Systemic dissemination of Clostridium difficile toxins A and B is associated with severe, fatal disease in animal models.

BACKGROUND: Clostridium difficile infection (CDI) can cause a wide range of disease, from mild diarrhea to fulminant systemic disease. The incidence of systemic CDI with fatal consequence has increased rapidly in recent years. METHODS: Using an ultrasensitive cytotoxicity assay, we measured C. difficile toxin A (TcdA) and C. difficile toxin B (TcdB) in sera and body fluids of piglets and mice exposed to C. difficile to investigate the relationship between the presence of toxins in body fluids and systemic manifestations of CDI. RESULTS: We found that both TcdA and TcdB disseminate systemically, with toxins present in the sera and body fluids of infected animals, and toxemia is significantly correlated with the development of systemic CDI. The systemic administration of neutralizing antibodies against both toxins blocked the development of systemic disease in mice. We measured cytokine concentrations in the sera of mice and piglets with systemic and nonsystemic CDI and found that proinflammatory mediators were considerably elevated in animals with systemic CDI. CONCLUSION: Our study demonstrates the existence of a strong correlation between toxemia and the occurrence of systemic disease, supporting the hypothesis that systemic CDI is most likely due to the toxicity of TcdA and TcdB and the induction of proinflammatory cytokines by the toxins.

[Fatality and secular trend of bloodstream infections during hospitalization in China: a systematic review and meta-analysis].

OBJECTIVE: To get an overview of the fatality and secular trend of bloodstream infection (BSI) during hospitalization in China. METHODS: Papers published between 1990 and Aug. 2008 on the core journals included by Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI) and VIP Chinese Periodical Database were systematically searched. Studies providing data of BSI fatality during hospitalization with a non-comparative, observational design were included. Meta-analysis was done using the generic inverse variance model. RESULTS: Overall, 72 studies were included for this analysis. The weighted BSI fatality in-hospital based on them was 28.7% (95%CI: 27.2%-30.3%), with substantial differences between study and heterogeneity. For BSI cases from across all departments of hospitals, the weighed fatality was 20.7% (95%CI: 17.8%-24.0%). In the departments of burn, hematology and/or malignant tumors, and ICU, BSI fatalities were even higher, but were relatively low among BSI cases from neonatal wards, and patients with liver diseases, or diabetes mellitus. Fatality of hospital acquired BSI (HA-BSIs, 26.8%, 95%CI: 22.4%-32.0%) was significantly higher than that of community acquired BSI (CA-BSIs). For the past decades, BSI fatality has declined in various kinds of inpatients. CONCLUSION: BSI fatality during hospitalization was at a high level in China, but with a downward trend over the past decades.

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.

Tranexamic acid, an inhibitor of plasminogen activation, aggravates staphylococcal septic arthritis and sepsis.

Haemostatic balance shifts towards pro-coagulation during infection. Plasminogen, a key molecule of fibrinolysis, may play an important role in the pathogenesis of staphylococcal infections. In the present study, we assessed the impact of inhibition of plasminogen activation by tranexamic acid on the course of staphylococcal sepsis and septic arthritis in mice. We found significantly down-regulated plasmin activity and increased D-dimer levels in the blood from the mice with staphylococcal sepsis. Treatment with tranexamic acid significantly increased the severity and mortality of staphylococcal infection. In addition, tranexamic acid reduced the survival rate in a murine model for staphylococcal enterotoxin A-induced death. The aggravation of diseases by tranexamic acid was due neither to the pro-inflammatory cytokine network, nor to impairment of bacterial clearance. Modulation of fibrinolysis, either by supplement of fibrinolytic molecules (tissue plasminogen activator or plasmin) or by fibrinogen depletion, did not reduce the mortality of staphylococcal sepsis. In conclusion, we report that treatment with tranexamic acid led to distinct aggravation of staphylococcal septic arthritis and sepsis in mice, suggesting the clinical importance of fibrinolytic balance in staphylococcal infection.

Reappraisal with meta-analysis of bacteremia, endotoxemia, and mortality in gram-negative sepsis.

