Predominant role for C5b-9 in renal ischemia/reperfusion injury.

Previous work has indicated that complement is a mediator of ischemia/reperfusion (I/R) injury. To investigate the components of complement responsible for this effect, we examined a model of renal I/R injury in C3-, C4-, C5-, and C6-deficient mice. We occluded the renal arteries and veins (40-58 minutes) and, after reperfusion (0-72 hours), assessed renal structural and functional injury. C3-, C5-, and C6-deficient mice were protected from renal I/R injury, whereas C4-deficient mice were not protected. C6-deficient mice treated with antibody to block C5a generation showed no additional protection from I/R injury. Reconstitution with C6 alone restored the I/R injury in C6-deficient mice. Tubular epithelial cells were the main structures damaged by complement-mediated attack, and, in contrast, the renal vessels were spared. Neutrophil infiltration and myeloperoxidase activity were reduced in C-deficient mouse kidney, but by a similar extent in C3-deficient and C6-deficient mice. We conclude that the membrane attack complex of complement (in which C5 and C6 participate) may account for the effect of complement on mouse renal I/R injury. Neither C5a-mediated neutrophil infiltration nor the classic pathway, in which C4 participates, appears to contribute to I/R injury in this model. By contrast with other organs, such as the heart, the primary effect of complement in the ischemic area is on the parenchymal cell rather than the vascular endothelial cell. The membrane attack complex of complement is a potential target for prevention of I/R injury in this model.

The allogeneic T and B cell response is strongly dependent on complement components C3 and C4.

BACKGROUND: The mechanisms controlling the production of antibodies against histocompatibility antigens are of prime importance in organ transplantation. METHODS: We investigated the role of complement in the response to allogeneic stimulation, using mice deficient in C3, C4, or C5 to dissect the role of the alternative, classical, and terminal complement pathways. RESULTS: After fully major histocompatibility complex disparate skin grafts, the allospecific immunoglobulin (Ig)G response was markedly impaired in C3- and C4-, but not in C5-deficient mice. This defect was most pronounced for second set responses. C3-deficient mice also demonstrated a decreased range of IgG isotypes. In contrast, there was no impairment of the allospecific IgM response. In functional T cell assays, the proliferative response and interferon-gamma secretion of recipient lymphocytes restimulated in vitro with donor antigen was decreased two- to threefold in C3-deficient mice. CONCLUSIONS: These data show impairment of allogeneic T cell and B cell function in mice with defective complement activation and suggest a predominant role for the classical pathway in stimulating alloimmunity. The terminal pathway seems unimportant in this regard. This extends the results reported for soluble protein antigens and demonstrates a surprisingly marked effect on the alloresponse despite the presence of a stringent antigenic stimulus. These results have implications for the prevention of sensitization in naïve transplant recipients.

Local tissue complement synthesis--fine tuning a blunt instrument.

Complement is important to host defense and the regulation of inflammation. The liver is overwhelmingly the major source of circulating complement. However, many other organs are capable of synthesizing some or all of the complement components in a regulated tissue-specific manner. There is increasing evidence that this locally generated complement is biologically active and exerts powerful effects within the local environment. We review the role of local complement synthesis within different organs and speculate on its implication for immune and metabolic functions.

Autoimmune renal injury in C3- and C4-deficient mice: a histological and functional study.

BACKGROUND: Complement deficiency predisposes to autoimmune renal disease. Since complement deficient mice are increasingly used to study the immunopathogenesis of renal disease we have determined whether mice deficient in C3 or C4 are susceptible to spontaneous immune-mediated renal injury. METHODS: C3-deficient, C4-deficient and complement-sufficient, wild-type mice were maintained in standard conditions for 1 year at which stage renal function, renal histology, circulating antibody and autoantibody levels were assessed. RESULTS: No significant decline in renal function was demonstrated in the complement-deficient mice. However, there was histological evidence of glomerular injury in both the C3- and C4-deficient mice, but of insufficient severity to alter function. Serum IgG2a concentration was significantly lower in C3- and C4-deficient mice. In contrast C3-deficient mice had higher concentrations of serum IgG2b. There was a tendency for mice from all groups, including the complement-sufficient mice, to develop autoantibodies. C4-deficient mice had higher titres of anti-dsDNA IgG but otherwise deficient mice had similar autoantibody titres to controls. CONCLUSION: We conclude that C4-deficient mice demonstrate a small increase in autoantibody production at 1 year of age compared to C3-deficient and wild-type mice. Furthermore, although complement-deficient mice exhibit glomerular changes, they are of minor functional significance, and are unlikely to affect the study of experimentally induced renal disease in these mice.

