Critical Reviews in Oral Biology & Medicine

The Official Publication of the American Association of Oral Biologists

A Publication of the International/American Associations for Dental Research
Table of Contents for Volume 9, 1998

Volume 9, Issue 1
Volume 9, Issue 2
Volume 9, Issue 3
Volume 9, Issue 4

Volume 9, Issue 1

• Castle D, Castle A.
• Department of Cell Biology, University of Virginia Health Sciences Center, Charlottesville 22908, USA.
• Pages 4-22

Intracellular transport and secretion of salivary proteins are major activities of salivary acinar cells. While the major intracellular pathway followed by salivary proteins following their synthesis has been described previously, there is only limited understanding of how this process is regulated at the molecular level. Studies of salivary proteins, especially proline-rich proteins, expressed in an endocrine cell line have begun to provide insight regarding intermolecular interactions during transport and the role played by structural signals during intracellular sorting. Analysis of the secretion of newly synthesized salivary proteins in parotid tissue has shown that there are multiple pathways of discharge from acinar cells. While granule exocytosis is the major pathway, at least two other pathways that export salivary proteins have been found to originate from maturing secretion granules. These pathways may contribute to other acinar cell functions, including secretion of proteins in the absence of acute stimulation and support of the secretory process for fluid and electrolytes.

• Moll UM, Schramm LM.
• Department of Pathology, Health Sciences Center, State University of New York at Stony Brook, 11794-8691, USA.
• Pages 23-37

The p53 tumor suppressor protein plays a central role in maintaining genomic integrity. It does so by occupying a nodal point in the DNA damage control pathway. When cells are subject to ionizing radiation or other mutagenic events, p53 mediates cell cycle arrest or programmed cell death (apoptosis). Furthermore, some evidence suggests that p53 plays a role in the recognition and repair of damaged DNA. Biochemically, p53 is a sequence-specific transcriptional stimulator and a non-specific transcriptional repressor but also engages in multiple protein-protein interactions. Conversely, disruption of the p53 response pathway strongly correlates with tumorigenesis. p53 is functionally inactivated by structural mutations, neutralization by viral products, and non-mutational cellular mechanisms in the majority of human cancers. p53-deficient mice have a highly penetrant tumor phenotype, with over 90% tumor incidence within nine months. In some cancers, direct physical evidence exists identifying the p53 gene as a target of known environmental carcinogens such as UV light and benzolalpyrene in cancers of the skin and lung. When p53 loss occurs, cells do not get repaired or eliminated but rather proceed to replicate damaged DNA, which results in more random mutations, gene amplifications, chromosomal re-arrangements, and aneuploidy. In some experimental models, loss of p53 confers resistance to anticancer therapy due to loss of apoptotic competence. The translational potential of these discoveries is beginning to be tested in novel p53-based therapies.

• Finnell RH, Greer KA, Barber RC, Piedrahita JA.
• Department of Veterinary Anatomy and Public Health, College of Veterinary Medicine, Texas A&M University, College Station 77843-4458, USA
• Pages 38-53

Neural tube and orofacial defects are common congenital malformations in humans. While etiologically heterogeneous, they are for the most part multifactorial in their pathogenesis, having both genetic and environmental components in their development. In recent years, there has been a great deal of epidemiologic evidence demonstrating that women who received multivitamins containing folic acid periconceptionally had significantly reduced occurrence and recurrence risks for producing infants with such malformations. This risk reduction is not observed in all populations, further suggestive of a genetic regulation of this phenomenon. Unfortunately, the mechanisms underlying the beneficial effects of folic acid are not well-understood. In this article, we review the relevant epidemiologic data on both neural tube defects and orofacial malformations, the fundamental embryological processes involved in closing the neural tube, and the development of the craniofacies, and propose a working hypothesis for susceptibility to these malformations. This hypothesis is based on the interworkings of cellular folate transport, focusing on the key elements involved in potocytosis. We propose that infants with mutations in the folate receptor alpha gene might be at increased risk for congenital anomalies due to a reduced binding affinity for 5-methyltetrahydrofolate, the physiologic form of folic acid. Various experimental approaches to test the working hypothesis are considered.

