Effects of dietary glycine supplementation and fish meal on inflammatory responses in broiler chicks.

1. The effect of dietary protein source and glycine (Gly) supplementation on inflammatory responses was investigated using broiler chicks. Birds (7 d of age) were fed on a maize-soybean meal based (CS) diet with or without 20 g fish meal (FM)/kg and/or 10 g Gly/kg for 14 d. 2. Inflammatory responses were assessed by determining changes in the plasma concentrations of nitrate plus nitrite (NO(x)), caeruloplasmin (Cer) and alpha-1 acid glycoprotein (AGP), and changes in the expression of mRNA encoding substances related to the inflammatory response, such as interleukin (IL)-1 beta and -6, tumour necrosis factor like ligand (TL)1A, inducible nitrite synthase (iNOS), interferon(IFN)-gamma, following lipopolysaccharide (LPS) injection. 3. IL-1 beta and TL1A mRNA expression in chicks fed on the FM diet was higher than in chicks fed on the CS diet. 4. Supplementing the CS diet with Gly resulted in smaller increases in the plasma concentrations of NO(x), Cer and AGP after LPS injection than were observed for chicks fed on the CS diet alone. In addition, 2 h after LPS challenge the expression of encoding inflammatory response-related substances was lower in the spleens of those chicks fed on the Gly-supplemented diet than in those fed the CS diet. 5. Supplementation of the FM diet with Gly reduced the plasma AGP concentration and IL-1 beta and TL1A expression. 6. These results suggest that modulation of inflammatory responses by dietary Gly supplementation is affected by dietary composition; Gly supplementation has different effects on the cytokine responses dependent on the diet.

Effects of a hydroxyl radical scavenger, EPC-K1, and neutrophil depletion on reperfusion injury in rat skeletal muscle.

Oxygen free radicals (OFR) and neutrophils are potent sources of reperfusion injury. We compared the effect of EPC-K1, a new OFR scavenger, and neutrophil depletion on the reperfusion injury in skeletal muscle, using an ischemic revascularized hindlimb model in rats. Warm ischemia, produced by vascular pedicle clamping, was sustained for 4 h. After 24 h of reperfusion, muscle function and damage were evaluated in 4 groups: a sham operation group, a control study group, a group treated by EPC-K1 (EPC group), and a group that received nitrogen mustard to induce neutropenia (NM group). Both the EPC and NM groups had limited muscle damage compared to the control group. The EPC group preserved muscle function significantly better than the control group and the mean isometric tetanic tension in the EPC group appeared to be higher than that in the NM group. Furthermore, levels of lipid peroxides in muscle and serum, and muscle edema in the EPC group, were significantly lower than in the NM group. Histological examinations supported these results. These findings suggest that limiting OFR generation by EPC-K1 in the early phase of reoxygenation is more potent than depletion of neutrophils in reducing reperfusion injury.

Effect of a moderately energy-restricted diet on obese patients with fatty liver.

The effects of a moderately energy-restricted (25 kcal/kg) diet on liver-function tests, anthropometric measurements, mononuclear-cell phospholipid fatty acid, lymphocyte blastogenesis, and plasma prostaglandin E2 and alpha-tocopherol levels were observed at weeks 0, 8, and 24 in 14 obese patients with fatty liver. Serum aminotransferase levels were improved significantly, with decreases in the body mass index and waist circumference. Decreases in energy intake from carbohydrate and increases in intake of vitamin A, vitamin C, and vegetables were observed at week 24. In mononuclear-cell phospholipids, linoleic acid (18:2omega 6), which was significantly lower in patients than in controls at week 0, was increased at week 24. In contrast, arachidonic acid was decreased. Plasma prostaglandin E2 levels were significantly lower in patients than in controls at week 0 and increased at week 24. The mononuclear-cell response for phytohemagglutinin correlated with 18:2omega 6 in mononuclear-cell phospholipids (r = 0.692, P < 0.01). Improvement of the serum alanine-aminotransferase level correlated with an increase in the plasma alpha-tocopherol level (r = -0.667, P < 0.01) and increases in consumption of vitamin A, omega 3 polyunsaturated fatty acids, and vegetables. These findings suggest that a hypoenergetic diet rich in omega 3 polyunsaturated fatty acids and antioxidants might be beneficial for obese patients with fatty liver.

