Biochemical and histopathological alterations induced in rats by Tityus serrulatus scorpion venom and its major neurotoxin tityustoxin-I

Intravenous injection into the rat of sublethal doses of Tityus serrulatus scorpion venom (100 micrograms protein/kg) or its major neurotoxin tityustoxin-I (TsTX-I, 20 micrograms/kg) caused, 30-180 min after injection, statistically significant increases in the serum levels of aspartate aminotransferase, amylase, creatine kinase and lactate dehydrogenase, as well as hyperglycemia, a high level of plasma free fatty acids and a low level of liver glycogen. The in vitro serum levels of the above enzymes did not change. For alanine aminotransferase, gamma-glutamyl transferase and alkaline phosphatase, neither in vitro nor in vivo alterations were observed. The whole venom and TsTX-I caused hepatic congestion with hemolysis and hydropic degeneration. Other histological lesions included edema and congestion with subpleural hemorrhage in the lungs, hypertrophy of fibers with degeneration areas in the heart, and congestion and hemorrhage in the kidneys. In the salivary glands, alterations to the acini and ductules were visible. In the adrenal glands no morphological alterations could be detected at the studied doses. The results suggest that the in vivo enzymatic and histopathological alterations are due to tissue lesions evoked by the whole venom and TsTX-I. An indirect effect, however, induced by stimulation of acetylcholine and catecholamine release in the postganglionic nerve terminals, cannot be excluded.     

Distribution of tritiated dihydromicrocystin in swine

The distribution of tritiated dihydromicrocystin [3H]2H-MCLR was studied in anesthetized specific-pathogen-free pigs. Two doses were administered i.m. and one dose was given via an isolated ileal loop. At 4 hr after i.v. administration of the toxin at 25 micrograms/kg, 64.6% of the total dose (%TD) was located in the liver, with smaller amounts distributed to the kidneys (1.2% TD), lungs (1.75% TD), heart (0.22% TD), ileum (0.13% TD) and spleen (0.04% TD). A similar distribution was found at 4 hr postdosing in pigs given 75 micrograms/kg, although the liver contained a lower fraction of the total dose, at 46.99% TD, and the kidneys had somewhat more, at 2.19% TD, than the low dose. At the high dose, the fractions of the amount given accounted for by the lungs (0.55% TD), heart (0.23% TD), ileum (0.20% TD) and spleen (0.07% TD) were similar to those at the low dose. The livers of the pigs given 75 micrograms/kg via the ileal loop, at 5 hr postdosing, contained 49.5% TD and the ileum had 33.94% TD. Smaller amounts were distributed to kidneys (1.04% TD), lungs (0.65% TD), heart (0.81% TD) and spleen (0.16% TD). The livers of both groups dosed at 75 micrograms/kg contained higher concentrations of toxin, but lower percentages of the total dose, than the livers of pigs dosed at 25 micrograms/kg. Larger increases in serum arginase in the two 75 micrograms/kg groups were associated with histological evidence of more severe liver damage than at the 25 micrograms/kg dose. Analysis of radiolabeled compounds from hepatic tissue using fast atom bombardment mass spectrometry determined that the primary constituent was [3H]2H-MCLR, but two minor radioactive components were also isolated. These findings indicate that [3H]2H-MCLR is rapidly concentrated in the liver of swine, whether given i.v. or via an isolated ileal loop, that at extremely toxic doses uptake is slowed, and that it is as toxicologically active as the parent compound.     

Influence of anti-inflammatory and antioxidant agents on endothelial permeability alterations induced by bradykinin

Increased vascular permeability to plasma proteins and altered hemodynamics at the site of inflammation are characteristics of inflammation. In the present study, alterations in endothelial barrier permeability were evaluated in different organs/tissues 6 h after a systemic inflammatory response induced by intravenous injection of bradykinin (BK; 1.7 mg/kg). The effect of intravenous pretreatment with indomethacin or ibuprofen (cyclooxygenase inhibitors), N-acetyl-L-cysteine (NAC, an oxygen free radical scavenger), and allopurinol (a xanthine oxidase inhibitor) was determined. Endothelial permeability was evaluated by determining tissue water content (TWC), 125I-labeled human serum albumin (HSA) flux, and albumin leakage index (ALI) in various organs/tissues. The vasodilation in the local tissues was reflected by tissue blood content (TBC), measured by 51Cr-labeled red blood cells. The results indicate that albumin flux significantly increased in the peritoneum, pancreas, stomach, PSI, DSI, colon, kidneys, liver, lungs, and brain, TBC significantly increased in the kidneys, liver, lungs, and heart, as well as in the intestine, and an increased ALI, assaying endothelial permeability considering local hemodynamic alterations was noted in the pancreas, kidneys, liver, lungs, PSI, and DSI in the group with BK alone. These changes were to varying degrees reversed by pretreatment with indomethacin, ibuprofen, N-acetyl-L-cysteine, or allopurinol, where the protective effect tended to be organ-dependent.     

