Time-course of functional and pathological changes after a single high acute inhalation of chlorine in rats

Reactive airways dysfunction syndrome (RADS) is an asthma-like condition that follows exposure to very high concentrations of an irritant material. We assessed the time-course of pathophysiological alterations in a model of RADS. Sprague-Dawley rats were exposed to 1,500 parts per million (ppm) of chlorine for 5 min. Lung resistance (RL), responsiveness to inhaled methacholine (MCh), the airway epithelium and bronchoalveolar lavage (BAL) were assessed over a 3 month period after exposure. RL increased significantly up to 3 days after exposure, reaching a maximal change of 110+/-16% from baseline. There was a significant decrease in the concentration of MCh required to increase RL by 0.20 cmH2O x mL(-1) x s from days 1-7 after exposure. In some rats, MCh hyperresponsiveness and RL changes persisted after exposure for as long as 1 and 3 months, respectively. Histological evaluation with morphometric evaluation revealed epithelial flattening, necrosis, increase in smooth muscle mass and evidence of epithelial regeneration. BAL showed an increased number of neutrophils. The timing of maximal abnormality in the appearance of the epithelium (days 1-3) corresponded to that of the maximal functional changes. Acute high chlorine exposure results in functional and pathological abnormalities that resolve in the majority of animals after a variable period; however, these changes can persist in some animals. Functional abnormalities in the initial stages may be related to airway epithelial damage.     

Modulation of airway hyperresponsiveness and eosinophilia by selective histamine and 5-HT receptor antagonists in a mouse model of allergic asthma

1. Since both histamine and 5-hydroxytryptamine (5-HT) can be released by murine mast cells, we investigated the possible role of these autacoids on airway hyperresponsiveness (AHR), eosinophil infiltration and serum-IgE levels in a murine model of allergic asthma. 2. Ovalbumin-sensitized mice were exposed to either ovalbumin (2 mg ml(-1)) or saline aerosols on 8 consecutive days. Starting one day before the challenge, animals were injected i.p. twice a day with a 5-HT-type 1 (5-HT1) or type 2 (5-HT2) receptor antagonist (methiotepine, 1.25 or 2.0 mg kg(-1) and ketanserin, 12 mg kg(-1), respectively) or a histamine-type 1 (H1) or type 2 (H2) receptor antagonist (mepyramine, 12 or 20 mg kg(-1) and cimetidine, 10 or 25 mg kg(-1), respectively). Furthermore, animals were injected with a combination of cimetidine and ketanserin or with an alpha-adrenoceptor antagonist (phentolamine, 5 mg kg(-1)). 3. In vehicle-treated ovalbumin-challenged animals airway responsiveness to intravenous injections of methacholine in vivo was significantly (9 fold increase, P<0.01) increased when compared to vehicle-treated saline-challenged animals. Furthermore, ovalbumin challenge of vehicle-treated animals induced a significant increase in both eosinophil numbers in bronchoalveolar lavage (BAL) fluid (0+/-0, vehicle/saline and 15.0+/-5.9 x 10(4) cells vehicle/ovalbumin, P<0.05) and ovalbumin-specific IgE levels in serum (157+/-69 and 617+/-171 units ml(-1), respectively, P<0.05) compared to saline-challenged mice. Virtually no eosinophils could be detected in saline-challenged animals after all different treatments. 4. Treatment with ketanserin or cimetidine resulted in a partial but significant decrease of the ovalbumin-induced AHR compared to ovalbumin-challenged controls (P<0.05) and reduced eosinophil infiltration after ovalbumin challenge by 60% and 58%, respectively. The combination of cimetidine and ketanserin almost completely abolished AHR whereas eosinophilia was decreased by 49%. No effects of these antagonists were observed on IL-16 levels in BAL fluid or on serum antigen-specific IgE levels. Treatment with either the H1-receptor, the 5-HT1-receptor or the alpha-adrenoceptor antagonist, did not decrease the observed ovalbumin-induced airway responsiveness or eosinophilia in vehicle-treated animals. Higher doses of either methiotepine (2.0 mg kg(-1)) or mepyramine (20 mg kg(-1)) did decrease ovalbumin-induced eosinophil infiltration (by 67%, P<0.05 and 73%, respectively), whereas no effects of these antagonists were observed on ovalbumin-specific IgE levels in serum. 5. From these data it can be concluded that both histamine and 5-HT play a role in antigen-induced AHR and eosinophilia in the mouse.     