Cardiac functional and structural alterations induced by endotoxin in rats: importance of platelet-activating factor.

OBJECTIVE: In this study, we evaluated the time course of the alterations in left ventricular (LV) dimensions, LV wall thickness, and LV systolic function in rats with endotoxemia by using echocardiography as well as myocardial histopathologic assessments. Our second goal was to examine whether pretreatment with a platelet-activating factor (PAF) antagonist would ameliorate the lipopolysaccharide (LPS)-induced cardiovascular collapse during the early phase. DESIGN: A prospective, controlled, in vivo animal laboratory study. SETTING: Research laboratory at a university. SUBJECTS: Male, Wistar rats (8-9 wks old; n = 83). INTERVENTIONS: In pentobarbital-anesthetized rats, the right carotid artery was cannulated to measure the arterial blood pressure and to sample blood. The right jugular vein also was catheterized for the administration of drugs. LPS (2 mg/kg) derived from Klebsiella pneumoniae or physiologic saline was administered in the presence or absence of pretreatment with TCV-309, a specific potent PAF antagonist. Echocardiographic studies were performed with an 8- to 13-MHz transducer. MEASUREMENTS AND MAIN RESULTS: LPS administration immediately induced progressive hypotension. The maximal hypotensive response was observed at 10 mins after LPS infusion with mean arterial pressure decreasing from 119 +/- 2 to 56 +/- 3 mm Hg (p < .001). LV end-diastolic internal dimensions decreased from 6.4 +/- 0.1 to 3.1 +/- 0.1 mm (p < .001) at 30 mins after LPS and remained significantly reduced compared with control rats. LV end-systolic dimensions also decreased dramatically from 3.5 +/- 0.2 to 0.5 +/- 0.1 mm (p < .001) at 30 mins after LPS and remained significantly reduced throughout the experiment. LV fractional shortening increased from 45 +/- 1% to 84 +/- 2% (p < .001) at 30 mins after LPS and remained elevated compared with control rats. LV wall thickness increased strikingly from 15 mins until 2 hrs after LPS infusion. Pathologic studies demonstrated marked congestion of capillaries and mild edema in the LV myocardium. The hematocrit increased after the administration of LPS. LPS markedly increased sympathetic tone as demonstrated by the elevation of plasma concentrations of epinephrine and norepinephrine. There was no elevation of concentrations of nitrite and nitrate. Pretreatment with TCV-309, a specific potent PAF antagonist, reduced LPS-induced hypotension and attenuated LV functional and structural changes. TCV-309 administration reduced the LPS-induced adrenergic activation and hemoconcentration. CONCLUSIONS: The hypotension that occurred during the initial phase of LPS-induced shock was accompanied by LV functional and structural alterations. The marked increase in LV wall thickness can be ascribed to the congestion of capillaries and edema in the LV myocardium. Pretreatment with a PAF antagonist reduced LPS-induced alterations. PAF may play a pivotal role during the initial phase of LPS-induced cardiovascular responses.

Mutations in interferon sensitivity-determining region of hepatitis C virus: its relation to change in viral load.

OBJECTIVE: Interferon sensitivity-determining region (ISDR) in nonstructural region 5A of hepatitis C virus (HCV) genotype-1b has been reported to be associated with viral load. Viral load is usually small in the patients with mutant type (four or more amino acid substitutions, compared with HCV-J) and large in those with wild (identical to HCV-J) or intermediate type (from one to three amino acid substitutions). A possible correlation was investigated between mutations in ISDR and alterations of viral load during the course of disease. METHODS: The sequences of ISDR were determined in eight patients with significant changes of viral load and in 11 patients without changes. RESULTS: In two of the eight patients with significant alterations of viral load, ISDR sequences changed significantly. In one patient whose viral load increased after a course of interferon therapy, the number of substitutions, compared with HCV-J, decreased from five to zero or one; the type of ISDR converted from mutant type to wild or intermediate type. In one patient whose viral load decreased significantly after two courses of interferon therapy, the number of substitutions increased from one to six; ISDR changed from intermediate type to mutant type. In the remaining six patients with changes of viral load and in the other 11 patients without changes, the sequences of ISDR did not change significantly. CONCLUSIONS: The mutations in ISDR are one of the viral factors involved in the changes in viral load during the course of disease, although the majority of other factors involved are still unknown.

