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.

Therapeutic effect of glass-ionomers: an overview of evidence.

The requirements for an ideal restorative material include adhesion to tooth structure (enamel and dentine) and an ability to withstand the traumas of occlusion. However, some level of an anticaries effect is also desirable. After a long history of glass-ionomer cement (GIC) development, an evidence base in support of the therapeutic effect of GIC, particularly with regard to its anticaries effect, is emerging. This evidence is increasingly presented through systematic reviews of clinical GIC application and, to a certain extent, relates to a caries-preventive effect of the material itself. However, the strength of evidence supporting other aspects of GIC, such as a higher remineralizing effect, fluoride uptake in hard tooth tissue and fluoride release of GIC, is limited. Nevertheless, the results of these in situ and laboratory trials provide valuable insights into factors that facilitate understanding of the clinical efficacy of GIC.

Emerging biological therapies in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a prototypic inflammatory autoimmune disorder characterized by multisystem involvement and fluctuating disease activity. Symptoms range from rather mild manifestations such as rash or arthritis to life-threatening end-organ manifestations such as glomerulonephritis or thrombosis. Virtually every organ system is subject to potential damage. Symptoms typically wax and wane over the course of the disease; yet unfortunately, many patients will experience a slow decline in their health because of the ongoing systemic inflammation. Effective treatment must be individualized and is often based on the specific manifestations that are seen in each patient. In a similar manner, prognosis is also dependent on the severity and the specific organ systems involved.

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.

Resin modified glass-ionomers: strength, cure depth and translucency.

BACKGROUND: According to the classification suggested by McLean, Wilson and Nicholson only three materials, currently marketed, fit the designation of resin modified glass-ionomers. These materials will undergo an acid/base setting reaction but also contain a limited quantity of a monomer that will polymerize as a result of irradiation. The quantity of polymer is limited to the extent that it will not interfere with the normal acid/base setting reaction and will therefore allow for the ion exchange adhesion with tooth structure that is typical of glass-ionomer. There is a third setting reaction incorporated to ensure remaining monomer, that is not affected by irradiation, will still polymerize. A series of experiments were carried out to determine the effect of the three types of setting reaction on the strength, depth of cure and translucency of these three materials. METHODS: Specimens, both with and without irradiation, were subjected to a shear punch strength test. To determine the depth of cure brought about through irradiation, specimens were tested immediately after construction according to the test in ISO - 4049 2000 (E). Translucency is clinically significant and will vary according to whether the material has been subjected to irradiation or cured through the acid/base reaction alone. RESULTS: The strength of all materials tested was higher in specimens subject to irradiation. The depth of cure was found to be both shade and irradiation time dependent. Irradiated specimens were found to be only marginally more translucent than those allowed to set without irradiation. CONCLUSIONS: It was concluded that, for cavities more than 3 mm deep, these materials should be placed incrementally to allow for a full irradiation initiated cure.

Orally bioavailable, indole-based nonpeptide GnRH receptor antagonists with high potency and functional activity.

Stereospecific introduction of a methyl group to the indole-3-side chain enhanced activity in our tryptamine-derived series of GnRH receptor antagonists. Further improvements were achieved by variation of the bicyclic amino moiety of the tertiary amide and by adjustment of the tether length to a pyridine or pyridone terminus. These modifications culminated in analogue 24, which had oral activity in a rat model and acceptable oral bioavailability and half-life in dogs and monkeys.

Potent nonpeptide GnRH receptor antagonists derived from substituted indole-5-carboxamides and -acetamides bearing a pyridine side-chain terminus.

A pyridine side-chain terminus has been incorporated into the indole-5-carboxamide and indole-5-acetamide series of GnRH antagonists. Potent activity was observed in binding and functional assays. Certain branched or cyclic tertiary amides were identified as preferred in each series. Alkylation of the side-chain secondary amine had generally unfavorable effects. Variations of the gem-dialkyl substituents in the indole-5-acetamide series were also investigated.

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.

Minimal intervention dentistry--a review. FDI Commission Project 1-97.

The concept of minimal intervention dentistry has evolved as a consequence of our increased understanding of the caries process and the development of adhesive restorative materials. It is now recognised that demineralised but noncavitated enamel and dentine can be 'healed', and that the surgical approach to the treatment of a caries lesion along with 'extension for prevention' as proposed by G V Black is no longer tenable. This paper gives an overview of the concepts of minimal intervention dentistry, describes suggested techniques for a minimally invasive operative approach, and reviews clinical studies which have been carried out in this area.