• Bowden GH, Hamilton IR.
• Department of Oral Biology, Faculty of Dentistry, University of Manitoba, Winnipeg, Canada.
• Pages 54-85

The global distribution of individual species of oral bacteria demonstrates their ability to survive among their human hosts. Such an ubiquitous existence is the result of efficient transmission of strains and their persistence in the oral environment. Genetic analysis has identified specific clones of pathogenic bacteria causing infection. Presumably, these express virulence-associated characteristics enhancing colonization and survival in their hosts. A similar situation may occur with the oral resident flora, where genetic variants may express specific phenotypic characteristics related to survival. Survival in the mouth is enhanced by dental plaque formation, where persistence is associated with the bacteria's capacity not only to adhere and grow, but also to withstand oxygen, wide fluctuations in pH and carbohydrate concentration, and a diverse array of microbial interactions. Streptococcus mutans has been discussed as a 'model' organism possessing the biochemical flexibility that permits it to persist and dominate the indigenous microflora under conditions of stress.

• Scully C, Beyli M, Ferreiro MC, Ficarra G, Gill Y, Griffiths M, Holmstrup P, Mutlu S, Porter S, Wray D.
• Eastman Dental Institute for Oral Health Care Sciences, University of London, United Kingdom.
• Pages 86-122

Lichen planus (LP) is a relatively common disorder of the stratified squamous epithelia, which is, in many ways, an enigma. This paper is the consensus outcome of a workshop held in Switzerland in 1995, involving a selection of clinicians and scientists with an interest in the condition and its management. The oral (OLP) eruptions usually have a distinct clinical morphology and characteristic distribution, but OLP may also present a confusing array of patterns and forms, and other disorders may clinically simulate OLP. Lesions may affect other mucosae and/or skin. Lichen planus is probably of multifactorial origin, sometimes induced by drugs or dental materials, often idiopathic, and with an immunopathogenesis involving T-cells in particular. The etiopathogenesis appears to be complex, with interactions between and among genetic, environmental, and lifestyle factors, but much has now been clarified about the mechanisms involved, and interesting new associations, such as with liver disease, have emerged. The management of lichen planus is still not totally satisfactory, and there is as yet no definitive treatment, but there have been advances in the control of the condition. There is no curative treatment available; immunomodulation, however, can control the condition. Based on the observed increased risk of malignant development, OLP patients should be offered regular follow-up examination from two to four times annually and asked to report any changes in their lesions and/or symptoms. Follow-up may be particularly important in patients with atrophic/ulcerative/erosive affections of the tongue, the gingiva, or the buccal mucosa. Much more research is required into the genetic and environmental aspects of lichen planus, into the premalignant potential, and into the possible associations with chronic liver, and other disorders. More clinical studies are required into the possible efficacy of immunomodulatory drugs such as pentoxifylline and thalidomide.

Volume 9, Issue 2

• Smith CE.
• Faculty of Dentistry, and Department of Anatomy & Cell Biology, McGill University, Montreal, Quebec, Canada.
• Pages 128-61

This review focuses on the process of enamel maturation, a series of events associated with slow, progressive growth in the width and thickness of apatitic crystals. This developmental step causes gradual physical hardening and transformation of soft, newly formed enamel into one of the most durable mineralized tissues produced biologically. Enamel is the secretory product of specialized epithelial cells, the ameloblasts, which make this covering on the crowns of teeth in two steps. First, they roughly "map out" the location and limits (overall thickness) of the entire extracellular layer as a protein-rich, acellular, and avascular matrix filled with thin, ribbon-like crystals of carbonated hydroxyapatite. These initial crystals are organized spatially into rod and interrod territories as they form, and rod crystals are lengthened by Tomes' processes in tandem with appositional movement of ameloblasts away from the dentin surface. Once the full thickness of enamel has been formed, ameloblasts initiate a series of repetitive morphological changes at the enamel surface in which tight junctions and deep membrane infoldings periodically appear (ruffle-ended), then disappear for short intervals (smooth-ended), from the apical ends of the cells. As this happens, the enamel covered by these cells changes rhythmically in net pH from mildly acidic (ruffle-ended) to near-physiologic (smooth-ended) as mineral crystals slowly expand into the "spaces" (volume) formerly occupied by matrix proteins and water. Matrix proteins are processed and degraded by proteinases throughout amelogenesis, but they undergo more rapid destruction once ameloblast modulation begins. Ruffle-ended ameloblasts appear to function primarily as a regulatory and transport epithelium for controlling the movement of calcium and other ions such as bicarbonate into enamel to maintain buffering capacity and driving forces optimized for surface crystal growth. The reason ruffle-ended ameloblasts become smooth-ended periodically is unknown, although this event seems to be crucial for sustaining long-term crystal growth.