Reduced reperfusion injury in muscle. A comparison of the timing of EPC-K1 administration in rats.

EPC-K1, a phosphate diester of alpha-tocopherol and ascorbic acid, is a new hydroxyl radical scavenger. We examined the effects of EPC-K1 according to differences in the timing of its administration. Warm ischemia, produced by vascular pedicle clamping, was sustained for 4 hours. After 24 hours of reperfusion, muscle injury was evaluated in 4 groups: the first group received a sham operation, the second group was treated with an intravenous injection of EPC-K1 prior to ischemia, the third group was treated with EPC-K1 prior to reperfusion, and the fourth group was controls. Compared with the control group, both the preischemic and pre-reperfusion EPC-K1-treated groups showed a statistically significant amelioration in the reduction of isometric muscle contraction. There were also significant reductions in the muscle and serum levels of thiobarbituric acid reactive substances (TBA-RS) and muscle damage, indicated by the biochemical and histological study. A comparison of the timing of EPC-K1 administration revealed that only the muscle TBA-RS level in the pre-reperfusion EPC-K1-treated group was significantly higher than that in the preischemic EPC-K1-treated group. These observations indicate that EPC-K1 not only by preischemic but also by pre-reperfusion administration acted effectively on reperfusion injury in muscle, thereby improving muscle function.

Effects of soybean oil emulsion and eicosapentaenoic acid on stress response and immune function after a severely stressful operation.

OBJECTIVE: To investigate the effects of soybean oil emulsion and oral or enteral administration of eicosapentaenoic acid (EPA) on stress response, cytokine production, protein metabolism, and immune function after surgery for esophageal cancer. SUMMARY BACKGROUND DATA: It has been reported that safflower oil, rich in n-6 polyunsaturated fatty acid (n-6 PUFA), affects the survival rate of septic animals and decreases the immune function. It has also been reported that the administration of fish oil, in contrast, reduces these stress responses and stress-induced immunosuppression. In humans, the effects of soybean oil emulsion and the administration of EPA on stress response and immune function after surgery have not been established. METHODS: Patients who underwent esophagectomy with thoracotomy were divided into three groups. Seven patients were fed by total parenteral nutrition (TPN) with soybean oil emulsion, which accounted for 20% of total calories. Seven patients were given oral or enteral administration of 1.8 g/day EPA, in addition to TPN with soybean oil emulsion. Nine patients served as the control group; these patients received fat-free TPN. Serum interleukin-6 (IL-6), C-reactive protein, concanavalin A (con A)- or phytohemagglutinin (PHA)-stimulated lymphocyte proliferation, natural killer cell activity, and stress hormones were measured. RESULTS: The postoperative level of serum IL-6 was significantly higher in the group receiving soybean oil emulsion than in the fat-free group. Oral or enteral supplementation of EPA with soybean oil emulsion significantly reduced the level of serum IL-6 compared with the patients receiving soybean oil emulsion. Con A- or PHA-stimulated lymphocyte proliferation decreased significantly on postoperative day 7 in all groups of patients. The supplementation of EPA with soybean oil emulsion significantly improved the lymphocyte proliferation and natural killer cell activity on postoperative day 21 compared with the group receiving soybean oil emulsion. CONCLUSIONS: Soybean oil emulsion amplifies, and the supplementation of EPA reduces, the stress response and stress-induced immunosuppression.

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

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.

Inhibition of beta-adrenergic desensitization by KCa channels in human trachealis.

