Analysis of fecal microbiome and metabolome changes in goats with pregnant toxemia.

BACKGROUND: Pregnancy toxemia is a common disease, which occurs in older does that are pregnant with multiple lambs in the third trimester. Most of the sick goats die within a few days, which can seriously impact the economic benefits of goat breeding enterprises. The disease is believed to be caused by malnutrition, stress, and other factors, that lead to the disorder of lipid metabolism, resulting in increased ketone content, ketosis, ketonuria, and neurological symptoms. However, the changes in gut microbes and their metabolism in this disease are still unclear. The objective of this experiment was to evaluate the effect of toxemia of pregnancy on the fecal microbiome and metabolomics of does. RESULTS: Eight pregnant does suspected of having toxemia of pregnancy (PT group) and eight healthy does during the same pregnancy (NC group) were selected. Clinical symptoms and pathological changes at necropsy were observed, and liver tissue samples were collected for pathological sections. Jugular venous blood was collected before morning feeding to detect biochemical indexes. Autopsy revealed that the liver of the pregnancy toxemia goat was enlarged and earthy yellow, and the biochemical results showed that the serum levels of aspartate aminotransferase (AST) and ß-hydroxybutyric acid (B-HB) in the PT group were significantly increased, while calcium (Ca) levels were significantly reduced. Sections showed extensive vacuoles in liver tissue sections. The microbiome analysis found that the richness and diversity of the PT microbiota were significantly reduced. Metabolomic analysis showed that 125 differential metabolites were screened in positive ion mode and enriched in 12 metabolic pathways. In negative ion mode, 100 differential metabolites were screened and enriched in 7 metabolic pathways. CONCLUSIONS: Evidence has shown that the occurrence of pregnancy toxemia is related to gut microbiota, and further studies are needed to investigate its pathogenesis and provide research basis for future preventive measures of this disease.

Definition of prepartum hyperketonemia in dairy goats.

A prospective cohort study was conducted on 1,081 dairy goats from 10 commercial herds in Québec (Canada) to define prepartum hyperketonemia based on optimal blood ß-hydroxybutyrate acid threshold values for the early prediction of pregnancy toxemia (PT) and mortality in late-gestation dairy goats. All pregnant goats had blood sampled weekly during the last 5wk of pregnancy. The blood was analyzed directly on the farm for ß-hydroxybutyrate acid quantification using a Precision Xtra meter (Abbott Diabetes Care, Saint-Laurent, QC, Canada). Body condition scores on the lumbar region and sternum were noted. Each goat was classified as being at low (n=973) or high risk (n=108) of having PT by producers based on a standardized definition. The optimal threshold for predicting a PT diagnosis or mortality for each week before kidding was determined based on the highest sum of sensitivity and specificity. The association between hyperketonemia and subsequent PT was tested using a multivariable logistic regression model considering hyperketonemia at wk 4 prepartum, litter size, and body condition score at wk 4 prepartum as covariates, and herd and parturition cohort as random effects. The association between mortality and hyperketonemia was also tested using a logistic regression model accounting for the presence or absence of treatment during the last month of pregnancy. The hyperketonemia definition based on PT varied between ≥0.4 and ≥0.9mmol/L during the last 5wk prepartum. Goats affected by hyperketonemia at wk 4 prepartum and with a large litter size (≥3 fetuses) had 2.1 and 40.5 times the odds, respectively, of subsequent PT than other goats. Hyperketonemia definitions based on mortality varied between ≥0.6 and ≥1.4mmol/L during the last 4wk prepartum, and was ≥1.7mmol/L during the first week postpartum. Goats affected by hyperketonemia and treated by producers had 3.4 and 11.8 times the odds, respectively, of subsequent mortality than did other goats. These results showed that prepartum hyperketonemia could be defined in dairy goats using subsequent risks of PT or mortality during the last month of pregnancy.

Hepatic Perisinusoidal Myofibroblast Proliferation and Systemic Inflammatory Response Precedes Sep/Tox Hepatitis in Broilers.