Role of interleukin-5 and substance P in development of airway hyperreactivity to histamine in guinea-pigs

In this study, we examined the mechanism by which bronchoalveolar lavage (BAL) cells induced hyperreactivity of the trachea in vitro. As both interleukin-5 (IL-5) and substance P (SP) appeared to be involved, the effect of these mediators was examined in vivo. Tracheae were incubated with BAL cells from ovalbumin or saline challenged animals, and from naive animals, in the absence or presence of either IL-5, SP, or both. In addition, the effect of intra-airway application of IL-5, SP, both, or vehicle on tracheal hyperreactivity was examined. Incubation of tracheae with BAL cells from ovalbumin challenged animals induced an increase (30 +/- 10%) in the maximal response to histamine. The hyperreactivity could be completely inhibited by co-incubation with 5-lipoxygenase inhibitor, AA861. The hyperreactivity could be mimicked by incubation of tracheae with BAL cells from naive animals in the presence of IL-5 and SP. After in vivo administration of either IL-5 or SP, maximal responses to histamine were increased and amounted to 105 +/- 35 and 101 +/- 37%, respectively. Administration of IL-5 but not SP induced a significant increase in the number of eosinophils (67 +/- 22%) and eosinophil peroxidase (EPO) activity (94 +/- 33%) in BAL cells. The simultaneous administration of IL-5 and SP did not potentiate the hyperreactivity and eosinophilia observed with IL-5 alone. These data suggest that IL-5 is important in the recruitment of eosinophils, whereas both IL-5 and substance P are involved in the induction of airway hyperreactivity.     

Mechanisms of insulin resistance during acute endotoxemia

We characterized the mechanisms underlying acute endotoxin-induced alterations in glucose metabolism and determined the extent to which catecholamines mediate these changes. Acute endotoxemia was induced in chronically catheterized awake rats by a bolus injection of lipopolysaccharide (LPS; 1 mg/kg; LD10). Basal glucose turnover (Rt; infusion of [5-3H]glucose), in vivo insulin action on overall glucose utilization (euglycemic clamp), glycolysis, and glycogen synthesis were determined in four groups of rats. These groups received 1) LPS (LPS rats; n = 6), 2) saline (control rats; n = 6), 3) LPS and alpha beta-blockade (alpha beta-blockade and LPS rats; n = 9), or 4) saline and alpha beta-blockade (alpha beta-blockade control rats; n = 9). In the basal state, LPS induced hypotension and transient hyperglycemia. These changes were associated with glycogen depletion in both skeletal muscle and liver, and increased Rt. During hyperinsulinemia, whole body glucose disposal was 37% decreased (105 vs. 166 mumol/kg.min; P < 0.01). This whole body insulin resistance was characterized by decreased glycogen synthesis and glycogen synthase activity, but not by altered whole body glycolysis. alpha beta-Blockade abolished transient hyperglycemia, increased Rt, and accelerated basal liver glycogen depletion (45 vs. 105 mmol/kg dry, LPS and alpha beta-blockade rats vs. LPS rats; P < 0.05), but inhibited muscle glycogenolysis. alpha beta-Blockade did not reverse the insulin resistance induced by endotoxin. These data suggest that catecholamines counteract the LPS-induced increase in basal glucose turnover and stimulate muscle glycogenolysis during acute endotoxemia. These effects might explain the better preservation of hepatic glycogen in the absence than in the presence of alpha beta-blockade and serve as a defense mechanism against hypoglycemia. Catecholamines do not seem to be the immediate causes of insulin resistance during acute endotoxemia.     

TRFK-5 reverses established airway eosinophilia but not established hyperresponsiveness in a murine model of chronic asthma

We studied the effects of an anti-interleukin (IL)-5 monoclonal antibody (TRFK-5) or dexamethasone (DEX) to reverse already established airway hyperresponsiveness (AHR) and tissue eosinophilia in a Schistosoma mansoni antigen-sensitized and airway-challenged mouse model of chronic asthma. In this model at 4 d after antigen challenge there is dramatic bronchoalveolar lavage fluid (BAL) eosinophilia, AHR to intravenous methacholine (MCh), and histologic evidence of peribronchial eosinophilic infiltration and mucoid cell hyperplasia. These changes persist for up to 2 wk after antigen challenge. Treatment with DEX from Days 4 through 10 significantly reduced established airway eosinophilia compared with animals sham-treated with saline from Days 4 -10 (120 +/- 29 eosinophils/microl BAL for DEX-treated mice versus 382 +/- 60 eosinophils/microl BAL for sham-treated animals, p < 0.01). DEX-treated mice also had dramatically reduced mucoid cell hyperplasia, and airway responsiveness returned to normal. In contrast, TRFK-5 given during the same time period reduced airway eosinophilia (86 +/- 32 eosinophils/microl BAL versus 382 +/- 60 eosinophils/microl BAL, p < 0.01) but did not reduce goblet cell hyperplasia or reverse already established AHR. Treatment with DEX but not TRFK-5 also inhibited interferon gamma (IFN-gamma) content of BAL fluid (0.49 +/- 0.09 ng/ml BAL fluid for DEX versus 1.50 +/- 0.24 ng/ml BAL fluid and 1.36 +/- 0.13 ng/ml BAL fluid for TRFK-5 and sham-treated mice, respectively, both p < 0.001 versus DEX). Thus, treatment with DEX reduces established eosinophilic airway inflammation and AHR in S. mansoni-sensitized and airway-challenged mice but treatment with TRFK-5 reversed established eosinophilia without ameliorating established AHR. Together, these data suggest that once airway inflammation develops, neutralizing the effects of IL-5 or reducing eosinophilia alone may not result in inhibiting established AHR in atopic asthma.     