We examined the reduced responsiveness to beta-adrenergic receptor agonists (beta-agonists) after exposure to beta-agonists, and the mechanisms underlying this phenomenon in isolated human tracheal smooth muscle, using isometric tension records to test the hypothesis that repeated inhalation of beta-agonists leads to reduced responsiveness to beta-agonists. The inhibitory effects of isoproterenol (ISO) on contraction by spasmogens participating in asthma attacks diminished markedly after continuous exposure to ISO (0.0003 to 3 microM) for 45 min; moreover, when ISO was repeatedly applied for 10 min to tissues precontracted by methacholine every 30 min, the relaxant effects of ISO gradually attenuated after these repeated applications. In contrast, reduced beta-adrenergic relaxation after continuous and repeated exposure to agonists did not occur when tissues were preincubated with 2 microg/ ml cholera toxin (CTX), which irreversibly activates guanosine triphosphate (GTP)-binding protein (Gs) coupled with beta-adrenergic receptors, for 6 h. However, the CTX inhibition disappeared in the presence of iberiotoxin, a selective inhibitor of large conductance Ca2+-activated K+ (KCa) channels. Our results demonstrate that continuous and repeated exposure to beta-agonists leads to beta-adrenergic desensitization, and that activation of KCa channels by Gs prevents this desensitization.

Effects of intravenous omega-3 and omega-6 fat emulsion on cytokine production and delayed type hypersensitivity in burned rats receiving total parenteral nutrition.

BACKGROUND: The effects of fat emulsions containing omega-3 and omega-6 polyunsaturated fatty acids (PUFAs) on fatty acid profile, cytokine production, and delayed type hypersensitivity (DTH) in burned rats receiving total parenteral nutrition (TPN) were investigated. METHODS: A fat emulsion containing only eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) was prepared (omega-3 fat emulsion). Sprague-Dawley rats were fed fat-free chow for 2 weeks and were divided into three groups according to the contents of TPN. Groups C (n = 11) and C' (n = 14) received fat-free TPN. Group omega6 received safflower oil emulsion containing linoleic acid (omega-6 PUFA) (n = 11). Group omega3 (n = 11) received safflower oil emulsion (19% of total caloric intake) and fat emulsion containing only EPA and DHA (1% of total calories). On day 5, all rats except for those in group C' were subjected to a 20% full-thickness burn. Group C' did not receive burns. After 48 hours, the rats were killed. RESULTS: The interleukin (IL)-8 concentration was significantly 45% lower in group omega3 than in group C (p < .05). The IL-10 concentration was significantly 15% lower in group omega3 than in group omega6 (p < .05). The IL-6 concentration was increased in group omega6 but not in group omega3 when compared with group C. The IL-6 and IL-8 were not detected in group C'. Prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) concentrations were increased by burn injury, but there were no significant differences among the burned groups. Cell-mediated immunity was thus significantly decreased in burned groups (groups C, omega6, and omega3; p < .01). However, the decrease of DTH was smaller in group omega3 and significantly greater when compared with groups C and omega6 (p < .05). CONCLUSIONS: omega-6 PUFAs increased serum inflammatory cytokine levels in a stressed state. omega-3 fat emulsion reduced IL-8 and IL-10 levels and prevented immunosuppression in burned rats that were receiving TPN.

Lipid peroxyl radicals from oxidized oils and heme-iron: implication of a high-fat diet in colon carcinogenesis.

A diet high in fat and iron is known as a risk factor in cancer epidemiology. However, the details of the molecular mechanism remains to be elucidated. We examined the possible implication of lipid peroxyl radicals generated from fatty acids and heme-iron in DNA damage, and hence in the possibility of colon cancer. F344 female rats were given N-nitroso-N-methylurea six times during a 2-week period and then fed diets containing different amounts of safflower oil and hemoglobin (rich in iron) for 36 weeks; the occurrence of colon cancer was determined by H&E staining. In this animal model, simultaneous feeding of a fat diet and heme-iron produced a significant increase (P < 0.05) in the incidence of colon cancer compared with a diet without hemoglobin. Electron paramagnetic resonance and chemiluminescence studies revealed that oxidized refined vegetable oils, particularly safflower oil, readily generated lipid peroxyl radicals in the presence of various heme compounds, and the peroxyl radicals did effectively cleave DNA. Unpurified native vegetable oils contain a high amount of peroxyl radical scavengers, whereas conventional refining processes seem to reduce the levels of many valuable anti-peroxyl radical compounds abundant in plant seeds. In conclusion, lipid peroxides and heme components generate peroxyl radical species that exert DNA-cleaving activity. A plausible explanation is that lipid peroxyl radicals thus generated, which originated from routine dietary components such as fat and red meat, may contribute, at least in part, to the high incidence of colon cancer.