Septicemia-toxemia (sep/tox) falls under U.S. Department of Agriculture (USDA) food safety Category 1 and is the most common and economically significant cause of broiler carcass condemnations. Hepatic lesions are considered a possible consequence of septicemia and associated bacterial contamination of the carcass. Thus, these lesions are considered an indicator of sep/tox (sep/tox hepatitis). This study was undertaken to analyze the histologic lesions preceding grossly visible liver lesions leading to condemnation because of sep/tox at the processing plant. Livers from carcasses of broilers condemned by USDA inspectors for sep/tox were used to establish microscopic and gross criteria of end-stage sep/tox hepatitis. Following the characterization of sep/tox hepatitis, broilers from a farm with a history of sep/tox condemnations were submitted for postmortem examination and bacteriologic investigation at four intervals during the final 20 days of production. Five healthy and five clinically ill chickens were submitted from four houses at 18, 25, 32, and 38 days of production (160 total). Microscopic lesions representing hepatic perisinusoidal myofibroblast proliferation (HPMP), periportal extramedullary granulopoiesis (PEMG), splenic follicular histiocytosis, and bone marrow cellularity (BMC) were graded subjectively for each bird, and subjective grading was evaluated with digital quantitative techniques. Perisinusoidal hepatic stellate cell morphology and progressive transformation of these cells into myofibroblasts was confirmed by immunohistochemistry for smooth muscle actin and desmin. Aerobic cultures of livers and gall bladders from sep/tox birds yielded no growth of bacteria associated with septicemia. Mild to severe HPMP was observed in all age groups, representing 28% of examined birds. Increases in inflammatory cells observed by PEMG and BMC were positively correlated with progressive HPMP and end-stage sep/tox hepatitis in broiler chickens.

Artículo regular­Proliferación de miofibroblastos perisinusoidales hepáticos y respuesta inflamatoria sistémica que precede a la hepatitis por septicemia y toxemia (sep/tox) en pollos de engorde. La septicemia-toxemia (sep/tox) se incluye en la Categoría 1 de seguridad alimentaria del Departamento de Agricultura de los Estados Unidos. (USDA) y es la causa más común y económicamente significativa de decomisos de canales de pollos de engorde. Las lesiones hepáticas se consideran una posible consecuencia de la septicemia y de la contaminación bacteriana asociada con la canal. Por lo tanto, estas lesiones se consideran un indicador de septicemia/toxemia (hepatitis sep/tox). Este estudio se llevó a cabo para analizar las lesiones histológicas que preceden a las lesiones hepáticas muy visibles que conducen a los decomisos debido a septicemia/toxemia en la planta de procesamiento. Se utilizaron hígados de canales de pollos de engorde decomisados por los inspectores del USDA por septicemia/toxemia para establecer criterios microscópicos y generales de hepatitis en etapa terminal de la septicemia/toxemia. Después de la caracterización de la hepatitis por septicemia/toxemia, los pollos de engorde de una granja con un historial de decomisos por septicemia/toxemia se sometieron a examen post mortem e investigación bacteriológica en cuatro intervalos durante los últimos 20 días de producción. Se enviaron cinco pollos sanos y cinco clínicamente enfermos de cuatro casetas a los 18, 25, 32 y 38 días de producción (160 en total). Las lesiones microscópicas que representan la proliferación de miofibroblastos perisinusoidales hepáticos (HPMP), la granulopoyesis extramedular periportal (PEMG), la histocitosis folicular esplénica y la celularidad de la médula ósea (BMC) se clasificaron subjetivamente para cada ave, y la clasificación subjetiva se evaluó con técnicas cuantitativas digitales. La morfología de las células estrelladas hepáticas perisinusoidales y la transformación progresiva de estas células en miofibroblastos se confirmó mediante inmunohistoquímica para actina y desmina del músculo liso. Los cultivos aeróbicos de hígados y vesícula biliar de aves con septicemia/toxemia no produjeron crecimiento de bacterias asociadas con la septicemia. Se observó proliferación de miofibroblastos perisinusoidales hepáticos de leve a severa en todos los grupos de edad, lo que representa el 28% de las aves examinadas. Los aumentos en las células inflamatorias observados por granulopoyesis extramedular periportal y celularidad de la médula ósea se correlacionaron positivamente con proliferación progresiva de miofibroblastos perisinusoidales hepáticos y con hepatitis por septicemia/toxemia en etapa terminal en pollos de engorde.

Distinct physiologic and inflammatory responses elicited in baboons after challenge with Shiga toxin type 1 or 2 from enterohemorrhagic Escherichia coli.

