A defective Vkappa A2 allele in Navajos which may play a role in increased susceptibility to haemophilus influenzae type b disease

The antibody response to H. influenzae type b (Hib) is pauciclonal, and is dominated by antibodies using the VkappaA2 gene. Navajos have a 5-10-fold increased incidence of Hib disease compared with control populations. We hypothesized that a polymorphism in one of the genes in this oligoclonal response may lead to increased disease susceptibility. Since the predominant A2+ anti-Hib antibodies have high avidity for Hib and can be unmutated, the A2 Vkappa gene was analyzed. Over half of the Navajos studied, but only one control individual, had a new allele of A2, termed A2b, with three changes from the published A2 germline sequence. One of the changes was in the recombination signal sequence, suggesting that the A2b allele might not undergo V-J rearrangement very frequently. This possibility was confirmed by analyzing the relative frequency of non-productive A2 rearrangements in A2a/b heterozygous Navajos. Many fewer A2b rearrangements were observed, showing that the A2b allele is defective in its ability to undergo rearrangement. The prevalence of this allele in Navajos may play a role in their increased susceptibility to invasive Hib disease. If so, it would underscore the importance of the germline Ig repertoire for protective antibody responses to pathogenic bacteria in unimmunized children.     

Perioperative ischaemia in aortic surgery: combined epidural/general anaesthesia and epidural analgesia vs general anaesthesia and i.v. analgesia

PURPOSE: The goal of this randomized study was to determine whether combined general and epidural anaesthesia with postoperative epidural analgesia, compared with general anaesthesia and postoperative intravenous analgesia, reduced the incidence of perioperative myocardial ischaemia in patients undergoing elective aortic surgery. METHOD: Patients were randomly assigned to one of two groups. One group (EPI, n = 48) received combined general and epidural anaesthesia and postoperative epidural analgesia for 48 hrs. The other group (GA, n = 51) received general anaesthesia followed by postoperative intravenous analgesia. Anaesthetic goals were to maintain haemodynamic stability (+/- 20% of preoperative values), and a stroke volume > 1 ml.kg-1. A Holter monitor was attached to each patient the day before surgery. Leads 11, V2, and V5 were monitored. Myocardial ischaemia was defined as ST segment depression > 1 mm measured at 80 millisec beyond the J point or an elevation of 2 mm 60 millisec beyond the J point which lasted > 60 sec. An event that lasted > 60 sec but returned to the baseline for > 60 sec and then recurred, was counted as two separate events. The Holter tapes were reviewed by a cardiologist blind to the patient's group. RESULTS: There were no demographic differences between the two groups. Myocardial ischaemia was common; it occurred in 55% of patients. In hospital, preoperative ischaemia was uncommon (GA = 3, EPI = 8). Intraoperative ischaemia was common (GA = 18, EPI = 25). Mesenteric traction produced the largest number of ischaemic (GA = 11, EPI = 11) events. Postoperative ischaemia was most common on the day of surgery. Termination of epidural analgesia produced a burst of ischaemia (60 events in 9 patients). CONCLUSION: Combined general and epidural anaesthesia and postoperative epidural analgesia do not reduce the incidence of myocardial ischaemia or morbidity compared with general anaesthesia and postoperative intravenous analgesia.     

Prostaglandins in liver disease and liver transplantation

This brief review summarizes the physiology and pharmacology of eicosanoids and describes how they have been tested for possible application in liver disease and transplantation. The objective is to trace the stepwise application from the laboratory to the bedside. Although many questions remain to be answered, the observations summarized in this article have opened up new and potentially rewarding prospects in application to liver disease.     

Death-effector filaments: novel cytoplasmic structures that recruit caspases and trigger apoptosis

The death-effector domain (DED) is a critical protein interaction domain that recruits caspases into complexes with members of the TNF-receptor superfamily. Apoptosis can also be induced by expressing certain DED-containing proteins without surface receptor cross-linking. Using Green Fluorescent Protein to examine DED-containing proteins in living cells, we show that these proteins cause apoptosis by forming novel cytoplasmic filaments that recruit and activate pro-caspase zymogens. Formation of these filaments, which we term death-effector filaments, was blocked by coexpression of viral antiapoptotic DED-containing proteins, but not by bcl-2 family proteins. Thus, formation of death-effector filaments allows a regulated intracellular assembly of apoptosis-signaling complexes that can initiate or amplify apoptotic stimuli independently of receptors at the plasma membrane.