suppressed in the arginine group (p < .05). The NO product in the supernatant without Con A was increased in the arginine group (p < .05). The mortality rate of the arginine group (0%) was lower than that in the control group (33.3%) on day 7 after the burn injury (p < .05).

CONCLUSIONS: The data suggest that dietary arginine supplementation decreases the mRNA expression of inflammatory cytokines in organs and improves the survival rate after thermal injury.

Enteral nutrition with supplemental arginine, RNA, and omega-3 fatty acids in patients after operation: immunologic, metabolic, and clinical outcome.

Daly JM, Lieberman MD, Goldfine J, Shou J, Weintraub F, Rosato EF, Lavin P. Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia 19104.

Surgery. 1992 Jul;112(1):56-67.

The individual nutrients arginine, RNA, and omega-3 fatty acids improve immune function, but prospective trials have not demonstrated their effects on clinical outcome. Patients (n = 85) who underwent operation for upper gastrointestinal malignancies were randomized to receive the supplemental diet or a standard enteral diet after surgery. Clinical patient characteristics were similar between the two groups. Mean caloric intakes (1421 vs 1285 kcal/day) were similar between groups. Mean nitrogen intakes (15.6 vs 9.0 gm/day) and nitrogen balances (-2.2 vs -6.6 gm/day) measured in the first 20 patients were significantly greater in the supplemented group than in the standard group (p =0.05). In vitro lymphocyte mitogenesis was measured in the first 31 patients and was decreased on postoperative day 1 in both groups, but normal levels were regained only in the supplemented group. In the cohort of 77 eligible patients, infectious and wound complications occurred significantly less often (11% vs 37%) in the supplemented group than in the standard group (p = 0.02). Linear logistic models for infectious/wound complications with control for the amount of nitrogen suggested (p = 0.10) dietary treatment as the major factor. Mean length of stay in the hospital was significantly shorter (p = 0.01) for the supplemented group (15.8 +/- 5.1 days) than for the standard group (20.2 +/- 9.4 days). These results suggest that postoperative enteral nutrition with supplemental arginine, RNA, and omega-3 fatty acids instead of a standard enteral diet significantly improved immunologic, metabolic, and clinical outcomes in patients with upper gastrointestinal malignancies who were undergoing major elective surgery.

Vitamin-C supplementation in the patient with burns and renal failure

Dylewski DF, Froman DM Parenteral Nutrition Support Service, Francis Scott Key Medical Center, Baltimore, MD.

J. Burn Care Rehabil. (USA), 1992, 13/3 (378-380)

Vitamin-C supplementation is an important component of nutritional management in patients with burns. To supply appropriate vitamin C therapy, complications such as renal failure must be considered. An understanding of current vitamin regimens and potential metabolic sequelae can assist the practitioner in providing safe and therapeutic Vitamin-C doses.

Antioxidant loading reduces oxidative stress induced by high-energy impulse noise (blast) exposure.

Elsayed NM, Armstrong KL, William MT, Cooper MF. Walter Reed Army Institute of Research, Washington, DC, USA. nabil.m.elsayed@sb.com

Toxicology 2000 Nov 30;155(1-3):91-9

Detonation of explosives, firing of large caliber weapons and occupational explosions, professional or accidental, produce high-energy impulse noise (blast) waves characterized by a rapid rise in atmospheric pressure (overpressure) followed by gradual decay to ambient level. Exposure to blast waves causes injury, predominantly to the hollow organs such as ears and lungs. We have previously reported that blast exposure can induce free radical-mediated oxidative stress in the lung characterized by antioxidant depletion, lipid peroxidation, and hemoglobin (Hb) oxidation. In this study, we examined whether pre-loading, adequately fed rats, with pharmacological doses of antioxidants would reduce the response to blast. Sprague-Dawley rats weighing 300-350 g were loaded with either 800 IU vitamin E (VE), 1000 mg vitamin C (VC) or 25 mg lipoic acid (LA) for 3 consecutive days by gavage before exposure to blast. Both VE, and LA were dissolved in 2 ml corn oil, but VC in 2 ml water. After the 3-day antioxidant loading, the rats were divided into six groups (five rats per group), deeply anesthetized with sodium pentobarbital (60 mg/kg body weight), then exposed to a low-level blast (622 kPa peak pressure and 5 ms duration). A matched number of groups were sham exposed and served as controls. One hour after exposure, all rats were euthanized then blood, and lung tissue was analyzed. We found that antioxidant loading resulted in restored Hb oxygenation, and reduced lipid peroxidation. Lung tissue VE content was elevated after loading but VC did not change possibly due to their different bioavailability and saturation kinetics. These observations, suggest that brief antioxidant loading with pharmacological doses can reduce blast-induced oxidative stress, and may have occupational and clinical implications.

Reversal of postburn immunosuppression by the administration of vitamin A.

Fusi S, Kupper TS, Green DR, Ariyan S.

Surgery. 1984 Aug;96(2):330-5.

The effect of high doses of vitamin A was evaluated on the suppression of cellular immunity after a 30% body surface area experimental scald burn in a mouse model. Male CBA/J mice were treated postburn with daily intraperitoneal injections of either 3000 IU of vitamin A or an equal volume of 0.9N saline. Similar groups of unburned mice were also studied as controls. At the seventh postburn day, one-way mixed lymphocyte reactions were tested for each group with whole spleen cells of CBA/J mice used as responders and mitomycin C-treated whole spleen cells of C57 BL/6 mice used as stimulators. When results were expressed as mean percentage of the values of control animals, no significant difference was observed between the saline-injected unburned control group (taken as 100%) and the vitamin A-treated unburned control groups (89%). The burned animals treated with saline showed suppression to 21% of the control values. However, the burned animals treated postburn with vitamin A improved the response rate dramatically to 52% of control values. This improvement over the untreated burned animals was significant in all experiments performed (p less than 0.02). This study suggests that vitamin A may be an effective agent in the reversal of cellular immunosuppression after burns.

An immune-enhancing enteral diet reduces mortality rate and episodes of bacteremia in septic intensive care unit patients.

Galban C, Montejo JC, Mesejo A, Marco P, Celaya S, Sanchez-Segura JM, Farre M, Bryg DJ. Complejo Hospitalario Universitario, Santiago de Compostela, La Coruna, Spain.

Crit Care Med. 2000 Mar;28(3):643-8.

OBJECTIVE: To determine whether early enteral feeding in a septic intensive care unit (ICU) population, using a formula supplemented with arginine, mRNA, and omega-3 fatty acids from fish oil (Impact), improves clinical outcomes, when compared with a common use, high protein enteral feed without these nutrients.

DESIGN: A prospective, randomized, multicentered trial.

SETTING: ICUs of six hospitals in Spain.

PATIENTS: One hundred eighty-one septic patients (122 males, 59 females) presenting for enteral nutrition in an ICU.

INTERVENTIONS: Septic ICU patients with Acute Physiology and Chronic Health Evaluation (APACHE) II scores of > or =10 received either an enteral feed enriched with arginine, mRNA, and omega-3 fatty acids from fish oil (Impact), or a common use, high protein control feed (Precitene Hiperproteico).

MEASUREMENTS AND MAIN RESULTS: One hundred seventy-six (89 Impact patients, 87 control subjects) were eligible for intention-to-treat analysis. The mortality rate was reduced for the treatment group compared with the control group (17 of 89 vs. 28 of 87; p < .05). Bacteremias were reduced in the treatment group (7 of 89 vs. 19 of 87; p = .01) as well as the number of patients with more than one nosocomial infection (5 of 89 vs. 17 of 87; p = .01). The benefit in mortality rate for the treatment group was more pronounced for patients with APACHE II scores between 10 and 15 (1 of 26 vs. 8 of 29; p = .02).

CONCLUSIONS: Immune-enhancing enteral nutrition resulted in a significant reduction in the mortality rate and infection rate in septic patients admitted to the ICU. These reductions were greater for patients with less severe illness.

The effect of a selenium supplementation on the outcome of patients with severe systemic inflammation, burn and trauma.

Gartner R, Albrich W, Angstwurm MW. Klinikum der Ludwig-Maximilians-Universitat Munchen, Medizinische Klinik- Innenstadt, Germany. rgartner@medinn.med.uni-muenchen.de

Biofactors 2001;14(1-4):199-204

Patients with systemic inflammatory response syndrome (SIRS) and sepsis exhibit decreased plasma selenium and glutathione peroxidase activity. This has been shown in several clinical studies. Moreover, the degree of selenium deficiency correlates with the severity of the disease and the incidence of mortality. Patients with SIRS and sepsis are exposed to severe oxidative stress. Selenoenzymes play a major role in protecting cells against peroxidation, especially lipid peroxidation and are involved in the regulation of inflammatory processes. Therefore, selenium substitution in those patients might be effective in the prevention of multiorgan failure. The results of randomised clinical trials investigating selenium substitution in critical ill patients with inflammation are reviewed. In two independently performed randomised, prospective clinical trials, including patients with systemic inflammatory response syndrome or sepsis, the supplementation of selenium revealed a significant reduction in multiorgan failure and, especially, a lower incidence of acute renal failure and respiratory distress syndrome. One of those trials also could demonstrate a significant reduction of mortality in the most severely ill patients. Two other studies, where selenium together with other trace elements or a mixture of antioxidants were used in the treatment of patients with severe burn injuries or trauma showed a significant reduction in the secondary infection rate, including sepsis. Thus, selenium supplementation seems to improve the outcome of patients with SIRS, sepsis and severe injury, however, pivotal prospective clinical trials with sufficient statistical power are now necessary to finally prove the efficacy of a selenium supplementation in these diseases.

Acceleration of corneal wound healing in diabetic rats by the antioxidant trolox.

Hallberg CK, Trocme SD, Ansari NH. Department of Human Biological Chemistry & Genetics, University of Texas Medical Branch, Galveston 77555-0647, USA.

Res Commun Mol Pathol Pharmacol 1996 Jul;93(1):3-12

Several corneal complications have been reported in patients with long standing diabetes, but their exact pathogenesis is not well understood. It has been observed that the rate of epithelial wound healing in diabetic rats is delayed compared to those in normal animals. Here we present the effect of the free radial scavenger, Trolox, a water soluble vitamin E analogue, on epithelial wound healing in diabetic rat cornea. Three groups of rats were included: 1) normal, 2) diabetic, 3) diabetic + Trolox. After 3 months, rats were sacrificed and corneas removed. Standard 3 mm diameter corneal epithelial defects were made and residual epithelial defects were measured after 18 hours at 37 degrees C in a sterile cell culture incubator. Wound healing data measured in mm2 was used for statistical analysis. There were significantly larger (p < 0.05) epithelial defects in diabetic corneas as compared to control. Treatment with Trolox antioxidant in diabetic rats produced a significantly smaller (p < 0.05) epithelial defect than that of untreated diabetic rats. These studies suggest the involvement of free radicals in the delay of corneal epithelial wound healing in diabetes.

Effect of intravenous omega-6 and omega-3 fat emulsions on nitrogen retention and protein kinetics in burned rats.

Hayashi N, Tashiro T, Yamamori H, Takagi K, Morishima Y, Otsubo Y, Sugiura T, Furukawa K, Nitta H, Nakajima N, Suzuki N, Ito I. First Department of Surgery, Chiba University, School of Medicine, Japan.

Nutrition 1999 Feb;15(2):135-9

The effect of omega-3 fat emulsion on nitrogen retention and kinetics in relation to fatty acid profile were investigated in burned rats receiving total parenteral nutrition (TPN). A fat emulsion of a structured symmetrical triacylglycerol containing only eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (2:1) was prepared. Sprague-Dawley rats were fed by fat-free chow for 2 wk. Then rats were fed exclusively with one of three types of TPN for 7 d. Animals in group C received fat-free TPN (n = 11). Group omega 6 received safflower oil fat emulsion, which accounted for 20% of total caloric intake (n = 11). Group omega 3 received fat emulsion containing only EPA and DHA (1% of total calories, n = 11), in addition to safflower oil emulsion (19% of total calories). On day 5, each rat was subjected to 20% full-thickness scald burns. Rats were sacrificed under ether anesthesia 48 h after burning. The rats in group C became deficient in omega-6 essential fatty acids. Cumulative nitrogen balance was decreased significantly in group omega 6. The rates of whole-body protein synthesis were increased significantly in both groups omega 6 and omega 3. In omega 6, however, the rates of whole-body protein breakdown were increased significantly. In conclusion, the rates of whole-body protein breakdown increased and nitrogen retention was aggravated significantly in animals administered the safflower oil emulsion. Significant increases of urinary excretion of total catecholamine were also observed. Prostaglandin E2 and thromboxane B2 concentrations were not significantly different among three groups. Supplementation with the new omega-3 fat emulsion, however, improved protein metabolism in burned rats receiving TPN.

Supplementation with vitamins C and E suppresses leukocyte oxygen free radical production in patients with myocardial infarction

Herbaczynska-Cedro K.; Klosiewicz-Wasek B.; Cedro K.; Wasek W.; Panczenko-Kresowska B.; Wartanowicz M. Medical Research Centre, Polish Academy of Sciences, Dworkowa 3, 00-754 Warsaw Poland

European Heart Journal (United Kingdom), 1995, 16/8 (1044-1049)

Clinical studies suggest that neutrophil activation during acute myocardial infarction (MI) aggravates tissue injury. Activated neutrophils are an important source of oxygen free radicals (OFR), the injurious effects of which are counteracted by endogenous antioxidants. We have previously shown in healthy subjects that supplementation with antioxidant vitamins C and E suppresses OFR production by isolated neutrophils assayed by chemiluminescence (CL). the present study, performed in patients with acute MI aimed (1) to investigate the effect of Vitamin-C and E supplementation upon neutrophil OFR production and serum lipid peroxides, (2) to evaluate serum levels of vitamins C and E in the course of MI. Forty-five patients with acute MI were randomized to receive either conventional treatment plus Vitamin-C and E aa 600 mg.day-1 p.o. for 14 days (VIT,n=23) or conventional treatment only (control, n=22). All measurements were performed on the 1st and 14th day. Neutrophil OFR production assayed by CL decreased significantly in VIT patients (Wilcoxon test for paired data P<0.01, Chi square test P<0.01). In the control group, changes in OFR production were not significant. Serum lipid peroxides (measured as TBARS) increased in controls (P<0.05), but remained stable in VIT patients. Mean (plus or minusSE) serum ascorbic acid and tocopherol on the 1st day were 0.43 plus or minus 0.18mg% and 3.25 plus or minus 1.32 microM.mM -1 cholesterol, respectively, in all patients. On the 14th day in non-supplemented patients mean tocopherol was unchanged, whereas ascorbic acid increased significantly (0.63 plus or minus 0.24 mg%, P<0.01) suggesting that a low basal level was associated at least in part with the acute phase of the disease. An expected increase in serum vitamin levels occurred in VIT patients. In conclusion, supplementation with vitamins C and E suppresses neutrophil OFR production and lowers the marker of lipid peroxidation in patients with MI. These effects, together with a deficiency of antioxidant vitamins, particularly vitamin C in the early phase of the disease, support the view that supplementation with antioxidant vitamins is advisable in patients with MI.