Solution structure of synthetic peptide inhibitor and substrate of cAMP-dependent protein kinase. A study by 2D H NMR and molecular dynamics

Altered hepatic expression of apolipoproteins occurs during the acute phase response. Here we examined whether the acute phase response alters extra hepatic expression of apolipoproteins. Syrian hamsters were injected with endotoxin (LPS), tumor necrosis factor (TNF), interleukin (IL)-1, or the combination of TNF + IL-1 and mRNAs for serum amyloid A (apoSAA), apolipoprotein (apo) J, apo E. apo A-I, and apo D, were analyzed. LPS increased mRNA levels for apoSAA in all tissues examined. LPS and TNF + IL-1 increased mRNA levels for apo J in kidney, heart, stomach, intestine, and muscle. Individually, TNF and IL-1 were less potent than the combination of the two cytokines. LPS decreased mRNA levels for apo E in all tissues, except for mid and distal intestine. TNF and IL-1 were less effective than LPS. LPS, TNF + IL-1 and TNF decreased mRNA levels for apo A-I in duodenum. mRNA for apo D decreased in heart, were unchanged in brain and increased in muscle, following LPS. The widespread extra hepatic regulation of the apolipoproteins during the acute phase response may be important for the alterations in lipid metabolism that occur during infection and inflammation as well as the immune response.     

Diffuse hemorrhagic gastroenteropathy: report of a new entity

An apparently novel entity, diffuse hemorrhagic gastroenteropathy (DHG), in a 70-year-old female who had an unremitting course of chronic gastrointestinal blood loss for 3 years requiring transfusion of more than 200 units of packed red blood cells over this period is reported here. Endoscopy showed diffusely hemorrhagic mucosa in the stomach, duodenum, and small bowel. Full-thickness biopsy of the stomach and small intestine revealed luminal narrowing of capillaries and post-capillary venules within the lamina propria due to swelling and some proliferation of the endothelial cells with margination and emigration by neutrophils as well as partial occlusion of some vessels by fibrin thrombi. DHG may represent a new entity characterized by mucosal hemorrhage due to local mucosal ischemia of the gastrointestinal tract secondary to a small vessel "vasculopathy" apparently restricted to this site.     

Histopathological changes in aluminium phosphide poisoning

A total of thirty cases of aluminium phosphide poisoning were studied for gross and microscopic changes in various organs of the body ie, lungs, liver, kidneys, heart, brain, stomach and adrenals. The histopathological changes revealed varying degrees of congestion, oedema and leucocytic infiltration, changes suggestive of cellular hypoxia. The most dramatic effects were produced in lungs, kidneys and adrenals.     

Metabolism of 109Cd in rats fed normal and low-calcium diets

Growing male rats were fed purified diets that contained either 0.6% or 0.1% calcium to investigate the relationship of calcium intake to the uptake, tissue distribution, and excretion of 109Cd. An equal number of rats were fed either the 0.6 or 0.1% calcium diets for 4 wk before they were used for experiments. In the first experiment 11 rats from each dietary group were administered 5 muCi 109Cd by stomach tube and were then maintained in metabolism cages for 72 hr. Animals fed the low-calcium diet took up more 109Cd, as significantly higher levels of radioactivity were found in the intestinal mucosa, serum, lungs, liver, kidneys, and urine and a significantly lower level was found in the feces. Higher levels of 109Cd, associated with low-molecular-weight proteins that may be related to the absorption process, were found in the intestinal mucosa of the low-calcium group. In the second experiment 10 rats from each dietary group were administered 5 muCi 109Cd by subcutaneous injection and then maintained in a metabolism cage for 72 hr. No significant differences were found in the distribution or excretion of 109Cd except for the lungs where radioactivity was greater in the low-calcium group. The results of the study indicate that the enhanced cadmium toxicity observed in calcium-deficient animals exposed to the heavy metal is the result of an increased uptake from the small intestine.     