• Dabelsteen E.
• Department of Oral Diagnostics, School of Dentistry, Faculty of Health Sciences, University of Copenhagen, Denmark.
• Pages 162-87

Bullous diseases of the oral mucosa and skin were originally classified on the basis of clinical and histological criteria. The discovery of autoantibodies in some of these patients and the introduction of molecular biology have resulted in a new understanding of the pathological mechanisms of many of the bullous lesions. In this article, updated topics of the immune-mediated bullous lesions which involve oral mucosa and skin are reviewed. Pemphigus antigens, which are desmosomal-associated proteins and belong to the cadherin superfamily of cell adhesion proteins, have been isolated, and their genes have been cloned. The antigens which react with autoantibodies from patients with bullous pemphigoid, cicatricial pemphigoid, acquired epidermolysis bullosa, and linear IgA disease are all proteins of the hemidesmosome basement membrane complex. Interestingly, most of the antigens also appear to be the target for mutations seen in patients with the inherited type of epidermolysis bullosa in which bullous lesions are a prominent clinical feature.

• Jontell M, Okiji T, Dahlgren U, Bergenholtz G.
• Department of Endodontology and Oral Diagnosis, Faculty of Odontology, Goteborg University, Sweden.
• Pages 179-200

Defense reactions of the dentin/pulp complex involve a variety of biological systems, in which the immune system plays a pivotal role. The knowledge of the organization and function of pulpal immunocompetent cells has been sparse, but in recent years a significant body of information of immune mechanisms in general has provided a footing for substantial new knowledge of the immune mechanisms of the dental pulp. The identification of pulpal dendritic cells (DCs) has generated research activities which have led to a concept of how an antigenic challenge may evoke a pulpal inflammatory response. Although DCs are not able to identify foreign antigens specifically, they provide necessary signals to activate T-lymphocytes which in turn will orchestrate other immunocompetent cells to mount the local immune defense of the dental pulp. The purpose of this review is to accent the organization and function of pulpal DCs and other tissue and cellular components and to provide a basis for how they may interact to instigate pulpal defense mechanisms.

• Gorski JP.
• Division of Molecular Biology and Biochemistry, School of Biological Sciences, University of Missouri-Kansas City, 64110, USA.
• Pages 201-23

The purpose of this review is to summarize recent functional and structural findings regarding non-collagenous matrix proteins in bone and teeth, to compare gene locations for bone and tooth matrix proteins with loci for hereditary skeletal diseases, and to present several provocative hypotheses which integrate this new information into a physiological context. Hypothesis I proposes that the molecular composition of rapidly deposited and mineralized woven bone, as well as the responsiveness of cells synthesizing woven bone to stimuli, is different from that for more slowly synthesized lamellar bone, implying the existence of distinctive osteogenic mechanisms. This review of recent research strongly supports this proposal. Briefly, the protein composition of woven bone matrix is enriched in acidic phosphoproteins BAG-75 and BSP, which are not expressed in lamellar bone, which is itself enriched in osteocalcin. De novo deposition and mineralization of woven bone occurs faster than in lamellar bone by means of a matrix-vesicle-assisted mechanism. Deposition of woven bone occurs at sites experiencing biomechanical strains higher than those experienced by lamellar bone. In addition, woven bone in metaphyseal regions is more susceptible to osteoclastic resorption after space flight, ovariectomy, and loss of weightbearing than is lamellar bone. Finally, osteoprogenitor cells responsive to parathyroid hormone reside in the metaphyseal region of long bones. Taken together, these findings suggest that Hypothesis I represents a useful paradigm for future studies. Specific functions mediated by most individual bone and tooth matrix proteins remain uncertain. A review of current literature suggests that the functionality of skeletal matrix proteins is expressed through specific binding sites composed of particular species-conserved structural motifs (Hypothesis 2). Examples include the previously recognized Asp-Ser-Ser motif of dentin phosphophoryns and the gamma-carboxyglutamic acid motif of matrix GLA protein and osteocalcin. A new polyacidic amino acid motif composed of consecutive Asp and Glu residues (n > 7) was defined in extracellular matrix components osteopontin, bone sialoprotein, and bone acidic glycoprotein-75 on the basis of strong functional analogies with similar polyacidic stretches in divalent metal storage proteins of the endoplasmic reticulum and sarcoplasmic reticulum. These structural motifs represent prime targets for future structure-function studies in vivo and in vitro.

