Vaccination with the Crimean-Congo hemorrhagic fever virus viral replicon vaccine induces NP-based T-cell activation and antibodies possessing Fc-mediated effector functions.

Crimean-Congo hemorrhagic fever virus (CCHFV; family Nairoviridae) is a tick-borne pathogen that frequently causes lethal disease in humans. CCHFV has a wide geographic distribution, and cases have been reported in Africa, Asia, the Middle East, and Europe. Availability of a safe and efficacious vaccine is critical for restricting outbreaks and preventing disease in endemic countries. We previously developed a virus-like replicon particle (VRP) vaccine that provides complete protection against homologous and heterologous lethal CCHFV challenge in mice after a single dose. However, the immune responses induced by this vaccine are not well characterized, and correlates of protection remain unknown. Here we comprehensively characterized the kinetics of cell-mediated and humoral immune responses in VRP-vaccinated mice, and demonstrate that they predominantly target the nucleoprotein (NP). NP antibodies are not associated with protection through neutralizing activity, but VRP vaccination results in NP antibodies possessing Fc-mediated antibody effector functions, such as complement activation (ADCD) and antibody-mediated cellular phagocytosis (ADCP). This suggests that Fc-mediated effector functions may contribute to this vaccine's efficacy.

"Peril in the means of its diffusion": William Godwin on Truth and Social Media.

In this article I explore how William Godwin depicted the social operation of media, and argue that his writing highlights a crosscurrent of alethic thought in Romantic-period Britain. I examine his direct assessments of the social merits of book-reading and conversation, revealing his ambivalence regarding sources of epistemic authority. I argue that he inherited this ambivalence from his Dissenting educational background, most especially the two-fold conception of truth that it negotiated. I thus situate Godwin's scrutiny of media in the alethic dialogue of his time, and offer this context as a helpful perspective upon his wider work.

Biosurfactant-enhanced solubilization of NAPL mixtures.

Remediation of nonaqueous phase liquids (NAPLs) by conventional pump-and-treat methods (i.e., water flushing) is generally considered to be ineffective due to low water solubilities of NAPLs and to mass-transfer constraints. Chemical flushing techniques, such as surfactant flushing, can greatly improve NAPL remediation primarily by increasing the apparent solubility of NAPL contaminants. NAPLs at hazardous waste sites are often complex mixtures. However, the equilibrium and nonequilibrium mass-transfer characteristics between NAPL mixtures and aqueous surfactant solutions are not well understood. This research investigates the equilibrium solubilization behavior of two- and three-component NAPL mixtures (containing akylbenzenes) in biosurfactant solutions. NAPL solubilization is found to be ideal in water (i.e., obeys Raoult's Law), while solubilization in biosurfactant solutions was observed to be nonideal. Specifically, the relatively hydrophobic compounds in the mixture experienced solubility enhancements that were greater than those predicted by ideal enhanced solubilization theory, while the solubility enhancements for the relatively hydrophilic compounds were less than predicted. The degree of nonideality is shown to be a nonlinear function of the NAPL-phase mole fraction. Empirical relationships based on the NAPL-phase mole fraction and/or micelle-aqueous partition coefficients measured in single-component NAPL systems are developed to estimate values for the multicomponent partition coefficients. Empirical relationships that incorporate both the NAPL-phase mole fraction and single-component partition coefficients yield much improved estimates for the multicomponent partition coefficient.

Schistosoma mansoni gene GP22 encodes the tegumental antigen sm25: (1) antibodies to a predicted B-cell epitope of Sm25 cross-react with other candidate vaccine worm antigens; (2) characterization of a recombinant product containing tandem-repeats of this peptide as a vaccine.

Monospecific antibodies against two putative epitopes of schistosome protein encoded by gene GP22 (182 codons, no introns) were used to probe worm extracts fractionated by lentil-lectin affinity chromatography or by electrophoresis. Anti-peptide-alpha (codons 70-84) exclusively identifies the N-glycanase-sensitive, 25 kDa tegumental glycoprotein Sm25 in the lectin-bound fraction of detergent-solubilized adult worm extract S3. In contrast, antipeptide-delta (codons 151-162) does not react with Sm25 but cross-reacts with other schistosome proteins, including candidate vaccine antigens paramyosin (Sm97) and glutathione-S-transferases (Sm26, Sm28, Sj26). Recombinant protein r4 x 47, constructed to express multiple copies of codon sequence 117-163 (containing delta), reacts with anti-delta and is uniquely recognized by protective Fischer twice-infected (F-2x) rat antiserum. Immunization with r4 x 47 induces antibodies with cross reactivities similar to anti-delta, but which also recognize Sm25. Despite these cross-reactivities with protective antigens, rodents vaccinated with r4 x 47 were not protected against cercarial infection. On the basis of these data, two hypotheses are proposed: (1) antigenic epitopes other than delta are present within the r4 x 47 sequence which induce antibodies reactive with Sm25 and/or (2) peptide-delta assumes alternative antigenic conformations, dependent upon the context of neighbouring sequences, some of which mimic epitopes of proteins encoded by other schistosome genes. These mimotopes are not targets of protective antibodies.