Absorption and metabolism of estrogens from the stomach and duodenum of pigs

To determine the absorption and metabolism of 17 beta-estradiol (E2) by the stomach and liver of the pig, crystalline E2 was placed in the stomach of prepubertal gilts. Blood samples were subsequently obtained from the hepatic portal and jugular veins and plasma was assayed for E2, estrone (E1), 17 beta-estradiol-glucuronide (E2G), estrone-glucuronide (E1G) and estrone-sulfate (E1S). Concentrations of E2, E1, E2G and E1S rose in the hepatic portal vein within five min and remained elevated for several hr. Concentration of E2 represented only 6% of the total estrogen detected in the hepatic portal vein during the sampling period, indicating that most of the E2 was converted or conjugated prior to entering the hepatic portal vein. The metabolism of E2 presumably occurred in the stomach mucosa because food had been withheld for 26 hr before infusion of E2. Concentrations of E2G, E1G and E1S, but not E2 and E1, rose in the jugular vein and remained elevated for several hr. The lack of a rise in E2 and E1 in the jugular vein indicates that the E2 and E1 from the hepatic portal vein were completely converted and/or removed by the liver. Most of E2 was converted to E1 and then to E1G. The infusion of bile containing normal estrogens from pregnant gilts into the duodenum of prepubertal gilts resulted in a peak of E1G and E2G in the hepatic portal and jugular veins within a few minutes. This was followed in about 180 min by a second sustained rise. The first peak was essentially abolished by extracting E1 and E2 from the bile before infusion. The second peak failed to occur in gilts given antibiotics orally to reduce gut bacteria before infusion of bile.     

Injections into the duodenum and the induction of satiety in the rat.

Examined ways in which the intestine might participate in the induction of satiety, using direct intestinal injections to alter the contents of the duodenum and then observing the effect on subsequent food intake over a 21/2-hr period. Ss were 24 male hooded rats, food-deprived for approximately 17 hr. The injection of either bulk or hypertonic solutions (NaCl or glucose) into the duodenum suppressed food intake. The injection of substantial amounts of food did not have an effect greater than that caused by equivalent amounts of nonnutritive bulk and the injection of acid material did not suppress eating more than basic material. These results suggest that bulk and osmotic pressure in the duodenum may initiate physiological changes which can ultimately participate in the regulation of meal size but that metabolites, duodenal hormones, and specific dynamic action do not. With the gastrointestinal system intact, the flow of material from the stomach to the intestine would be sufficiently slow that neither changes in duodenal bulk nor osmotic pressure would be involved in the regulation of meal size. When the stomach is partially removed or denervated, the rate of passage of food into the duodenum may increase enough so that osmotic and bulk signals originating in the duodenum would help to regulate meal size. (French summary) (33 ref.) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Colon-specific genotoxicity of heterocyclic amines detected by the modified alkaline single cell gel electrophoresis assay of multiple mouse organs

The in vivo genotoxicity of five heterocyclic amines-Trp-P-2 (13 mg/kg), IQ (13 mg/kg), MeIQ (13 mg/kg), MeIQx (13 mg/kg), and PhIP (40 mg/kg)-in the mucosa of gastrointestinal and urinary tract organs (stomach, duodenum, jejunum, ileum, colon, and bladder) was studied by the alkaline single cell gel electrophoresis (SCG) (Comet) assay. Male CD-1 mice were sacrificed 1, 3, and 8 h after intraperitoneal injection. All the heterocyclic amines studied yielded statistically significant DNA damage in the colon but not the small intestine (duodenum, jejunum, and ileum) or urinary bladder. In this study, five heterocyclic amines were injected intraperitoneally to avoid the consequences of ingestion. Thus, the extensive damage to colon DNA was concluded to be due, at least in part, to a systemic effect.     

Microsphere uptake by the intestine of White Leghorn chickens

A study was conducted to determine the effective size for latex microsphere uptake in the intestine of white leghorn chickens. Three trials were conducted in which ligated intestinal segments of anesthetized 8-wk-old chickens were injected with 0.2-, 0.5-, 2-, 6-, 10-, or 20-mu diameter fluoresceinated latex microspheres. Microspheres were counted in brush border, epithelium, and lamina propria of each intestinal segment, liver, and spleen. After 1 hr, the 0.2-, 0.5-, and 2-mu microspheres were oriented along the brush border of epithelial cells and microsphere uptake into the epithelium and lamina propria was observed in the duodenum, ileum, cecum, cecal tonsil, and colon. Uptake of microspheres of 6, 10, and 20 mu diameter into epithelium and lamina propria was not observed in any intestinal segment. Also, no microspheres of any diameter were observed in sections of liver and spleen to suggest that there was no appreciable entry of microspheres into the bloodstream within 1 hr after administration. The results indicated that uptake of microspheres by the chicken intestine is a size-dependent process with microspheres < or = 2 mu being taken up to an equal extent by most segments of intestine.     