Shiga toxin-producing Escherichia coli is a principal source of regional outbreaks of bloody diarrhea and hemolytic-uremic syndrome in the United States and worldwide. Primary bacterial virulence factors are Shiga toxin types 1 and 2 (Stx1 and Stx2), and we performed parallel analyses of the pathophysiologies elicited by the toxins in nonhuman primate models to identify shared and unique consequences of the toxemias. After a single intravenous challenge with purified Stx1 or Stx2, baboons (Papio) developed thrombocytopenia, anemia, and acute renal failure with loss of glomerular function, in a dose-dependent manner. Differences in the timing and magnitude of physiologic responses were observed between the toxins. The animals were more sensitive to Stx2, with mortality at lower doses, but Stx2-induced renal injury and mortality were delayed 2 to 3 days compared to those after Stx1 challenge. Multiplex analyses of plasma inflammatory cytokines revealed similarities (macrophage chemoattractant protein 1 [MCP-1] and tumor necrosis factor alpha [TNF-alpha]) and differences (interleukin-6 [IL-6] and granulocyte colony-stimulating factor [G-CSF]) elicited by the toxins with respect to the mediator induced and timing of the responses. Neither toxin induced detectable levels of plasma TNF-alpha. To our knowledge, this is the first time that the in vivo consequences of the toxins have been compared in a parallel and reproducible manner in nonhuman primates, and the data show similarities to patient observations. The availability of experimental nonhuman primate models for Stx toxemias provides a reproducible platform for testing antitoxin compounds and immunotherapeutics with outcome criteria that have clinical meaning.

Changes in cardiac biomarkers in goats naturally affected by pregnancy toxemia.

Pregnancy toxemia (PT) is considered one of the most common metabolic diseases with high impact on the production of small ruminants. The objective of this study was investigate possible myocardial damage in goats affected with PT by the determination of serum myocardial biomarkers CK-MB and cTnI. A total of 44 goats affected with PT, and 10 apparently healthy goats (control group or CG) were used in the study. In goats with PT, the serum concentrations of cTnI (0.43 ng/mL) were significantly higher than that in CG goats (0.06 ng/mL). Although CK-MB showed no significant difference, it was approximately three times higher in animals with PT. The serum concentrations of insulin were significantly lower in PT goats (5.03 ppmol/L) compared to CG goats (10.66 pmol/L). The serum concentrations of cortisol in PT goats (155.41 nmol/L) were significantly higher than that in CG goats (36.58 nmol/L). Results of this study indicate that a clinically significant myocardial damage might occur in goats affected with PT leading to significant elevations in values of cTnI and CK-MB. Therefore, these parameters could be used as a potential prognostic indicator in goats affected with this important disease.

Identification of the 1B vaccine strain of Chlamydia abortus in aborted placentas during the investigation of toxaemic and systemic disease in sheep.

CASE HISTORY: One hundred and forty Cheviot and 100 Suffolk cross Mule primiparous 1-2-year-old ewes, from a flock of about 700 ewes, were vaccinated with an attenuated live 1B strain Chlamydia abortus vaccine about 4 weeks before ram introduction (September 2011). Between 08 March and 01 April 2012, 50 2-year-old ewes aborted and 29 of these died, despite antimicrobial and anti-inflammatory treatment and supportive care. PATHOLOGICAL FINDINGS: Seven fetuses and three placentae from five 2-year-old ewes were submitted for pathological investigation. The aborted fetuses showed stages of autolysis ranging from being moderately fresh to putrefaction. Unusual, large multifocal regions of thickened membranes, with a dull red granular surface and moderate amounts of grey-white surface exudate were seen on each of the placentae. Intracellular, magenta-staining, acid fast inclusions were identified in Ziehl Neelsen-stained placental smears. Immunohistochemistry for Chlamydia-specific lipopolysaccharide showed extensive positive labelling of the placental epithelia. LABORATORY FINDINGS: Molecular analyses of the aborted placentae demonstrated the presence of the 1B vaccine-type strain of C. abortus and absence of any wild-type field strain. The vaccine strain bacterial load of the placental tissue samples was consistent with there being an association between vaccination and abortion. DIAGNOSIS: Initial laboratory investigations resulted in a diagnosis of chlamydial abortion. Further investigations led to the identification of the 1B vaccine strain of C. abortus in material from all three of the submitted aborted placentae. CLINICAL RELEVANCE: Timely knowledge and understanding of any potential problems caused by vaccination against C. abortus are prerequisites for sustainable control of chlamydial abortion. This report describes the investigation of an atypical abortion storm in sheep, and describes the identification of the 1B vaccine strain of C. abortus in products of abortion. The significance of this novel putative association between the vaccine strain of C. abortus and severe clinical disease is unknown. Aspects of the approach that is described are relevant to the investigation of all outbreaks of ovine abortion, irrespective of the diagnosis. Awareness of the changing role of C. abortus as a major global cause of abortion ought to reinforce the importance of monitoring of adequate biosecurity in those countries which are currently free from chlamydial abortion.