Antioxidant vitamin therapy alters burn trauma-mediated cardiac NF-kappaB activation and cardiomyocyte cytokine secretion.

Horton JW, White DJ, Maass DL, Hybki DP, Haudek S, Giroir B. Department of Surgery, University of Texas Southwestern Medical Center, Dallas, Texas, USA. jureta.horton@utsouthwestern.edu

J Trauma 2001 Mar;50(3):397-406; discussion 407-8

BACKGROUND: This study examined the effects of antioxidant vitamins A, C, and E on nuclear transcription factor-kappa B (NF-kappaB) nuclear translocation, on secretion of inflammatory cytokines by cardiac myocytes, and on cardiac function after major burn trauma.

METHODS: Adult rats were divided into four experimental groups: group I, shams; group II, shams given oral antioxidant vitamins (vitamin C, 38 mg/kg; vitamin E, 27 U/kg; vitamin A, 41 U/kg 24 hours before and immediately after burn); group III, burns (third-degree scald burn over 40% total body surface area) given lactated Ringer's solution (4 mL/kg/% burn); and group IV, burns given lactated Ringer's solution plus vitamins as described above. Hearts were collected 4, 8, 12, and 24 hours after burn to assay for NF-kappaB nuclear translocation, and hearts collected 24 hours after burn were examined for cardiac contractile function or tumor necrosis factor-alpha secretion by cardiomyocytes.

RESULTS: Compared with shams, left ventricular pressure was lower in burns given lactated Ringer's solution (group III) (88 3 vs. 64 5 mm Hg, p < 0.01) as was ? max (2,190 30 vs. 1,321 122 mm Hg/s) and -dP/dt max (1,775 71 vs. 999 96 mm Hg, p < 0.01). Burn injury in the absence of vitamin therapy (group III) produced cardiac NF-kappaB nuclear migration 4 hours after burn and cardiomyocyte secretion of tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 by 24 hours after burn. Antioxidant therapy in burns (group IV) improved cardiac function, producing left ventricular pressure and dP/dt (82 2 mm Hg, 1,880 44 mm Hg, and 1,570 46 mm Hg/s) comparable to those measured in shams. Antioxidant vitamins in burns inhibited NF-kappaB nuclear migration at all times after burn and reduced burn-mediated cytokine secretion by cardiomyocytes.

CONCLUSION: These data suggest that antioxidant vitamin therapy in burn trauma provides cardioprotection, at least in part, by inhibiting translocation of the transcription factor NF-kappaB and interrupting cardiac inflammatory cytokine secretion.

Effect of antioxidant vitamin supplementation on muscle function after eccentric exercise

Jakeman P.; Maxwell S. Applied Physiology Research Unit, School Sport and Exercise Sciences, University of Birmingham, Birmingham B15 2TT United Kingdom

Eur. J. Appl. Physiol. Occup. Physiol. (Germany), 1993, 67/5 (426-430)

This study investigated the effects of antioxidant vitamin supplementation upon muscle contractile function following eccentric exercise and was performed double blind. Twenty-four physically active young subjects ingested either placebo (400 mg; n = 8), vitamin E (400 mg; n = 8) or Vitamin-C (400 mg; n = 8) for 21 days prior to and for 7 days after performing 60 min of box-stepping exercise. Contractile function of the triceps surae was assessed by the measurement of maximal voluntary contraction (MVC) and the ratio of the force generated at 20 Hz and 50 Hz tetanic stimulation before and after eccentric exercise and for 7 days during recovery. Following eccentric exercise, MVC decreased to 75 (4)% (mean (SE); n = 24; P < 0.05) of the preexercise values and the 20/50 Hz ratio of tetanic tension from 0.76 (0.01) to 0.49 (0.03) (mean (SE); n = 24; P < 0.05). Compared to the placebo group no significant changes in MVC were observed immediately post-exercise, though recovery of MVC in the first 24 h post-exercise was greater in the group supplemented with Vitamin-C. The decrease in 20/50 Hz ratio of tetanic tension was significantly less (P < 0.05) postexercise and in the initial phase of recovery in subjects supplemented with Vitamin-C but not with vitamin E. These data suggest that prior Vitamin-C supplementation may exert a protective effect against eccentric exercise-induced muscle damage.

Effect of dietary Vitamin-C on compression injury of the spinal cord in a rat mutant unable to synthesize ascorbic acid and its correlation with that of vitamin E

Katoh D, Ikata T, Katoh S, Hamada Y, Fukuzawa K Department of Orthopedic Surgery, School of Medicine, Tokushima, Japan.

Spinal Cord (United Kingdom), 1996, 34/4 (234-238)

The roles of vitamines after spinal cord injury were investigated by evaluating the effects of dietary Vitamin-C on experimental spinal cord injury in a mutant strain of Wistar rats unable to synthesize ascorbic acid (ODS rats). Two groups of ODS rats were given Vitamin-C-deficient or Vitamin-C-supplemented diet for 1 week before injury. Motor disturbance induced by spinal cord injury was found to be greater in the Vitamin-C-deficient group. Histologically, the area of bleeding in the spinal cord was also greater in the Vitamin-C-deficient group. The levels of ascorbic acid and alpha-tocopherol in the spinal cord tissue and serum decreased during and after compression injury of the spinal cord. The decrease of alpha-tocopherol was similar in the two groups. However, the decrease of ascorbic acid was greater in the Vitamin-C-supplemented group. These results indicated that their protective effects against spinal cord injury are through scavenging water-soluble free radicals by vitamin C and lipid-soluble by vitamin E, and the effects of these vitamins were suggested to be independent.

A randomized trial of isonitrogenous enteral diets after severe trauma. An immune-enhancing diet reduces septic complications.

Kudsk KA, Minard G, Croce MA, Brown RO, Lowrey TS, Pritchard FE, Dickerson RN, Fabian TC. Department of Surgery, University of Tennessee, Memphis, USA.

Ann Surg. 1996 Oct;224(4):531-40; discussion 540-3.

OBJECTIVE: The authors randomized patients to an enteral diet containing glutamine, arginine, omega-3 fatty acids, and nucleotides or to an isonitrogenous, isocaloric diet to investigate the effect of septic outcome. A third group of patients, without enteral access but eligible by severity of injury, served as unfed controls and were studied prospectively to determine the risk of infection.

SUMMARY BACKGROUND DATA: Laboratory and clinical studies suggest that diets containing specialty nutrients, such as arginine, glutamine, nucleotides, and omega-3 fatty acids, reduce septic complications. Unfortunately, most clinical trials have not compared these diets versus isonitrogenous, isocaloric controls. This prospective, blinded study randomized 35 severely injured patients with an Abdominal Trauma Index > or = 25 or a Injury Severity Score > or = 21 who had early enteral access to an immune-enhancing diet ([IED] Immun-Aid, McGaw, Inc., Irvine, CA; n = 17) or an isonitrogenous, isocaloric diet (Promote [Ross Laboratories, Columbus, OH] and Casec [Mead-Johnson Nutritionals, Evansville, IN]; n = 18) diet. Patients without early enteral access but eligible by severity of injury served as contemporaneous controls (n = 19). Patients were evaluated for septic complications, antibiotic usage, hospital and intensive care unit (ICU) stay, and hospital costs.

RESULTS: Two patients died in the treatment group and were dropped from the study. Significantly fewer major infectious complications (6%) developed in patients randomized to the IED than patients in the isonitrogenous group (41%, p = 0.02) or the control group (58%, p = 0.002). Hospital stay, therapeutic antibiotics, and the development of intra-abdominal abscess was significantly lower in patients receiving the IED than the other two groups. This improved clinical outcome was reflected in reduced hospital costs.

CONCLUSIONS: An IED significantly reduces major infectious complications in severely injured patients compared with those receiving isonitrogenous diet or no early enteral nutrition. An IED is the preferred diet for early enteral feeding after severe blunt and penetrating trauma in patients at risk of subsequent septic complications. Unfed patients have the highest complication rate.

Effects of vitamin E on T cell lipid peroxidation, membrane fluidity and T cell functions in traumatized mice

Liang H.-P.; Wang Z.-G. Research Institute of Surgery, Third Military Medical College, Chongqing 630042 China

Chinese Pharmacological Bulletin (China), 1996, 12/1 (47-49)

SUBFILES:Ranges of T cell malondialdehyde (MDA) contents, membrane fluidity, Tcell functions and therapeutic effects of vitamin E (V-E) were observed in traumatized mice. The results showed that T cell MDA contents were increased after trauma, membrane fluidity of T cell plasmalemma, mitochondria and microsome reduced and T lymphocytes transformation, interleukin 2 (IL-2) production, IL-2 receptor (IL-2R) expression and IL-2 mediated lymphocytes proliferation response were suppressed, which were related closely to MDA alteration. In vivo administration of V-E (50 or 100 mg/kg.d-1, im x 4 d) could reverse ahove parameters, indicating lipid peroxidation after trauma is an important cause resulting in reduced T cell membrane fluidity and were suppressed T cell functions, on which V-E shows significant therapeutic effects.

Reduced fluid volume requirement for resuscitation of third-degree burns with high-dose Vitamin-C

Matsuda T.; Tanaka H.; Williams S.; Hanumadass M.; Abcarian H.; Reyes H. Burn Center, Cook County Hospital, 700 S. Wood St., Chicago, IL 60612 USA

J. Burn Care Rehabil. (USA), 1991, 12/6 (525-532)

The effects of high-dose Vitamin-C therapy (170 mg, 340 mg, and 680 mg/kg/day) were evaluated in 70% body surface area third-degree burns in guinea pigs that were resuscitated with 1 ml/kg/%burn Ringer's lactate solution. The water content measurements of the burned skin at 24 hours after burn injury in the Vitamin-C-treated groups were significantly lower than those of the control group (1 ml/kg/%burn) and those of the standard resuscitation group (4 ml/kg/%burn). The cardiac outputs in the group that received 340 mg Vitamin-C were significantly higher than those of the control group but not significantly different than those of the standard therapy group at 2 hours after burn injury and thereafter. In comparison with the regimen of 340 mg Vitamin-C, the regimen of 680 mg Vitamin-C was no more beneficial, and the regimen of 170 mg was less effective. With administration of adjuvant high-dose Vitamin-C, we were able to reduce the total 24-hour resuscitation volume from 4 ml/kg/%burn to 1 ml/kg/%burn, while a comparable cardiac output was maintained.

High-dose Vitamin-C therapy for extensive deep dermal burns

Matsuda T.; Tanaka H.; Shimazaki S.; Matsuda H.; Abcarian H.; Reyes H.; Hanumadass M. Burn Center, Cook County Hospital, 700 S. Wood Street, Chicago, IL 60612 USA

USA Burns (United Kingdom), 1992, 18/2 (127-131)

We studied the haemodynamic effects of antioxidant therapy with high-dose Vitamin-C administration (170 mg/kg/24h) in guinea-pigs with 70 per cent body surface area deep dermal burns. The animals were divided into three groups of six animals each. Group 1 was resuscitated with Ringer's lactate solution according to the Parkland formula; group 2 with 25 per cent of the Parkland formula with Vitamin-C; and group 3 with 25 per cent of the Parkland formula without Vitamin-C. There were no significant differences in heart rates or in blood pressures between the groups throughout the 24-h study period. Group 3 showed significantly higher haematocrit values at 3 h postburn and thereafter as compared with those of group 2. The cardiac output values of group 2 were significantly higher than those of group 3, but equivalent to those of group 1. The water content of the burned skin in group 2 was significantly lower than that in the other groups, indicating that increased postburn capillary permeability was minimized by the administration of Vitamin-C. With adjuvant high-dose Vitamin-C administration, we were able to reduce the 24-h resuscitation fluid volume from 4 ml/kg/per cent burn to 1 ml/kg/per cent burn, while maintaining adequate cardiac output.

Effects of high-dose vitamin C administration on postburn microvascular fluid and protein flux.

Matsuda T, Tanaka H, Hanumadass M, Gayle R, Yuasa H, Abcarian H, Matsuda H, Reyes H. Burn Center, Cook County Hospital, Chicago, IL 60612.

J Burn Care Rehabil. 1992 Sep-Oct;13(5):560-6.

The effects of vitamin C treatment (14 mg/kg/hr) on burn injury were evaluated in the hind paws of 12 mongrel dogs. A lymph duct above one hind paw of each dog was cannulated. Hourly lymph flow rates (QL) and plasma and lymph total protein concentrations were measured before the burn injury and for 6 hours after the burn injury. Data from 24 paws were divided into four groups: nonburn without treatment, nonburn with treatment, burn without treatment, and burn with treatment. The nonburn groups showed no significant differences in QL or in total protein flux. In the burn groups the postburn hourly QL increased by sevenfold in the nontreatment group and only by threefold in the treatment group, whereas the postburn hourly total protein flux increased by fifteenfold and fivefold, respectively. We conclude that administration of high-dose vitamin C reduces early postburn microvascular leakage of fluid and protein.

The effects of high-dose Vitamin-C therapy on postburn lipid peroxidation

Matsuda T, Tanaka H, Yuasa H, Forrest R, Matsuda H, Hanumadass M, Reyes H Burn Center, Cook County Hospital, Chicago, IL 60612 USA

J. Burn Care Rehabil. (USA), 1993, 14/6 (624-629)

The effects of Vitamin-C treatment (14 mg/kg/hr) on postburn lipid peroxidation were evaluated in 12 dogs. A lymph duct above the ankle was cannulated bilaterally. Hourly lymph flow rates, plasma and lymph total protein concentrations, and plasma and lymph malondialdehyde concentrations were measured before the burn injury and for 24 hours after the burn injury. Four groups were employed: nonburn without treatment, nonburn with Vitamin-C treatment, burn without treatment, and burn with Vitamin-C treatment. The nonburn groups showed no significant differences in lymph flow rates, total protein flux, or lymph malondialdehyde level. In the burn groups the postburn hourly lymph flow rate increased by 850% without treatment and by 500% with Vitamin-C treatment, whereas the postburn hourly total protein flux increased by fiftyfold and twentyfold, respectively. There was a significant reduction in the postburn lymph malondialdehyde level in the group treated with Vitamin-C as compared with the nontreatment group. We conclude that high-dose Vitamin-C administration diminishes early postburn lipid peroxidation and reduces microvascular leakage of fluid and protein.