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.

Minimal intervention: a new concept for operative dentistry.

The term minimal intervention is relatively new in dentistry and has been introduced to suggest to the profession that it is time for change in the principles of operative dentistry. The disease should be treated first; the surgical approach should be undertaken only as a last resort and then with the removal of as little natural tooth structure as possible. This article discusses the advances in techniques and materials that have led to change and attempts to put them into perspective. Treatment should begin with identification and elimination of the disease. There will then be a need for limited restoration of actual cavitation arising from demineralization of the tooth crown. Restorations, per se, will not prevent or eliminate disease. Caries is a bacterial infection and, until the microflora is controlled, all restorations are at risk of further demineralization in remaining tooth structure. This leads to the continuum of replacement dentistry that keeps the profession occupied for much of its productive time. If this cycle is to be broken, the profession must first acknowledge the primacy of prevention.

Minimal intervention: early lesions.

The use of modified cavity designs for the treatment of initial carious lesions can be justified on the grounds that, because no restorative material can adequately replace natural tooth structure for the long term, preservation of natural tooth structure is important. It is apparent that it is possible to remineralize and heal demineralized tooth structure to some degree. Therefore, neither enamel nor dentin should be removed simply because it has lost calcium and phosphate ions as a result of acid attack. The older surgical approach to cavity design was adopted in the absence of adhesive techniques and on the basis of Black's principle of "extension for prevention," but this theory is no longer tenable. The current availability of adhesive bioactive restorative materials makes it possible to maintain areas of tooth structure even though they appear to be undermined and weakened. Thus, the concept of geometric designs for prescribed cavities is no longer valid. The purpose of this article is to describe a series of simplified, modified cavity designs for small initial lesions; preservation of natural tooth structure is the principle objective of these designs.

Minimal intervention: advanced lesions.

Minimal intervention techniques are generally considered in relation to initial carious lesions. However, it appears logical to apply the same principles to extensive cavities as well as to the replacement of failed existing restorations. As the cavity becomes larger, there is an increasing need to consider protection of remaining cusps because they become seriously weakened by loss of the central core of the crown and therefore become subject to the development of splits at the base. However, it is possible to develop a protective cavity design without undue sacrifice of remaining tooth structure, at the same time that maintenance of occlusal anatomy and correct contact with the opposing arch are ensured. For larger cavities, special consideration needs to be given to the strength of the restorative material. Glass ionomer is relatively brittle and should not be exposed to undue occlusal load. Resin composites cannot be regarded as universal in their physical properties, and placement is time-consuming. A lamination technique is often useful, combining the advantages of both glass ionomer and resin composite. Amalgam should not be entirely discarded as an option because it has greater strength than both glass ionomer and resin composite and is still useful for the restoration of extensive cavities and for protection and retention of weakened cusps. Minimal intervention principles, designed to limit the loss of natural tooth structure, should be applied to all restorative dentistry. None of the available restorative materials is entirely satisfactory in the long term.

Focused ion beam in dental research.

Focused ion beam (FIB) has been available for over 10 yrs but until recently its usage has been confined to the semiconductor industry. It has been developed as an important tool in defect analysis, circuit modification and recently transmission electron microscope sample preparation. This paper introduces FIB and demonstrates its application in dental research. Its ion and electron imaging modes complement the SEM while its ability to prepare TEM samples from a wide range of material will allow the study of new types of adhesive interface. As an example, its use is described in the characterization of the interface of resin to a tribochemically treated surface of an experimental fiber-reinforced resin-based composite. As with all new techniques, the initial learning curve was difficult to manage. This new instrument offers opportunities to expand research in dental materials to areas not possible before.

Assessing the prevention effectiveness of local Lyme disease control.

The effectiveness of any public health intervention is determined by its theoretical efficacy and by the level of engagement of the target population. A computer simulation model and basic epidemiologic concepts were used to estimate the effectiveness of interventions for preventing Lyme disease in a hypothetical community. The process for estimating numbers of Lyme disease cases prevented by each intervention is described. This assessment compares the effectiveness of alternative community-based prevention strategies, illuminates the limitations and distributive effects of interventions, and helps clarify available prevention options for community residents.