Among patients with suspected sepsis, endotoxemia is variably present in association with gram-negative bacteremia. A total of 738 patients with suspected sepsis from 11 studies could be classified into four groups: 131 (18%) patients had both endotoxemia and gram-negative bacteremia (group 1), 87 (12%) had only gram-negative bacteremia (group 2), and 143 (19%) had only endotoxemia (group 3); in 377 (51%) patients neither could be detected (group 4). By the statistical techniques of meta-analysis, the fatality risk for patients with either endotoxemia or gram-negative bacteremia or both was estimated with group-specific case fatality rates from these studies and expressed as an odds ratio (OR; 95% confidence interval [95% CI]) versus patients with these factors absent. This risk was increased marginally when endotoxemia was detected without gram-negative bacteremia (OR, 2.3; 95% CI, 1.3 to 4.0) or the converse (OR, 2.0; 95% CI, 1.0 to 3.8), in contrast to the striking increase when both endotoxemia and gram-negative bacteremia were detected (OR, 6.3; 95% CI, 4.0 to 10.0). Alone, neither endotoxemia nor gram-negative bacteremia is a strong predictor of outcome in patients with suspected sepsis. However, in combination, the two identify a subpopulation with a substantially increased risk of mortality.

Vesnarinone prolongs survival and reduces lethality in a murine model of lethal endotoxemia.

Vesnarinone (3,4-Dihydro-6-[4(3,4-dimethoxybenzoyl)-1-piperanizyl]-2(1H)-quino linone), a recently synthesized quinolinone derivative with positive inotropic properties, has been reported the survival of patients with chronic congestive heart failure. However, the mechanisms that contribute to this improvement are not yet well understood. There is increasing evidence that vesnarinone has novel immunosuppressive properties related to its inhibition of cytokine production. Cytokines have been shown to play a pivotal role in the pathophysiologic consequences of fatal bacteremic shock. In this study, we investigated the effects of vesnarinone in a murine model of lethal endotoxemia induced by lipopolysaccharide (LPS). Eight-week-old female BALB/c mice were given 300 or 400 micrograms of LPS, and 50 or 100 mg/kg of vesnarinone was administered by oral gavage and/or 10 or 30 micrograms of vesnarinone was given intra peritoneally. Vesnarinone prolonged the median survival time and reduced lethality when given at the same time as the LPS injection. However, vesnarinone did not have a beneficial effect when administered 2 hours after LPS treatment. Plasma TNF-alpha reached a maximum level 1 hour after LPS challenge, and vesnarinone reduced the plasma level of TNF-alpha, when administered at the same time as LPS injection. Vesnarinone had protective effects against lethal endotoxemia; these effects were considered to be due to the suppression of TNF-alpha production. These findings suggest that vesnarinone may be a promising agent for the treatment of bacterial sepsis and shock.

Translocation. Incidental phenomenon or true pathology?

OBJECTIVE: This study was conducted to determine if reduction of early postburn endotoxemia influences the cytokine cascade, clinical manifestations of sepsis, and mortality rate. SUMMARY BACKGROUND DATA: Translocational endotoxemia has been demonstrated postburn in animals and humans. Endotoxin is known to induce the cytokine cascade, which leads to the clinical manifestations of sepsis. Whether reduction of postburn endotoxemia could influence the induction of cytokines has not been demonstrated. METHODS: In a prospective, randomized study, 76 burn patients were given polymyxin intravenously or served as control subjects. Polymyxin B was given intravenously for 1 week postburn in doses designed to neutralize circulating endotoxemia. RESULTS: In the polymyxin group, there was a statistically significant reduction in the plasma endotoxin concentration. There was, however, no reduction in the sepsis score or the interleukin-6 levels, and no differences in mortality rates were seen between the two groups. CONCLUSIONS: Early postburn translocational endotoxemia can be treated with anti-endotoxin agents such as polymyxin B. This, however, does not influence the cytokine cascade or the mortality rate. The systemic inflammatory response syndrome is caused by cytokine induction from the injury and is unaffected by a reduction in the plasma endotoxin concentration.