Endogenous tumor necrosis factor (TNF) production and modification of pathological lesions in experimental Escherichia coli endotoxemia of piglets.

We examined the kinetics of tumor necrosis factor (TNF) production induced by Escherichia coli lipopolysaccharide (LPS) in relation to LPS tolerance and endotoxemic lesions of piglets. The plasma of piglets demonstrated cytotoxicity to TNF-sensitive L929 cells between 0.5 and 4 h after inoculation with 200 micrograms kg-1 of LPS. This cytotoxicity was neutralized by anti-bovine TNF serum. These piglets had disseminated intravascular coagulation (DIC) and meningoencephalitis. However, if piglets were first treated with three doses of 40 micrograms kg-1 of LPS, both TNF production and the occurrence of DIC were inhibited when 200 micrograms kg-1 of LPS was inoculated into these piglets. Repetitive inoculation with increasing doses of LPS induced fibrinoid vasculitis, meningoencephalitis and pneumonitis, while hemorrhage was minimal. A very low amount of TNF activity was detected from most of the samples of a piglet after repeated LPS inoculation. These results suggested that severity of the hemorrhagic and thrombotic lesions might relate to the amount of endogenous TNF activity, and that LPS tolerance might relate to inhibition of TNF production.

Possibilities of bacteremia and toxemia in death of chickens infected with Eimeria tenella.

The possibility that bacteremia and toxemia were the causes of death in cases of cecal coccidiosis was investigated. Germ-free and ordinary chickens with microflora were inoculated with sporulated oocysts of Eimeria tenella. At 5 days postinoculation, cecal lesions in ordinary chickens were more severe than those in germ-free ones. Cardiac blood, spleen, and liver were examined in ordinary chickens for bacteremia and endotoxemia, and small numbers of bacteria were recovered from both infected and uninfected birds. Endotoxin levels in plasma of E. tenella-infected birds were low and not different from the levels of uninfected controls. To examine unknown toxic factors, a large volume of serum from infected chickens was injected intravenously into uninfected birds. No significant clinical signs were observed. It is concluded that the intestinal bacteria increase the severity of coccidial lesions without bacteremia and toxemia.

Effects of an infusion of dopamine on the cardiopulmonary effects of Escherichia coli endotoxin in anaesthetised horses.

Horses with colic may be endotoxaemic and subsequently develop hypotension during anaesthesia for surgical operation. The aim of this study was to evaluate the efficacy of dopamine as a means to improve cardiovascular function in anaesthetised endotoxaemic horses. Nine horses (five in group 1 and four in group 2) were anaesthetised with thiopentone and guaifenesin and anaesthesia was maintained with halothane. After approximately one hour, facial artery pressure, heart rate, pulmonary artery pressure, cardiac output, temperature, pHa, PaCO2, PaO2, base excess, packed cell volume, plasma protein concentration and white cell count were measured (time 0). Escherichia coli endotoxin was infused intravenously over 15 minutes in both groups. Group 2 horses were given an intravenous infusion of dopamine (5 micrograms kg-1 min-1) starting five minutes after the start of the endotoxin infusion and continuing for 60 minutes. Measurements were made at 15 minute intervals for 120 minutes. In group 1, one horse died during the endotoxin infusion and in two other horses mean facial artery pressures decreased to 50 mm Hg. Total pulmonary vascular resistance and packed cell volume were significantly increased. Cardiac output, cardiac index and change in mean arterial pressure were significantly greater in group 2 horses than in group 1 horses. Conversely, diastolic pulmonary artery pressure, total vascular resistance and total pulmonary resistance were significantly less in group 2 than in group 1. PaO2, base excess and white blood cell count were significantly decreased in both groups. It was concluded that dopamine improved cardiovascular function in the presence of endotoxaemia and attenuated the rate of haemoconcentration, but had no effect on the development of decreased PaO2 or metabolic acidosis.