Mathematical modeling of air sparging for subsurface remediation: state of the art.

A review of published mathematical models used to simulate air sparging is provided. Applicability of the models, efforts to test the models using experimental data and contributions of modeling efforts to the practice of air sparging are also discussed. Compartmentalized lumped-parameter models and multiphase flow models have dominated air-sparging modeling efforts. In essence, each class of models requires the assumption of a continuum over some model domain. Each approach has significant benefits as well as some inherent disadvantages. Based on the literature, both lumped-parameter modeling and multiphase-flow modeling have been successful in improving our theoretical understanding of the air-sparging process and in facilitating practical development of sparging systems. Lumped-parameter models are simpler to use, and can lend considerable insight to sparging operations. Multiphase flow models have the potential to offer a more realistic simulation of the airflow process, but may require a considerable amount of data collection for model input. The literature suggests that for any air-sparging model to be useful for field applications, detailed model calibration is necessary. It is recommended that models incorporate, in some fashion, the diffusion and dispersion of contaminants to macro-scale air channels, and nonequilibrium interphase mass transfer of contaminants. These mass-transfer-limited processes are frequently listed as causes for the "tailing" of vapor-extraction effluent contaminant concentrations that are frequently observed during field applications. However, time-varying mixing of relatively clean and contaminated vapors in the extraction system may also explain this tailing. Geophysical imaging techniques and inverse modeling combined with air-sparging pilot tests and measurement of traditional hydrogeologic parameters may allow for successful modeling efforts.

Delivering health information statewide via the Internet in a collaborative environment: impact on individual member institutions.

The Arizona Health Information Network (AZHIN) is a statewide member-driven organization committed to improving access to information for health sciences students and practitioners. Members include several hospitals and hospital systems, an academic health sciences center, and other diverse health care organizations. AZHIN offers its members unlimited Web access to ten well-known health sciences databases. This paper explores the impact that AZHIN has had on its member institutions. A survey asked members to reflect on AZHIN and its possible effects on the visibility of the librarian within the institution, relative dollars spent on AZHIN and range of resources available, Internet connectivity within their institution, access to AZHIN and other Internet resources, teaching, and benefits of collaboration. Results indicated that AZHIN members have access to a wider range of resources than they would otherwise. There are financial savings for some. Internet connectivity and AZHIN membership can provide the librarian with a broadened role and increased visibility. The availability of MEDLINE and other AZHIN resources encouraged some institutions to install Internet connectivity more quickly. Teaching library users has increased. Overall, AZHIN members recognized many benefits of their collaboration.

Clinical endoscopic evaluation of the gastroduodenal tolerance to (R)- ketoprofen, (R)- flurbiprofen, racemic ketoprofen, and paracetamol: a randomized, single-blind, placebo-controlled trial.

Ketoprofen, a nonsteroidal anti-inflammatory drug (NSAID) of the 2-arylpropionic acid class, causes gastroduodenal hemorrhages and erosions in 10-15% of patients. The (S)- enantiomer exhibits most of the anti-inflammatory properties, with concomitant gastrointestinal toxicity. The (R)- enantiomer, however, was recently found to have analgesic properties independent of prostaglandin inhibition. Seventy-two healthy male volunteers not receiving NSAIDs, alcohol, or anti-ulcer drugs, were enrolled in a randomized, investigator-blind, placebo-controlled trial to evaluate the gastroduodenal tolerance of (R)- ketoprofen 100 mg b.i.d., (R)- flurbiprofen 100 mg b.i.d., racemic ketoprofen 100 mg b.i.d., and paracetamol 1,000 mg b.i.d. Gastroduodenal endoscopies at baseline and after 2.5 days of dosing were used to detect newly occurring hemorrhages and erosions. Adverse events were also recorded. The incidence of submucosal hemorrhages was 4/16 in the (R)- ketoprofen group, 5/16 in the (R)- flurbiprofen group, 12/16 in the racemic ketoprofen group, 1/16 in the paracetamol group, and 1/8 in the placebo group. The incidence of erosions was 2/16 in the (R)- ketoprofen group, 4/16 in the (R)- flurbiprofen group, 10/16 in the racemic ketoprofen group, 0/16 in the paracetamol group, and 2/8 in the placebo group. The differences in hemorrhages and erosions among treatments were statistically significant (gastric hemorrhages P = 0.0008; duodenal hemorrhages P = 0.00062; gastric erosions P = 0.0004; duodenal erosions P = 0.0062, Kruskal-Wallis test). At 100 mg b.i.d., (R)- ketoprofen caused fewer gastroduodenal hemorrhages and erosions than racemic ketoprofen (P = 0.019, P = 0.0112, P = 0.0097, P = 0.0139 for gastric, duodenal hemorrhages and gastric, duodenal erosions, respectively). The difference between 100 mg b.i.d. (R)- ketoprofen and 100 mg b.i.d. (R)- flurbiprofen was not statistically significant. The dissociation between analgesic and anti-inflammatory properties for (R)- ketoprofen suggests that it may represent a unique analgesic with a favorable safety profile.