Protection against lethal endotoxemia by anti-lipid A murine monoclonal antibodies: comparison of efficacy with that of human anti-lipid A monoclonal antibody HA-1A.

The protective capacities of murine anti-lipid A monoclonal antibodies (MAbs) 8-2 and 26-20 were examined and compared with those of the human MAb HA-1A with respect to inhibition of lipopolysaccharide (LPS) priming of human polymorphonuclear leukocytes (PMNL) in vitro and protection against lethal endotoxemia in mice. HA-1A did not prevent the priming effect of either rough or smooth LPS, while MAb 26-20 effectively inhibited LPS priming of human PMNL. Also, both murine MAbs protected mice against an otherwise lethal challenge with rough Re LPS of S. minnesota R595 as well as with smooth LPS of E. coli O111:B4. HA-1A exerted no protection against the lethal effects of Re LPS in this in vivo model. The enhanced survival in mice by treatment with MAbs 8-2 and 26-20 was associated with decreased levels of LPS-induced tumor necrosis factor. Neutralization of lipid A as a mechanism of protection was strongly suggested by efficacious inhibition of LPS priming of human PMNL by MAbs 8-2 and 26-20 in vitro.

[Effects of sublethal endotoxemia to the hepatic reticuloendothelial system after massive hepatectomy].

Sublethal doses (1mg/kg) of endotoxin (ET) were intravenously administered on the first, third and fifth days after 34%, 70%, and 84% hepatectomies in rats. The same hepatectomy groups of rats without ET administration were made. Survival rates, distribution of Kupffer cells (Kc), regeneration rate of the liver weight, carbon clearance test (K value) and PTAH staining were compared between ET treated and untreated groups. Survival rates of 84% hepatectomy rats with ET injection on the 3rd postoperative day (POD) was significantly lower than those of 70% hepatectomy rats with ET on the 1st or 3rd POD. ET activated reticuloendothelial function of the non-hepatectomized and 34% hepatectomy rats, but reduced the number of the Kc in the central zone, especially in 84% hepatectomized rats. K values and the number of Kc in the central zone showed a good correlationship (r = 0.9) after 70% and 84% hepatectomies. Patchy hepatic necrosis and fibrin clots were observed histologically in the liver, kidney and spleen of rats died after ET administration. In conclusion, sublethal endotoxemia reduces the function and number of Kupffer cells in the regenerating liver and causes postoperative death in the rats with massive hepatectomy.

[The prognosis of the course of endogenous intoxication in emergency surgery]. / Prognozirovanie techeniia éndogennoi intoksikatsii v neotlozhnoi khirurgii.

On the basis of an analysis of 256 patients with diffuse peritonitis, destructive pancreatitis, mechanical jaundice and purulent cholangitis and complex investigations it was established that the degree of clinical manifestations of endointoxication corresponded to a definite degree of disorders of the central nervous system. The most adequate indices of the course and prognosing the toxic process are thought to be the level of the leukocytic index of intoxication, the prothrombin index, the degree of monocytopenia and proteinuria. Their dynamics reflects changes of the concentration of toxic intermediary metabolites and main characteristics of electron paramagnetic resonance of blood plasma.

[Endogenous intoxication in chest and abdominal injuries]. / Endogennaia intoksikatsiia pri povrezhdenii grudi i zhivota.

Results of clinico-laboratory examinations of the endogenic intoxication in patients with injuries of the chest and abdomen are presented. Correlative relationships of the endogenic intoxication parameters and their association with the degree and character of injuries were established, the clinical informative value and prognostic significance of certain laboratory tests were determined. A conclusion is made on the necessity of a correction of endogenic intoxication in complex treatment of these patients.

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.

[Changes in the severity of burn shock in irradiated animals under the influence of blood serum alpha- and beta-globulins]. / Izmenenie tiazhesti ozhogovogo shoka u obluchennykh zhivotnykh pod vliianiem al'fa- i beta-globulinov syvorotki krovi.