Low dose flunixin meglumine: effects on eicosanoid production and clinical signs induced by experimental endotoxaemia in horses.

The efficacy of low doses of flunixin meglumine in reducing eicosanoid generation and clinical signs in response to experimentally induced endotoxaemia was investigated. Thromboxane B2 and 6-keto-prostaglandin F1 alpha were measured in serum and plasma by radioimmunoassay. Plasma flunixin concentrations were determined by high performance liquid chromatography and pharmacokinetic parameters derived non-compartmentally. In horses administered flunixin meglumine before endotoxin challenge, a significant suppression in plasma thromboxane B2 and 6-keto-prostaglandin F1 alpha generation was observed. Elevations in blood lactate were significantly suppressed in horses pretreated with 0.25 mg/kg bodyweight flunixin meglumine. Reduction of the clinical signs of endotoxaemia by flunixin meglumine was dose dependent. Low doses of flunixin inhibited eicosanoid production without masking all of the physical manifestations of endotoxaemia necessary for accurate clinical evaluation of the horse's status.

Regulation of equine fibrinolysis in blood and peritoneal fluid based on a study of colic cases and induced endotoxaemia.

Much of the pathophysiology associated with equine gastrointestinal diseases is attributed to the effects of endotoxin on haemostasis. Because little is known about the responses of the equine fibrinolytic system to endotoxin, regulation of the system was investigated. Tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1) were identified as the primary plasminogen activator and plasminogen activator inhibitor, respectively, in equine blood. Under experimental conditions, the equine fibrinolytic system responded to endotoxin in a manner similar to that reported in man, with an early, transient increase in t-PA activity followed by an overwhelming and prolonged increase in activity of PAI-1. To investigate the response of the equine fibrinolytic system to clinical endotoxaemia, endotoxin concentrations were measured in plasma and peritoneal fluid, and activities of t-PA and PAI-1 were compared between healthy horses (n = 38) and horses with naturally occurring gastrointestinal diseases (n = 150). It was observed that plasma PAI-1 and peritoneal t-PA were increased concurrently in abnormal horses; and that these increases were associated with the presence of endotoxin. The results of this study suggest that 1) fibrinolysis is regulated in horses in a manner similar to that in man; 2) regulation of fibrinolysis is altered in endotoxaemic horses with gastrointestinal diseases; 3) events occurring in the vascular system may not reflect those in the peritoneal cavity; and 4) t-PA activity is increased in the peritoneal fluid of endotoxaemic horses with gastrointestinal diseases.

Endotoxaemia in the horse.

Endotoxins are non-protein fragments of the cell wall of Gram-negative bacteria. They must be absorbed into the circulation to produce disease and systemic effects are similar, regardless of bacterial source. Absorption of endotoxins occurs in obstructive bowel disease and may play a significant part in determining the severity of the disease. Many of the responses to experimentally administered endotoxin are identical to those of bowel diseases or the horse and include circulatory, haematological and metabolic alterations. Therapeutic approaches are indirect and include many drugs currently employed in equine practice. The agents are directed toward mediators of the disease rather than the endotoxins themselves and include fluids, corticosteroids, anti-inflammatory drugs, energy sources and vasoactive drugs. The rationale for use and dosages are discussed.

Alterations in clinical, hematological and metabolic variables in bovine neonatal endotoxemia.

Endotoxemia is an important cause of morbidity and mortality in the neonate. Although many models are used to study the problem, none completely simulates the natural disease. To more clearly define a bovine neonatal endotoxemia model we studied the effects of dose of endotoxin on clinical, hematological and biochemical variables. Thirty-four neonatal calves were administered Escherichia coli endotoxin (LPS) at 0 (0.9% saline solution), 0.2, 2.0 or 20 micrograms/kg, by either IV bolus or infusion over 50 minutes. Variables monitored included mean arterial blood pressure (MAP), leukocyte (WBC) count, plasma glucose and lactate concentrations and clinical status. All LPS-treated calves displayed similar clinical signs within one hour. Dose-dependent differences in response to LPS among groups became evident over time. Substantial dose-dependent changes in attitude, appetite, mucous membrane character, capillary refill time, MAP, plasma glucose and lactate concentrations, and WBC count were noted in LPS-treated calves. Higher doses of LPS induced a more prolonged clinical response and significantly (p < 0.05) greater hypotension, lacticemia and hypoglycemia. While dose altered the response to endotoxin, the method of administration had no overall effect on the variables measured.

