Challenges of managing snakebite envenomation in a deployed setting.

Snake bite envenomation causes a significant health burden globally, especially in austere or resource poor settings. This case series describes envenomation in two adults and two children presenting to the Role 3 Medical Treatment Facility in Camp Bastion, Afghanistan. Each case has similarities with respect to the coagulopathy of envenomation but differs in terms of time delay to presentation and response to treatment, including reactions to antivenom. We discuss the challenges and ethical dilemmas in delayed-presentation snakebite, the diagnosis and treatment of coagulopathy and the role of antivenom and surgical debridement.

An Intercomparison of Tropospheric OH Measurements at Fritz Peak Observatory, Colorado.

The hydroxyl radical (OH) controls the lifetimes and therefore the concentrations of many important chemical species in Earth's lower atmosphere including several greenhouse and ozone-depleting species. Two completely different measurement techniques were used in an informal intercomparison to determine tropospheric OH concentrations at Fritz Peak concentrations by chemical analysis; the other used spectroscopic absorption on a long path. The intercomparison showed that ambient OH concentrations can now be measured with sufficient sensitivity to provide a test for photochemical models, with the derived OH concentrations agreeing well under both polluted and clean atmospheric conditions. Concentrations of OH on all days were significantly lower than model predictions, perhaps indicating the presence of an unknown scavenger. The change in OH concentration from early morning to noon on a clear day was found to be only a factor of 2.

Observations of the Nighttime Abundance of OClO in the Winter Stratosphere Above Thule, Greenland.

Observations at Thule, Greenland, that made use of direct light from the moon on 2,3, 4,5, and 7 February 1988 revealed nighttime chlorine dioxide (OClO) abundances that were less than those obtained in Antarctica by about a factor of 5, but that exceeded model predictions based on homogeneous (gas-phase) photochemistry by about a factor of 10. The observed time scale for the formation of OClO after sunset strongly supports the current understanding of the diurnal chemistry of OClO. These data suggest that heterogeneous (surface) reactions due to polar stratospheric clouds can occur in the Arctic, providing a mechanism for possible Arctic ozone depletion.

Observations of Stratospheric NO2 and O3 at Thule, Greenland.

Scattered sunlight and direct light from the moon was used in two wavelength ranges to measure the total column abundances of stratospheric ozone(O(3)) and nitrogen dioxide (NO(2)) at Thule, Greenland (76.5 degrees N), during the period from 29 January to 16 February 1988. The observed O(3) column varied between about 325 and 400 Dobson units, and the lower values were observed when the center of the Arctic polar vortex was closest to Thule. This gradient probably indicates that O(3) levels decrease due to dynamical processes near the center of the Arctic vortex and should be considered in attempts to derive trends in O(3) levels. The observed NO(2) levels were also lowest in the center of the Arctic vortex and were sometimes as low as 5 x 10(14) molecules per square centimeter, which is even less than comparable values measured during Antarctic spring, suggesting that significant heterogeneous photochemistry takes place during the Arctic winter as it does in the Antarctic.

A new paradigm for operative dentistry.

It is over 100 years since GV Black gathered together most of the knowledge then current on the caries process and set clear parameters for the discipline of operative dentistry. His four-volume treatise set standards that were relevant for the times and, in fact, were so well described that they remained dominant in this discipline until quite recently. However, over the last 50 years there has been great progress in scientific method and in knowledge of the common diseases of the oral environment, including the caries process, so maybe it is time for change. The term "paradigm" describes a philosophy of science, a generally accepted model of how ideas relate to one another, forming a conceptual framework within which scientific research is carried out. Black defined the paradigm within which further research was to be conducted during the following years and the profession accepted his lead. However, it is not expected that the parameters of a profession should remain unchanged over a substantial period so it is suggested that the dental profession should, at this time, recognize a new paradigm. Improvements in scientific method have led to a better understanding of the oral environment, resulting in extensive changes for this profession. It is suggested that the standards set by Black should be now consigned to history and an entirely new paradigm adopted. First, the profession must recognize that dental caries is a bacterial disease and its primary efforts should be directed towards identification and elimination of the disease prior to initiating repair of the damage that it has caused. Preservation of natural tooth structure is then the next responsibility. There should be maximum use made of preventive strategies, including remineralization, followed by minimal intervention cavity designs and the use of bioactive restorative materials to restore the lesions. The profession should be prepared to move on.