Preclinical enantioselective pharmacology of (R)- and (S)- ketorolac.

Many of the nonsteroidal anti-inflammatory drugs (NSAIDs) are marketed as racemic mixtures, composed of (R)- and (S)- enantiomers. Racemic NSAIDs are potent cyclooxygenase (COX) inhibitors only through the action of the (S)- enantiomers, as the (R)- enantiomers do not exhibit COX inhibition. However, the (R)- enantiomer of ketoprofen exhibits potent analgesic activity and minimal ulcerogenic potential. To extend these observations, we examined the (R)- and (S)- enantiomers of RS- ketorolac, (S)- ketorolac exhibited potent COX1 and COX2 enzyme inhibition, whereas (R)- ketorolac was > 100-fold less active on both COX subtypes. Both enantiomers did not affect norepinephrine or serotonin uptake sites, and nitric oxidase or lipoxygenase activities, nor did they demonstrate any affinity for opioid receptors (mu, delta, or kappa). In experimental models, (S)- ketorolac exhibited about 10-fold greater activity than (R)- ketorolac in the murine phenylquinone writhing model. In this model, morphine sulfate was effective at much lower doses, however, and neither (R)- nor (S)- ketorolac showed any morphine-sparing effect. In the rat gait test for analgesia in the foot paw after injection of brewers yeast suspension, neither (R)- nor (S)- ketorolac affected paw volume. However, both provoked changes in gait scores, the (S)- enantiomer being 30-fold more potent than the (R)- enantiomer. A similar reduction was observed with respect to ulcerogenic potential, measured by direct microscopic changes after test conclusion. These findings suggest that (R)- ketorolac may possess analgesic activity that is independent of COX inhibition and may be associated with reduced ulcerogenic potential compared to effects exhibited by (S)- ketorolac.

Secondary conditions following spinal cord injury in a population-based sample.

This prospective study investigates the frequency of both medical and non-medical complications reported by the population based cohort of SCI survivors reported to the Colorado Spinal Cord Injury Early Notification System (ENS). Persons reported to the ENS between January 1 1986 and December 31 1993, representing the broad spectrum of all severities of spinal cord injury and potential complications, were solicited to participate in comprehensive follow-up interviews at their first, third and fifth year post injury. Hospitalizations of a week or longer were experienced by more than 10% of the participants at each of the three interview years. Similarly, the medical complications of spasticity or pain were reported by more than 25% of the participants, and pressure sores were reported by more than 10% at all three time periods. The chief non-medical complications (conditions) were financial concerns and transportation problems. Although these reported medical and non-medical complications present significant obstacles to be overcome, less than three percent of those surveyed at any of the time periods reported experiencing depression; and only 14% rated their quality of life as being poor.

Evaluating sources of traumatic spinal cord injury surveillance data in Colorado.

The purpose of this study is to evaluate the sources reporting hospitalized spinal cord injury cases to the statewide, population-based surveillance system in Colorado for the year 1994. Three reporting sources were evaluated: clinical contact persons, medical records departments, and a centralized statewide hospital discharge database. Two evaluation strategies were utilized; these include both measures of accuracy and estimates of missed cases. For the latter, capture-recapture techniques were used to estimate the number of hospitalized spinal cord injury cases missed by all three reporting sources. The clinical contact persons reported 84 confirmed cases, missed 80 confirmed cases, and reported 10 cases that were later determined not to have spinal cord injuries, resulting in a sensitivity of 0.51. Medical records departments and the discharge database reported 143 and 147 cases, respectively, missed 21 and 17 confirmed cases, and reported 118 and 69 cases that were later determined not to be cases of hospitalized injuries of the spinal cord, resulting in sensitivities of 0.87 and 0.90. Capture-recapture results indicate all three sources combined missed an estimated 1-5 cases, yielding a total annual incidence rate for hospitalized spinal cord injury ranging from 45.1 to 46.3 per million population.