Regional blood redistribution following blood loss in unanesthetized rats

The authors describe relative changes in the blood filling of 46 vascular areas of the body in rats after a moderate and severe blood loss. Moderate blood loss caused redistribution of the blood from the skin of the chest and from the skin of the posterior limbs, the majority of the abdominal and pelvis minor organs, muscular and bone tissues of the abdomen, pelvis minor and extremities into the brain, heart, lungs, kidneys, stomach and into the muscles of the head and neck. In severe blood loss the changes were analogous, but the blood content in the kidneys and the stomach decreased, and there was also a relative elevation of the blood in the muscles and bones of the chest. The intensity of the redistributive reaction in severe blood loss was less than in moderate blood loss.     

Morphological studies on experimental oleander poisoning in cattle

Oleander poisoning has been reported in man and animals. The present experiments address the gross and microscopic changes due to oleander poisoning in cattle. Minimum lethal doses (50 mg/kg) of oleander leaves were orally administered to three calves in a single dose each of the other three animals received the same lethal dose in three equal parts with 24-h intervals. The lesions in the three animals which received 50 mg/kg in a single dose resulted from the direct effect of the toxin on the vascular endothelial bed and demonstrated as petechial and diffused haemorrhages, congestion, oedema, cell degeneration and inflammatory cell infiltration in the lungs, heart, mesentry, kidneys, serosal and mucosal surfaces of omasum, abomasum and the intestine. The lungs also showed atelectasis, emphysema and disseminated intravascular coagulation. On the other hand, the animals which received divided doses showed lesions due to long-term exposure to the toxic agent and/or as the result of tissue ischaemia. The lungs also showed cell necrosis and mononuclear cell infiltration in the interstitial tissue, and some of the cardiac muscle fibres rather showed fibromyolysis and cell infiltration between muscle fibres, epicardium and endocardium. The intestinal villi showed haemorrhagic, degenerative and necrotic changes and the eosinophils were infiltrated in mucosal and submucosal layers of this organ. Multifocal degenerative and necrotic changes with inflammatory cell infiltration were also present in the liver parenchyma.     

Respiratory system: Part 2. Tuberculosis

AIM: The insight into the causes of late diagnosis and analysis of clinical variants of nonspecific aortic arteritis (NSAA) including rare forms--with involvement of the kidneys, intestine, lungs, heart. MATERIALS AND METHODS: Physical, laboratory and immunological tests, angiography, ultrasound dopplerography were employed in examination of 65 NSAA patients observed in 1955-1996. RESULTS: Accurate diagnosis of NSAA is made late (5 years from the first symptoms, on the average) when ischemic damage has become irreversible. The causes of such situation are outlined with special emphasis on NSAA variants running with affection of the lesser circulation vessels, coronary flow, kidneys (nephritis, amyloidosis), intestine (Crohn's disease, nonspecific ulcerative colitis). Men suffer more than women: they develop more frequently myocardial infarctions, thromboembolism. However, their arteries look better. Mechanisms of NSAA onset and progression may be related to defects in vascular endothelium, hyperproduction of antibodies to cardiolipin, antiendothelial antibodies. CONCLUSION: Management of NSAA meets with the problem of late diagnosis which means greater risk of severe vascular complications and deterioration of the prognosis.     

The analgesic activity of crotamine, a neurotoxin from Crotalus durissus terrificus (South American rattlesnake) venom: a biochemical and pharmacological study

Crotamine, a 4.88 kDa neurotoxic protein, has been purified to apparent homogeneity from Crotalus durissus venom by gel filtration on Sephadex G-75. When injected (i.p. or s.c.) in adult male Swiss mice (20-25 g), it induced a time-dose dependent analgesic effect which was inhibited by naloxone, thus suggesting an opioid action mechanism. When compared with morphine (4 mg/kg), crotamine, even in extremely low doses (133.4 microg/kg, i.p., about 0.4% of a LD50 is approximately 30-fold more potent than morphine (w/w) as an analgesic. On a molar basis it is more than 500-fold more potent than morphine. It is also much more potent than the lower molecular weight crude fractions of the same venom. The antinociceptive effects of crotamine and morphine were assayed by the hot plate test and by the acetic acid-induced writhing method. Therefore, both central and peripheral mechanisms should be involved. Histopathological analysis of the brain, liver, skeletal muscles, stomach, lungs, spleen, heart, kidneys and small intestine of the crotamine injected mice did not show any visible lesion in any of these organs by light microscopy. Since crotamine accounted for 22% (w/w) of the desiccated venom, it was identified as its major antinociceptive low molecular weight peptide component.     