Evaluation of plasma alpha-2-macroglobulin and interactions with tumour necrosis factor-alpha in horses with endotoxemic signs.

The electrophoretic position and behavior of the native and activated forms of equine plasma alpha-2-macroglobulin (alpha 2M) were characterized and compared to human alpha 2M by nondenaturing polyacrylamide-gel electrophoresis (PAGE). Plasma alpha 2M was also compared between 6 normal horses and 6 horses with clinical signs of colic and endotoxemia due to volvulus or enteritis. Native and activated forms of alpha 2M were quantified by PAGE and densitometry. Binding of radio-labeled recombinant human tumour necrosis factor-alpha (125I-rhTNF-alpha) to native and activated forms of equine alpha 2M was also evaluated by autoradiography and densitometry of PAGE. Equine plasma alpha 2M migrated as a single band at a position equivalent to native human alpha 2M. Methylamine-reacted equine plasma samples resulted in faster migration of alpha 2M in a similar position to activated human alpha 2M. However, in methylamine-reacted equine plasma, an intermediate alpha 2M band was consistently present between the bands corresponding to native and activated alpha 2M. Amounts of plasma alpha 2M were similar in normal and endotoxemic horses, and remained in the electrophoretically slow or unreacted native form. The vast majority of 125I-rHuTNF-alpha did not bind to alpha 2M or other equine plasma proteins. 125I-rHuTNF-alpha bound weakly to both native and fast methylamine-reacted equine forms of alpha 2M, although binding was better to the activated form. This study indicates that: (1) equine plasma alpha 2M behaves similarly to human alpha 2M on PAGE, (2) plasma alpha 2M of horses can be activated to electrophoretically fast forms, but it is neither activated nor depleted during endotoxemia, and (3) the binding interactions between equine alpha 2M and TNF-alpha are too low to implicate equine alpha 2M as a regulator of TNF-alpha during endotoxemia in horses.

Use of a conductance catheter to assess the effect of endotoxemia on left ventricular end-systolic pressure-volume relationships in anesthetized swine.

Effects of endotoxemia on left ventricular contractility and systemic hemodynamics were determined in pentobarbital-anesthetized swine. A multielectrode conductance (volume) catheter and a high-fidelity pressure transducer catheter were passed retrograde into the left ventricle to continuously measure pressure and volume. End-systolic pressure-volume relationships were determined during transient (8 to 10 s) caudal vena caval balloon occlusion. Lactated Ringer's solution was administered at a rate sufficient to maintain left ventricular end-diastolic pressure > or = 6 mm of Hg. Following baseline measurements, Escherichia coli endotoxin (O55-B5) was infused IV at 2.5 micrograms/kg of body weight/h for 3 hours. Left ventricular end-systolic elastance (Ees), the slope of the end-systolic pressure-volume relationship; end-systolic elastance normalized for left ventricular end-diastolic volume (Ees norm); the rate of increase of left ventricular pressure (dP/dt max); and preload recruitable stroke work (PRSW, stroke work-to-end-diastolic volume relationship) did not change in endotoxemic swine, compared with baseline measurements or with values from control (physiologic saline solution-treated) swine. Left ventricular pressures and volumes had marked pig-to-pig variability in the control and endotoxin-treated groups. Determination of Ees, Ees norm, and PRSW was further confounded by development of frequent premature ventricular contractions during caudal vena caval balloon occlusion. Endotoxin significantly (P < 0.05) decreased left ventricular end-diastolic pressure, compared with that in control swine, and significantly (P < 0.01) decreased left ventricular end-diastolic volume, compared with baseline. Endotoxin decreased cardiac index and arterial blood pressure, whereas heart rate, central venous pressure, and mean pulmonary arterial pressure increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Lactic acidosis and arterial hypoxemia during sublethal endotoxemia in conscious ponies.

Effects of a sublethal IV dose (10 micrograms/kg of body weight) of Escherichia coli endotoxin were studied in 7 conscious ponies. Arterial blood gases and plasma lactic acid were determined periodically throughout the 180 minutes of the study. Arterial hypoxemia occurred within 5 minutes despite intense hyperventilation. Colic and diarrhea occurred in all ponies within 30 minutes after endotoxin administration. Metabolic acidosis developed within 30 minutes and persisted throughout the study, indicating widespread reduced tissue perfusion.