A proposal for a new classification of lesions of exposed tooth surfaces.

In the presence of improved methods of identification and treatment of lesions on the exposed surfaces of teeth, it should now be acknowledged that the GV Black "classification of carious cavities" is out of date. This paper describes a new system, proposed in 1997, discussed broadly throughout the profession, and eventually modified. The system has been adopted in several regions around the world as being a useful corollary to the current developing concept of minimal intervention dentistry. It is now desirable to adopt a new approach to the identification and recording of the lesions caused by both caries and non-carious tooth loss. A major advantage arising from its adoption would be that it would encourage the profession to minimise the amount of normal healthy tooth structure that is often sacrificed in pursuit of the cavity designs as suggested by Black. The authors are members of a Project Group of the FDI Science Committee, and this paper explains the concept and offers justification for the adoption of the system.

Identification of Phe313 of the gonadotropin-releasing hormone (GnRH) receptor as a site critical for the binding of nonpeptide GnRH antagonists.

The dog GnRH receptor was cloned to facilitate the identification and characterization of selective nonpeptide GnRH antagonists. The dog receptor is 92% identical to the human GnRH receptor. Despite such high conservation, the quinolone-based nonpeptide GnRH antagonists were clearly differentiated by each receptor species. By contrast, peptide antagonist binding and functional activity were not differentiated by the two receptors. The basis of the differences was investigated by preparing chimeric receptors followed by site-directed mutagenesis. Remarkably, a single substitution of Phe313 to Leu313 in the dog receptor explained the major differences in binding affinities and functional activities. The single amino acid replacement of Phe313 of the human receptor with Leu313 resulted in a 160-fold decrease of binding affinity of the nonpeptide antagonist compound 1. Conversely, the replacement of Leu313 of the dog receptor with Phe313 resulted in a 360-fold increase of affinity for this compound. These results show that Phe313 of the GnRH receptor is critical for the binding of this structural class of GnRH antagonists and that the dog receptor can be "humanized" by substituting Leu for Phe. This study provides the first identification of a critical residue in the binding pocket occupied by nonpeptide GnRH antagonists and reinforces cautious extrapolation of ligand activity across highly conserved receptors.

A potent, nonpeptidyl 1H-quinolone antagonist for the gonadotropin-releasing hormone receptor.

Extensive development of the structure-activity relationships of a screening lead determined three important pharmacophores for gonadotropin-releasing hormone (GnRH) receptor antagonist activity. Incorporation of the 3,4,5-trimethylphenyl group at the 3-position, 2-(2(S)-azetidinyl)ethoxy group at the 4-position, and N-4-pyrimidinylcarboxamide at the 6-position of the quinolone core resulted in the identification of 4-(2-(azetidin-2(S)-yl)ethoxy)-7-chloro-2-oxo-3-(3,4,5-trimethylphenyl)-1,2-dihydroquinoline-6-carboxylic acid pyrimidin-4-ylamide (1) as a potent antagonist of the GnRH receptor. A 10(4)-fold increase in in vitro binding affinity is observed for the GnRH receptor as compared to the initial screening lead. Compound 1 exhibits nanomolar binding activity and functional antagonism at the human receptor and is 7-fold less active at the rhesus receptor. Intravenous administration of compound 1 to rhesus monkeys results in a significant decrease of the serum levels of downstream hormones, luteinizing hormone (79% decrease in area under the curve) and testosterone (92% decrease in area under the curve), at a dose of 3 mg/kg. Quinolone 1 is a potent nonpeptidyl antagonist for the human GnRH receptor that is efficacious for the suppression of luteinizing hormone and testosterone in primates.