Bronchodilatation in vivo by carbon monoxide, a cyclic GMP related messenger

1. Recent studies suggest that gaseous carbon monoxide (CO) is involved in neurotransmission and that this molecule also is an important vasodilator in vivo. In the present study we evaluated the effect of inhaled CO on guinea-pig airway smooth muscle tone. The mechanisms involved were characterized by use of a cyclic GMP antagonist, Rp-8Br-cyclic GMPS, and a nitric oxide synthase inhibitor, L-NAME. 2. Anaesthetized, ventilated guinea-pigs were given a bolus injection of histamine (0.12 mg kg(-1), i.v.), followed by a continuous infusion of histamine (0.30 microg kg(-1) min(-1)) to increase total pulmonary resistance (RL). Subsequent exposure to 7, 15 or 30 breaths of CO (100%), resulted in a dose-dependent inhibition of the bronchoconstriction. In the highest dose tested (30 breaths), CO inhibited 80% of the histamine-induced increase in RL. 3. In separate experiments, animals receiving histamine infusions followed by 30 breaths of CO, were pretreated with Rp-8Br-cyclic GMPS (0.05 mg kg(-1)). This pretreatment abolished >60% of the CO-induced reduction in RL, but it had no effect on the bronchodilator response induced by salbutamol. In another set of experiments animals were pretreated with L-NAME (1.60 mg kg(-1)). In contrast to the Rp-8Br-cyclic GMPS pretreatment, the pretreatment with L-NAME did not affect the CO-induced reduction in RL. 4. The present findings indicate that CO causes bronchodilatation in vivo via cyclic GMP.     

Pre-exercise branched-chain amino acid administration increases endurance performance in rats

This study investigated the effects of pre-exercise branched-chain amino acid (BCAA) administration on blood ammonia levels and on time to exhaustion during treadmill exercise in rats. Adult female Wistar rats were trained on a motor driven treadmill. After a 24-h fast, rats were injected intraperitoneally (i.p.) with 1 mL of placebo or BCAA (30 mg), 5 min before performing 30 min of submaximal exercise (N = 18) or running to exhaustion (N = 12). In both cases, rats were sacrificed immediately following exercise, and blood was collected for the measurement of glucose, nonesterified fatty acid (NEFA), lactic acid, BCAA, ammonia, and free-tryptophan (free-TRP) levels. Control values were obtained from sedentary rats that were subjected to identical treatments and procedures (N = 30). Plasma BCAA levels increased threefold within 5 min after BCAA administration. Mean run time to exhaustion was significantly longer (P < 0.01) after BCAA administration (99 +/- 9 min) compared with placebo (76 +/- 4 min). During exercise, blood ammonia levels were significantly higher (P < 0.01) in the BCAA treated compared with those in the placebo treated rats both in the 30-min exercise bout (113 +/- 25 mumol.L-1 (BCAA) vs 89 +/- 16 mumol.L-1) and following exercise to exhaustion (186 +/- 44 mumol.L-1 (BCAA) vs 123 +/- 19 mumol.L-1). These data demonstrate that BCAA administration in rats results in enhanced endurance performance and an increase in blood ammonia during exercise.     

Bronchodilator and anti-inflammatory activities of SCA40: studies in human isolated bronchus, human eosinophils, and in the guinea-pig in vivo