Antioxidant therapy using high dose Vitamin-C: Reduction of postburn resuscitation fluid volume requirements

Matsuda T.; Tanaka H.; Reyes H.M.; Richter H.M. III; Hanumadass M.M.; Shimazaki S.; Matsuda H.; Nyhus L.M.; Baxter C.R. Department of Surgery/Burn Center, Cook County Hospital, University of Illinois, 700 S. Wood Street, Chicago, IL 60612 USA

World Journal of Surgery (USA), 1995, 19/2 (287-291)

Twenty-four guinea pigs with third degree burns over 70% of the body surface area were divided equally into four groups. At 0.5 hours postburn, all groups received Ringer's lactate solution (R/L) according to the Parkland formula. The infusion rate was then reduced to 25% of the Parkland formula at 1.5 hours postburn. Group 1 received only R/L, and groups 2, 3 and 4 received adjuvant Vitamin-C (14.2 mg/kg/hr) until 4, 8, and 24 hours postburn, respectively. The volume of R/L was reduced by that of Vitamin-C solution so that the hourly sodium and fluid intake in each group was the same. Groups 1 and 2 demonstrated higher hematocrit and lower cardiac output values than did group 3, suggesting hypovolemia and hemoconcentration in these groups. Group 3 showed hematocrit and cardiac output values equivalent to those in group 4. We conclude that high dose Vitamin-C infusion maintains hemodynamic stability in the presence of a reduced resuscitation fluid volume provided Vitamin-C is administered for a minimum of 8 hours postburn.

Effect of allopurinol, sulphasalazine, and Vitamin-C on aspirin induced gastroduodenal injury in human volunteers

McAlindon ME, Muller AF, Filipowicz B, Hawkey CJ Division of Gastroenterology, University Hospital, Nattingham.

United Kingdom Gut (United Kingdom), 1996, 38/4 (518-524)

Background - The mechanisms of aspirin induced gastroduodenal injury are not fully understood. Aspirin induces the release of reactive oxygen metabolites in animal models, which may contribute to mucosal injury.

Aims - To investigate the effects of aspirin administered with placebo or antioxidants on gastric mucosal reactive oxygen metabolite release and gastroduodenal injury in human volunteers. Subjects - Fourteen healthy volunteers participated in the study (seven male; mean age 27 years, range 20-40).

Methods - In a double blind, randomised, crossover study, volunteers received aspirin 900 mg twice daily and either placebo, allopurinol 100 mg twice daily, sulphasalazine l g twice daily or Vitamin-C 1 g twice daily for three days. Injury was assessed endoscopically and by quantifying mucosal reactive oxygen metabolite release by measuring chemiluminescence before and after each treatment. The effect on prostanoids was determined by measuring ex vivo antral prostaglandin E2 (PGE2) synthesis and serum thromboxane B2 (TXB2).

Results - No drug reduced any parameter of gastric injury but Vitamin-C reduced duodenal injury assessed by Lanza score (p < 0.005). Chemiluminescence increased after aspirin both with placebo (p < 0.05) and vitamin C (p < 0.05). Post-treatment chemiluminescence was lower in subjects taking allopurinol (p < 0.05) or sulphasalazine (p < 0.005) than in those taking placebo with aspirin.

Conclusions - In this study, aspirin induced gastric injury was associated with reactive oxygen metabolite release. This was reduced by sulphasalazine and allopurinol, although macroscopic injury was not affected. Vitamin-C, however, was shown to have a previously unrecognised protective effect against aspirin induced duodenal injury.

Clinical benefits of an immune-enhancing diet for early postinjury enteral feeding.

Moore FA, Moore EE, Kudsk KA, Brown RO, Bower RH, Koruda MJ, Baker CC, Barbul A. Department of Surgery, Denver General Hospital, CO 80204-4507.

J Trauma. 1994 Oct;37(4):607-15.

In this multicenter prospective controlled trial, 98 evaluable patients sustaining major torso trauma were randomized to receive early enteral nutrition with a new "immune-enhancing" diet (study: n = 51) or a standard stress enteral formula (control: n = 47). At baseline, both groups had comparable demographics and Injury Severity Scores. After 7 days of feeding, the groups had equivalent increases in serum total protein, albumin, and transferrin concentrations. Patients receiving the "immune-enhancing" diet, however, experienced significantly greater increases in total lymphocyte (p = 0.014), T lymphocyte (p = 0.04), and T-helper (p = 0.004) cell numbers. Additionally, these patients had significantly fewer intraabdominal abscesses (study, 0% vs. control, 11%; p = 0.023) and significantly less multiple organ failure (study, 0% vs. control, 11%; p = 0.023). In conclusion, this multicenter trial suggests this "immune-enhancing" enteral diet offers clinical benefits in stressed surgical patients.

Ascorbic acid metabolism in trauma

Mukherjee D.; Som S.; Chatterjee I.B. Dep. Biochem., Univ. Coll. Sci., Calcutta 700019 India

Indian J. Med. Res. (India), 1982, 75/5 (748-751)

In major trauma such as severe head injury, burns or lacerated injury, there was a precipitous fall in plasma ascorbic acid level accompanied by a significant rise in blood dehydroascorbate level. However, this change was temporary and normal Vitamin-C status was regained after recovery from the stress condition. A similar alteration in plasma ascorbate level was also found after major surgery. This alteration in ascorbic acid status was not due to lack of reduction of dehydroascorbic acid to ascorbic acid but due to a high turnover of ascorbic acid in trauma. Supplementation of ascorbic acid in trauma resulted in a temporary increase in the plasma ascorbic acid level.

Biochemical basis of ozone toxicity

Mustafa M.G. Department of Environmental Health Sciences, University of California, School of Public Health, Los Angeles, CA 90024 USA

Free Radic. Biol. Med. (USA), 1990, 9/3 (245-265)

Ozone (O3) is the major oxidant of photochemical smog. Its biological effect is attributed to its ability to cause oxidation or peroxidation of biomolecules directly and/or via free radical reactions. A sequence of events may include lipid peroxidation and loss of functional groups of enzymes, alteration of membrane permeability, and cell injury or death. An acute exposure to O3 causes lung injury involving the ciliated cell in the airways and the type 1 epithelial cell in the alveolar region. The effects are particularly localized at the junction of terminal bronchioles and alveolar ducts, as evident from a loss of cells and accumulation of inflammatory cells. In a typical short-term exposure the lung tissue response is biphasic: an initial injury-phase characterized by cell damage and loss of enzyme activities, followed by a repair-phase associated with increased metabolic activities, which coincide with a proliferation of metabolically active cells, for example, the alveolar type 2 cells and the bronchiolar Clara cells. A chronic exposure to O3 can cause or exacerbate lung diseases, including perhaps an increased lung tumor incidence in susceptible animal models. Ozone exposure also causes extrapulmonary effects involving the blood, spleen, central nervous system, and other organs. A combination of O3 and NO2, both of which occur in photochemical smog, can produce effects which may be additive or synergistic. A synergistic lung injury occurs possibly due to a formation of more powerful radicals and chemical intermediates. Dietary antioxidants, for example, vitamin E, Vitamin-C, and selenium, can offer a protection against O3 effects.

Metabolic and immune effects of enteral ascorbic acid after burn trauma

Nelson J.L.; Alexander J.W.; Jacobs P.A.; Ing R.D.; Ogle C.K. Shriners Burns Institute, 202 Goodman Street, Cincinnati, OH 45219 USA

Burns (United Kingdom), 1992, 18/2 (92-97)

A burned guinea-pig model (30 per cent BSA) was used to study the effect of Vitamin-C on immune and metabolic responses following burn trauma. Thirty-six guinea-pigs received identical enteral diets (175 kcal/kg) except for the amount of Vitamin-C. Groups I, II, III and IV were given formulae delivering no Vitamin-C (1 RDA) 15 mg/kg/day 75 mg/kg/day or 375 mg/kg/day respectively. Resistance to infection was evaluated by injecting each animal with 0.1 ml of 1 x 109 Staph. aureus 502A subcutaneously on day 10. On day 14, Staph. aureus abscesses were excised and the numbers of viable colonies were determined. Results showed no statistical differences between groups in the clearance of Staph. aureus. From days 2 to 12, animals in groups I, II and III had body weights of approximately 97 per cent of preburn body weight. Animals in group IV however, had a body weight gain, 102 per cent of preburn body weight on day 12. Animals in group IV also had significantly lower metabolic rates on day 12 as compared to the animals in the other groups. These results suggest that large amounts of Vitamin-C have beneficial effects on the maintenance of body weight and metabolic rate following burn trauma.

Antioxidant therapy in the prevention of organ dysfunction syndrome and infectious complications after trauma: early results of a prospective randomized study.

Porter JM, Ivatury RR, Azimuddin K, Swami R. The Lincoln Medical Center, Bronx, New York, USA.

Am Surg 1999 May;65(5):478-83

Reactive oxygen species have been implicated in the etiology of multiorgan dysfunction syndrome and infectious complications in trauma patients by either direct cellular toxicity and/or the activation of intracellular signaling pathways. Studies have shown that the antioxidant defenses of the body are decreased in trauma patients; these include glutathione, for which N-acetylcysteine is a precursor, and selenium, which is a cofactor for glutathione. Eighteen trauma patients were prospectively randomized to a control or antioxidant group where they received N-acetylcysteine, selenium, and vitamins C and E for 7 days. As compared with the controls, the antioxidant group showed fewer infectious complications (8 versus 18) and fewer organs dysfunctioning (0 versus 9). There were no deaths in either group. We conclude that these preliminary data may support a role for the use of this antioxidant mixture to decrease the incidence of multiorgan dysfunction syndrome and infectious complications in the severely injured patient. This remains to be confirmed in larger trials.

Experimental studies on the treatment of frostbite in rats

Purkayastha S.S.; Chhabra P.C.; Verma S.S.; Selvamurthy W. Defence Institute of Physiology, and Allied Sciences, Delhi Cantt 110010 India

Indian J. Med. Res. Sect. B Biomed. Res. Other than Infect. Dis. (India), 1993, 98/Aug. (178-184)

The effect of treatment by high dose of Vitamin-C, rapid rewarming by 37degreeC water alone and with Vitamin-C, rapid rewarming by 37degreeC decoction of Indian black tea alone and with vitamin C for experimentally produced frostbite was evaluated in 6 groups (25 each) of rats. Frostbite was produced experimentally in the hind limbs by exposing the animals at -15 degree C for 1h using the harness technique. The degree of injury was assessed and classified on the basis of tissue necrosis at the end of 15 days. Administration of high dose of Vitamin-C for prolonged period and rapid rewarming at 37degreeC water bath immediately after cold exposure apparently reduced the tissue damage. High dose of Vitamin-C therapy preceded by rapid rewarming in plain water showed additional benefit. Rapid rewarming in decoction of Indian tea resulted in identical beneficial effect. The degree of tissue preservation was highest with rapid rewarming in tea decoction followed by high dose of Vitamin-C.

An experimental study on the protection against reperfusion myocardial ischemia by using large doses of Vitamin-C

Qiao S.; Chen Z.; Song L. Cardiovascular Institute, CAMS, Beijing 100037 China

Chin. J. Cardiol. (China), 1994, 22/1 (52-54+80)

To obtain the practical measure for the ischemia-reperfusion injury, we developed an open chest pig model (occlusion for 1 hour and reperfusion for 2 hours). Vitamin-C (Vit C 0.2 g/kg) was intravenously given within five minutes to 8 pigs and 12 pigs received only saline as control. The results showed that there were no differences in the hemodynamic parameters, but the release of the creatine kinase isoenzyme after the reperfusion was significantly decreased in the vit C group (P < 0.05-0.01), and the ratio of the infarct area and the risk area was 30.2% in the vit C group and 49.2% in controls respectively (P < 0.05). Furthermore, the content of myocardial malondialdehyde was significantly decreased in the vit C group. In order to observe the protective effect of vitamin C we also developed an open chest rabbit model. After four-hour reperfusion, vit C group had less severe bleeding and milder damage to the capillary endothelium than that of control group. On the rabbit model, the myocardial free radicals were directly measured with the electron resonance spectrograph after one half hour reperfusion (P < 0.05). It was found that the free radical content was significantly elevated in the control group (P < 0.05), vit C could inhibit such elevation (P < 0.01). So it was evident that the protection of vit C was directly related to scavenging the free radicals.

[Therapeutic value of antioxidants and calcium channel blockers in patients in the acute phase of closed head injuries] [Article in Serbo-Croatian (Cyrillic)]

Raicevic R, Jovicic A, Markovic T, Marenovic T, Djordjevic D, Magdic B, Peric P.

Vojnosanit Pregl 2000 Nov-Dec;57(6):647-55

Knowing that uncontrolled calcium signalization with excessive production of reactive oxidative matters is present in case of neurotrauma, aim of the investigation was to establish therapeutic value of combined administration of antioxidants (AO) and calcium channel blockers (CCB) in patients with closed head injury (CHI). Investigation comprised 120 patients with CHI who received AO (vitamins C and E) parenterally during 10 days and CCB (nimodipine), and control group was comprised of 60 patients with CHI who did not receive these medicinals in therapeutic program. We have established the influence of the therapy on neurologic and functional deficiency and consciousness disorder, respectively. Results of the investigation confirmed better recovery of all three observed parameters (degree of neurologic deficiency, degree of functional deficiency and consciousness disorder) in a group of patients receiving AO and CCB, which was statistically significant. It can be concluded that the administration of AO and CCB in patients with CHI in the acute phase should be included into therapeutic program of this significant clinical syndrome.

Vitamin E ameliorates adverse effects of endothelial injury in brain arterioles

Rosenblum W.I.; Nelson G.H.; Bei R.A.; Brandt R.B.; Chan W. Dept. of Pathology (Neuropathology), Medical College of Virginia, Virginia Commonwealth Univ., Richmond, VA 23298-0017 USA

American Journal of Physiology - Heart and Circulatory Physiology (USA), 1996, 271/2 40-2 (H637-H642)

Endothelium-dependent dilation, pros unaffected after 6 mo of a diet with zero vitamin E or 8 mo of a vitamin E-enriched diet. The enriched diet did not affect constriction produced by topically applied N(G)-monomethyl-L-arginine, an inhibitor of the synthesis of endothelium-derived relaxing factor (EDRF). EDRF mediates the response to ACh and is a basally released dilator and antiplatelet paracrine substance. Endothelial injury produced by a helium- neon laser and Evans blue technique eliminates the response to ACh, but in vitamin E-enriched mice the response to ACh was unaffected by the injury. More prolonged exposure of the laser induces platelet adhesion/aggregation at the injured site. A significantly longer exposure to the laser was required to initiate adhesion/aggregation in vitamin E-enriched mice. Because effects of endothelial damage in this model are mediated at least in part by singlet oxygen produced by injured tissue, we conclude that the antioxidant, radical-scavenging actions of vitamin E explain the protective action of the vitamin E-enriched diet. However, raising vitamin E levels did not protect against putative adverse effects of normally occurring oxidants.