• Kjaer I.
• Department of Orthodontics, School of Dentistry, Faculty of Health Sciences, University of Copenhagen, Denmark.
• Pages 224-44

Neuro-osteology stresses the biological connection during development between nerve and hard tissues. It is a perspective that has developed since associations were first described between pre-natal peripheral nerve tissue and initial osseous bone formation in the craniofacial skeleton (Kjaer, 1990a). In this review, the normal connection between the central nervous system and the axial skeleton and between the peripheral nervous system and jaw formation are first discussed. The early central nervous system (the neural tube) and the axial skeleton from the lumbosacral region to the sella turcica forms a unit, since both types of tissue are developmentally dependent upon the notochord. In different neurological disorders, the axial skeleton, including the pituitary gland, is malformed in different ways along the original course of the notochord. Anterior to the pituitary gland/sella turcica region, the craniofacial skeleton develops from prechordal cartilage, invading mesoderm and neural crest cells. Also, abnormal development in the craniofacial region, such as tooth agenesis, is analyzed neuro-osteologically. Results from pre-natal investigations provide information on the post-natal diagnosis of children with congenital developmental disorders in the central nervous system. Examples of these are myelomeningocele and holoprosencephaly. Three steps are important in clinical neuro-osteology: (1) clinical definition of the region of an osseous or dental malformation, (2) embryological determination of the origin of that region and recollection of which neurological structure has developed from the same region, and (3) clinical diagnosis of this neurological structure. If neurological malformation is the first symptom, step 2 results in the determination of the osseous region involved, which in step 3 is analyzed clinically. The relevance of future neuro-osteological diagnostics is emphasized.

Volume 9, Issue 3

• Okada H, Murakami S.
• Department of Periodontology and Endodontology, Osaka University Faculty of Dentistry, Japan.
• Pages 248-66

Soluble proteins that serve as mediators of cell function and are produced by various cell types, such as structural and inflammatory cells, are collectively called cytokines. Several lines of evidence have revealed that cytokines play important roles not only in tissue homeostasis but also in the pathogenesis of many infectious diseases. Recent research on biological activities in normal periodontium and the pathogenesis of periodontal diseases has clarified the involvement of various cytokines in the biological activities observed in the sites. Cytokines play crucial roles in the maintenance of tissue homeostasis, a process which requires a delicate balance between anabolic and catabolic activities. In particular, growth factors--such as fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), insulin-like growth factor (IGF), transforming growth factor-beta (TGF-beta)--are thought to play important roles in modulating the proliferation and/or migration of structural cells in the periodontium and the production of various extracellular matrices by these cells. On the other hand, there is little doubt that excessive and/or continuous production of cytokines in inflamed periodontal tissues is responsible for the progress of periodontitis and periodontal tissue destruction. Particularly, inflammatory cytokines--such as IL-1 alpha, IL-1 beta, IL-6, and IL-8--are present in the diseased periodontal tissues, and their unrestricted production seems to play a role in chronic leukocyte recruitment and tissue destruction. It is possible that monitoring cytokine production or its profile may allow us to diagnose an individual's periodontal disease status and/or susceptibility to the disease. In addition, although the hypothesis is still controversial, it has been suggested that discrete T-cell subsets (Th1 and Th2) with different cytokine profiles play specific roles in the immunopathogenesis of periodontal diseases.

• Spielman AI.
• Basic Science Division, New York University College of Dentistry, New York 10010, USA.
• Pages 267-91

Taste and smell are fundamental sensory systems essential in nutrition and food selection, for the hedonic and sensory experience of food, for efficient metabolism, and, in general, for the maintenance of a good quality of life. The gustatory and olfactory systems demonstrate a diversity of transduction mechanisms, and during the last decade, considerable progress has been made toward our understanding of the basic mechanisms of taste and smell. Understanding normal chemosensory function helps clarify the molecular events that underlie taste and smell disorders. At least 2,000,000 Americans suffer from chemosensory disorders--a number that is likely to grow as the aging segment of the population increases. Smell disorders are more frequent than taste disturbances, due to the vulnerability and anatomical distinctiveness of the olfactory system, and because a decline in olfactory function is part of the normal aging process. Common gustatory and olfactory complaints are due to a number of medications, to upper respiratory infections, to nasal and paranasal sinus diseases, and to damage to peripheral nerves supplying taste and smell. Most chemosensory complaints have an identifiable cause. Although diagnosis of taste and smell disorders has improved considerably over the last two decades, treatment of these disorders is still limited to conditions with discernible and reversible causes. Future research is needed for a better understanding of chemosensory mechanisms, establishing improved diagnostic procedures, and disseminating knowledge on chemosensory disorders among practitioners and the general public.