There is currently interest in the use of inhibitors of cyclic nucleotide phosphodiesterases (PDE) as potential anti-asthma agents. In this study we examined the effects of SCA40 (6-bromo-8-methylaminoimidazol-[1,2-a] pyrazine-2-carbonitrile), a preferential inhibitor of PDE 3 also endowed with PDE 4 and 5 inhibitory activities, on isolated bronchus and eosinophil functions and in an animal model of asthma. SCA40 (1 nM-0.1 mM) produced concentration-dependent inhibition of spontaneous and stimulated tone of human isolated bronchus and reached a maximal relaxation similar to that of theophylline (3 mM). The potency (-log EC50 values) of SCA40 against spontaneous tone (6.52 +/- 0.10) was greater than against tone raised by equieffective concentrations (approximately 70%) of histamine (5.76 +/- 0.06), leukotriene C4 (5.44 +/- 0.11), and acetylcholine (4.98 +/- 0.09). In the presence of cytochalasin B, the chemotactic peptide N-formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP; 0.5 microM) induced leukotriene C4 production in human eosinophils isolated in discontinuous metrizamide gradients. The production of leukotriene C4 was inhibited by SCA40 in a concentration-related fashion (-log IC50 = 6.04 +/- 0.20; n = 6). Rolipram, a selective PDE 4 inhibitor, was also effective (-log IC50 = 7.29 +/- 0.32) but the selective PDE 3 inhibitor SKF94120 was scarcely effective (< 10% inhibition for 10 microM). In ovalbumin sensitized guinea-pigs, SCA40 (1 mg kg(-1), i.p.) given 30 min before antigen challenge significantly inhibited the acute bronchoconstriction produced by aerosol antigen (5 mg ml(-1), 30 s) (antigen response was 185 +/- 13 and 91 +/- 21 cmH2O l(-1) s(-1) in control and SCA40-treated animals, respectively, P < 0.05). Pretreatment with SCA40 (1 mg kg(-1), i.p., 30 min pre- and 3 h post-antigen exposure) prevented airway hyperreactivity to histamine which developed 24 h after exposure of conscious guinea-pigs to aerosol antigen. Eosinophil lung accumulation that accompanied airway hyperreactivity was also inhibited by SCA40 (from 6.15 +/- 0.86 in control to 1.27 +/- 0.27 in treated animals; expressed as eosinophils x 10(6); P < 0.05). SCA40 (1 mg kg(-1), i.p.) also inhibited the microvascular leakage produced after inhaled antigen (5 mg ml(-1), 30 s) at all airway levels. The haemodynamic effects of SCA40 (1 mg kg(-1), i.p.) consisted of a rapid decrease (peak at 5 min) in mean arterial blood pressure (-39.4 +/- 2.4%) and tracheal mucosal blood flow (-13.5 +/- 2.0%) that slowly recovered with time. These data support previous work showing that PDE inhibition results in antispasmogenic and anti-inflammatory effects. SCA40 was effective in vitro and in vivo and these effects are probably related to its activity as a mixed PDE inhibitor.     

Deregulated production of interleukin-8 (IL-8) in autoimmune thyroid disease studied by newly developed IL-8 radioimmunoassay

Glucagon may regulate FFA metabolism in vivo. To test this hypothesis, six healthy male volunteers were infused with somatostatin, to inhibit endogenous hormone secretion, and insulin, glucagon, and GH to replace endogenous secretion of these hormones. In the hypoglucagonemia experiments, the glucagon infusion was omitted, and in the hyperglucagonemic experiments glucagon was infused at 1.3 ng/kg.min, to produce physiological hyperglucagonemia. In two sets of control experiments, glucagon was infused at 0.65 ng/kg.min, in order to maintain peripheral euglucagonemia, and the plasma glucose concentrations were clamped at the levels observed in either the hypo- or hyperglucagonemic experiments. Rates of FFA and glycerol (an index of lipolysis) appearance (Ra) were estimated with the isotope dilution method using [1-14C]palmitate and [2H5] glycerol. Plasma glucagon concentrations decreased during the hypoglucagonemic experiments (85 +/- 12 vs. 123 +/- 22 ng/L, P < 0.05) and increased during the hyperglucagonemic experiments (186 +/- 20 vs. 125 +/- 15 ng/L, P < 0.05), whereas other hormone concentrations remained the same. Hypoglucagonemia resulted in equivalent suppression of FFA Ra (3.7 +/- 0.2 vs. 5.9 vs. 0.3 mumol/kg.min, P < 0.01) and glycerol Ra (1.2 +/- 0.2 vs. 2.2 +/- 0.5 mumol/kg.min, P < 0.05). Similarly, hyperglucagonemia resulted in equivalent stimulation of FFA Ra (5.2 +/- 0.4 vs. 3.7 +/- 0.3 mumol/kg.min, P < 0.05) and glycerol Ra (1.5 +/- 0.3 vs. 1.1 +/- 0.1 mumol/kg.min, P < 0.05). These results indicate that glucagon has a physiological role in the regulation of FFA metabolism in vivo.     