Clinical performance of glass-ionomers.

Glass-ionomers were introduced to the profession 20 years ago and have been shown to be a very useful adjunct to restorative dentistry. Their major advantages include the ion exchange adhesion to both enamel and dentine and a continuing fluoride release throughout the life of the restoration. The chemistry of the setting reaction is essentially an acid/base reaction but recent research has introduced variations in an effort to improve clinical handling. Small additions of resin increase the physical properties to a degree and allow for a light-initiated setting mechanism. However, it is essential that the acid/base reaction remains dominant if the full advantages of the glass-ionomer are to be retained. The material has multiple uses in dentistry and it shows a high degree of biocompatibility to the pulp and surrounding soft tissues. The main limitation at this time is a relatively low fracture resistance but it is possible to protect it through lamination with stronger materials if the need arises. This paper examines the essential parameters for successful clinical placement and comments on its longevity.

In vitro studies on the potential for pulpal cytotoxicity of glass-ionomer cements.

Elution samples of glass-ionomer cement were prepared in sterile tissue culture medium either by direct contact between the fluid and standard cement samples or through a layer of human dentin, and then tested for toxicity to cultured mouse fibroblasts (L929). The directly-prepared eluates of the cements were highly cytotoxic, but those prepared through dentin were of either limited or no cytotoxicity. The degree of toxicity of some directly-prepared eluates was reduced by adjustment of the pH to neutrality. It was apparent that dentin reduced the potential for cytotoxicity of glass-ionomer cements to a large degree. Proposed mechanisms for the reduction were limited availability of water at the dentin-cement interface and thus limited dissolution of components, buffering of acid components of the cements by dentin, or other chemical interactions with dentin.

Comparison of fluoride profiles by SIMS with mineral density of subsurface enamel lesions treated intra-orally with a fluoride-releasing device.

A variety of intra-oral model systems has evolved which allows for the study of remineralization of coronal and/or root-surface lesions following application of topical fluoride (F) agents. The problem of interpretation of the results has led to a variety of analytical methods (i.e., microhardness, F biopsy, microradiography, and polarizing light microscopy), each of which provides important but limited information related to the overall understanding of remineralization. Microhardness measures change in mineral content which is more precisely localized by microradiography and polarized light microscopy. F biopsy allows for assessment of the F uptake of lesions, but does not suggest the chemical state of the F. Previous work has demonstrated that patterns of mineral deposition during remineralization do not necessarily parallel the F uptake profiles, and fluoridated apatites cannot be distinguished from non-specifically-adsorbed F (Clark et al., 1988). Because artificial lesions demonstrate variations in depth and mineral content, complementary analytical methods that demonstrate profiles of both F content and mineral density curves on the same section are needed so that the process of remineralization can be more clearly understood. This study used secondary ion mass spectrometry (SIMS) for F profiles and quantitative microradiography for assessment of mineral deposition on the same section. These state-of-the-art methods demonstrate the precision with which information about remineralization can be obtained. Subsurface lesions in human enamel specimens were developed by immersion in 0.1 M lactate buffer with 1% CMC at a pH of 4.5 for 48 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Computer simulation of population dynamics of the American dog tick (Acari: Ixodidae).

A comprehensive computer model was developed for simulation of the population dynamics of the American dog tick (ADT), Dermacentor variabilis Say, in North America. The model simulates the effects of major environmental variables, such as ambient temperature, saturation deficit, kind of habitat, and host density, on ADT population dynamics in ecosystems with small mammals as hosts for immature ticks and medium-sized mammals or domestic dogs as hosts for adult ticks. General validity of the model was established by comparisons between simulated and actual population densities for a series of years at locations in Virginia, Maryland, and Massachusetts using actual weekly weather data for each year as a model input. Using historical-average weather data for 11 locations within the known geographic range of ADT and 3 locations outside this range, the model produced acceptable values for initial population growth rate and generation time, as well as realistic equilibrium population densities and seasonal activity patterns. This model can be used as a framework for additional modeling efforts to simulate the transmission of Rocky Mountain spotted fever and to study various strategies for management of ADT populations.

