An investigation into the role of time-dependent cohesion in interseismic fault restrengthening.

Earthquakes typically exhibit recurrence times that far exceed time-scales attainable in a laboratory setting. To traverse the temporal gap between the laboratory and nature, the slide-hold-slide test is commonly employed as a laboratory analogue for the seismic cycle, from which the time-dependence of fault strength may be assessed. In many studies it is implicitly assumed that all fault restrengthening emanates from an increase in the internal friction coefficient, neglecting contributions from cohesion. By doing so, important information is lost that is relevant for numerical simulations of seismicity on natural faults, as well as for induced seismicity. We conduct slide-hold-slide experiments on granular halite gouge at various normal stresses to assess the time-dependence of the internal coefficient of friction, and of the cohesion, independently of one another. These experiments reveal that both the internal friction coefficient and cohesion increase over time, but that these quantities do not share a common evolution, suggesting different underlying mechanisms.

Investigating Compaction by Intergranular Pressure Solution Using the Discrete Element Method.

Intergranular pressure solution creep is an important deformation mechanism in the Earth's crust. The phenomenon has been frequently studied and several analytical models have been proposed that describe its constitutive behavior. These models require assumptions regarding the geometry of the aggregate and the grain size distribution in order to solve for the contact stresses and often neglect shear tractions. Furthermore, analytical models tend to overestimate experimental compaction rates at low porosities, an observation for which the underlying mechanisms remain to be elucidated. Here we present a conceptually simple, 3-D discrete element method (DEM) approach for simulating intergranular pressure solution creep that explicitly models individual grains, relaxing many of the assumptions that are required by analytical models. The DEM model is validated against experiments by direct comparison of macroscopic sample compaction rates. Furthermore, the sensitivity of the overall DEM compaction rate to the grain size and applied stress is tested. The effects of the interparticle friction and of a distributed grain size on macroscopic strain rates are subsequently investigated. Overall, we find that the DEM model is capable of reproducing realistic compaction behavior, and that the strain rates produced by the model are in good agreement with uniaxial compaction experiments. Characteristic features, such as the dependence of the strain rate on grain size and applied stress, as predicted by analytical models, are also observed in the simulations. DEM results show that interparticle friction and a distributed grain size affect the compaction rates by less than half an order of magnitude.

The use of thermostable Vero cell-adapted rinderpest vaccine as a heterologous vaccine against peste des petits ruminants.

The thermostable Vero cell-adapted rinderpest vaccine was evaluated in terms of immunogenicity as a heterologous vaccine against peste des petits ruminants. A titration to establish the minimum immunising dose was performed in American mixed breed goats by vaccinating test subjects with dilutions of Vero cell-adapted rinderpest vaccine and then challenging 26 days later with virulent peste des petits ruminants virus. All animals were followed for virus neutralising antibodies against both rinderpest and peste des petits ruminants virus after vaccination and challenge. The antibody response to vaccination was primarily against rinderpest virus with very low levels of cross-reactivity to peste des petits ruminants virus. Following challenge, animals which possessed anti-rinderpest neutralising antibodies remained clinically normal but mounted strong anti-peste des petits ruminants virus neutralising antibody responses indicating that replication of challenge virus took place without the induction of illness. The 50 per cent minimum goat immunising dose was 3 tissue culture infectious doses 50 per cent (TCID50) as established by serological response and protection against challenge. The thermostable Vero cell-adapted rinderpest vaccine is a suitable immunogen for the protection of goats against peste des petits ruminants.

The serological response to a thermostable Vero cell-adapted rinderpest vaccine under field conditions in Niger.

A lyophilized thermostable Vero cell-adapted ringerpest vaccine, stabilized with lactalbumin hydrolysate and sucrose, was tested for safety, serological response and suitability for use with an abbreviated cold chain under field conditions in Niger. A total of 480 cattle, 90 goats and 55 sheep of unknown serological status were vaccinated on government ranches and observed for at least 22 days. No untoward effects of the vaccine were detected. The serological response to the vaccine stored at environmental temperatures for 30 to 34 days was determined in 144 previously unvaccinated yearling calves. Seroconversion was demonstrated in 98% of the yearling calves using seroneutralization. The un-refrigerated vaccine retained a titer of 3.69 log10 TCID50 per dose through day 34.

Comparison of the effect of various chemical stabilizers and lyophilization cycles on the thermostability of a Vero cell-adapted rinderpest vaccine.