Myocardial bridging in a survivor of sudden cardiac near-death: role of intracoronary doppler flow measurements and angiography during dobutamine stress in the clinical evaluation

Studies were carried out using DBA/2 mice on the relationship between the behavioral effects of antagonists of different types of 5-HT receptors and the level of activity of alpha 2-adrenoceptors. The 5-HT1c receptor antagonists mianserin (2 mg/kg) and cyproheptadine (2 mg/kg) and the 5-HT2 receptor antagonist ketanserin (3 mg/kg) had no effect on movement activity, while the 5-HT3 and 5-HT4 receptor antagonists zacopride (1 mg/kg) and ICS 205-930 (1 mg/kg) reduced movement behavior in intact animals. On a background of treatment with the alpha 2-adrenoceptor blocker yohimbine (0.5 mg/kg), mianserin, cyproheptadine, and ketanserin inhibited movement activity and significantly reduced the sensitivity of animals to audiogenic convulsions. These data indicate that administration of alpha 2-adrenoceptor antagonists increases the efficiency with which serotonin receptors regulate behavior.     

The three-dimensional bone interface of an osseointegrated implant. I: A morphometric evaluation in initial healing

This study was designed to determine the effect of a potent cholecystokinin antagonist, L-364,718, on canine pancreatic endocrine function following partial pancreatectomy. Plasma glucose, insulin, and glucagon were determined over a 2-hr interval following an intravenous bolus of 0.5 g/kg glucose in a 50% solution. The following groups were established: normal animals (group A, n = 5), normal animals pretreated with 20 nmole/kg L-364,178 (group B, n = 5), partially pancreatectomized animals (group C, n = 5), and partially pancreatectomized animals pretreated with 20 nmole/kg L-364,178 (group D, n = 5). In contrast to animals with an intact pancreas, pretreatment with L-364,718 following partial pancreatectomy resulted in a significant decrease in peak insulin (group C = 132.8 +/- 13.0 microU/ml vs Group D = 90.4 +/- 16.1 microU/ml, P < 0.05) and the basal-to-peak insulin difference (group C = 111.9 +/- 11.5 microU/ml vs group D = 77.5 +/- 16.6 microU/ml, P < 0.05). Despite this, the rate of glucose utilization (K value) was significantly increased in the partially pancreatectomized animals given the antagonist (group C = -1.22 +/- 0.22%/min vs group D = -2.79 +/- 0.427%/min) and there were no significant differences in basal or peak glucose when comparing the groups given L-364,718 with the groups given placebo (group A vs B and group C vs D). Thus, the CCK antagonist L-364,718 significantly decreases peak insulin in partially pancreatectomized animals but not in nonoperative control animals. There is a paradoxical increase in the rate of glucose utilization but no effect on glucose homeostasis. The effect of this antagonist in other models of reduced islet cell reserve (i.e., pancreas transplantation) remains to be determined.     

Persistent airway hyperresponsiveness and histologic alterations after chronic antigen challenge in cats

We studied the effect of chronic immune sensitization on the airway reactivity and associated cytologic and histologic alterations in initially nonatopic cats, a species that spontaneously develops idiopathic asthma. Seven cats were sensitized by intramuscular injection of Ascaris suum antigen (AA) for 4 wk, and four other cats served as sham controls. Airway sensitization was demonstrated by an increased response to nebulized AA in sensitized animals (RL = 45.9 +/- 6.1 cm H2O/L/s, versus a baseline response of 24.7 +/- 1.5 cm H2O/L/s, p < 0.01), and hyperresponsiveness was demonstrated by an increased response to acetylcholine (ACh)-challenge 24 h after AA (approximately 1.0 log decrease in PD200, p < 0.01). The number of eosinophils in the sensitized animals' bronchoalveolar lavage (BAL) fluid increased 12-fold (p < 0.01 versus control) in response to AA challenge; 32 +/- 5% of the BAL eosinophils had a specific density < 1.050, versus 8 +/- 2% prior to AA challenge (p < 0.05). There was no change in airway reactivity, eosinophil recovery, or density in the control group 24 h after sham challenge with saline. The same seven sensitized cats further received nebulized AA three times weekly for 4 to 6 wk, after which BAL samples were again obtained and ACh dose-response curves generated 72 h after the final administration of nebulized AA. Airway hyperresponsiveness increased (approximately 1.5 log decrease in PD200, p < 0.001) and the number of eosinophils recovered in BAL fluid was increased 11-fold (p < 0.05). Necropsy specimens demonstrated bronchoconstriction in AA-challenged animals but not controls; luminal narrowing was accompanied by: (1) a 29.0 +/- 0.34% increase in smooth-muscle thickness (p < 0.05); (2) goblet-cell and submucosal-gland hypertrophy and hyperplasia; and (3) epithelial erosion and eosinophilic infiltration. We demonstrate in nonhuman species persistent airway hyperreactivity associated with a complete constellation of histologic changes in epithelium, smooth muscle, and mucus glands, and cytologic changes in BAL fluid, all induced by immune sensitization. Our data suggest that chronic immune sensitization per se could be a salient factor in causing many of the changes associated with chronic bronchial asthma.     