Clinical outcome and immunology of postoperative arginine, omega-3 fatty acids, and nucleotide-enriched enteral feeding: a randomized prospective comparison with standard enteral and low calorie/low fat i.v. solutions.

Schilling J, Vranjes N, Fierz W, Joller H, Gyurech D, Ludwig E, Marathias K, Geroulanos S. Department of Surgery, University and University Hospital of Zurich, Switzerland.

Nutrition. 1996 Jun;12(6):423-9.

In a prospective randomized trial in patients undergoing major abdominal surgery, the impact of a new enteral formula supplemented with arginine, omega-3 fatty acids, and nucleotides (A, n = 14) on immunological parameters was compared with a standard enteral formula (B, n = 14) and a low calorie/low fat intravenous solution (C, n = 13). Four days postoperatively, a statistically significant decrease in total leukocyte count (A, 9.0 +/- 2.9; B, 8.0 +/- 2.4; C, 11.1 +/- 3.5 x 10(6) cells/mL; A versus C, B versus C; p < 0.05), higher percentage of lymphocytes (A, 14.3 +/- 4.9; C, 8.2 +/- 6.1; p < 0.05), and decreased median CRP levels (A, 80.4 [69.9]; B, 70 [74]; C, 88.5 [142] in mg/L; A versus C, p < 0.05; B versus C; p < 0.05) were observed in the enteral nutrition groups. The expression of activated surface antigen HLA-DR was diminished on CD14+ cells over 4 d (A, 58.2 [39.2]; B, 52.2 [36.2]; C, 76.6 [25.2] in %; A versus C, p < 0.05; B versus C, p < 0.05) and 8-10 d (A, 37.9 [31.4]; C, 58.5 [37.6]; p < 0.05) postoperatively. Significantly enhanced median phagocytic activity of CD14+ monocytes and granulocytes was observed in group C 8-10 days postoperatively (A, 83.3 [11.8]; B, 71.6 [34.1]; C, 87.4 [10.8]; A versus B, B versus C, p < 0.05; and A, 75.7 [10.0]; B, 69.0 [37.8]; C, 80.0 [10.1] in %, B versus C, p < 0.05, respectively). Postoperative hospital and intensive care unit stay was similar among the three groups; however, infectious complications were less frequent in group A (A versus C, p = 0.15). Thus, a modified enteral nutritional support and supplementation may influence the immune competence toward a more efficient defense response.

Early postoperative enteral immunonutrition: clinical outcome and cost-comparison analysis in surgical patients.

Senkal M, Mumme A, Eickhoff U, Geier B, Spath G, Wulfert D, Joosten U, Frei A, Kemen M. Department of Surgery, Ruhr-University Bochum, St. Josef Hospital, Germany.

Crit Care Med. 1997 Sep;25(9):1489-96.

OBJECTIVE: To determine if early postoperative feeding of patients with upper gastrointestinal malignancy, using an enteral diet supplemented with arginine, dietary nucleotides, and omega-3 fatty acids (IMPACT, Sandoz Nutrition, Bern, Switzerland) results in an improved clinical outcome, i.e., reduced infectious and wound complications and decreased treatment costs when compared with an isocaloric, isonitrogenous control diet.

DESIGN: A prospective, randomized, placebo-controlled, double-blind, multicenter trial of the clinical outcome and a retrospective cost-comparison analysis.

SETTING: Surgical intensive care units in three different German university hospitals.

PATIENTS: Of 164 patients enrolled in the study, 154 patients were eligible for analysis. They were admitted to the intensive care unit after upper gastrointestinal surgery for cancer and they received an enteral diet via needle catheter jejunostomy. Infectious complications were defined as sepsis or systemic inflammatory response syndrome, pneumonia, urinary tract infection, central venous catheter sepsis, wound infection, and anastomotic leakage. The complication events were prospectively divided into two groups: early (postoperative days 1 to 5) and late (after the fifth postoperative day) postoperative complications. The treatment costs of each complication were analyzed and compared in both groups.

INTERVENTIONS: Patients were randomized to receive either the immunonutritional diet (n = 77) or an isocaloric and isonitrogenous placebo diet (n = 77). Enteral feeding was initiated 12 to 24 hrs after surgery, starting with 20 mL/hr and advanced to a target volume of 80 mL/hr by postoperative day 5.

MEASUREMENTS AND MAIN RESULTS: Clinical examination and adverse gastrointestinal symptoms were recorded on a daily basis. Both groups tolerated early enteral feeding well, and the rate of tube feeding-related complications was low. Postoperative complications occurred in 17 patients in the immunonutrition group vs. 24 patients in the control group (NS). Further, in the early phase (postoperative day 1 to 5), complications occurred to a similar extent in both groups (12 patients in the immunonutritional group vs. 11 patients in the control group). However, in the late phase (after postoperative day 5), considerably fewer patients in the experimental diet group experienced complications compared with the control group (5 vs. 13, p < .05). In addition, the frequency rate of complicating events were recorded in each group. In the experimental diet group, a total of 22 complicating events were recorded vs. a total of 32 events in the placebo diet group (NS). However, the occurrence of late complicating events, i.e., complicating events after the fifth postoperative day, was significantly reduced in the immunonutrition group when compared with the control group (8 vs. 17 events, p < .05). The total costs for the treatment of the complications were 83,563 German marks in the experimental diet group vs. 122,430 German marks in the control group, resulting in a cost-reduction of 38,867 German marks. (At the end of December 1995, the conversion rate from German marks to U.S. dollars was 1.4365 German marks to $1.00.)

CONCLUSIONS: Early enteral feeding with an arginine, dietary nucleotides, and omega-3 fatty acids supplemented diet, as well as an isonitrogenous, isocaloric control diet (placebo) were well tolerated in patients who underwent upper gastrointestinal surgery. In patients who received the supplemented diet, a significant reduction in the frequency rate of late postoperative infectious and wound complications was observed. Thereby, the treatment costs were substantially reduced in the immunonutrition group as compared with the control group.

Supplemental dietary arginine enhances wound healing in normal but not inducible nitric oxide synthase knockout mice.

Shi HP, Efron DT, Most D, Tantry US, Barbul A. Departments of Surgery, Sinai Hospital of Baltimore and the Johns Hopkins Medical Institutions, Baltimore, MD 21215, USA.

Surgery 2000 Aug;128(2):374-8

BACKGROUND: Although generation of nitric oxide (NO) from inducible nitric oxide synthase (iNOS) has been shown to be required for cutaneous wound healing, no differences have been noted in incisional healing between iNOS knockout (iNOS-KO) and wild type (WT) mice. Because supplemental dietary arginine enhances cutaneous healing in normal rodents and is the sole substrate for NO synthesis, we studied whether arginine can enhance cutaneous wound healing in iNOS-KO mice.

METHODS: Twenty iNOS-KO and 20 WT mice, all on a C57BL/6 background, were divided into 4 groups of 10 animals each. Ten animals with each trait were randomized to receive either normal food and tap water or food and water each supplemented with 0.5% arginine (w/w). All animals underwent a 2.5-cm dorsal skin incision with implantation of four 20-mg polyvinyl alcohol sponges into subcutaneous pockets. On postoperative day 14 the animals were killed. The dorsal wound was harvested for breaking strength determination and the wound sponges were assayed for hydroxyproline content and total wound fluid nitrite/nitrate concentration.

RESULTS: Dietary arginine supplementation enhanced both wound breaking strength and collagen deposition in WT but not iNOS-KO mice. Wound fluid nitrite/nitrate levels were higher in WT than iNOS-KO animals but were not significantly influenced by additional arginine.

CONCLUSIONS: These data demonstrate that supplemental dietary arginine enhances wound healing in normal mice. The loss of a functional iNOS gene abrogates the beneficial effect of arginine in wound healing. This suggests that the metabolism of arginine via the NO pathway is one mechanism by which arginine enhances wound healing.

Closed head injury in the rat induces whole body oxidative stress: overall reducing antioxidant profile.

Shohami E, Gati I, Beit-Yannai E, Trembovler V, Kohen R. Department of Pharmacology, Hebrew University of Jerusalem, Israel. esty@cc.huji.ac.il

J Neurotrauma 1999 May;16(5):365-76

Traumatic injury to the brain triggers the accumulation of harmful mediators, including highly toxic reactive oxygen species (ROS). Endogenous defense mechanism against ROS is provided by low molecular weight antioxidants (LMWA), reflected in the reducing power of the tissue, which can be measured by cyclic voltammetry (CV). CV records biological peak potential (type of scavenger), and anodic current intensity (scavenger concentration). The effect of closed head injury (CHI) on the reducing power of various organs was studied. Water and lipid soluble extracts were prepared from the brain, heart, lung, kidney, intestine, skin, and liver of control and traumatized rats (1 and 24 h after injury) and total LMWA was determined. Ascorbic acid, uric acid, alpha-tocopherol, carotene and ubiquinol-10 were also identified by HPLC. The dynamic changes in LMWA levels indicate that the whole body responds to CHI. For example, transient reduction in LMWA (p<0.01) in the heart, kidney, lung and liver at 1 h suggests their consumption, probably due to interaction with locally produced ROS. However, in some tissues (e.g., skin) there was an increase (p<0.01), arguing for recruitment of higher than normal levels of LMWA to neutralize the ROS. alpha-Tocopherol levels in the brain, liver, lung, skin, and kidney were significantly reduced (p<0.01) even up to 24 h. We conclude that although the injury was delivered over the left cerebral hemisphere, the whole body appeared to be under oxidative stress, within 24 h after brain injury.

Oxidative stress following traumatic brain injury in rats: quantitation of biomarkers and detection of free radical intermediates.

Tyurin VA, Tyurina YY, Borisenko GG, Sokolova TV, Ritov VB, Quinn PJ, Rose M, Kochanek P, Graham SH, Kagan VE. Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15238, USA.

J Neurochem 2000 Nov;75(5):2178-89

Oxidative stress may contribute to many pathophysiologic changes that occur after traumatic brain injury. In the current study, contemporary methods of detecting oxidative stress were used in a rodent model of traumatic brain injury. The level of the stable product derived from peroxidation of arachidonyl residues in phospholipids, 8-epi-prostaglandin F(2alpha), was increased at 6 and 24 h after traumatic brain injury. Furthermore, relative amounts of fluorescent end products of lipid peroxidation in brain extracts were increased at 6 and 24 h after trauma compared with sham-operated controls. The total antioxidant reserves of brain homogenates and water-soluble antioxidant reserves as well as tissue concentrations of ascorbate, GSH, and protein sulfhydryls were reduced after traumatic brain injury. A selective inhibitor of cyclooxygenase-2, SC 58125, prevented depletion of ascorbate and thiols, the two major water-soluble antioxidants in traumatized brain. Electron paramagnetic resonance (EPR) spectroscopy of rat cortex homogenates failed to detect any radical adducts with a spin trap, 5,5-dimethyl-1-pyrroline N:-oxide, but did detect ascorbate radical signals. The ascorbate radical EPR signals increased in brain homogenates derived from traumatized brain samples compared with sham-operated controls. These results along with detailed model experiments in vitro indicate that ascorbate is a major antioxidant in brain and that the EPR assay of ascorbate radicals may be used to monitor production of free radicals in brain tissue after traumatic brain injury.

Influence of arginine, omega-3 fatty acids and nucleotide-supplemented enteral support on systemic inflammatory response syndrome and multiple organ failure in patients after severe trauma.

Weimann A, Bastian L, Bischoff WE, Grotz M, Hansel M, Lotz J, Trautwein C, Tusch G, Schlitt HJ, Regel G. Klinik fur Abdominal- und Transplantationschirurgie, Medizinische Hochschule Hannover, Germany.

Nutrition. 1998 Feb;14(2):165-72.

This study investigated the influence of an enteral diet supplemented with arginine, omega-3 fatty acids, and nucleotides (Impact, Sandoz Nutrition, Berne, Switzerland) on the incidence of systemic inflammatory response syndrome (SIRS) and multiple organ failure (MOF) in patients after severe trauma. Thirty-two patients with an injury-severity score > 20 were included in this prospective, randomized, double-blind, controlled study. Primary endpoints were the incidence of SIRS and MOF. Secondary endpoints were parameters of acute phase and immune response as well as infection rate, mortality, and hospital stay. For statistical analysis 29 patients (test group n = 16, control n = 13) were eligible. In the test group, significantly fewer SIRS days per patient were found during 28 d. The difference was highly significant between d 8-14 (P < 0.001). MOF score was significantly lower in the test group on d 3 and d 8-11 (P < 0.05). Acute phase parameters showed lower C-reactive protein serum levels (significant on D day 4) and fibrinogen plasma levels (significant on d 12 and 14; P < 0.05). HLA-DR expression on monocytes showed significantly higher fluorescence activity on d 7. No significant difference was found for T-lymphocyte CD4/CD8 ratio, interleukin-2 receptor expression, infection rate, mortality (2/16 vs. 4/13), and hospital stay. The results of the study provide further support for beneficial effects of arginine, omega-3-fatty acids and nucleotide-supplemented enteral diet in critically ill patients.

Effects of vitamin E on T cell lipid peroxidation, membrane fluidity and T cell functions in traumatized mice

Liang H.-P.; Wang Z.-G.
Research Institute of Surgery, Third Military Medical College, Chongqing 630042 China
Chinese Pharmacological Bulletin (China), 1996, 12/1 (47-49)

SUBFILES:Ranges of T cell malondialdehyde (MDA) contents, membrane fluidity, Tcell functions and therapeutic effects of vitamin E (V-E) were observed in traumatized mice. The results showed that T cell MDA contents were increased after trauma, membrane fluidity of T cell plasmalemma, mitochondria and microsome reduced and T lymphocytes transformation, interleukin 2 (IL-2) production, IL-2 receptor (IL-2R) expression and IL-2 mediated lymphocytes proliferation response were suppressed, which were related closely to MDA alteration. In vivo administration of V-E (50 or 100 mg/kg.d-1, im x 4 d) could reverse ahove parameters, indicating lipid peroxidation after trauma is an important cause resulting in reduced T cell membrane fluidity and were suppressed T cell functions, on which V-E shows significant therapeutic effects.