Simulation of blacklegged tick (Acari:Ixodidae) population dynamics and transmission of Borrelia burgdorferi.

A model (LYMESIM) was developed for computer simulation of blacklegged tick, Ixodes scapularis Say, population dynamics and transmission of the Lyme disease agent. Borrelia burgdorferi Johnson. Schmid, Hyde, Steigerwalt & Brenner, LYMESIM simulates the effects of ambient temperature, saturation deficit, precipitation, habitat type, and host type and density on tick populations. Epidemiological parameters including host infectivity, tick infectivity, transovarial transmission, and transstadial transmission are included in the model to simulate transmission of the Lyme disease spirochete between vector ticks and vertebrate hosts. Validity of LYMESIM was established by comparing simulated and observed populations of immature I. scapularis on white-footed mice. Peromyscus leucopus, (Rafinesque), at 2 locations in Massachusetts. Validity also was indicated by comparisons of simulated and observed seasonality of blacklegged ticks in New York, Massachusetts, Florida, and Oklahoma-Arkansas. Further model validity was shown by correlation between simulated and observed numbers of immature ticks engorging on white-footed mice at 3 sites in Massachusetts. The model produced acceptable values for initial population growth rate, generation time, and 20-yr population density when historical meteorological data for 16 locations in eastern North America were used. Realistic rates of infection in ticks were produced for locations in the northeastern and northcentral United States. LYMESIM was used to study the effect of white-footed mouse and white-tailed deer, Odocoileus virginianus (Zimmerman), densities on tick density and infection rates. The model was also used to estimate tick density thresholds for maintenance of B. burgdorferi.

Simulation of management strategies for the blacklegged tick (Acari: Ixodidae) and the Lyme disease spirochete, Borrelia burgdorferi.

A computer model (LYMESIM) was developed to simulate the effects of management technologies on populations of the blacklegged tick, Ixodes scapularis Say, and the Lyme disease spirochete Borrelia burgdorferi Johnson, Schmid, Hyde, Steigerwalt & Brenner in eastern North America. Technologies considered in this study were area-wide acaricide, acaricide self-treatment of white-footed mice and white-tailed deer, vegetation reduction, and white-tailed deer density reduction. Computer simulations were run with normal weather patterns for coastal Connecticut and New York. Results showed that area-wide acaricide, vegetation reduction, or a combination of these technologies would be useful for short-term seasonal management of ticks and disease in small recreational or residential sites. Acaricide self-treatment of deer appears to be the most cost-effective technology for use in long-term management programs in large areas. Simulation results also suggested that deer density reduction should be considered as a management strategy component. Integrated management strategies are presented that could be used in pilot tests and operational tick and tick-borne disease programs.

Dynamic life table model for Aedes aegypti (Diptera: Culicidae): analysis of the literature and model development.