• Suchett-Kaye G, Morrier JJ, Barsotti O.
• Laboratoire d'Etude des Interfaces en Odontologie, Universite Claude Bernard, UFR d'Odontologie, Lyon, France.
• Pages 292-305

Periodontal disease and inflammatory dermatoses, such as psoriasis, are characterized by the accumulation of dense inflammatory infiltrates immediately beneath the epithelial cell layer of the gingiva and skin, respectively. Dermatologists are increasingly aware that the epidermal keratinocyte probably contributes to inflammatory disease progression by secreting a number of pro-inflammatory cytokines and expressing various adhesion molecules. In psoriatic lesions, it is now believed that epidermal keratinocytes may also act as antigen-presenting cells and participate directly in the superantigenic activation of T-cell clones, some of which may initiate, contribute to, or maintain the disease process. Although the role of the host response in periodontal disease has been extensively studied over the years, very little is known about the contribution of the gingival keratinocyte to the inflammatory response. The available published information is discussed in this review, and we suggest that, like its epidermal counterpart, the gingival keratinocyte may participate actively in the pathogenesis of periodontal disease.

• Porter SR, Scully C, Pedersen A.
• Department of Oral Medicine, Eastman Dental Institute for Oral Health Care Sciences, University of London, United Kingdom.
• Pages 306-21

Recurrent aphthous stomatitis (RAS) is one of the most common oral mucosal disorders. Nevertheless, while the clinical characteristics of RAS are well-defined, the precise etiology and pathogenesis of RAS remain unclear. The present article provides a detailed review of the current knowledge of the etiology, pathogenesis, and management of RAS.

• Weinberg MA, Bral M.
• Department of Periodontics, New York University College of Dentistry, New York, 10010, USA.
• Pages 322-32

This article discusses the use of tetracyclines in the clinical management of periodontal infections. A review of the drugs pharmacology, pharmacokinetics, and potential adverse effects shows that they are relatively safe if used in appropriate dosages and under controlled conditions. Current data suggest that the routine use of tetracyclines in conjunction with the treatment of periodontitis is unnecessary. However, their distinctive characteristics can be utilized in different delivery systems as an adjunctive aid to conventional treatment of juvenile and refractory forms of periodontitis.

• Pomahac B, Svensjo T, Yao F, Brown H, Eriksson E.
• Division of Plastic Surgery, Brigham/Children's/Harvard, Boston, Massachusetts 02115, USA.
• Pages 333-44

The skin plays a crucial role in protecting the integrity of the body's internal milieu. The loss of this largest organ is incompatible with sustained life. In reconstructive surgery or burn management, substitution of the skin is often necessary. In addition to traditional approaches such as split- or full-thickness skin grafts, tissue flaps and free-tissue transfers, skin bioengineering in vitro or in vivo has been developing over the past decades. It applies the principles and methods of both engineering and life sciences toward the development of substitutes to restore and maintain skin structure and function. Currently, these methods are valuable alternatives or complements to other techniques in reconstructive surgery. This review article deals with the evolution and current approaches to the development of in vitro and in vivo epidermis and dermis.

• Dao TT, Lavigne GJ.
• Faculty of Dentistry, University of Toronto, Ontario, Canada.
• Pages 345-61

Despite the extensive use of oral splints in the treatment of temporomandibular disorders (TMD) and bruxism, their mechanisms of action remain controversial Various hypotheses have been proposed to explain their apparent efficacy (i.e., true therapeutic value), including the repositioning of condyle and/or the articular disc, reduction in the electromyographic activity of the masticatory muscles, modification of the patient's "harmful" oral behavior, and changes in the patient's occlusion. Following a comprehensive review of the literature, it is concluded that any of these theories is either poor or inconsistent, while the issue of true efficacy for oral splints remains unsettled. However, the results of a controlled clinical trial lend support to the effectiveness (i.e., the patient's appreciation of the positive changes which are perceived to have occurred during the trial) of the stabilizing splint in the control of myofascial pain. In light of the data supporting their effectiveness but not their efficacy, oral splints should be used as an adjunct for pain management rather than a definitive treatment. For sleep bruxism, it is prudent to limit their use as a habit management aid and to prevent/limit dental damage potentially induced by the disorder. Future research should study the natural history and etiologies of TMD and bruxism, so that specific treatments for these disorders can be developed.