Improving access to knowledge-based health sciences information: early results from a statewide collaborative effort.

Access to biomedical literature has been shown to reduce the patient's length of stay and thus reduce the cost of the hospital visit. Unfortunately, access to the most current information, at the time and place of need, requires a substantial commitment of resources in the form of staff expertise, computer hardware and software, and user training. The cost of these resources may be prohibitively high for all but the largest institutions. The Arizona Health Information Network (AZHIN) brings together librarians, information systems specialists, and health care professionals from hospitals throughout the state in an effort to share resources and expertise. By reducing the cost of access, AZHIN has increased the availability of health-related information across the state. Progress in AZHIN's first two years is described.

Evaluation of recombinant protein r140, a polypeptide segment of tegumental glycoprotein Sm25, as a defined antigen vaccine against Schistosoma mansoni.

To investigate the role of tegumental glycoprotein Sm25 in protective immunity against schistosomiasis, codons 43-182 of its gene (GP22) were amplified by PCR and cloned in the pET 15b bacterial expression system. Recombinant protein r140 was inducibly expressed in the presence of rifampicin and purified by Ni-affinity chromatography. In different vaccination trials, Balb/c mice and Fischer rats repeatedly immunized with r140 in combination with one of several adjuvants (alum, cholera toxin or complexed into proteosomes) produced high titre anti-r140 responses. These antibodies detected an N-glycanase sensitive. 25 kDa antigen in a detergent solubilized worm fraction using Western immunoblotting. The choice of adjuvant affected the isotype distribution of the specific anti-r140 antibodies. Despite the presence of high antibody titres and isotypes which have been shown to correlate with protective immunity, protection against subsequent cercarial challenge was not observed. In addition, no appreciable effects on worm sex ratios or liver egg yields were detected in mice. Studies involving biotin labelling of membrane proteins in live worms showed that the majority of anti-r140 reactive molecules present in adult schistosomes are biotinylated after permeabilization of the parasite surface. Several possibilities to account for the lack of protective immunity are analysed.

Chemotactic signal integration in bacteria.

Chemotactic signaling in Escherichia coli involves transmission of both negative and positive signals. In order to examine mechanisms of signal processing, behavioral responses to dual inputs have been measured by using photoactivable "caged" compounds, computer video analysis, and chemoreceptor deletion mutants. Signaling from Tar and Tsr, two receptors that sense amino acids and pH, was studied. In a Tar deletion mutant the photoactivated release of protons, a Tsr repellent, and of serine, a Tsr attractant, in separate experiments at pH 7.0 resulted in tumbling (negative) or smooth-swimming (positive) responses in ca. 50 and 140 ms, respectively. Simultaneous photorelease of protons and serine resulted in a single tumbling or smooth-swimming response, depending on the relative amounts of the two effectors. In contrast, in wild-type E. coli, proton release at pH 7.0 resulted in a biphasic response that was attributed to Tsr-mediated tumbling followed by Tar-mediated smooth-swimming. In wild-type E. coli at more alkaline pH values the Tar-mediated signal was stronger than the Tsr signal, resulting in a strong smooth-swimming response preceded by a diminished tumbling response. These observations imply that (i) a single receptor time-averages the binding of different chemotactic ligands generating a single response; (ii) ligand binding to different receptors can result in a nonintegrated response with the tumbling response preceding the smooth-swimming response; (iii) however, chemotactic signals of different intensities derived from different receptors can also result in an apparently integrated response; and (iv) the different chemotactic responses to protons at neutral and alkaline pH may contribute to E. coli migration toward neutrality.

Arizona Health Information Network: the collaborative administration and management of a statewide computing resource for health information.

The need to access current, relevant health care information transcends the boundaries of the library. Many computer-based tools are now available that provide access to this information where and when it is needed. However, the provision of these tools often requires a substantial commitment of resources in the form of staff expertise, computer hardware and software, and user training. The need to access current information is critical for health care providers and students at all points of care regardless of the institution size or location. Unfortunately, the resources necessary to provide access to information may not be equally available at all sites. The Arizona Health Information Network (AZHIN) joins together librarians and information systems specialists from eleven institutions throughout the state in an effort to share computing resources and expertise in order to improve the quality of health care delivery, education and research. This cooperative effort allows each institution to contribute both financially and in the form of staff expertise, based upon its size and available resources. Although the benefits of this type of cooperation seem obvious, in a competitive environment it is necessary for each member to retain independence. To balance cooperation and independence, a framework has been established to enable individual AZHIN member institutions to administer local access to the shared resources.