Injection of blood serum alpha-beta-globulins during burn shock normalizes the amount of middle mass molecular peptides, acid proteinase activity, acid-base balance, and hemodynamics in irradiated rats. The survival of animals in this period increases from 23% to 52%.

The neonatal fundus in maternal toxemia.

Toxemic changes in the maternal fundus and their relationship to fetal prognosis have been studied. A study of the neonatal fundus in maternal toxemia revealed a 76.67% incidence of vascular changes similar to those seen in the maternal fundus. Arteriolar spasm, focal or generalized, was present in 23 of the 30 neonates seen. A pallor of the disc was present in six cases. Four infants, 13.33%, had either extensive dot and blot retinal hemorrhages with soft exudates, or a serous retinal detachment. The last four neonates died within the first postnatal week. This work highlights the fact that retinal vascular decompensation mirrors similar changes in the cardiopulmonary or cerebral circulation and should be considered as a determinant of the fetal prognosis in maternal toxemia.

Therapeutic effect of dexamethasone in T-2 toxicosis.

T-2 Toxin is a mycotoxin that induces toxemia characterized by numerous hematological and biochemical changes. We have previously shown that prostaglandin (PG) production in brain tissue is increased following T-2 toxin. The present study was designed in order to test the effect of dexamethasone on brain prostaglandins and survival of rats subjected to T-2 toxin. Furthermore, the effect of BW 755c, a dual inhibitor of the cyclooxygenase and lipoxygenase pathways of arachidonate metabolism, on the survival of rats exposed to T-2 toxin was also examined. The present study demonstrated that dexamethasone increases the survival of rats exposed to a highly lethal T-2 toxicosis. This effect was demonstrated at low as well as high doses and at different times after T-2 administration. Dexamethasone depressed PGE2 levels in the brain cortex 6 hr after T-2 toxin but abolished the reduction of PGE2 in brain cortex seen 24 hr after T-2. BW 755c had no consistent effect on the survival of rats in T-2 toxicosis. It is suggested that dexamethasone might be a useful therapeutic agent in T-2 toxicosis in animals and humans, but its mechanism of action remains obscure.

[Causes of fatal outcomes in acute pancreatitis]. / Prichiny letal'nykh iskhodov pri ostrom pankreatite.

An analysis of case histories of 142 patients dead from acute pancreatitis has been made. The most frequent cause of death at early terms was the syndrome of endogenous intoxication and bleeding from upper portions of the gastro-intestinal tract. Death at later terms was usually caused by pyo-septic complications and arrosive bleedings. It was established that in the recent years acute pancreatitis made its appearance against the background of chronic inflammatory alterations in the pancreas.

[Characteristics of sepsis in burn patients today]. / Osobennosti sepsisa u obozhzhennykh v nastoiashchee vremia.

An analysis of lethal outcomes following thermal traumas during the recent 8 years has shown sepsis to occupy one of the leading places as a cause of death of burned people. During the recent years the incidence of early sepsis has been increased. This kind of sepsis develops in the period of shock and acute toxemia, is often of lightening character, possesses certain specific morphological features and is caused predominantly by gram-negative flora threatening to patients with critical burns of more than 40% of the body surface.

Death of an African elephant from probable toxemia attributed to chronic pulpitis.

A 31-year-old captive male African elephant (Loxodonta africana) of 5,000-kg body weight died suddenly in ventral recumbency. Lesions seen at necropsy were bilateral purulent pulpitis and periodontitis of both tusks, serous atrophy of coronary groove fat, Grammocephalus cholangitis, myocardial and skeletal lipofuscinosis, and scattered segmental necrosis in the pectoral muscles. Nonhemolytic streptococci, Corynebacterium sp, Peptostreptococcus anaerobius, Fusobacterium nucleatum, and Bacteroides sp, were recovered from the exudate around one or both tusks. We postulated that the elephant died of hypoxia from prolonged ventral recumbency because of weakness and inability to rise secondary to toxemia from bilateral pulpitis and periodontitis.