Volume 9, Issue 4

• Weiss KM, Stock DW, Zhao Z.
• Department of Anathropology, Penn State University, University Park 16802, USA.
• Pages 369-98

The mammalian dentition is a segmental, or periodically arranged, organ system whose components are arrayed in specific number and in regionally differentiated locations along the linear axes of the jaws. This arrangement evolved from simpler dentitions comprised of many single-cusp teeth of relatively indeterminate number. The different types of mammalian teeth have subsequently evolved as largely independent units. The experimentally documented developmental autonomy of dental primordia shows that the basic dental pattern is established early in embryogenesis. An understanding of how genetic patterning processes may work must be consistent with the different modes of development, and partially independent evolution, of the upper and lower dentition in mammals. The periodic nature of the location, number, and morphological structure of teeth suggests that processes involving the quantitative interaction of diffusible signaling factors may be involved. Several extracellular signaling molecules and their interactions have been identified that may be responsible for locating teeth along the jaws and for the formation of the incisor field. Similarly, the wavelike expression of signaling factors within developing teeth suggests that dynamic interactions among those factors may be responsible for crown patterns. These factors seem to be similar among different tooth types, but the extent to which crown differences can be explained strictly in terms of variation in the parameters of interactions among the same genes, as opposed to tooth-type-specific combinatorial codes of gene expression, is not yet known. There is evidence that combinatorial expression of intracellular transcription factors, including homeobox gene families, may establish domains within the jaws in which different tooth types are able to develop. An evolutionary perspective can be important for our understanding of dental patterning and the designing of appropriate experimental approaches, but dental patterns also raise basic unresolved questions about the nature of the evolutionary assumptions made in developmental genetics.

• Weinberg A, Krisanaprakornkit S, Dale BA.
• Department of Periodontics, Case Western Reserve University, Cleveland, Ohio 44106-4905, USA.
• Pages 399-414

Epithelial tissues provide the first line of defense between an organism and the environment. Disruption of this barrier leads to bacterial invasion and subsequent inflammation. This is precisely the situation existing in the human oral cavity, where tissues are constantly exposed to a variety of microbial challenges that can lead to bacterially induced periodontal diseases, and to infections of the oral mucosa by bacteria, fungi, and viruses. With the recent discoveries of host-derived peptide antibiotics in mammalian mucosal epithelium, a new line of investigation is emerging to test the hypothesis that one class of these peptides, called "beta-defensins", functions to protect the host against microbial pathogenesis at these critical, confrontational sites. In that light, impairment of beta-defensin activity has recently been implicated in chronic bacterial infections in cystic fibrosis patients. The first direct evidence of expression of defensin peptides in the oral mucosa was the identification of a novel epithelial beta-defensin in mammalian tongue. It was shown to be upregulated in inflammation, suggesting that it participates in host defense. It is theorized that epithelial cell-derived antimicrobial peptides function to keep the natural flora of micro-organisms in a steady state in different niches such as the skin, the intestines, the airway, the endocervix, and the mouth. There is now evidence indicating that normal gingival epithelial cells and tissues express two beta-defensins, hBD-1 and the newly described hBD-2. In addition, a cathelin-class antimicrobial peptide, designated LL-37 and found in human neutrophils, is also expressed in skin and gingiva. It is highly likely that these and/or other epithelial antimicrobial peptides play an important role in determining the outcome of the host-pathogen interaction at the oral mucosal barrier, and that they may have important future applications in antibiotic treatment.

• Kukuruzinska MA, Lennon K.
• Department of Molecular and Cell Biology, School of Dental Medicine, Boston University Medical Center, Massachusetts 02118, USA.
• Pages 415-48