Vitamin E ameliorates adverse effects of endothelial injury in brain arterioles

Rosenblum W.I.; Nelson G.H.; Bei R.A.; Brandt R.B.; Chan W.
Dept. of Pathology (Neuropathology), Medical College of Virginia, Virginia Commonwealth Univ., Richmond, VA 23298-0017 USA
American Journal of Physiology - Heart and Circulatory Physiology (USA), 1996, 271/2 40-2 (H637-H642)

Endothelium-dependent dilation, pros unaffected after 6 mo of a diet with zero vitamin E or 8 mo of a vitamin E-enriched diet. The enriched diet did not affect constriction produced by topically applied N(G)-monomethyl-L-arginine, an inhibitor of the synthesis of endothelium-derived relaxing factor (EDRF). EDRF mediates the response to ACh and is a basally released dilator and antiplatelet paracrine substance. Endothelial injury produced by a helium- neon laser and Evans blue technique eliminates the response to ACh, but in vitamin E-enriched mice the response to ACh was unaffected by the injury. More prolonged exposure of the laser induces platelet adhesion/aggregation at the injured site. A significantly longer exposure to the laser was required to initiate adhesion/aggregation in vitamin E-enriched mice. Because effects of endothelial damage in this model are mediated at least in part by singlet oxygen produced by injured tissue, we conclude that the antioxidant, radical-scavenging actions of vitamin E explain the protective action of the vitamin E-enriched diet. However, raising vitamin E levels did not protect against putative adverse effects of normally occurring oxidants.

Vitamin E, thiobarbituric acid reactive substance concentrations and superoxide dismutase activity in the blood of children with juvenile rheumatoid arthritis

Sklodowska M.; Gromadzinska J.; Biernacka M.; Wasowicz W.; Wolkanin P.; Marszalek A.; Brozik H.; Pokuszynska K.
Dept. of Plant Physiology/Biochem., University of Lodz, Banacha St. 12/16, 90-237 Lodz Poland
Clinical and Experimental Rheumatology (Italy), 1996, 14/4 (433-439)

Objective: To study the role of amined the levels of thiobarbituric acid reactive substances (TBARS) and antioxidants of the first line antioxidative defence of the organism, i.e. vitamin E (VE) and superoxide dismutase (SOD) in the blood of 74 young patients with juvenile rheumatoid arthritis (JRA) and in 138 healthy children, all aged 3-15.

Results: A statistically significant increase of TBARS was found in the blood plasma of the children with JRA compared with the control group. In the whole group of patients and in the patients over 6 years of age, the VE concentration was significantly lower in the blood plasma and significantly higher in the erythrocytes than in the control groups. SOD activity in the red blood cells (RBC) was significantly lower in children who had suffered from JRA for more than one year and in those with the systemic form of the disease. The type of treatment also affected the values for the plasma VE and SOD in the RBC.

Conclusion: Our results seem to confirm the supposition of increased oxidative stress in children with JRA and low antioxidant levels in terms of SOD activity and vitamin E concentrations.

Acceleration of corneal wound healing in diabetic rats by the antioxidant trolox

Hallberg CK, Trocme SD, Ansari NH
Department of Human Biological Chemistry & Genetics, University of Texas Medical Branch, Galveston 77555-0647, USA.
Res Commun Mol Pathol Pharmacol 1996 Jul;93(1):3-12

Several corneal complications have been reported in patients with long standing diabetes, but their exact pathogenesis is not well understood. It has been observed that the rate of epithelial wound healing in diabetic rats is delayed compared to those in normal animals. Here we present the effect of the free radial scavenger, Trolox, a water soluble vitamin E analogue, on epithelial wound healing in diabetic rat cornea. Three groups of rats were included:

1) normal,
2) diabetic,
3) diabetic + Trolox.

After 3 months, rats were sacrificed and corneas removed. Standard 3 mm diameter corneal epithelial defects were made and residual epithelial defects were measured after 18 hours at 37degreeC in a sterile cell culture incubator. Wound healing data measured in mm2 was used for statistical analysis. There were significantly larger (p < 0.05) epithelial defects in diabetic corneas as compared to control. Treatment with Trolox antioxidant in diabetic rats produced a significantly smaller (p < 0.05) epithelial defect than that of untreated diabetic rats. These studies suggest the involvement of free radicals in the delay of corneal epithelial wound healing in diabetes.

Antioxidant vitamins in hospitalized elderly patients: Analysed dietary intakes and biochemical status

Schmuck A.; Ravel A.; Coudray C.; Alary J.; Franco A.; Roussel A.-M.
GREPO, Universite Joseph Fourier, Domaine de la Merci, 38700 La Tronche France
European Journal of Clinical Nutrition (United Kingdom), 1996, 50/7 (473-478)

Design: Descriptive study. Setting: Geriatric department of the Grenoble University Hospital.

Subjects: 24 hospitalized elderly women: 13 long-stay patients and 11 in rehabilitation after femoral neck fracture.

Main outcome measures: Retinol, carotene, tocopherol and Vitamin-C dietary intakes were evaluated by 5-day duplicate portion analysis. Circulating levels of retinol, beta-carotene, alpha-tocopherol and Vitamin-C were determined in parallel (HPLC).

Results: Mean intake of Vitamin-C (21 mg/d), and vitamin E (3.1 mg alpha-tocopherol equivalents TE/d) were low compared to recommendations, in relation with poor energy intake (5.27 MJ/d) and nutrient densities. More than 85% of the patients exhibited Vitamin-C and vitamin E intakes below two-thirds the recommendations (60 mg/d and 10 mg TE/d, respectively) and 50% did not meet recommendations for vitamin A (800 microg retinol equivalents/d). With the exception of retinol, dietary vitamin intakes were positively correlated to corresponding blood concentrations. No values below cut-off levels were found concerning plasma retinol, plasma tocopherol or ratio of alpha-tocopherol to cholesterol. In contrast, 26% and 32% of the elderly patients had low circulating levels of beta-carotene and Vitamin-C, respectively.

Conclusions: The present study highlights low antioxidant vitamin intakes, particularly concerning vitamin E and Vitamin-C, and an important proportion of low blood Vitamin-C and beta-carotene concentrations in hospitalized elderly women. Further studies are needed to determine the actual requirements of hospitalized elderly patients and to evaluate the potential benefits of providing micronutrient-enriched foods to this population.

Effect of dietary Vitamin-C on compression injury of the spinal cord in a rat mutant unable to synthesize ascorbic acid and its correlation with that of vitamin E

Katoh D, Ikata T, Katoh S, Hamada Y, Fukuzawa K
Department of Orthopedic Surgery, School of Medicine, Tokushima, Japan.
Spinal Cord (United Kingdom), 1996, 34/4 (234-238)

The roles of vitamines after spinal cord injury were investigated by evaluating the effects of dietary Vitamin-C on experimental spinal cord injury in a mutant strain of Wistar rats unable to synthesize ascorbic acid (ODS rats). Two groups of ODS rats were given Vitamin-C-deficient or Vitamin-C-supplemented diet for 1 week before injury. Motor disturbance induced by spinal cord injury was found to be greater in the Vitamin-C-deficient group. Histologically, the area of bleeding in the spinal cord was also greater in the Vitamin-C-deficient group. The levels of ascorbic acid and alpha-tocopherol in the spinal cord tissue and serum decreased during and after compression injury of the spinal cord. The decrease of alpha-tocopherol was similar in the two groups. However, the decrease of ascorbic acid was greater in the Vitamin-C-supplemented group. These results indicated that their protective effects against spinal cord injury are through scavenging water-soluble free radicals by vitamin C and lipid-soluble by vitamin E, and the effects of these vitamins were suggested to be independent.

Antioxidant depletion, lipid peroxidation, and impairment of calcium transport induced by air-blast overpressure in rat lungs

Elsayed NM, Tyurina YY, Tyurin VA, Menshikova EV, Kisin ER, Kagan VE
Department of Respiratory Research, Walter Reed Army Institute of Research, Washington, DC 20307-5100, USA.
Experimental Lung Research (USA), 1996, 22/2 (179-200)

Exposure to blast overpressure, or the sudden rise in atmospheric pressure after explosive detonation, results in damage mainly of the gas-filled organs. In addition to the physical damage, in the lung, injury may proceed via a hemorrhage-dependent mechanism initiating oxidative stress and accumulation of lipid peroxidation products. Massive rupture of capillaries and red blood cells, release of hemoglobin, its oxidation to met-hemoglobin and degradation sets the stage for heme-catalyzed oxidations. The authors hypothesized that lipid hydroperoxides interact with met-hemoglobin in the lungs of exposed animals to produce ferryl-hemoglobin, an extremely potent oxidant that induces oxidative damage by depleting antioxidants and initiating peroxidation reactions. Oxidation-induced disturbance of Ca2+ homeostasis facilitates further amplification of the damage. To test this hypothesis, groups of anesthetized rats (6 rats/group) were exposed to blast at 3 peak pressures: low (61.2 kPa), medium (95.2 kPa), high (136 kPa). One group served as an unexposed control. Immediately after exposure, the rats were euthanized and the lungs were analyzed for biochemical parameters. Blast overpressure caused:

(1) depletion of total and water-soluble pulmonary antioxidant reserves and individual antioxidants (ascorbate, vitamin E, GSH),

(2) accumulation of lipid peroxidation products (conjugated dienes, TBARS), and

(3) inhibition of ATP-dependent Ca2+ transport. The magnitude of these changes in the lungs was proportional to the peak blast overpressure. Inhibition of Ca2+ transport strongly correlated with both depletion of antioxidants and enhancement of lipid peroxidation. In model experiments, met-hemoglobin/H2O2 produced damage to Ca2+ transport in the lungs from control animals similar to that observed in the lungs from blast overpressure-exposed animals. Ascorbate, which is known to reduce ferryl- hemoglobin, protected against met-hemoglobin/H2O2-induced damage of Ca2+ transport. If ferryl-hemoglobin is the major reactive oxygen species released by hemorrhage, then its specific reductants (e.g., nitric oxide) along with other antioxidants may be beneficial protectants against pulmonary barotrauma.

The use of antioxidants in healing

Martin A
Warner-Lambert Company, Morris Plains, New Jersey 07950, USA.
Dermatologic Surgery (USA), 1996, 22/2 (156-160)

BACKGROUND. Antioxidants enhance the healing of infected and noninfected wounds by reducing the damage caused by oxygen radicals.

OBJECTIVE. Studies were conducted to determine if the CRT components (vitamin E, sodium pyruvate, and specific fatty acids) could synergistically enhance healing.

METHODS. In vitro and in vivo studies were used to assess the effect of various combination of CRT components.

RESULTS. CRT reduced oxidative damage to keratinocytes and monocytes exposed to ultraviolet light and toxic chemicals and provided protection to human subjects exposed to ultraviolet irradiation. CRT dramatically facilitated healing of infected and noninfected wounds. In herpes-infected guinea pigs, CRT reduced vaginal viral lesion development, severity, and duration, thus facilitated healing of the lesions. CRT also reversed doxorubicin cytotoxicity in monocytes and reversed doxorubicin-impaired wound healing in rats.

CONCLUSION: The CRT colly to enhancing healing of injuries.

Effect of vitamin e on hydrogen peroxide production by human vascular endothelial cells after hypoxia/reoxygenation

Martin A, Zulueta J, Hassoun P, Blumberg JB, Meydani M
Antioxidant Research Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA, USA.
Free Radical Biology and Medicine (USA), 1996, 20/1 (99-105)

Changes in oxidative stress status play an important role in tissue injury associated with ischemia-reperfusion events such as those that occur during stroke and myocardial infarction. Endothelial cells (EC) from human saphenous vein and aorta were incubated for 22 h and found to take up vitamin E from media containing 0-60 mM vitamin E in a dose-dependent manner. EC supplemented with 23 or 28 mM vitamin E in the media for 22 h were maintained at normoxia (20% O2, 5% CO2, and balance N2) or exposed to hypoxic conditions (3% 30 min. Saphenous EC supplemented with 23 mM vitamin E produced less (p < 0.05) H2O2 than unsupplemented controls, both at normoxic condition (supplemented: 4.9 plus or minus 0.05 vs. control:10.9 plus or minus 1.3 pmol/min/106 cells) and following hypoxia/reoxygenation (supplemented: 6.4 plus or minus 0.78 vs. control:17.0 plus or minus 2.7 nmol/min/106 cells). In contrast, aortic EC, which were found to have higher superoxide dismutase and catalase activity than EC from saphenous vein, did not produce any detectable levels of H2O2. Following hypoxia/reoxygenation, the concentration of vitamin E in supplemented saphenous EC was 62% lower than cells maintained at normoxia (0.19 plus or minus 0.03 vs. 0.5 plus or minus 0.12 nmoles/106 cells. p < 0.001); in aortic EC vitamin E content was reduced by 18% following reoxygenation (0.86 plus or minus 0.16 vs, 070 plus or minus 0.09 nmoles/106 cells, p < 0.05). Therefore, enrichment of vitamin E in EC decreases H2O2 production and thus may reduce the injury associated with ischemia-reperfusion events.

Cerebral astrocytes transport ascorbic acid and dehydroascorbic acid through distinct mechanisms regulated by cyclic AMP.

Siushansian R, Tao L, Dixon SJ, Wilson JX
Department of Physiology, Faculty of Medicine, University of Western Ontario, London, Canada.
J Neurochem (United States) Jun 1997, 68 (6) p2378-85

Cerebral ischemia and trauma lead to rapid increases in cerebral concentrations of cyclic AMP and dehydroascorbic acid (DHAA; oxidized Vitamin-C), depletion of intracellular ascorbic acid (AA; reduced Vitamin-C), and formation of reactive astrocytes. We investigated astrocytic transport of AA and DHAA and the effects of cyclic AMP on these transport systems. Primary cultures of astrocytes accumulated millimolar concentrations of intracellular AA when incubated in medium containing either AA or DHAA. AA uptake was Na+-dependent and inhibited by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), whereas DHAA uptake was Na+-independent and DIDS-insensitive. DHAA uptake was inhibited by cytochalasin B, D-glucose, and glucose analogues specific for facilitative hexose transporters. Once inside the cells, DHAA was reduced to AA. DHAA reduction greatly decreased astrocytic glutathione concentration. However, experiments with astrocytes that had been previously depleted of glutathione showed that DHAA reduction does not require physiological concentrations of glutathione. Astrocyte cultures were treated with a permeant analogue of cyclic AMP or forskolin, an activator of adenylyl cyclase, to induce cellular differentiation and thus provide in vitro models of reactive astrocytes. Cyclic AMP stimulated uptake of AA, DHAA, and 2-deoxyglucose. The effects of cyclic AMP required at least 12 h and were inhibited by cycloheximide, consistent with a requirement for de novo protein synthesis. Uptake and reduction of DHAA by astrocytes may be a recycling pathway that contributes to brain AA homeostasis. These results also indicate a role for cyclic AMP in accelerating the clearance and detoxification of DHAA in the brain.