Developing a health information infrastructure for Arizona.

Network connectivity is critical in Arizona, where travel distances are great, academic programs dispersed, and health care practitioners often geographically isolated. Accordingly, the University of Arizona (UA) applied for $50,000.00 in National Library of Medicine/National Science Foundation (NLM/NSF) Connections Program funding to promote statewide collaboration in supporting UA's health sciences education and research programs by expanding network connectivity to hospitals and other health-related institutions. The proposal outlined three strategies: Each major nonuniversity teaching hospital would secure and maintain a leased communications line dedicated to network connectivity, and NSF funds would be used to buy some necessary hardward. NSF funds would be used to establish a modern bank for dial-up Internet access by rural practitioners and teaching sites. Co-principal investigators of the project would promote and support the use of this new statewide connectivity and foster its continued expansion. The proposal was based on a conservative philosophy: familiar technologies and, where possible, existing networks and equipment would be used. The proposal was approved, and NSF funds hastened creation of an expanded health information network in Arizona. Once that network was in place, participants moved quickly from managing the mechanics of connectivity to planning for a computing and communications platform with services. Private funds were obtained to help organize the Arizona Health Information Network to direct these expanded services.

Balloon occlusion scintigraphy of aortopulmonary collaterals.

We evaluated two children with pulmonary atresia for coil embolization of aortopulmonary collateral vessels after placement of palliative aortopulmonary shunts. To determine vessel distribution and lung perfusion prior to collateral embolization, perfusion scintigraphy with technetium 99m-labeled macroaggregated albumin assessed pulmonary blood flow before and after balloon wedge catheter occlusion of the collaterals. In the first patient we found no perfusion defect during collateral occlusion, and we proceeded with embolization. In the second child, perfusion scintigraphy during occlusion of the collateral vessels demonstrated a filling defect, and embolization was not performed, thus avoiding the creation of a potential perfusion defect in this patient. Assessing the physiologic significance of aortopulmonary collateral vessels by utilizing temporary balloon occlusion of the collateral vessels and concurrent perfusion scintigraphy as an adjunct to selective angiography can provide a significant contribution to the safety and accuracy of coil embolization.

Excitatory signaling in bacterial probed by caged chemoeffectors.

Chemotactic excitation responses to caged ligand photorelease of rapidly swimming bacteria that reverse (Vibrio alginolyticus) or tumble (Escherichia coli and Salmonella typhimurium) have been measured by computer. Mutants were used to assess the effects of abnormal motility behavior upon signal processing times and test feasibility of kinetic analyses of the signaling pathway in intact bacteria. N-1-(2-Nitrophenyl)ethoxycarbonyl-L-serine and 2-hydroxyphenyl 1-(2-nitrophenyl) ethyl phosphate were synthesized. These compounds are a 'caged' serine and a 'caged' proton and on flash photolysis release serine and protons and attractant and repellent ligands, respectively, for Tsr, the serine receptor. The product quantum yield for serine was 0.65 (+/- 0.05) and the rate of serine release was proportional to [H+] near-neutrality with a rate constant of 17 s-1 at pH 7.0 and 21 degrees C. The product quantum yield for protons was calculated to be 0.095 on 308-nm irradiation but 0.29 (+/- 0.02) on 300-350-nm irradiation, with proton release occurring at > 10(5) s-1. The pH jumps produced were estimated using pH indicators, the pH-dependent decay of the chromophoric aci-nitro intermediate and bioassays. Receptor deletion mutants did not respond to photorelease of the caged ligands. Population responses occurred without measurable latency. Response times increased with decreased stimulus strength. Physiological or genetic perturbation of motor rotation bias leading to increased tumbling reduced response sensitivity but did not affect response times. Exceptions were found. A CheR-CheB mutant strain had normal motility, but reduced response. A CheZ mutant had tumbly motility, reduced sensitivity, and increased response time to attractant, but a normal repellent response. These observations are consistent with current ideas that motor interactions with a single parameter, namely phosphorylated CheY protein, dictate motor response to both attractant and repellent stimuli. Inverse motility motor mutants with extreme rotation bias exhibited the greatest reduction in response sensitivity but, nevertheless, had normal attractant response times. This implies that control of CheY phosphate concentration rather than motor reactions limits responses to attractants.