Drugs in pregnancy. Renal disease.

The management of pregnant women with renal impairment presents a major challenge to obstetricians, nephrologists, and ultimately paediatricians. As renal failure progresses there is an increase in both maternal and fetal complications. Often these women have intercurrent medical conditions and, prior to conception, are receiving a broad range of prescribed medications. A successful obstetric outcome relies upon careful pre-pregnancy counselling and planning, obsessive monitoring during pregnancy, and close liaison between different specialist teams. Experience is mounting in the management of pregnant transplant recipients, but the introduction of newer immunosuppressive agents which have great promise in prolonging graft survival present new problems for those recipients of a kidney transplant who are planning to conceive. We review drug prescription for pregnant patients with renal impairment, end-stage renal failure, or a kidney transplant.

Registered Replication Report: Schooler and Engstler-Schooler (1990).

Trying to remember something now typically improves your ability to remember it later. However, after watching a video of a simulated bank robbery, participants who verbally described the robber were 25% worse at identifying the robber in a lineup than were participants who instead listed U.S. states and capitals-this has been termed the "verbal overshadowing" effect (Schooler & Engstler-Schooler, 1990). More recent studies suggested that this effect might be substantially smaller than first reported. Given uncertainty about the effect size, the influence of this finding in the memory literature, and its practical importance for police procedures, we conducted two collections of preregistered direct replications (RRR1 and RRR2) that differed only in the order of the description task and a filler task. In RRR1, when the description task immediately followed the robbery, participants who provided a description were 4% less likely to select the robber than were those in the control condition. In RRR2, when the description was delayed by 20 min, they were 16% less likely to select the robber. These findings reveal a robust verbal overshadowing effect that is strongly influenced by the relative timing of the tasks. The discussion considers further implications of these replications for our understanding of verbal overshadowing.

Early tracheal intubation with thiopentone in elective surgery.

We have studied tracheal intubating conditions within 30 s of administration of thiopentone in 24 patients and compared this with our usual method of tracheal intubation, which involves 3 min of manual ventilation in 29 patients. All patients received papaveretum 10 mg 3 min before induction and alcuronium at induction of anaesthesia. Satisfactory intubating conditions were observed in 83% of patients in both groups. There were no difficult or failed intubations and no patient had laryngospasm. The duration of laryngoscopy in the control group was 14.1 (SD 8.6) s (range 7-50 s), compared with 12.4 (3.1) s (range 6-20 s), in the early intubation group (ns). In the control group there was a significant decrease in systolic pressure before tracheal intubation and a significant increase in heart rate after intubation, compared with baseline values. The average systolic pressure in the early intubation group increased only minimally: from a pre-intubation value of 143.3 (21.2) mm Hg to 145.5 (25.1) mm Hg after intubation. Our results demonstrate that early tracheal intubation under thiopentone supplemented with an opioid and a non-depolarizing neuromuscular block is feasible, associated with minimal changes in arterial pressure and not accompanied by an increased incidence of side effects.

Targeting the complement system.

Interest has blossomed in the development of complement inhibitors, in parallel with a growth in our understanding of the biology of the complement cascade. The first generation of designed inhibitors was based on naturally occurring complement receptors and regulatory molecules. These agents provided useful tools for exploring the role of complement in experimental models of disease, but may have limited therapeutic application in humans because of their short half-lives, limited bioavailability and possible antigenicity. More recently, humanized antibodies and synthetic molecules that block the activation of complement have been developed, which look as though they may overcome some of these difficulties. The possibility for precision inhibition of a limited part of the complement cascade, or for inhibition confined to a single organ, may offer effective therapeutic results, while avoiding the disadvantages of nonselective complement blockade. This review examines the recent evidence that complement inhibition will reduce tissue damage resulting from organ transplantation, ischaemia-reperfusion injury, cancer, glomerulonephritis and the use of extracorporeal circuits.

Intrarenal synthesis of complement.

During the past decade, research has shown that the kidney has the capacity to synthesize most of the activation pathway components of the complement cascade. As well as implying physiological roles in local clearance of immune complexes and defense against invasive organisms, an increasing amount of evidence indicates that the intrarenal synthesis of complement makes an important contribution in the pathogenesis of renal injury. Here we review this evidence and present a case for more definitive investigation of these functions.