Clinical efficacy of tirilazad mesylate for treatment of endotoxemia in neonatal calves.

The clinical efficacy of the lazaroid, tirilazad mesylate, a new therapeutic agent for prophylaxis and treatment of endotoxemia, was evaluated in 24 neonatal Holstein calves. Endotoxemia was induced by IV infusion of commercial Escherichia coli lipopolysaccharide (3.25 micrograms/kg of body weight) over 3 hours. Group-1 calves were given endotoxin alone; group-2 calves were given an infusion of 0.9% sterile saline solution, then were treated with tirilazad mesylate (1.5 mg/kg) 1 hour after the infusion was started. Group-3 calves were treated with tirilazad mesylate 1 hour after the start of the endotoxin infusion, and group-4 calves were given tirilazad mesylate 1 hour before the start of the endotoxin infusion. Clinical signs of endotoxemia were mitigated by tirilazad mesylate. In addition, tirilazad mesylate protected calves from endotoxin-induced hyperglycemia; treatment after endotoxin infusion decreased the severity of hypoglycemia and prevented lactic acidosis. Treatment with tirilazad mesylate after initiation of endotoxin infusion was as protective as was pretreatment.

Serum tumor necrosis factor alpha concentrations and clinical abnormalities in colostrum-fed and colostrum-deprived neonatal foals given endotoxin.

We examined the effect of infusion of lipopolysaccharide (LPS) on serum tumor necrosis factor alpha (TNF alpha) concentration and clinical attitude in 2- 3-day-old colostrum-fed (CF) and colostrum-deprived (CD) foals. Eleven CF and 8 CD neonatal foals were given a bolus i.v. infusion of Escherichia coli O55:B5 lipopolysaccharide (0.5 microgram/kg of body weight) in sterile saline (0.9% NaCl) solution. Four CF and 2 CD foals were given saline solution alone. Serum IgG concentration and serum anti-LPS IgG(T) antibody titer were determined for each foal prior to infusion. A depression index was used to score clinical abnormalities. Serum TNF alpha concentration was estimated by use of an in vitro cytotoxicity bioassay that used WEHI 164 clone 13 cells as targets. The cytotoxic serum factor was identified as TNF alpha by immunoprecipitation with caprine antisera raised against the 15 NH2-terminal amino acids of human TNF alpha. Tumor necrosis factor alpha was not detected in any preinfusion serum samples nor in any samples from foals given saline solution alone. Serum TNF alpha concentration increased in all LPS-infused foals and peaked between 60 and 90 minutes after infusion. Serum TNF alpha concentrations, expressed as mean percentage of peak serum TNF alpha concentration, persisted longer in CD foals given LPS than in CF foals given LPS. All LPS-infused foals displayed clinical signs of endotoxemia, but mean depression index scores of the CF and CD foals given LPS were not significantly different at any time. Serum TNF alpha concentrations were correlated with depression index scores in both LPS-infused groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative efficacy of flunixin, ketoprofen, and ketorolac for treating endotoxemic neonatal calves.

Saline (0.9% NaCl) solution or 1 of 3 nonsteroidal anti-inflammatory drugs (NSAID) was administered i.v. to 5 neonatal calves 15 minutes after the start of a 3-hour i.v. infusion of Escherichia coli lipopolysaccharide (LPS; 2 micrograms/kg/h). Four additional calves were given a 3-hour i.v. infusion of saline solution alone. Clinical attitude, mean arterial blood pressure, PCV, WBC, and plasma lactate, glucose, and eicosanoid concentrations (thromboxane B2, 6-keto-PGF1 alpha) were monitored for 12 hours. Flunixin meglumine (1.1 mg/kg of body weight, i.v.), ketoprofen (2.2 mg/kg, i.v.), and ketorolac tromethamine (1.1 mg/kg, i.v.) each ameliorated the clinical signs of endotoxemia and LPS-induced lacticemia, but failed to significantly alter the degree of leukopenia or hypoglycemia associated with infusion of LPS. Although the 3 NSAID prevented eicosanoid production, they provided only partial protection against LPS-induced hypotension. Each NSAID modified the response to LPS, but none was clearly superior to the others in modulating the clinical signs or physiologic alterations induced by infusion of LPS in neonatal calves.