Protein N-glycosylation is a metabolic process that has been highly conserved in evolution. In all eukaryotes, N-glycosylation is obligatory for viability. It functions by modifying appropriate asparagine residues of proteins with oligosaccharide structures, thus influencing their properties and bioactivities. N-glycoprotein biosynthesis involves a multitude of enzymes, glycosyltransferases, and glycosidases, encoded by distinct genes. The majority of these enzymes are transmembrane proteins that function in the endoplasmic reticulum and Golgi apparatus in an ordered and well-orchestrated manner. The complexity of N-glycosylation is augmented by the fact that different asparagine residues within the same polypeptide may be modified with different oligosaccharide structures, and various proteins are distinguished from one another by the characteristics of their carbohydrate moieties. Furthermore, biological consequences of derivatization of proteins with N-glycans range from subtle to significant. In the past, all these features of N-glycosylation have posed a formidable challenge to an elucidation of the physiological role for this modification. Recent advances in molecular genetics, combined with the availability of diverse in vivo experimental systems ranging from yeast to transgenic mice, have expedited the identification, isolation, and characterization of N-glycosylation genes. As a result, rather unexpected information regarding relationships between N-glycosylation and other cellular functions--including secretion, cytoskeletal organization, proliferation, and apoptosis--has emerged. Concurrently, increased understanding of molecular details of N-glycosylation has facilitated the alignment between N-glycosylation deficiencies and human diseases, and has highlighted the possibility of using N-glycan expression on cells as potential determinants of disease and its progression. Recent studies suggest correlations between N-glycosylation capacities of cells and drug sensitivities, as well as susceptibility to infection. Therefore, knowledge of the regulatory features of N-glycosylation may prove useful in the design of novel therapeutics. While facing the demanding task of defining properties, functions, and regulation of the numerous, as yet uncharacterized, N-glycosylation genes, glycobiologists of the 21st century offer exciting possibilities for new approaches to disease diagnosis, prevention, and cure.

• Klinger MM, Rahemtulla F, Prince CW, Lucas LC, Lemons JE.
• Department of Biomedical Engineering, University of Alabama at Birmingham 35294, USA.
• Pages 449-63

The widespread success of clinical implantology stems from bone's ability to form rigid, load-bearing connections to titanium and certain bioactive coatings. Adhesive biomolecules in the extracellular matrix are presumably responsible for much of the strength and stability of these junctures. Histochemical and spectroscopic analyses of retrievals have been supplemented by studies of osteoblastic cells cultured on implant materials and of the adsorption of biomolecules to titanium powder. These data have often been interpreted to suggest that proteoglycans permeate a thin, collagen-free zone at the most intimate contact points with implant surfaces. This conclusion has important implications for the development of surface modifications to enhance osseointegration. The evidence for proteoglycans at the interface, however, is somewhat less than compelling due to the lack of specificity of certain histochemical techniques and to possible sectioning artifacts. With this caveat in mind, we have devised a working model to explain certain observations of implant interfaces in light of the known physical and biological properties of bone proteoglycans. This model proposes that titanium surfaces accelerate osseointegration by causing the rapid degradation of a hyaluronan meshwork formed as part of the wound-healing response. It further suggests that the adhesive strength of the thin, collagen-free zone is provided by a bilayer of decorin proteoglycans held in tight association by their overlapping glycosaminoglycan chains.

• Soderholm KJ, Tyas MJ, Jokstad A.
• Department of Dental Biomaterials, College of Dentistry, Gainesville, Florida 32610-0446, USA.
• Pages 464-79

The definition of quality in operative dentistry has often, at least in part, been related to how well a cut preparation compares with an ideal preparation. The ideal preparation follows well-defined design principles. These design principles have their roots in empirical dentistry and scientific evaluations, the latter often being conducted in vitro. Because of the complexity of following these design principles practically, a large portion of dental education consists of perfecting cavity preparations. By focusing on how to cut these cavity preparations as closely as possible to the ideal preparation, dentists with high psycho-motor skills have been able to provide the public with restorative procedures of high standards over the years. However, because of the tendency of relating quality in operative dentistry to the ideal preparation, we found it justifiable to review the literature dealing with the cavity design principles of the Class II amalgam preparation. What triggered this review was a request from the International Dental Federation (FDI) to start a process leading to a scientifically based quality definition of dental restorations, a definition that determines how different factors, including cavity design principles, affect the longevity of both tooth and restoration. From our review, we conclude that patient response and restoration performance over time, rather than how closely a cavity preparation compares with the ideal preparation, will be of more significance in determining the longevity of a Class II amalgam restoration.