The thermostability of a rinderpest vaccine produced on Vero cells was evaluated using a variety of chemical stabilizers and lyophilization protocols. Three stabilizer preparations and three lyophilization schedules were examined using accelerated stability testing at 37 degrees C. The vaccine preparation exhibiting the greatest stability at 37 degrees C was tested at three additional temperatures, 42, 45 and 56 degrees C, and an Arrhenius plot was constructed from the data. The stability of the reconstituted vaccine produced with the two most efficacious stabilizers was examined using three different diluent preparations. The stabilization method and high Vero cell virus batch titers resulted in a lyophilized vaccine which maintained the minimum required dose of log10 2.5 TCID50 tissue culture infectious dose for more than 20 weeks at 37 degrees C.

Wegener's granulomatosis autoantibodies identify a novel diisopropylfluorophosphate-binding protein in the lysosomes of normal human neutrophils.

Anti-neutrophil cytoplasmic autoantibodies (ANCA) specifically associated with Wegener's granulomatosis were found to be directed against a saline-soluble glycoprotein triplet that migrates on SDS gels as distinct bands of Mr 29,000, 30,500, and 32,000 and is present in the azurophilic granules. This antigen was specifically recognized by all cytoplasmic-staining (C)-ANCA-positive sera from patients with Wegener's disease. C-ANCA antigen bound [3H]diisopropylfluorophosphate, which indicates that it is a serine protease, but it could clearly be distinguished from the serine proteases elastase and cathepsin G. Stimulation of cytochalasin B-treated neutrophils with FMLP induced release of C-ANCA antigen. This indicates that in vivo C-ANCA might interact with the C-ANCA antigen after its release upon inflammatory stimulation. We further demonstrate that in some perinuclear staining (P-ANCA) patients' sera autoantibodies against other myeloid lysosomal enzymes can be detected, such as antimyeloperoxidase and antielastase. C-ANCA and P-ANCA thus represent a novel class of autoantibodies directed against myeloid lysosomal enzymes. The originally described Wegener-specific C-ANCA show an apparently uniform specificity for the 29,000 serine protease. In contrast, P-ANCA may recognize myeloperoxidase as well as elastase and/or other antigens.

Detection of serum antibodies and circulating antigens in a chimpanzee experimentally infected with Onchocerca volvulus.

The course of the humoral immune response was followed in a chimpanzee experimentally infected over 27 weeks with a total of 168 Onchocerca volvulus 3rd-stage larvae obtained from naturally infected wild-caught blackflies. Antibodies against an adult worm extract could be detected by ELISA from week 16 onwards (after the inoculation of 44 larvae). Peak antibody levels were observed between weeks 66 and 74 (about one year after the last larval injection). Thereafter, antibody levels markedly decreased but rose again after week 120. First microfilariae could be detected from week 124 onwards. Microfilarial counts remained low (not more than two microfilariae per skin snip) until the end of the observation period. High levels of IgM antibodies against adult O. volvulus antigens were detectable between weeks 26 and 80 by ELISA. Total IgE levels were found to be only marginally elevated during the course of the infection. Circulating parasite antigens were only detectable for a short time (weeks 34 to 44) of the prepatent period by immuno-radiometric assays (IRMAs) using monoclonal antibodies which were raised against O. gibsoni eggs. Competitive radio-immuno-assays detected host antibodies inhibiting binding of 125I-labelled monoclonal antibodies to parasite antigens from week 28 onwards. Host antibodies clearly interfere later in infection with the detection of circulating antigens.

Onchocerca volvulus: transplantation of adult worms into chimpanzees.

Adult Onchocerca volvulus were transplanted into chimpanzees with or without complete or partial digestion of associated nodule tissue. Survival of adults worms was limited, but low level microfilarial densities remained detectable in skin over partially digested nodule transplants for 12 months. Human nodule tissue transplanted with adult worms showed enhanced survival as compared to subcutaneous tissue transplanted without worms. It is postulated that this reflects the action of an immunosuppressive factor utilized by the parasite to permit its own survival.

Inactivation of hepatitis B and Hutchinson strain non-A, non-B hepatitis viruses by exposure to Tween 80 and ether.