Liver regulation of acid-base balance

Traditionally, lungs and kidneys have been viewed as the sole and principal organs involved in systemic acid-base homeostasis in mammals, but this view is not entirely compatible with basic principles of chemistry. Recent conceptual developments point to a role for the liver in pH homeostasis in addition to the well-established role of lungs and kidneys. Hepatic and renal nitrogen metabolism are linked by an interorgan glutamine flux, which couples both renal ammoniagenesis and hepatic ureogenesis to systemic acid-base regulation. Hepatic urea synthesis is a major pathway for the removal of metabolically generated bicarbonate. A structural-functional organization in the liver acinus uncouples urea cycle flux control from the vital need to maintain ammonium homeostasis. There is a sensitive and complex control of bicarbonate disposal via hepatic ureogenesis by the extracellular acid-base status, suggestive of a feedback control loop between acid-base status and the rate of bicarbonate elimination, i.e., a hepatic bicarbonate-homeostatic response. Some pathophysiological implications arising from the pH-stat function of the liver are discussed.     

Small intestinal sarcoidosis with massive hemorrhage: report of a case

Sarcoidosis of the small intestine is a rarely described complication of systemic sarcoidosis. Although bleeding from sarcoidosis of the esophagus, stomach, and colon has been reported, massive bleeding from this condition in the small intestine has not been previously described. We present here the first case of hemorrhage from a jejunal sarcoid lesion that was unsuspected and undiagnosed until laparotomy with resection was performed. As with most pathologic conditions of the small intestine, preoperative diagnosis is difficult. Furthermore, the refractory nature of bleeding from this lesion made resection necessary in this patient, suggesting the need for similar therapy in other affected patients.     

Covalent binding of agaritine to DNA in vivo

14C-Ring-labelled agaritine was administered orally to eight C57BL/6 mice at a chemical dose of 7.5 mg and radioactive dose of 1.2 x 10(9) dpm/kg body weight. After 24 hr, the animals were killed and DNA from stomach, liver and kidneys was purified by a phenol-free method involving proteinase K digestion of chromatin and coprecipitated proteins, followed by hydroxylapatite chromatography, dialysis and precipitation with ethanol. An increase in radioactivity was found in DNA of all three organs examined. Stomach DNA had the highest levels: 160 and 30 dpm/mg DNA in males and females, respectively. Liver and kidney DNA both showed levels of approximately 1 dpm/mg, with no measurable gender differences. Expressed in the units of the covalent binding index (CBI), agaritine has a potency of 42 in mouse stomach in males and 8 in females. The CBI of agaritine in liver and kidney was 0.2-0.3 in both sexes. The genotoxic activity of agaritine is thus very weak. The cumulative lifetime cancer risk of agaritine consumption in mushrooms is estimated to lie at approximately 10(-5).     

Physiologically based pharmacokinetic model for digoxin distribution and elimination in the rat

A plasma flow rate-limited pharmacokinetic model was developed to describe the distribution of digoxin to the heart, liver, kidneys, skeletal muscle, and GI tract in the rat. The model also provides for renal, hepatic (metabolic and biliary), and GI clearance as well as for biliary and GI secretion and GI reabsorption of digoxin. Predicted concentrations of digoxin in the heart, liver, skeletal muscle, and plasma were consistent with experimental observations in conscious rats after an intravenous dose. The model was extended to describe digoxin concentrations in the plasma of bile duct-ligated rats and ureter-ligated rats, simply by modifying appropriate clearance parameters. Excellent agreement was obtained between predicted and observed urinary excretion rates of digoxin for 12 hr after in intravenous dose to normal and bile duct-ligated rats.     

Effect of postweanling pyridoxine deficiency on growth and concentration of the coenzyme pyridoxal-5'-phosphate in heart, kidneys, lungs, and adrenals in rats

Dietary pyridoxine deficiency induced in postweanling rats to led to severe growth retardation and growth failure, with a sharp increase in the mortality rate after about 8 weeks on the diet. The absolute weights of heart, lungs, kidneys, and adrenals were all lower in the deficient animals than those of the controls. However, when the weights were expressed in terms of percentage of body weight, a 2-fold increase was observed indicative of marked hypertrophy. The depletion of the coenzyme pyridoxal-5'-phosphate from these tissues was extensive (heart 48%, lungs 85%, and kidneys and adrenals 88%.) The extent of loss of the coenzyme from the tissues suggests possible functional changes.