Some experiences with hospital-based psychiatric aftercare over ten years

Smooth muscle cells represent a significant percentage of the total cells in the airway but their contribution to the inflammatory response seen in airway disease has not been studied. Hence, we have looked at the release of the cytokine granulocyte-macrophage colony stimulating factor (GM-CSF) in response to bacterial lipopolysaccharide (LPS) and the pro-inflammatory cytokines interleukin-1 beta (IL-1 beta), tumour necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma). Human airway smooth muscle (HASM) cells released GM-CSF under basal conditions (45.4 +/- 13.1 pg ml-1) that was significantly enhanced by IL-1 beta and TNF alpha with a maximal effect seen at 10 ng ml-1 (1.31 +/- 0.07 ng ml-1 and 0.72 +/- 0.16 ng ml-1, respectively). In contrast, neither LPS nor IFN gamma produced a significant increase in GM-CSF release. However, HASM cells exposed to IL-1 beta, TNF alpha and IFN gamma generated more GM-CSF than that evoked by any cytokine alone (2.2 +/- 0.15 ng ml-1). The release of GM-CSF elicited by the cytokine mixture was inhibited by cycloheximide and dexamethasone. These data suggest that HASM cells might play an active part in initiating and/or perpetuating airway inflammation in addition to controlling airway calibre.     

Pharmacological doses of vitamin E and insulin action in elderly subjects

Twenty elderly (77 +/- 0.4 y), nonobese [body mass index (in kg/m2) 26.4 +/- 0.5] subjects with normal glucose tolerance were submitted to a euglycemic hyperinsulinemic (3.5 pmol.min/kg) glucose clamp in a double-blind, crossover, randomized procedure after 4 mo treatment with either vitamin E (900 mg d-alpha-tocopherol/d, Ephynal; Roche, Milan, Italy) or placebo. Body mass index was practically unchanged throughout the study. After the glucose clamp, insulin-mediated stimulation 2 of whole-body glucose disposal (18.4 +/- 0.5 vs 26.1 +/- 0.6 mumol.min/kg lean body mass P < 0.02) was significantly potentiated by vitamin E rather than placebo administration. Furthermore, net changes in plasma vitamin E concentrations correlated with net changes in insulin-stimulated whole-body glucose disposal (r = 0.60 P < 0.003). Plasma vitamin E concentrations seem to play an important role in the modulation of insulin action in elderly people.     

MDMA induced dopamine release in vivo: role of endogenous serotonin

Acting as a substrate at the serotonin (5-HT) transporter, (+)-MDMA (3,4-methylenedioxymethamphetamine), is a potent releaser of 5-HT and causes toxicity to 5-HT neurons after repeated exposure. (+)-MDMA also releases dopamine (DA), although with less potency. Since we have shown previously that the intrastriatal application of 5-HT facilities DA release, it was hypothesized that increased release of striatal 5-HT after MDMA may influence extracellular levels of DA. Using microdialysis in vivo, we found that (+)-MDMA (4.7 mumol/kg, i.v.) administration increased extracellular striatal DA levels to 501% of control (p < 0.01, n = 12). However, in the presence of fluoxetine (14.4 mumol/kg, s.c.), which prevents (+)-MDMA effects on 5-HT release, the (+)-MDMA-induced increase in DA was significantly less (to 375% of control, p < 0.05, vs. no fluoxetine, n = 8). In vitro studies with striatal slices, to test drug selectivity, showed that (+)-MDMA (0.3-3 microM) increased extracellular levels of both DA and 5-HT in a dose-dependent manner. Fluoxetine (3 microM) completely blocked the effects of (+)-MDMA on 5-HT release, but did not alter (+)-MDMA-induced DA release in vitro. The selective DA transport inhibitor GBR-12909 (1 microM), blocked (+)-MDMA's effect on DA release. It is concluded that 5-HT release after (+)-MDMA treatment partially contributes to (+)-MDMA's effect on DA release in vivo.     