A comparison of biopsy through a parasternal anterior mediastinotomy under local anesthesia and percutaneous needle biopsy for malignant anterior mediastinal tumors.

The various methods of treating the numerous types of anterior mediastinal neoplasms are undergoing refinements; however, prior to the commencement of any treatment, an accurate histologic diagnosis must be established. We conducted a retrospective analysis of biopsies performed through a parasternal anterior mediastinotomy (PAM) on 21 patients with an anterior mediastial mass suspected of being malignant by computed tomography (CT) and other clinical information. Patients with possible localized thymomas were excluded. Mediastinotomy, which enables relatively large tissue samples to be taken, was performed through the bed of the second or third costal cartilage under local anesthesia. In 19 of the 21 patients (90%), the histologic diagnosis made from the mediastinotomy biopsy was identical to the final diagnosis. Conversely, although the tissue obtained from needle biopsy was sufficient for a histologic diagnosis in 11 of 12 patients, the histologic diagnosis made from the needle biopsy was the same as the final diagnosis in only 5 of 10 patients (50%). Thus, diagnostic accuracy was significantly higher in the mediastinotomy biopsies than in the needle biopsies (P = 0.0318). Moreover, the mediastinotomy biopsy specimens revealed subtypes of lymphomas and germ cell tumors. All of the patients from whom a mediastinotomy biopsy had been taken began appropriate therapy without delay according to the histologic diagnosis. These results suggest that the PAM approach should be chosen as the preferred method of biopsy for suspected malignant anterior mediastinal tumors.

n-3 versus n-6 polyunsaturated fatty acids in critical illness.

The effects of n-6 and n-3 polyunsaturated fatty acids (PUFA) on protein metabolism, cell-mediated immunity, and production of cytokines and prostanoids were studied in experimental animals and patients with esophageal cancer. In the experimental study using a rat burn model, n-6 PUFA increased serum interleukin-6 (IL-6) and tumor necrosis factor (TNF), alpha (P < 0.05), and decreased nitrogen balance (NB) (P < 0.05), when compared with a fat-free control. But addition of n-3 PUFA reduced TNF-alpha and IL-10 (P < 0.05) and improved NB (P < 0.05). Suppressed delayed type hypersensitivity (DTH) induced by burn injury, which was not influenced by n-6 PUFA, was significantly improved by the administration of n-3 PUFA. n-6 PUFA tended to increase, and n-3 PUFA significantly decreased the endotoxin translocation. DTH, granulocyte-macrophage colony-stimulating factor, and eicosapentaenoic acid (EPA) content increased proportionately with the intravenous dose of fish oil emulsion. The effects of n-6 and n-3 PUFA were studied in the patients who underwent surgery for esophageal cancer. In the group of patients fed by total parenteral nutrition with soybean oil emulsion, the serum IL-6 significantly increased at 2 and 6 h after operation (P < 0.05). Oral/enteral supplementation of EPA ethyl ester (1.8 g/d) significantly reduced the postoperative IL-6 production (P < 0.05 at 1, 2, and 6 h after operation), and improved cell-mediated immune function 3 wk after operation (P = 0.05). During the chemoradiation therapy, cell-mediated immune function was improved significantly in the patients fed enterally with EPA ethyl ester (n = 5), when compared with the patients without EPA (n = 14).

Growth hormone improves the resistance of thermally injured mice infected with herpes simplex virus type 1.