The container-inhabiting mosquito simulation model (CIMSiM) is a weather-driven, dynamic life table simulation model of Aedes aegypti (L.). It is designed to provide a framework for related models of similar mosquitoes which inhibit artificial and natural containers. CIMSiM is an attempt to provide a mechanistic, comprehensive, and dynamic accounting of the multitude of relationships known to play a role in the life history of these mosquitoes. Development rates of eggs, larvae, pupae, and the gonotrophic cycle are based on temperature using an enzyme kinetics approach. Larval weight gain and food depletion are based on the differential equations of Gilpin & McClelland compensated for temperature. Survivals are a function of weather, habitat, and other factors. The heterogeneity of the larval habitat is depicted by modeling the immature cohorts within up to nine different containers, each of which represents an important type of mosquito-producing container in the field. The model provides estimates of the age-specific density of each life stage within a representative 1-ha area. CIMSiM is interactive and runs on IBM-compatible personal computers. The user specifies a region of the world of interest; the model responds with lists of countries and associated cities where historical data on weather, larval habitat, and human densities are available. Each location is tied to an environmental file containing a description of the significant mosquito-producing containers in the area and their characteristics. In addition to weather and environmental information, CIMSiM uses biological files that include species-specific values for each of the parameters used in the model. Within CIMSiM, it is possible to create new environmental and biological files or modify existing ones to allow simulations to be tailored to particular locations or to parameter sensitivity studies. The model also may be used to evaluate any number and combination of standard and novel control methods.

Dynamic life table model for Aedes aegypti (diptera: Culicidae): simulation results and validation.

The container-inhabiting mosquito simulation model (CIMSiM) is a weather-driven, dynamic life table simulation model of Aedes aegypti (L.) and similar nondiapausing Aedes mosquitoes that inhabit artificial and natural containers. This paper presents a validation of CIMSiM simulating Ae. aegypti using several independent series of data that were not used in model development. Validation data sets include laboratory work designed to elucidate the role of diet on fecundity and rates of larval development and survival. Comparisons are made with four field studies conducted in Bangkok, Thailand, on seasonal changes in population dynamics and with a field study in New Orleans, LA, on larval habitat. Finally, predicted ovipositional activity of Ae. aegypti in seven cities in the southeastern United States for the period 1981-1985 is compared with a data set developed by the U.S. Public Health Service. On the basis of these comparisons, we believe that, for stated design goals, CIMSiM adequately simulates the population dynamics of Ae. aegypti in response to specific information on weather and immature habitat. We anticipate that it will be useful in simulation studies concerning the development and optimization of control strategies and that, with further field validation, can provide entomological inputs for a dengue virus transmission model.

New version of LSTSIM for computer simulation of Amblyomma americanum (Acari: Ixodidae) population dynamics.

A previous version of Lone Star Tick Simulation Model (LSTSIM) for a wildlife ecosystem was revised and expanded to include a beef cattle forage area and improved handling of tick-host-habitat interactions. Relationships between environmental and biological variables were also refined in the new version. General validity of the revised model was established by comparing simulated and observed host-seeking populations of Amblyomma americanum (L.) at five geographic locations, three in Oklahoma and two in Kentucky-Tennessee. Additional validity was indicated from comparisons of simulated and observed seasonality of lone star ticks at one location in Kentucky. The model produced acceptable values for initial population growth rate, generation time, and 15-yr population density when historical weather files for 14 locations in the United States were used. The model of A. americanum population dynamics was used to study the relationship between tick density and density of white-tailed deer, Odocoileus virginianus (Zimmerman), and cattle. The revised model can be used for additional simulation studies on effects of tick control technologies and integrated management strategies.

Computer simulation of Rocky Mountain spotted fever transmission by the American dog tick (Acari: Ixodidae).

A computer model was developed for simulation of the transmission of Rickettsia rickettsii, the causative agent of Rocky Mountain spotted fever (RMSF), by the American dog tick, Dermacentor variabilis (Say). The model of RMSF was combined with a model for population dynamics of the American dog tick and included simulation of infection and transmission of rickettsiae between ticks and host mammals and transmission of RMSF to humans. The model simulated the effects of biotic and environmental variables such as weather, host density, habitat, transovarial transmission, fecundity of infected ticks, and infectivity level of ticks and mammals. Some parameters in the model were fitted by iterative simulations to produce realistic rates of R. rickettsii infection in adult ticks and small and medium-sized mammal hosts. Parameters also were fitted to yield the historical average number of RMSF cases for Virginia. Comparisons of the simulated and actual number of cases for nine other states indicated a reasonable level of validity for the model. A theoretical tick density threshold of 252 unfed adult ticks/ha for transmission of RMSF was determined from a relationship between rate of transmission to humans and density of ticks. The transmission threshold can be used for additional modeling efforts to study the effects of management technologies on tick densities and RMSF human cases. The model can serve as a framework for modeling other tick-borne diseases such as Lyme disease, babesiosis, and heartwater.

