Increased susceptibility to endotoxin shock in complement C3- and C4-deficient mice is corrected by C1 inhibitor replacement.

Endotoxin shock is a life-threatening syndrome associated with a Gram-negative infection and mediated by a systemic inflammatory response. As a major effector of inflammation, the complement system has been implicated in both the pathogenesis and the protection from endotoxin shock. To clarify the role of complement in endotoxin shock, we have used mice totally deficient in either complement component C3 or C4. We found that both the C3- and C4-deficient mice were significantly more sensitive to endotoxin than wild-type controls. The endotoxin-challenged complement-deficient mice failed to clear endotoxin efficiently from the circulation and this led to excess consumption of C1 inhibitor protein (C1 INH), a major regulator of both complement and the contact system of blood coagulation. Replacement of C1 INH rescued the endotoxin-challenged complement-deficient mice from shock and death. These findings suggest a novel therapy for treatment of endotoxemia with C1 INH protein.

Studies of group B streptococcal infection in mice deficient in complement component C3 or C4 demonstrate an essential role for complement in both innate and acquired immunity.

Group B streptococci (GBS) cause sepsis and meningitis in neonates and serious infections in adults with underlying chronic illnesses. Specific antibodies have been shown to be an important factor in protective immunity for neonates, but the role of serum complement is less well defined. To elucidate the function of the complement system in immunity to this pathogen, we have used the approach of gene targeting in embryonic stem cells to generate mice totally deficient in complement component C3. Comparison of C3-deficient mice with mice deficient in complement component C4 demonstrated that the 50% lethal dose for GBS infection was reduced by approximately 50-fold and 25-fold, respectively, compared to control mice. GBS were effectively killed in vitro by human blood leukocytes in the presence of specific antibody and C4-deficient serum but not C3-deficient serum. The defective opsonization by C3-deficient serum in vitro was corroborated by in vivo studies in which passive immunization of pregnant dams with specific antibodies conferred protection from GBS challenge to normal and C4-deficient pups but not C3-deficient pups. These results indicate that the alternative pathway is sufficient to mediate effective opsonophagocytosis and protective immunity to GBS in the presence of specific antibody. In contrast, the increased susceptibility to infection of non-immune mice deficient in either C3 or C4 implies that the classical pathway plays an essential role in host defense against GBS infection in the absence of specific immunity.

The prevalence and distribution of proliferative and metaplastic changes in normal appearing canine bladders.

The prevalence and distribution of Brunn's nests, simple hyperplasia, simple squamous metaplasia, cystitis glandularis/cystica, atypical hyperplasia, and lymphocytic infiltration were studied by multiple histologic sections in 30 grossly normal urinary bladders obtained from a controlled population of dogs ranging in age from two to 14 years. The data were statistically analyzed using Fisher's exact test and logistic regression. A comparison of urothelial changes was made between dog and human. Brunn's nests were the most prevalent urothelial change and were observed at one or more locations in 80% of the cases. Simple hyperplasia was the second most common proliferative change and was observed at one or more locations in 66.7% of all cases. Brunn's nests (p less than 0.0001) and simple hyperplasia (p = .003) were significantly more likely to be found in the trigone. Simple squamous metaplasia was observed at one more more locations in 23.3% of all cases. Lymphocytic infiltration was observed in 20% of the animals; however, there was no statistically significant correlation between it and the urothelial changes. The trigone was by far the most common site (86.6% of all cases) for one or more lesions to be found. There was no evidence that inflammation was the cause of these urothelial changes. The data supports the concept that Brunn's nests, simple hyperplasia, and simple squamous metaplasia are normal variants of bladder urothelium in dogs and further that they are not precancerous changes. There was a similarity in prevalence, distribution, and significance of many urothelial changes between the dog and human which indicates that the dog is a good comparative model for studying diseases of the urinary bladder.

Pregnancy toxemia (eclampsia) in Syrian golden hamsters.

Late-term pregnant Syrian golden hamsters (Mesocricetus auratus) died within 24 hours of arrival in our facility. Disseminated thrombi were found in many organs, particularly in the kidneys, liver, intestines, and placenta. Pathogenic bacteria were not identified in bacterial cultures of the liver.

House mouse mites infesting laboratory rodents.

Liponyssoides sanguineus, principal vector of Rickettsia akari, infested mongolian gerbils (Meriones unguiculatus) mice (Mus musculus) and laboratory-reared egyptian gerbils (Meriones libycus). Only a few mites were present on each animal and no manifestations of disease were observed. Numerous mites were present in the bedding.

Segmental replacement of the ureter using tapered and nontapered ileum.

We attempted to reduce the absorptive surface area and maintain the natural antireflux mechanism of the distal ureter by using ileum as an interposed segment rather than a total ureteral substitute in six dogs. In each dog we compared the physiologic effects of a longitudinally tapered ileal segment versus a simple nontapered segment. Information from the intravenous pyelogram, renal function tests, and the pressure flow studies showed preservation of renal function and parenchyma, no secondary dilation of the upper tracts, continued peristaltic activity, no evidence of obstruction or stone formation secondary to mucus production, no early pyelographic abnormalities, and no differences in pressure flow characteristics between the tapered and nontapered segments. We believe that incorporating ileum into the urinary tract to bridge a ureteral defect is a safe and effective clinical alternative.