BACKGROUND: Growth hormone (GH) has been shown to promote wound healing and to improve protein metabolism in burned patients. Through immunomodulation, GH has also protected rats infected with Salmonella typhimurium and mice infected with Escherichia coli. In spite of advances in the management of patient care for those with thermal injuries, high mortality rates of burned patients as a result of infections are of special concern. An improvement in the resistance of burned patients to certain infections will make the beneficial role of GH very clear. In this study, therefore, the immunomodulating effects of recombinant human GH (rhGH) in thermally injured mice exposed to opportunistic herpesvirus infections were investigated. METHODS: (1) Burned mice, exposed to herpes simplex virus type 1 (HSV-1), were treated subcutaneously with rhGH (4 mg/kg) and observed for 21 days to determine the protective antiviral effect of rhGH. (2) Because of reports describing a lack of interferon-gamma (IFN-gamma) responsiveness in burned mice, the IFN-gamma-producing ability of the splenic mononuclear cells (SMNC) from burned mice treated with rhGH was examined. (3) Because the generation of burn-associated suppressor macrophages that can inhibit the IFN-gamma production by SMNC has been previously described, the suppressor cell activities of macrophages from burned mice treated with rhGH were examined. RESULTS: After exposure to lethal amounts of HSV-1, mice treated with rhGH displayed a reduced mortality rate compared with control mice treated with saline. SMNC from burned mice treated with rhGH produced IFN-gamma, whereas this cytokine was not produced by SMNC from burned mice treated with saline. Also, an inhibition of the generation of burn-associated suppressor macrophages was displayed in burned mice treated with rhGH. CONCLUSION: Exogenous administration of rhGH caused an improvement in the resistance of burned mice to HSV-1 infection. In burned mice treated with rhGH, the impaired IFN-gamma responsiveness was restored and the generation of burn-associated suppressor macrophages was inhibited. IFN-gamma, a typical antiviral cytokine induced by rhGH through the regulation of the suppressor macrophage generation, may therefore play a role in the protection of burned mice infected with a lethal amount of HSV-1.

[The effect of hepatic arterial infusion chemotherapy on the prognosis after hepatectomy for hepatocellular carcinoma].

The effect of hepatic arterial infusion chemotherapy on the prognosis after hepatectomy for hepatocellular carcinoma was investigated in patients with risk factors for recurrence. The risk factors for recurrence after hepatectomy were defined to be metastasis in the liver (+), portal tumor embolus (+), and tumor larger than 5 cm in diameter. Out of 87 patients with hepatocellular carcinoma who underwent an operation in the past 7 years in our hospital, 60 survived for more than 1 year and were enrolled in our study. Thirty-eight of them showed one or more risk factors for recurrence, and were considered to be the high-risk group. These 38 patients were divided into two groups: one group of 19 treated by hepatic arterial infusion chemotherapy using mitoxantrone, and the other group of 19 given no treatment. The survival rates and non-recurrence rates were compared between the two groups. The survival rates after 1 and 3 years for the group treated by hepatic arterial infusion chemotherapy were 94.7% and 54.7%, respectively. The survival rates for the non-treated group were 53.9% and 32.8%, respectively (p = 0.012). The non-recurrence rates after 1 year and 3 years were 94.7% and 44.2% for the treated group and 52.6% and 23.6% for the non-treated group (p = 0.005), respectively. The survival rates and non-recurrence rates after 3 years in the treated group were significantly higher (p = 0.012, 0.005), respectively. It was concluded, therefore, that post-operation hepatic arterial infusion chemotherapy improved the prognosis of the high-recurrence probability group.

Reduced ischemia-reperfusion injury in muscle. Experiments in rats with EPC-K1, a new radical scavenger.

L-ascorbic acid 2-[3,4-dihydro-2,5,7,8-tetramethyl- 2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl hydrogen phosphate] potassium salt (EPC-K1), a phosphate diester of alpha-tocopherol and ascorbic acid, is a potent antioxidant. We examined the effects of EPC-K1 on ischemia-reperfusion injury in the skeletal muscle of rats, using an ischemic revascularized hind limb model. Warm ischemia (25 degrees C), produced by vascular pedicle clamping, was sustained for 4 hours. After 24 hours of reperfusion, skeletal muscle injury was evaluated in 2 groups: one group treated by intravenous injection of EPC-K1 (10 mg/kg) prior to ischemia, and a group of controls. The EPC-K1-treated group showed a statistically significant amelioration in the reduction of the isometric muscle contraction, inhibition of the elevation of the muscle wet- to dry-weight ratio, limitation of the muscle level of thiobarbituric acid reactive substances and the serum levels of creatine phosphokinase, lactate dehydrogenase and mitochondrial glutamic oxaloacetic transaminase, and reduction of the extent of muscle injury according to the histological findings. These observations indicate that EPC-K1 acted effectively on ischemia-reperfusion injury in the rat skeletal muscle and thereby improved muscle function.