Computer simulation of management strategies for American dog ticks (Acari: Ixodidae) and Rocky Mountain spotted fever.

Computer models were developed to simulate the effects of management technologies on populations of the American dog tick, Dermacentor variabilis (Say), principal vector of Rocky Mountain spotted fever (RMSF) in eastern North America. The technologies modeled were area-wide acaricide application, acaricide-food-baited tubes for self-treatment by small mammals, dipping of dogs in acaricides, acaricide-impregnated plastic dog collars, reduction of small mammal host populations (host management), and removal of vegetation that protects free-living tick stages (vegetative management). Submodels for each of these technologies were incorporated into a model (ADTSIM) for the population dynamics of the tick and RMSF transmission. Comparisons of simulated and observed data were used to verify reasonable accuracy of the submodels. Repetitive simulations were made to identify levels and timing of each control method (alone or combined) required to reduce tick populations below a RMSF transmission threshold of 252 unfed adults/ha. Eight to 30 acaricide applications, depending on acaricide and percentage of population treated, were needed during a 10-yr period to reduce densities of ticks below the threshold. The baited-tube method, host management, and vegetative management (depending on level and frequency of treatment) also were capable of reducing tick density below the threshold. However, acaricide-impregnated plastic dog collars did not reduce tick density below the threshold unless at least 50% of the hosts of adult ticks were domestic dogs. Integrated strategies were developed for management of ticks and RMSF in six selected states. These strategies reduced numbers of human cases of RMSF 90% or more by year 20 by maintaining tick densities between 100 and 252 unfed adults/ha.

Integrated management strategies for Amblyomma americanum (Acari: Ixodidae) on pastured beef cattle.

Data on tick control and knowledge of the damage caused to beef cattle by tick feeding were incorporated into a computerized dynamic life table model (LSTSIM) for Amblyomma americanum (L.). Simulations were made to determine economically feasible, 5-yr integrated pest management (IPM) strategies for A. americanum in forage areas utilized by Bos taurus, Bos indicus, and crossbred cattle (B. taurus x B. indicus). The effects of host resistance, pasture rotation, habitat conversion, topical acaricides, systemic acaricides, and the area-wide application of acaricides to pastures on populations of parasitic female ticks were simulated as individual control technologies and as components of multiple-factor IPM strategies. The most effective, single-factor control strategy for A. americanum in beef cattle forage areas is the use of tick-resistant B. indicus cattle. Pasture rotation combined with area-wide acaricide applications was the only economically feasible IPM strategy for B. indicus cattle and reduced tick densities by 89% after 5 yr. Thirteen economically feasible IPM strategies were identified for use with B. taurus cattle. Of these, the most efficacious was pasture rotation in May combined with systemic or topical acaricide applications. Other strategies included systemic acaricides with area-wide acaricide applications to pastures, topical acaricides with area-wide acaricide applications, pasture rotation with habitat conversion and topical acaricides, and pasture rotation with habitat conversion, topical acaricides, and area-wide acaricide applications. Each technology reduced tick densities on B. taurus cattle by > 80% over a 5-yr period. Nine IPM strategies were economically feasible for use with crossbred cattle. Of these, pasture rotation combined with systemic or topical acaricide applications reduced the number of female ticks on cattle by > 84%; pasture rotation combined with habitat conversion reduced tick numbers by 77%. The most effective nonacaricide-based IPM strategy for B. taurus and crossbred cattle was pasture rotation combined with habitat conversion. No acaricide-free IPM strategy was economically feasible for use with B. indicus cattle.