Osmotic swelling stimulates ascorbate efflux from cerebral astrocytes.

Siushansian R, Dixon SJ, Wilson JX
Department of Physiology, University of Western Ontario, London, Canada.
J Neurochem (United States) Mar 1996, 66 (3) p1227-33

Ascorbate (reduced Vitamin-C) is an important enzyme cofactor, neuromodulator, and antioxidant that is stored at millimolar concentrations in the cytosol of cerebral astrocytes. Because these cells swell during hyponatremia, cerebral ischemia,sport of ascorbate. Ascorbate efflux from primary cultures of rat astrocytes was rapidly (within 1 min) increased by incubation in hypotonic medium. Efflux also increased when astrocytes, which had been adapted to a hypertonic environment, were swollen by transfer to isotonic medium. Swelling-induced ascorbates efflux was inhibited by the anion-transport inhibitors 4,4'-diisothiocyanostilbene-2,2 '-disulfonic acid (DIDS) and 4,4'-dinitrostilbene-2,2'-disulfonic acid (DNDS). The pathway that mediates ascorbate efflux was found to be selective because a larger anion, 2',7'-bis(carboxyethyl)-5-(or -6)-carboxyfluorescein (BCECF), was retained in the swollen astrocytes. Na(+)-dependent ascorbate uptake into astrocytes was inhibited slightly during the first minute of hypotonic stress, indicating that the sodium ascorbate cotransporter does not mediate swelling-induced efflux. Cell concentration of authentic ascorbate was measured by HPLC with electrochemical detection. When astrocytes were incubated in ascorbate-free medium, hypotonicity decreased cell ascorbate concentration by 50% within 3 min. When astrocytes were incubated in ascorbate-supplemented hypotonic medium, intracellular ascorbate concentration was restored within 10 min because uptake remained effective. Many pathological conditions cause brain cell swelling and formation of reactive oxygen species. Ascorbate release during during astrocytic swelling may contribute to cellular osmoregulation in the short-term and the scavenging of reactive oxygen species.

Amphiphilic alpha-tocopherol analogues as inhibitors of brain lipid peroxidation.

Bolkenius FN, Verne-Mismer J, Wagner J, Grisar JM
Marion Merrell Dow Research Institute, Strasbourg, France
FrankBolkenius@mmd.com
Eur J Pharmacol (Netherlands) Feb 29 1996, 298 (1) p37-43

Neurological disorders, such as stroke, trauma, tardive dyskinesia, Alzheimer's and Parkinson's diseases, may be partially attributed to excessive exposition of the nervous tissue to oxygen-derived radicals. A novel water-soluble alpha-tocopherol analogue, 2,3-dihydro-2 ,2,4,6,7-pentam ethyl-3methylpiperazino) methyl-1-benzofuran-5-ol dihydrochloride (MDL), is a potent radical scavenger. Following subcutaneous administration to mice, MDL inhibited the lipid peroxidation induced in the 100-fold diluted brain homogenates, with an ID50 of 8 mg/kg. Rapid brain penetration, within 30-60 min postadministration, and even distribution into different brain areas were observed. MDL was also detected after oral administration. In brain homogenate undergoing lipid peroxidation, MDL prevented the consumption of an equal amount of alpha-tocopherol, while inhibiting the concomitant malondialdehyde formation. The radical scavenging capacity of MDL was superior to that of alpha-tocopherol, although the peak and half-peak potentials were not significantly different. However, MDL was much less lipophilic, the partition coefficient (log P) at the octanol/water interface being 1.91. Although it is yet unknown, whether the applied criteria sufficiently predict its usefulness, beneficial effects of MDL may be expected in the above mentioned disorders.

Update on the biological characteristics of the antioxidant micronutrients: Vitamin-C, vitamin E, and the carotenoids.

Rock CL, Jacob RA, Bowen PE
Program in Human Nutrition, University of Michigan, Ann Arbor 48109-2029, USA.
J Am Diet Assoc (United States) Jul 1996, 96 (7) p693-702; quiz 703-4

Under normal circumstances, free radicals that are produced through biological processes and in response to exogenous stimuli are controlled by various enzymes and antioxidants in the body. Laboratory evidence suggests that oxidative stress, which occurs when free radical formation exceeds the ability to protect against them, may form the biological basis of several acute medical problems, such as tissue injury after trauma, and chronic conditions, such as atherosclerosis and cancer. A potential role for the antioxidant micronutrients (Vitamin-C, vitamin E, and the carotenoids) in modifying the risk for conditions that may result from oxidative stress has stimulated intense research efforts, increased interest in micronutrient supplements, and heightened consumer interest in these compounds. Much remains to be learned, however, about the bioavailability, tissue uptake, metabolism, and biological activities of these micronutrients. These biological characteristics will ultimately determine their clinical usefulness in modulating oxidative stress. Also, whether the antioxidant mechanism explains their relationship with risk for acute and chronic disease in epidemiologic studies remains to be determined. Increased knowledge in this area of nutrition science will have an impact on both clinical dietetics practice and public health nutrition guidelines.

Effect of allopurinol, sulphasalazine, and Vitamin-C on aspirin induced gastroduodenal injury in human volunteers

McAlindon ME, Muller AF, Filipowicz B, Hawkey CJ
Division of Gastroenterology, University Hospital, Nattingham.
United Kingdom Gut (United Kingdom), 1996, 38/4 (518-524)

Background - The mechanisms of aspirin induced gastroduodenal injury are not fully understood. Aspirin induces the release of reactive oxygen metabolites in animal models, which may contribute to mucosal injury.

Aims - To investigate the effects of aspirin administered with placebo or antioxidants on gastric mucosal reactive oxygen metabolite release and gastroduodenal injury in human volunteers. Subjects - Fourteen healthy volunteers participated in the study (seven male; mean age 27 years, range 20-40).

Methods - In a double blind, randomised, crossover study, volunteers received aspirin 900 mg twice daily and either placebo, allopurinol 100 mg twice daily, sulphasalazine l g twice daily or Vitamin-C 1 g twice daily for three days. Injury was assessed endoscopically and by quantifying mucosal reactive oxygen metabolite release by measuring chemiluminescence before and after each treatment. The effect on prostanoids was determined by measuring ex vivo antral prostaglandin E2 (PGE2) synthesis and serum thromboxane B2 (TXB2).

Results - No drug reduced any parameter of gastric injury but Vitamin-C reduced duodenal injury assessed by Lanza score (p < 0.005). Chemiluminescence increased after aspirin both with placebo (p < 0.05) and vitamin C (p < 0.05). Post-treatment chemiluminescence was lower in subjects taking allopurinol (p < 0.05) or sulphasalazine (p < 0.005) than in those taking placebo with aspirin.

Conclusions - In this study, aspirin induced gastric injury was associated with reactive oxygen metabolite release. This was reduced by sulphasalazine and allopurinol, although macroscopic injury was not affected. Vitamin-C, however, was shown to have a previously unrecognised protective effect against aspirin induced duodenal injury.

Hemodynamic effects of delayed initiation of antioxidant therapy (beginning two hours after burn) in extensive third-degree burns

Tanaka H, Hanumadass M, Matsuda H, Shimazaki S, Walter RJ, Matsuda T
Burn Center, Cook County Hospital, Chicago, IL 60612, USA.
Journal of Burn Care and Rehabilitation (USA), 1995, 16/6 (610-615)

The hemodynamic effects of the delayed initiation of antioxidant therapy with high-dose Vitamin-C were studied in 12 guinea pigs with third-degree burns over 70% of their body surface area. All animals were resuscitated with Ringer's lactate solution (RE) according to the Parkland formula (4 ml/kg/% burn during the first 24 hours) from one-half to 2 hours after burn, and the infusion rate was reduced thereafter to 23% of that of the Parkland formula. The Vitamin-C group (n = 6) received RL with Vitamin-C (14 mg/kg/hr), and the control group (n = 6) received RE only. The 24-hour fluid intake for each group was 32.5% of the Parkland formula volume. Burn wound edema in the Vitamin-C group was significantly less than that in the control group. The Vitamin-C group maintained adequate hemodynamic stability as determined with hematocrit and cardiac output values, but the control group did not. Even though the initiation of the Vitamin-C administration is delayed until 2 hours after burn, the hourly infusion rate of the resuscitation fluid can be reduced to 25% once it is started. Thus antioxidant therapy with adjuvant Vitamin-C administration may be applicable to the clinical setting in which a patient with burns arrives at the burn care facility a few hours after the burn injury occurred.

Dietary intake and plasma levels of antioxidant vitamins in health and disease: A hospital-based case-control study

Singh R, Niaz M, Ghosh S, Beegum R
Journal of Nutritional and Environmental Medicine (United Kingdom), 1995, 5/3, p 235

Of 1667 subjects that attended the hospital, 1335 were patients with diagnosed medical conditions, together with 202 randomly selected apparently healthy controls from the same population, were studied in detail for demographic variables, dietary and biochemical data. Dietary consumption of antioxidant vitamins A, E, and C and beta-carotene and soluble fibre was lower in the majority of conditions compared to controls. Plasma concentrations of Vitamin-C and beta-carotene were significantly lower in all patient groups. Reduced vitamin E levels were noted in patients with cardiovascular diseases, stroke, Parkinson's disease, chronic renal failure, nephrotic syndrome, type A behaviour, post-partum psychosis, burns, liver diseases, cancer, rheumatoid arthritis and aluminium phosphide poisoning. Lipid peroxides (thiobarbituric acid reactive substances), which are an indicator of oxygen-derived free radical damage, were significantly higher than controls in most conditions and marginally higher in respiratory and psychiatric conditions. Lipid peroxides levels were much greater over all in acute myocardial infarction, cancer, stroke, nephrotic syndrome, chronic renal failure, liver diseases, post-partum psychosis, pregnancy, burns and aluminium phosphide poisoning. Pool dietary intake alone does not explain the decreases in plasma levels of antioxidants and increases in lipid peroxides. Decreases may also be due to increased demands for antioxidants to counter free radical damage.

Vitamin-C and pressure sores

Galley H
Journal of Dermatological Treatment (United Kingdom), 1995, 6/3, p 195

This review describes 50 years of studies on the relationship between Vitamin-C and wound healing. Several early studies in animals reported a clear link between Vitamin-C depletion and impaired wound healing, shown later to be due to an effect on collagen synthesis. Further clinical studies found that supplementary Vitamin-C improves wound healing even in apparently Vitamin-C-replete individuals. Associations between Vitamin-C and pressure sore development, and healing of pre-existing pressure sores have been described, suggesting a therapeutic role for Vitamin-C supplementation. However, this would be complementary to current nursing and skin care strategies in patients with, or at risk of developing, pressure sores, such as those elderly patients admitted with femoral neck fractures, or paraplegic subjects.

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Supplementation with vitamins C and E suppresses leukocyte oxygen free radical production in patients with myocardial infarction

Herbaczynska-Cedro K.; Klosiewicz-Wasek B.; Cedro K.; Wasek W.; Panczenko-Kresowska B.; Wartanowicz M.
Medical Research Centre, Polish Academy of Sciences, Dworkowa 3, 00-754 Warsaw Poland
European Heart Journal (United Kingdom), 1995, 16/8 (1044-1049)

Clinical studies suggest that neutrophil activation during acute myocardial infarction (MI) aggravates tissue injury. Activated neutrophils are an important source of oxygen free radicals (OFR), the injurious effects of which are counteracted by endogenous antioxidants. We have previously shown in healthy subjects that supplementation with antioxidant vitamins C and E suppresses OFR production by isolated neutrophils assayed by chemiluminescence (CL). the present study, performed in patients with acute MI aimed

(1) to investigate the effect of Vitamin-C and E supplementation upon neutrophil OFR production and serum lipid peroxides,

(2) to evaluate serum levels of vitamins C and E in the course of MI.

Forty-five patients with acute MI were randomized to receive either conventional treatment plus Vitamin-C and E aa 600 mg.day-1 p.o. for 14 days (VIT,n=23) or conventional treatment only (control, n=22). All measurements were performed on the 1st and 14th day. Neutrophil OFR production assayed by CL decreased significantly in VIT patients (Wilcoxon test for paired data P<0.01, Chi square test P<0.01). In the control group, changes in OFR production were not significant. Serum lipid peroxides (measured as TBARS) increased in controls (P<0.05), but remained stable in VIT patients. Mean (plus or minusSE) serum ascorbic acid and tocopherol on the 1st day were 0.43 plus or minus 0.18mg% and 3.25 plus or minus 1.32 microM.mM -1 cholesterol, respectively, in all patients. On the 14th day in non-supplemented patients mean tocopherol was unchanged, whereas ascorbic acid increased significantly (0.63 plus or minus 0.24 mg%, P<0.01) suggesting that a low basal level was associated at least in part with the acute phase of the disease. An expected increase in serum vitamin levels occurred in VIT patients. In conclusion, supplementation with vitamins C and E suppresses neutrophil OFR production and lowers the marker of lipid peroxidation in patients with MI. These effects, together with a deficiency of antioxidant vitamins, particularly vitamin C in the early phase of the disease, support the view that supplementation with antioxidant vitamins is advisable in patients with MI.

Antioxidant therapy using high dose Vitamin-C: Reduction of postburn resuscitation fluid volume requirements

Matsuda T.; Tanaka H.; Reyes H.M.; Richter H.M. III; Hanumadass M.M.; Shimazaki S.; Matsuda H.; Nyhus L.M.; Baxter C.R.
Department of Surgery/Burn Center, Cook County Hospital, University of Illinois, 700 S. Wood Street, Chicago, IL 60612 USA
World Journal of Surgery (USA), 1995, 19/2 (287-291)

Twenty-four guinea pigs with third degree burns over 70% of the body surface area were divided equally into four groups. At 0.5 hours postburn, all groups received Ringer's lactate solution (R/L) according to the Parkland formula. The infusion rate was then reduced to 25% of the Parkland formula at 1.5 hours postburn. Group 1 received only R/L, and groups 2, 3 and 4 received adjuvant Vitamin-C (14.2 mg/kg/hr) until 4, 8, and 24 hours postburn, respectively. The volume of R/L was reduced by that of Vitamin-C solution so that the hourly sodium and fluid intake in each group was the same. Groups 1 and 2 demonstrated higher hematocrit and lower cardiac output values than did group 3, suggesting hypovolemia and hemoconcentration in these groups. Group 3 showed hematocrit and cardiac output values equivalent to those in group 4. We conclude that high dose Vitamin-C infusion maintains hemodynamic stability in the presence of a reduced resuscitation fluid volume provided Vitamin-C is administered for a minimum of 8 hours postburn.