Overnight normalization of glucose concentrations improves hepatic but not extrahepatic insulin action in subjects with type 2 diabetes mellitus

Subjects with poorly controlled type 2 diabetes are both hyperglycemic and insulin resistant. To determine whether short term restoration of normoglycemia improves insulin action, hyperinsulinemic (approximately 300 pmol/L) euglycemic clamps were performed in diabetic subjects after either overnight infusion of saline or overnight infusion of insulin in amounts sufficient to maintain euglycemia throughout the night. Fasting glucose concentrations (5.2 +/- 0.2 vs. 11.9 +/- 1.4 mmol/L; P < 0.01) and rates of endogenous glucose production (13.0 +/- 1.1 vs. 18.6 +/- 1.6 mumol/kg.min; P < 0.05) were both lower after overnight insulin than overnight saline. Insulin-induced stimulation of glucose uptake (to 34.9 +/- 6.8 vs. 28.8 +/- 3.4 mumol/kg.min; P = 0.2) and inhibition of free fatty acids (to 0.13 +/- 0.03 vs. 0.12 +/- 0.04 mmol/L; P = 0.6) did not differ after overnight saline and overnight insulin. In contrast, endogenous glucose production during the final hour of the hyperinsulinemic clamps (i.e. when glucose concentrations were the same) remained higher (P = 0.05) after overnight saline than after overnight insulin (5.5 +/- 1.5 vs. 0.02 +/- 1.4 mumol/kg.min). Thus, acute restoration of euglycemia by means of an overnight insulin infusion improves hepatic (and perhaps renal) but not extrahepatic insulin action.     

Characteristics of gene 28 product, the constituent of the central part of bacteriophage T4 baseplate

This study investigated the effects of indomethacin at clinically relevant doses and its chronic usage on intestinal pathology, survival time and intestinal tissue 6-keto prostaglandin F1 alpha and leukotriene B4 level in rats during various periods with different doses. Indomethacin was administered ranging from 0.625 to 5 mg/kg. When used in doses of 0.625 and 1.25 mg/kg, indomethacin caused no apparent intestinal lesions or death during a treatment period of 30 days. On the other hand, all rats died in 7 days when 5 mg/kg of indomethacin was given. Mortality rate reached 53.3% in seven days in the group where 3.75 mg/kg indomethacin was given. The minimal dose of indomethacin, which induced intestinal ulcer and death, was 2.5 mg/kg. The main pathological findings were intestinal ulcers, but no macroscopic and microscopic changes were observed in the stomach. Intestinal tissue 6-keto prostaglandin F1 alpha and leukotriene B4 levels were quantified by enzyme immunoassay after homogenisation and extraction of tissue. In dose-dependent studies, only the dose of indomethacin, 3.75 mg/kg, significantly inhibited intestinal tissue 6-keto prostaglandin F1 alpha levels during seven days application period (197.39 +/- 24.26 vs 383.66 +/- 46.68 ng/g tissue, treatment vs control). 2.5 mg/kg of indomethacin caused no intestinal ulceration on 4th day, however, it significantly inhibited intestinal tissue 6-keto prostaglandin F1 alpha levels on 4th day in time-dependent studies (190.3 +/- 26.62 vs 383.66 +/- 46.68 ng/g tissue, treatment vs control). Neither dose-dependent nor time-dependent indomethacin administration changed intestinal tissue leukotriene B4 level. The results of this study indicated that indomethacin produced enteropathy rather than gastropathy when used chronically in clinically relevant doses in rats. Inhibition of prostaglandin synthesis, which was estimated by quantification of intestinal tissue 6-keto prostaglandin F1 alpha level, seemed not to be a prerequisite for its enteropathic effect.     

Central pathology review in clinical trials for patients with malignant glioma. A Report of Radiation Therapy Oncology Group 83-02

We previously described delayed pressor response (DPR) 3 h after endothelin (ET)-1 injection in normotensive rats. In the current study, we examined effects of the ETA receptor antagonist BQ123 (0.01 mumol/kg/min intravenously, i.v.), phosphoramidon (100 mumol/kg i.v.), the neutral endopeptidase inhibitor SQ28603 (112 mumol/kg + 0.04 mumol/kg/min i.v.), the angiotensin-converting enzyme inhibitor enalaprilat (10 mumol/kg i.v.), and the thromboxane receptor antagonist, SQ29548 (0.5 mumol/kg + 0.5 mumol/kg/h i.v.) on DPR. Vehicle and ET-1 (1.0 nmol/kg i.v.) were administered on day 1; vehicle or drug and ET-1 were administered on day 2. BQ123 inhibited DPR 36% (vehicle 44 +/- 5, BQ123 28 +/- 3 mm Hg); phosphoramidon inhibited DPR 56% (vehicle 45 +/- 4, and phosphoramidon 20 +/- 5 mm Hg). DPR was unchanged after SQ28603 (vehicle 39 +/- 2 and SQ28603 44 +/- 2 mm Hg), enalaprilat (vehicle 39 +/- 2 and enalaprilat 38 +/- 7 mm Hg), or SQ29548 (vehicle 46 +/- 6 and SQ29548 43 +/- 3 mm Hg). The results suggest that DPR 3 h after ET-1 injection in rats is mediated in part through ETA receptors. DPR does not appear to involve thromboxane or synthesis of angiotensin II (AII), but may be related to synthesis of ET-1.     