Inhibitory effects of pituitary adenylate cyclase activating polypeptide on histamine-induced respiratory resistance in anesthetized guinea pigs.

Asthma is a chronic inflammatory disorder of the airways in which many cells participate. This inflammation causes recurrent episodes and symptoms that are associated with widespread but variable airflow limitation that is at least partly reversible either spontaneously or with treatment. Therefore, an investigation of useful remedies for the treatment of bronchial asthma is proposed. In this study, we determined whether both forms of pituitary adenylate cyclase activating polypeptide (PACAP 38 and PACAP 27) belonging to the vasoactive intestinal peptide (VIP) family of peptides could inhibit the effects of histamine-induced respiratory resistance (Rr) in anesthetized guinea pigs, when compared with VIP. The order for 50% suppression (ED50) of Rr induced by peptides was VIP > PACAP 27 > PACAP 38. The inhibitory effects induced by PACAP 38 on histamine-induced Rr in guinea pigs were more prolonged than with the other two peptides. Moreover, adding the endopeptidase inhibitor phosphoramidon prolonged the inhibitory effects of PACAPs. These results suggested that the exogenous peptides of the inhibitory nonadrenergic noncholinergic nervous (i-NANC) peptides could become a useful remedy for treatment of bronchial asthma, because these belong to an important intrinsic hormone.

Failure in learning task and loss of cortical cholingergic fibers in microsphere-embolized rats.

The present study was undertaken to elucidate the pathological changes in learning and memory functions and in the metabolism of cortical cholinergic neurons following microsphere embolism in the rat. Microspheres (48 microm) were injected into the right internal carotid artery of rats. Learning and memory functions were measured 7 or more days after the embolism by active and passive avoidance, and water maze tasks. In the biochemical study, cortical acetylcholine and choline contents, and choline acetyltransferase activity were measured. Cortical acetylcholinesterase-containing fibers were quantitatively estimated in the embolized rat. The active and passive avoidance, and water maze tasks were impaired in the microsphere-embolized rat. In the histochemical study, the density of cortical acetylcholinesterase-containing fibers of the ipsilateral hemisphere of the microsphere-embolized rat was decreased, but cell density was unchanged. Furthermore, microsphere embolism decreased the cortical acetylcholine concentration and choline acetyltransferase activity and increased the choline concentration. The results suggest that microsphere embolism causes severe damage to cortical cholinergic neurons, which may be, at least in part, related to the impairment of learning and memory functions in the sustained brain ischemia.

Apophysitis of the acromion.

We treated three patients with apophysitis of the acromion. These patients were two male athletes 12 and 14 years of age, respectively, and one female athlete 13 years of age. They reported pain at the top of the shoulder during and after shoulder movement while playing sports but had no rest pain or disturbance of daily activities. Physical examination demonstrated marked local tenderness at the acromion and slight warmth. X-ray films showed sclerosis and irregularity of the secondary ossification center of the acromion. Bone scintigraphy carried out on one patient demonstrated increased uptake in that region. Conservative treatment was used for these patients. Recovery was gradual but satisfactory.

Effects of traditional Chinese medicines on pharmacokinetics of levofloxacin.

The effects of single coadministrations of one of three traditional Chinese medicines, Hotyu-ekki-to, Rikkunshi-to, and Juzen-taiho-to, on the pharmacokinetics of levofloxacin (LVFX) were investigated with eight healthy volunteers in an open, random crossover fashion. Subjects each received a single oral dose of LVFX (200 mg) alone and then with a single coadministration of each Chinese medicine. There were no significant differences in any pharmacokinetic parameters of LVFX between the groups. Also, no significant changes in the urinary recovery (> 80%) and renal clearance of LVFX were observed. These results indicate that the Chinese medicines tested have no significant effect on the rate and extent of bioavailability or renal excretion of LVFX.