Vitamin-C reduces ischemia-reperfusion injury in a rat epigastric island skin flap model

Zaccaria A.; Weinzweig N.; Yoshitake M.; Matsuda T.; Cohen M.
Division of Plastic Surgery, University of Illinois, M/C 958, 820 S Wood St, Chicago, IL 60612-7316 USA
Ann. Plast. Surg. (USA), 1994, 33/6 (620-623)

Free radicals have been implicated in the cause of ischemia-reperfusion injury. Various agents have been used in an attempt to reduce ischemia-reperfusion injury pharmacologically, including free radical scavengers. Vitamin-C (ascorbic acid), a well-known free radical scavenger, has not, to the best of our knowledge, been evaluated in this respect. Previous work at our institution has shown that Vitamin-C decreases capillary permeability, thus significantly reducing fluid resuscitation requirements in postburn cases. Because this is due in part to the scavenging effect of Vitamin-C on free radicals, we investigated the role, if any, of Vitamin-C on ischemia-reperfusion injury in a rat epigastric island skin flap model. Twenty-four adult Sprague-Dawley rats were divided into control and vitamin C groups. Superficial epigastric island skin flaps measuring 6.0 x 3.5 cm were raised. Pedicles were isolated and occluded with microvascular clamps for 6 hours. The flaps were then sutured back to their beds over Steri-Drape barriers. Fifteen minutes before reperfusion, the control group flaps were perfused via femoral artery cannulation with normal saline (2.5 ml/kg). The Vitamin-C- treated group was perfused in a similar fashion with 2.5 ml/kg of a Vitamin-C/normal saline solution (27 mg/ml). The animals were observed for 7 days, and the percentage of flap survival was determined using a paper template technique. The Vitamin-C-treated group demonstrated a significantly higher percentage of flap survival than did the control group (25.8% mean vs. 7.5% mean, p < 0.025). In this animal model, Vitamin-C reduced or limited reperfusion injury after 6 hours of ischemia. Its presumed mechanisms of free radical reduction and its relative safety make Vitamin-C a promising area of investigation in future animal studies as well as in human studies examining reperfusion injury.

An experimental study on the protection against reperfusion myocardial ischemia by using large doses of Vitamin-C

Qiao S.; Chen Z.; Song L.
Cardiovascular Institute, CAMS, Beijing 100037 China
Chin. J. Cardiol. (China), 1994, 22/1 (52-54+80)

To obtain the practical measure for the ischemia-reperfusion injury, we developed an open chest pig model (occlusion for 1 hour and reperfusion for 2 hours). Vitamin-C (Vit C 0.2 g/kg) was intravenously given within five minutes to 8 pigs and 12 pigs received only saline as control. The results showed that there were no differences in the hemodynamic parameters, but the release of the creatine kinase isoenzyme after the reperfusion was significantly decreased in the vit C group (P < 0.05-0.01), and the ratio of the infarct area and the risk area was 30.2% in the vit C group and 49.2% in controls respectively (P < 0.05). Furthermore, the content of myocardial malondialdehyde was significantly decreased in the vit C group. In order to observe the protective effect of vitamin C we also developed an open chest rabbit model. After four-hour reperfusion, vit C group had less severe bleeding and milder damage to the capillary endothelium than that of control group. On the rabbit model, the myocardial free radicals were directly measured with the electron resonance spectrograph after one half hour reperfusion (P < 0.05). It was found that the free radical content was significantly elevated in the control group (P < 0.05), vit C could inhibit such elevation (P < 0.01). So it was evident that the protection of vit C was directly related to scavenging the free radicals.

Vitamins as radioprotectors in vivo. I. Protection by Vitamin-C against internal radionuclides in mouse testes: Implications to the mechanism of damage caused by the auger effect

Narra VR, Harapanhalli RS, Howell RW, Sastry KS, Rao DV
Department of Radiology, University of Medicine and Dentistry of New Jersey, Newark 07103.
USA Radiat. Res. (USA), 1994, 137/3 (394-399)

The potential of Vitamin-C, an antioxidant, to protect the radiosensitive spermatogonial cells in mouse testes against the effects of chronic irradiation by radionuclides incorporated into tissue was investigated. Interestingly, when injected intratesticularly, a small and nontoxic amount of Vitamin-C (1.5 microg in 3 microl saline) protected the spermatogonia against the damage associated with high-LET radiation caused by Auger electrons from similarly administered 5-(125I)-iodo-2'-deoxyuridine (125IdU). A dose modification factor (DMF) of 2.3 was obtained. In contrast, no protection was observed when 210Po, an alpha-particle emitter, was administered similarly. These findings suggest that the mechanism of action of the Auger effect is of an indirect nature, which is in contrast to the direct action generally believed to be responsible for biological damage caused by high-LET radiations.

Experimental studies on the treatment of frostbite in rats

Purkayastha S.S.; Chhabra P.C.; Verma S.S.; Selvamurthy W.
Defence Institute of Physiology, and Allied Sciences, Delhi Cantt 110010 India
Indian J. Med. Res. Sect. B Biomed. Res. Other than Infect. Dis. (India), 1993, 98/Aug. (178-184)

The effect of treatment by high dose of Vitamin-C, rapid rewarming by 37degreeC water alone and with Vitamin-C, rapid rewarming by 37degreeC decoction of Indian black tea alone and with vitamin C for experimentally produced frostbite was evaluated in 6 groups (25 each) of rats. Frostbite was produced experimentally in the hind limbs by exposing the animals at -15degreeC for 1h using the harness technique. The degree of injury was assessed and classified on the basis of tissue necrosis at the end of 15 days. Administration of high dose of Vitamin-C for prolonged period and rapid rewarming at 37degreeC water bath immediately after cold exposure apparently reduced the tissue damage. High dose of Vitamin-C therapy preceded by rapid rewarming in plain water showed additional benefit. Rapid rewarming in decoction of Indian tea resulted in identical beneficial effect. The degree of tissue preservation was highest with rapid rewarming in tea decoction followed by high dose of Vitamin-C.

The effects of high-dose Vitamin-C therapy on postburn lipid peroxidation

Matsuda T, Tanaka H, Yuasa H, Forrest R, Matsuda H, Hanumadass M, Reyes H
Burn Center, Cook County Hospital, Chicago, IL 60612 USA
J. Burn Care Rehabil. (USA), 1993, 14/6 (624-629)

The effects of Vitamin-C treatment (14 mg/kg/hr) on postburn lipid peroxidation were evaluated in 12 dogs. A lymph duct above the ankle was cannulated bilaterally. Hourly lymph flow rates, plasma and lymph total protein concentrations, and plasma and lymph malondialdehyde concentrations were measured before the burn injury and for 24 hours after the burn injury. Four groups were employed: nonburn without treatment, nonburn with Vitamin-C treatment, burn without treatment, and burn with Vitamin-C treatment. The nonburn groups showed no significant differences in lymph flow rates, total protein flux, or lymph malondialdehyde level. In the burn groups the postburn hourly lymph flow rate increased by 850% without treatment and by 500% with Vitamin-C treatment, whereas the postburn hourly total protein flux increased by fiftyfold and twentyfold, respectively. There was a significant reduction in the postburn lymph malondialdehyde level in the group treated with Vitamin-C as compared with the nontreatment group. We conclude that high-dose Vitamin-C administration diminishes early postburn lipid peroxidation and reduces microvascular leakage of fluid and protein.

Effect of antioxidant vitamin supplementation on muscle function after eccentric exercise

Jakeman P.; Maxwell S.
Applied Physiology Research Unit, School Sport and Exercise Sciences, University of Birmingham, Birmingham B15 2TT United Kingdom
Eur. J. Appl. Physiol. Occup. Physiol. (Germany), 1993, 67/5 (426-430)

This study investigated the effects of antioxidant vitamin supplementation upon muscle contractile function following eccentric exercise and was performed double blind. Twenty-four physically active young subjects ingested either placebo (400 mg; n = 8), vitamin E (400 mg; n = 8) or Vitamin-C (400 mg; n = 8) for 21 days prior to and for 7 days after performing 60 min of box-stepping exercise. Contractile function of the triceps surae was assessed by the measurement of maximal voluntary contraction (MVC) and the ratio of the force generated at 20 Hz and 50 Hz tetanic stimulation before and after eccentric exercise and for 7 days during recovery. Following eccentric exercise, MVC decreased to 75 (4)% (mean (SE); n = 24; P < 0.05) of the preexercise values and the 20/50 Hz ratio of tetanic tension from 0.76 (0.01) to 0.49 (0.03) (mean (SE); n = 24; P < 0.05). Compared to the placebo group no significant changes in MVC were observed immediately post-exercise, though recovery of MVC in the first 24 h post-exercise was greater in the group supplemented with Vitamin-C. The decrease in 20/50 Hz ratio of tetanic tension was significantly less (P < 0.05) postexercise and in the initial phase of recovery in subjects supplemented with Vitamin-C but not with vitamin E. These data suggest that prior Vitamin-C supplementation may exert a protective effect against eccentric exercise-induced muscle damage.

Vitamin-C as a radioprotector against iodine-131 in vivo

Narra VR; Howell RW; Sastry KS; Rao DV
Department of Radiology, University of Medicine and Dentistry of New Jersey, Newark.
J Nucl Med 1993 Apr;34(4):637-40

The capacity of Vitamin-C (ascorbic acid) to mitigate radiation damage resulting from the tissue-incorporated radionuclide 131I is examined. Spermatogenesis in mice is the experimental model and spermhead survival is the biological endpoint. When a small nontoxic amount of Vitamin-C was injected, followed by a similar injection of 131I, the 37% spermhead survival dose (D37) increased by a factor of 2.2 compared with the D37 in animals receiving only the radionuclide. Similar radioprotection was also observed when the animals were maintained on a diet enriched with 1% vitamin C (by weight). These results suggest that Vitamin-C may play an important role as a radioprotector against accidental or medical radiation exposures, especially when radionuclides are incorporated in the body and deliver the dose in a chronic fashion.

Effects of high-dose Vitamin-C administration on postburn microvascular fluid and protein flux

Matsuda T, Tanaka H, Hanumadass M, Gayle R, Yuasa H, Abcarian H, Matsuda H, Reyes H
Burn Center, Cook County Hospital, Chicago, IL 60612.
J Burn Care Rehabil 1992 Sep-Oct;13(5):560-6

The effects of Vitamin-C treatment (14 mg/kg/hr) on burn injury were evaluated in the hind paws of 12 mongrel dogs. A lymph duct above one hind paw of each dog was cannulated. Hourly lymph flow rates (QL) and plasma and lymph total protein concentrations were measured before the burn injury and for 6 hours after the burn injury. Data from 24 paws were divided into four groups: nonburn without treatment, nonburn with treatment, burn without treatment, and burn with treatment. The nonburn groups showed no significant differences in QL or in total protein flux. In the burn groups the postburn hourly QL increased by sevenfold in the nontreatment group and only by threefold in the treatment group, whereas the postburn hourly total protein flux increased by fifteenfold and fivefold, respectively. We conclude that administration of high-dose Vitamin-C reduces early postburn microvascular leakage of fluid and protein.

Modification of the daily photoreceptor membrane shedding response in vitro by antioxidants

Williams D.S.; Roberts E.A.
Indiana University, 800 East Atwater Avenue, Bloomington, IN 47405 USA
Invest. Ophthalmol. Visual Sci. (USA), 1992, 33/10 (3005-3008)

The shedding of rod outer segment disc membrane was investigated in a commonly used frog eyecup preparation, with respect to length of time in vitro. It was found that the amplitude, but not the timing, of the 'dawn' (ie, when the lights are turned on) shedding response was increased threefold if the time in vitro was increased from 1.5-2 hr to 12-13 hr before dawn. After the overnight incubation, morphologic deterioration of the photoreceptors was not apparent by light or electron microscopy. The addition of the antioxidants, Vitamin-C or alpha-tocopherol (vitamin E), inhibited the increase in shedding, suggesting that it was induced by oxidation. These results help define conditions necessary for the maintenance of normal retinal metabolism in vitro. They also suggest a link between the amplitude of the dawn disc membrane shedding response and oxidation.

Ascorbate treatment prevents accumulation of phagosomes in RPE in light damage

Blanks J.C.; Pickford M.S.; Organisciak D.T.
Doheny Eye Institute, 1355 San Pablo Street, Los Angeles, CA 90033 USA
Invest. Ophthalmol. Visual Sci. (USA), 1992, 33/10 (2814-2821)

In dark-reared albino rats, exposure to 2 or 3 hr of intense light interrupted by 2 hr dark periods resulted in extensive degeneration of photoreceptor cells and degeneration of the retinal pigment epithelium (RPE). Ascorbate (ie, Vitamin-C) administration prior to light exposure protected photoreceptors and the RPE from light damage. In the present study, ascorbate-treated and untreated rats were exposed to various cycles of intermittent light. Immediately after this light exposure, phagosome frequency in the RPE was morphologically evaluated in comparable 50 microm sections. In untreated rats, exposure to 2 or 3 hr of intermittent light resulted in a five- to sixfold increase in phagosome density compared to unexposed controls. In contrast, no increase in phagosome density was observed in ascorbate-treated rats. In these animals, under all lighting regimens, phagosome levels remained essentially identical to those in rats not exposed to light. After a single nondamaging light exposure, phagosome density remained at the level of dark controls in ascorbate-treated and untreated rats. These results indicate that phagosome frequency may serve as an index for light damage and that the protective effect of ascorbate may be linked to its capacity to prevent rod outer segment shedding and phagocytosis under intense light conditions.

Topical Vitamin-C protects porcine skin from ultraviolet radiation-induced damage

Darr D.; Combs S.; Dunston S.; Manning T.; Pinnell S.
Box 3135, Duke University Medical Center, Durham, NC 27710 USA
Br. J. Dermatol. (United Kingdom), 1992, 127/3 (247-253)

Ultraviolet radiation damage to the skin is due, in part, to the generation of reactive oxygen species. Vitamin-C (L-ascorbic acid) functions as a biological co-factor and antioxidant due to its reducing properties. Topical application of Vitamin-C has been shown to elevate significantly cutaneous levels of this vitamin in pigs, and this correlates with protection of the skin from UVB damage as measured by erythema and sunburn cell formation. This protection is biological and due to the reducing properties of the molecule. Further, we provide evidence that the vitamin C levels of the skin can be severely depleted after UV irradiation, which would lower this organ's innate protective mechanism as well as leaving it at risk of impaired healing after photoinduced damage. In addition, Vitamin-C protects porcine skin from UVA-mediated phototoxic reactions (PUVA) and therefore shows promise as a broad-spectrum photoprotectant.