Serial prognostic capabilities of electrocardiographic indices of infarcted and hibernating myocardium in predicting short- and long-term outcome following coronary artery bypass surgery

Concentrations and ex vivo production of interleukin 1 beta (IL-1), tumour necrosis alpha (TNF), interleukin 6 (IL-6), interleukin-1 receptor antagonist (IL-1RA) and TNF soluble receptors (sTNF-receptors, P55 and P75) were measured in bronchoalveolar lavage (BAL) fluid and blood in 23 HIV-seropositive (HIV+) patients with Pneumocystis carinii pneumonia (PCP) and compared with values found in healthy HIV-seronegative (HIV-) controls and asymptomatic HIV+ subjects. Concentrations of the proinflammatory cytokine IL-1 beta were increased in BAL fluid of HIV+ patients with PCP (184 +/- 47 pg mL-1) compared with undetectable levels in healthy control subjects (P = 0.0001). In plasma of these patients higher concentrations of the anti-inflammatory cytokine IL-1RA were found during acute PCP than after recovery (2.1 +/- 0.7 vs. 0.5 +/- 0.2 ng mL-1, P = 0.01). No correlations could be found between cytokine concentrations and clinical severity of the infection. Corticosteroid treatment did not influence cytokine concentrations in BAL or blood, nor did it suppress the production in alveolar cells. In whole-blood cultures, however, lipopolysaccharide (LPS)-stimulated production was significantly suppressed for IL-1 (1.3 vs. 5.5 ng mL-1, P = 0.009) and for IL-6 (0.6 vs. 2.5 ng mL-1, P = 0.01). The overall data show that in HIV+ patients with PCP (similar to what we had found previously in HIV-patients with PCP) proinflammatory cytokines are more prominently present in BAL, whereas anti-inflammatory reaction is predominant in the circulation.     

Pulmonary responses to 5-hydroxytryptamine and endothelin-1 in a rabbit model of left ventricular dysfunction

OBJECTIVE: To determine whether pulmonary hypertension developed in a coronary artery-ligated rabbit model of left ventricular dysfunction (LVD) and to examine the effects of i.v. 5-hydroxytryptamine (5-HT) and endothelin-1 (ET-1) on pulmonary arterial pressure (PAP). METHODS: Eight weeks after experimental coronary artery ligation or sham operation, ejection fractions were assessed by echocardiography. The rabbits were later anaesthetised and pulmonary arterial pressure was measured via a catheter inserted into the pulmonary artery via the right external jugular vein. 5-HT (1-400 micrograms/kg) and ET-1 (0.001-4 nmol/kg) were administered i.v. RESULTS: Ejection fraction was significantly decreased from 76.6 +/- 1.4% in sham-operated to 42.2 +/- 1.3% in coronary artery-ligated rabbits (n = 9 in each group; P < 0.001), consistent with LVD. Baseline mean pulmonary arterial pressure was significantly increased in the coronary artery-ligated group compared to the shams, (16.5 +/- 0.5 vs. 11.5 +/- 0.8 mmHg; P < 0.001). A significant degree of right ventricular hypertrophy was found in the coronary artery-ligated rabbits (0.70 +/- 0.04 g/kg final body weight (f.b.wt.), n = 8 cf. 0.48 +/- 0.02 g/kg f.b.wt. in sham-operated controls, n = 8; P < 0.001). There was a significant increase in the percentage of muscularised pulmonary vessels adjacent to alveolar ducts and alveoli < 60 microns i.d. in the LVD rabbits compared with their sham-operated controls (8.5 +/- 0.4 cf. 20 +/- 0.5%; P < 0.0005). 5-HT produced a greater response in the coronary artery-ligated rabbits (a maximum increase of 8.7 +/- 1.0 mmHg in mean pulmonary artery pressure vs. 4.6 +/- 1.5 mmHg for sham-operated controls; P < 0.05). ET-1 did not have any effect on pulmonary arterial pressure in either group. CONCLUSION: In the rabbit, LVD secondary to coronary artery ligation, causes right ventricular hypertrophy, pulmonary vascular remodelling, and an increased PAP consistent with the onset of pulmonary hypertension (PHT). The greater PAP response to i.v. 5-HT in the PHT group supports the hypothesis that this substance could be involved in the development of PHT. A role for ET-1 cannot be excluded, despite its lack of effect on PAP when intravenously administered in either group.