Titrated stocks of hepatitis B virus and Hutchinson strain non-A, non-B hepatitis virus were diluted in normal serum to contain, respectively, greater than or equal to 10(6) and greater than or equal to 10(4) chimpanzee infectious doses (CID50) per milliliter and exposed to 1% Tween 80 and 20% ether at 4 degrees C for 18 h. After evaporation of the ether, the treated sera were each inoculated into two chimpanzees. The animals remained free of serologic and biochemical evidence of hepatitis during a 6-month follow-up period, and were then shown to be susceptible to infection by challenge with the original untreated inocula. To assess the effect of exposure to Tween 80/ether on coagulation factors, four lots of antihemophilic factor (AHF) concentrate and 2 lots of commercial factor IX concentrate were treated as above. For the AHF concentrate there was an average of 70% recovery of factor VIII procoagulant activity, 93% recovery of factor VIII-related antigen, and 73% recovery of fibronectin opsonin activity and no detectable change in ristocetin cofactor activity or in fibronectin antigen. Crossed immunoelectrophoresis revealed no change in migration rate of fibrinogen, fibronectin, and von Willebrand factor (vWF), although the quantity of fibrinogen was reduced. Factor VIII procoagulant activity and vWF activity remained associated during chromatography on BioGel A15.

Blood-borne non-A, non-B hepatitis: lack of infectivity of feces from chimpanzees infected with a strain producing cytoplasmic tubular alterations.

Fecal and serum samples from a chimpanzee with acute-phase, blood-borne non-A, non-B hepatitis were administered to four chimpanzees. Fecal material given either intravenously or orally did not result in abnormal levels of alanine aminotransferase or the occurrence of ultrastructural alterations in hepatocellular cytoplasm characteristic of non-A, non-B hepatitis during a one-year period of follow-up. Definite non-A, non-B hepatitis was later demonstrated in two of these animals four weeks after inoculation of acute-phase serum. Thus, feces do not appear to transmit this human strain of blood-borne non-A, non-B hepatitis.

Interference between non-A, non-B and hepatitis B virus infection in chimpanzees.

Pre-existing chronic or concurrent acute non-A, non-B (NANB) virus infection has been found to interfere with hepatitis B virus (HBV) replication and to delay and moderate markedly the appearance of disease related to HBV infection in chimpanzees. The mechanism for this phenomenon remains unclear. These findings are of practical significance for vaccine safety testing and evaluation of methods for virus inactivation in chimpanzees. The possible occurrence of dual NANB and HBV infection requires that prolonged follow-up be carried out. Attempts to carry out inactivation studies on materials containing both types of virus may also provide misleading observations.

Evaluation of the effect of betapropiolactone/ultraviolet irradiation (BPL/UV) treatment of source plasma on hepatitis transmission by factor IX complex in chimpanzees.

To evaluate the safety of a beta-Propiolactone/Ultraviolet (BPL/UV), irradiated Factor IX complex preparation we inoculated 8 chimpanzees with 25 units Factor IX/Kilo from a pool of 5 production lots which had been treated in this manner. These lots were derived from approximately 1,000 donors. Animals were followed with weekly tests for hepatitis B serologic markers and transaminases, and biweekly liver biopsies, for 6 months. No evidence of transmission of hepatitis B, or non-A, non-B viruses was observed. To further evaluate the BPL/UV procedure a plasma pool was intentionally contaminated with hepatitis B virus and one half of the pool treated with BPL/UV. Factor IX complex was isolated from the treated and untreated pools and each was inoculated into 4 chimpanzees. The Factor IX derived from untreated plasma infected all four animals with an average incubation period of 10.5 weeks, whereas that prepared from PBL/UV treated plasma infected only one of four animals with an incubation period of 21 weeks. These results were interpreted as suggesting that BPL/UV can inactivate approximately 99.9% of hepatitis B virus infectivity.

An open air holding system for chimpanzees in medical experiments.

Chimpanzee models often impose severe mental and physical suffering on these animals. We have developed an alternative system which provides for considerably more three dimensional movement and animal-to-animal interaction. It has been used for a period of 20 months in nonexperimental and 8 months in experimental animals. Presently 24 experimental animals, previously held in isolation cages for up to 4 years, are held on outside pads. Animals were transferred from isolation to large outdoor cages for readjustment prior to being put out on pads. Animals that had acquired behavioral abnormalities during their stay in isolation had a longer period of adjustment but now appear happy and are capable of normal interaction with their companions. Chimpanzees approaching sexual maturity and individuals over 5 years that have undergone hepatitis B and non-A, non-B infections are being transferred to a 6 hectare island situated in a river 10 km from the laboratory. Six animals present on the island since October 1978 are in good physical health and are the beginning of a future semi-free-ranging colony. They are fed daily on the same regimen as the main colony and receive monthly anthelmintic treatment in milk. There are presently no caged animals in the colony.