The synergism of gamma-interferon and tumor necrosis factor in whole body hyperthermia with vitamin C to control toxicity

Rosen P.
Hasbrouck Laboratory, University of Massachusetts, Amherst, MA 01003 USA
Med. Hypotheses (United Kingdom), 1992, 38/3 (257-258)

In a previous paper, the synergism of gamma-interferon and tumor necrosis factor was considered with whole body hyperthermia. Because of the toxic effect of TNF due to oxygen radicals, it is suggested that Vitamin-C be added.

Tirilazad mesylate protects vitamins C and E in brain ischemia-reperfusion injury

Sato P.H.; Hall E.D.
Department of Pharmacology, Michigan State University, East Lansing, MI 48824 USA
J. Neurochem. (USA), 1992, 58/6 (2263-2268)

Brain concentrations of the antioxidant vitamins C and E decreased following unilateral carotid occlusion and reperfusion for 2 or 24 h in gerbils. Administration of the 21-aminosteroid inhibitor of lipid peroxidation, tirilazad mesylate (U74006F), prevented the decrease in level of both of these vitamins following 2 h of reperfusion. After 24 h of reperfusion, however, alpha-tocopherol (vitamin E) continued to be protected, but ascorbic acid (vitamin C) showed a pronounced decrease in content. The changes in concentrations of these vitamins are consistent with U74006F acting to inhibit peroxidation in the CNS by scavenging of lipid peroxyl radicals and suggest that, in the presence of this agent, injury-induced depletion of ascorbic acid may occur without irreversible tissue damage.

Vitamin-C supplementation in the patient with burns and renal failure

Dylewski DF, Froman DM
Parenteral Nutrition Support Service, Francis Scott Key Medical Center, Baltimore, MD.
J. Burn Care Rehabil. (USA), 1992, 13/3 (378-380)

Vitamin-C supplementation is an important component of nutritional management in patients with burns. To supply appropriate vitamin C therapy, complications such as renal failure must be considered. An understanding of current vitamin regimens and potential metabolic sequelae can assist the practitioner in providing safe and therapeutic Vitamin-C doses.

High-dose Vitamin-C therapy for extensive deep dermal burns

Matsuda T.; Tanaka H.; Shimazaki S.; Matsuda H.; Abcarian H.; Reyes H.; Hanumadass M.
Burn Center, Cook County Hospital, 700 S. Wood Street, Chicago, IL 60612 USA
USA Burns (United Kingdom), 1992, 18/2 (127-131)

We studied the haemodynamic effects of antioxidant therapy with high-dose Vitamin-C administration (170 mg/kg/24h) in guinea-pigs with 70 per cent body surface area deep dermal burns. The animals were divided into three groups of six animals each. Group 1 was resuscitated with Ringer's lactate solution according to the Parkland formula; group 2 with 25 per cent of the Parkland formula with Vitamin-C; and group 3 with 25 per cent of the Parkland formula without Vitamin-C. There were no significant differences in heart rates or in blood pressures between the groups throughout the 24-h study period. Group 3 showed significantly higher haematocrit values at 3 h postburn and thereafter as compared with those of group 2. The cardiac output values of group 2 were significantly higher than those of group 3, but equivalent to those of group 1. The water content of the burned skin in group 2 was significantly lower than that in the other groups, indicating that increased postburn capillary permeability was minimized by the administration of Vitamin-C. With adjuvant high-dose Vitamin-C administration, we were able to reduce the 24-h resuscitation fluid volume from 4 ml/kg/per cent burn to 1 ml/kg/per cent burn, while maintaining adequate cardiac output.

Metabolic and immune effects of enteral ascorbic acid after burn trauma

Nelson J.L.; Alexander J.W.; Jacobs P.A.; Ing R.D.; Ogle C.K.
Shriners Burns Institute, 202 Goodman Street, Cincinnati, OH 45219 USA
Burns (United Kingdom), 1992, 18/2 (92-97)

A burned guinea-pig model (30 per cent BSA) was used to study the effect of Vitamin-C on immune and metabolic responses following burn trauma. Thirty-six guinea-pigs received identical enteral diets (175 kcal/kg) except for the amount of Vitamin-C. Groups I, II, III and IV were given formulae delivering no Vitamin-C (1 RDA) 15 mg/kg/day 75 mg/kg/day or 375 mg/kg/day respectively. Resistance to infection was evaluated by injecting each animal with 0.1 ml of 1 x 109 Staph. aureus 502A subcutaneously on day 10. On day 14, Staph. aureus abscesses were excised and the numbers of viable colonies were determined. Results showed no statistical differences between groups in the clearance of Staph. aureus. From days 2 to 12, animals in groups I, II and III had body weights of approximately 97 per cent of preburn body weight. Animals in group IV however, had a body weight gain, 102 per cent of preburn body weight on day 12. Animals in group IV also had significantly lower metabolic rates on day 12 as compared to the animals in the other groups. These results suggest that large amounts of Vitamin-C have beneficial effects on the maintenance of body weight and metabolic rate following burn trauma.

Reduced fluid volume requirement for resuscitation of third-degree burns with high-dose Vitamin-C

Matsuda T.; Tanaka H.; Williams S.; Hanumadass M.; Abcarian H.; Reyes H.
Burn Center, Cook County Hospital, 700 S. Wood St., Chicago, IL 60612 USA
J. Burn Care Rehabil. (USA), 1991, 12/6 (525-532)

The effects of high-dose Vitamin-C therapy (170 mg, 340 mg, and 680 mg/kg/day) were evaluated in 70% body surface area third-degree burns in guinea pigs that were resuscitated with 1 ml/kg/%burn Ringer's lactate solution. The water content measurements of the burned skin at 24 hours after burn injury in the Vitamin-C-treated groups were significantly lower than those of the control group (1 ml/kg/%burn) and those of the standard resuscitation group (4 ml/kg/%burn). The cardiac outputs in the group that received 340 mg Vitamin-C were significantly higher than those of the control group but not significantly different than those of the standard therapy group at 2 hours after burn injury and thereafter. In comparison with the regimen of 340 mg Vitamin-C, the regimen of 680 mg Vitamin-C was no more beneficial, and the regimen of 170 mg was less effective. With administration of adjuvant high-dose Vitamin-C, we were able to reduce the total 24-hour resuscitation volume from 4 ml/kg/%burn to 1 ml/kg/%burn, while a comparable cardiac output was maintained.

Biochemical basis of ozone toxicity

Mustafa M.G.
Department of Environmental Health Sciences, University of California, School of Public Health, Los Angeles, CA 90024 USA
Free Radic. Biol. Med. (USA), 1990, 9/3 (245-265)

Ozone (O3) is the major oxidant of photochemical smog. Its biological effect is attributed to its ability to cause oxidation or peroxidation of biomolecules directly and/or via free radical reactions. A sequence of events may include lipid peroxidation and loss of functional groups of enzymes, alteration of membrane permeability, and cell injury or death. An acute exposure to O3 causes lung injury involving the ciliated cell in the airways and the type 1 epithelial cell in the alveolar region. The effects are particularly localized at the junction of terminal bronchioles and alveolar ducts, as evident from a loss of cells and accumulation of inflammatory cells. In a typical short-term exposure the lung tissue response is biphasic: an initial injury-phase characterized by cell damage and loss of enzyme activities, followed by a repair-phase associated with increased metabolic activities, which coincide with a proliferation of metabolically active cells, for example, the alveolar type 2 cells and the bronchiolar Clara cells. A chronic exposure to O3 can cause or exacerbate lung diseases, including perhaps an increased lung tumor incidence in susceptible animal models. Ozone exposure also causes extrapulmonary effects involving the blood, spleen, central nervous system, and other organs. A combination of O3 and NO2, both of which occur in photochemical smog, can produce effects which may be additive or synergistic. A synergistic lung injury occurs possibly due to a formation of more powerful radicals and chemical intermediates. Dietary antioxidants, for example, vitamin E, Vitamin-C, and selenium, can offer a protection against O3 effects.

Decreases in tissue levels of ubiquinol-9 and -10, ascorbate and alpha-tocopherol following spinal cord impact trauma in rats

Lemke M.; Frei B.; Ames B.N.; Faden A.I.
Center for Neural Injury, Department of Neurology, University of California, San Francisco, CA USA
USA Neurosci. Lett. (Netherlands), 1990, 108/1-2 (201-206)

Generation of free radicals and subsequent lipid peroxidation have been proposed to contribute to delayed tissue damage following traumatic spinal cord injury (SCI). Ubiquinols (reduced coenzyme Q), ascorbate (Vitamin-C), and alpha-tocopherol (vitamin E) are endogenous antioxidants; decreases in tissue levels of these compounds may, therefore, reflect ongoing oxidative reactions. In the present studies, alterations in tissue levels of ubiquinol-9 and -10, ascorbate, and alpha-tocopherol were examined after SCI of varying severity in the rat. Levels of alpha-tocopherol did not change significantly after injury. Ascorbate and ubiquinol levels were decreased after trauma. Changes in tissue levels of ubiquinol, but not ascorbate reflected the degree of trauma. Thus, ubiquinol levels may provide a useful marker of the oxidative component of the secondary injury response.

Nutritional considerations for the burned patient

Pasulka P.S.; Wachtel T.L.
Burn and Trauma Service, Good Samaritan Medical Center, Phoenix, AZ 85006 USA
Surg. Clin. North Am. (USA), 1987, 67/2 (109-131)

The metabolic response to injury is one of marked catabolic hormonal predominance resulting in hypermetabolism and protein wasting. Energy expenditure increases with increasing severity of injury, but reaches a maximum of twice resting energy expenditure when 50 percent TBSA is burned. We agree with the nutritional recommendations of the group at the Boston Shriner's Burn Institute and the Massachusetts General Hospital. These include providing calories at twice the resting energy expenditure, as predicted by the Harris-Benedict equations, for patients with greater than 30 percent BSAB; protein is provided at 2.5 gm per kg per day based on ideal body weight. It is important to recognize that these are optimal goals, but their attainment must be governed by safety considerations for the patient. It is probably safe to supplement intake with a multivitamin and Vitamin-C, as well as zinc, but our understanding of micronutrient therapy for stressed patients is rudimentary.

Ascorbic acid metabolism in trauma

Mukherjee D.; Som S.; Chatterjee I.B.
Dep. Biochem., Univ. Coll. Sci., Calcutta 700019 India
Indian J. Med. Res. (India), 1982, 75/5 (748-751)

In major trauma such as severe head injury, burns or lacerated injury, there was a precipitous fall in plasma ascorbic acid level accompanied by a significant rise in blood dehydroascorbate level. However, this change was temporary and normal Vitamin-C status was regained after recovery from the stress condition. A similar alteration in plasma ascorbate level was also found after major surgery. This alteration in ascorbic acid status was not due to lack of reduction of dehydroascorbic acid to ascorbic acid but due to a high turnover of ascorbic acid in trauma. Supplementation of ascorbic acid in trauma resulted in a temporary increase in the plasma ascorbic acid level.

Multiple pathologic fractures in osteogenesis imperfecta

Gerber B.E.; Jani L.
Orthop. Klin., Chir. Dept., Univ. Basel, 4055 Basel Switzerland
Orthopade (Germany, West), 1982, 11/3 (101-108)

The authors survey the current orthopedic possibilities in treating multiple fractures in osteogenesis imperfecta. Also the general influence of Vitamin-C treatment is discussed.

Effect of zinc supplementation in fracture healing

Chaturvedi S.N.; Singh K.N.; Shukla R.K.; Singh R.K.
Dept. Orthop. Surg., G.S.V.M. Med. Coll., Kanpur India
Indian J. Orthop. (India), 1980, 14/1 (62-71)

In the present experimental study, 36 rabbits were subjected to fracture of the of the fibula and were treated in 3 groups viz., Control group, Zinc sulphate supplemented group and Zinc sulphate vit. C. + Methandienone supplemented group. Each group consisted of 12 rabbits. After roentgenological, macroscopic and histological examination of healing of fractures of weekly intervals, it was concluded that the Zinc supplementation to an appreciable extent enhanced the process of bone healing which could be further hastened by addition of Vitamin-C and Dianabol. No significant toxic or side effect of zinc supplementation was observed in any of the rabbits. A clinical trial of the same drugs was also conducted in patients with fractures of the shaft of the femur.

Treatment results of spinal cord injuries in the Swiss paraplegic centre of Basle

Zaech G.A.; Seiler W.; Dollfus P.
Swiss Paraplegic Cent., Basle Switzerland
Paraplegia (Edinb.) (Scotland), 1976, 14/1 (58-65)

The results concerning the last 117 acute traumatic spinal cord lesions admitted in the Swiss Paraplegic Centre of Basle have been analysed as regards the rate of neurological recovery. The treatment not only concerns the vertebral damage but also the medical aspects of the spinal cord lesion itself. The routine use of combined Dexamethasone, Rheomacrodex and Hydergine in the very early treatment might have accounted for encouraging results which need to be confirmed in the future.

Effect of piracetam on electroshock induced amnesia and decrease in brain acetylcholine in rats

Bhattacharya S.K.; Upadhyay S.N.; Jaiswal A.K.
Department of Pharmacology, Institute of Medical Sciences, Banaras Hindu University, Varanasi 221 005 India
Indian J. Exp. Biol. (India), 1993, 31/10 (822-824)

Piracetam, a prototype of a new class of psychotropic agents, the nootropic agents, which improve learning ability and memory retention, was found to induce a dose-related prevention of disruption of acquisition of a passive avoidance response produced by electroshock application. The amnesia attenuating effect of piracetam was accompanied by prevention of the decrease in acetylcholine concentrations of rat brain induced by electroshock. The study indicates that the cognition enhancing effect of piracetam may be due to a facilitatory effect on cholinergic transmission.

Use of piracetam in treatment of head injuries. Observations in 903 cases.

Cicerchia G.; Santucci R.; Palmieri M.
Ospedale della Misericordia, Servizio di Pronto Soccorso, Area di Degenza per l'Emergenza, Grosseto Italy
Clin. Ter. (Italy), 1985, 114/6 (481-487)

The authors report on 903 patients with head concussion of varying degrees of severity who were treated with anti-oedema drugs associated with an activator of cerebral metabolism. This treatment resulted in a swift disappearance of symptoms and in a quick recovery of normal cerebral activity, and moreover in a noticeable decrease of the time of hospitalisation.