• Tsai H, Bobek LA.
• Department of Oral Biology, School of Dental Medicine, State University of New York at Buffalo 14214, USA.
• Pages 480-97

Histatins constitute a group of small, cationic multifunctional proteins present in the saliva of human and some non-human primates. The most significant function of histatins may be their anti-fungal activity against Candida albicans and Cryptococcus neoformans. Histatins have been extensively studied at both the protein and gene levels. The structure-function relationship of histatins with respect to their candidacidal activity has also been studied by means of recombinant histatin variants, as well as by chemically synthesized histatin fragments. The mechanism of histatins' action on Candida albicans is not clear, but it appears to be different from that of azole-based anti-fungal drugs which interrupt ergosterol synthesis. During the past 20 years, fungal infections have become more prevalent as a result of the emergence of AIDS, as well as, paradoxically, modern medical advances. The toxicity of current anti-fungal medicine, the emergence of drug-resistant strains, and the availability of only a few types of anti-fungal agents are the major disadvantages of current anti-fungal therapy. Therefore, the importance of the search for new, broad-spectrum anti-fungals with little or no toxicity cannot be overemphasized. The following properties make histatins promising anti-fungal therapeutic agents: (1) They have little or no toxicity; (2) they possess high cidal activities against azole-resistant fungal species and most of the fungal species tested; and (3) their candidacidal activity is similar to that of azole-based antifungals. Current research efforts focus on the development of improved histatins with enhanced cidal activity and stability, and of suitable and effective histatin delivery systems. These and other approaches may help to outpace the growing list of drug-resistant and opportunistic fungi causing life-threatening, disseminating diseases. The histatins with improved protective properties may also be used as components of artificial saliva for patients with salivary dysfunction.

• Stashenko P, Teles R, D'Souza R.
• Department of Cytokine Biology, Forsyth Dental Center, Boston, Massachusetts, USA.
• Pages 498-521

Periapical inflammatory responses occur as a consequence of bacterial infection of the dental pulp, as a result of caries, trauma, or iatrogenic insult. Periapical inflammation stimulates the formation of granulomas and cysts, with the destruction of bone. These inflammatory responses are complex and consist of diverse elements. Immediate-type responses--including vasodilatation, increased vascular permeability, and leukocyte extravasation--are mediated by endogenous mediators, including prostanoids, kinins, and neuropeptides. Non-specific immune responses--including polymorphonuclear leukocyte and monocyte migration and activation, and cytokine production--are elicited in response to bacteria and their products. Interleukin-1 and prostaglandins in particular have been implicated as central mediators of periapical bone resorption. Chronic periapical inflammation further involves specific T- and B-cell-mediated anti-bacterial responses, and activates a network of regulatory cytokines which are produced by Th1- and Th2-type T-lymphocytes. Various naturally occurring and genetically engineered models of immunodeficiency are beginning to help elucidate those components of the immune system which protect the pulpal/periapical complex. Both specific and non-specific responses interface with and are regulated by the neural system. The modulation of these responses by immune response modifies, cytokine antagonists, and other novel therapeutic agents is discussed. As an experimental model, periapical inflammation has many advantages which permit it to be used in studies of microbial ecology and pathogenesis, host response, neuroimmunology, and bone resorption and regeneration.

• Roberts MC.
• Department of Pathobiology, School of Public Health and Community Medicine, University of Washington, Seattle 98195-7238, USA.
• Pages 522-40

In the last 20 years, changes in world technology have occurred which have allowed for the rapid transport of people, food, and goods. Unfortunately, antibiotic residues and antibiotic-resistant bacteria have been transported as well. Over the past 20 years, the rise in antibiotic-resistant gene carriage in virtually every species of bacteria, not just oral/respiratory bacteria, has been documented. In this review, the main mechanisms of resistance to the important antibiotics used for treatment of disease caused by oral/respiratory bacteria--including beta-lactams, tetracycline, and metronidazole--are discussed in detail. Mechanisms of resistance for macrolides, lincosamides, streptogramins, trimethoprim, sulfonamides, aminoglycosides, and chloramphenicol are also discussed, along with the possible role that mercury resistance may play in the bacterial ecology.

• Miller CS, Danaher RJ, Jacob RJ.
• Department of Oral Health Science, University of Kentucky Colleges of Dentistry and Medicine, Lexington 40536-0084, USA.
• Pages 541-62

The application of molecular biology in the study of the pathogenesis of herpes simplex virus type 1 (HSV-1) has led to significant advances in our understanding of mechanisms that regulate virus behavior in sensory neurons and epithelial tissue. Such study has provided insight into the relationship of host and viral factors that regulate latency, reactivation, and recurrent disease. This review attempts to distill decades of information involving human, animal, and cell culture studies of HSV-1 with the goal of correlating molecular events with the clinical and laboratory behavior of the virus during latency, reactivation, and recurrent disease. The purpose of such an attempt is to acquaint the clinician/scientist with the current thinking in the field, and to provide key references upon which current opinions rest.