bluuebunny/crossref_metadata_2025 huggingface dataset:
(C3) The Oral Epithelial Cell and First Encounters with HIV-1
Authors: Herzberg M.C. , Weinberg A. , Wahl S.M.
Published: January 2009

The oral epithelium is the site of first exposure of HIV-1 to host tissues during oral sex with an infected partner or through breast-feeding by an infected mother. Although the oral epithelium is distinguishable by its apparent resistance, the mucosal surfaces represent a primary target of HIV-1. After oral exposure and swallowing, infection is detected prominently in the gastrointestinal tract, which becomes depleted of CD4+ T-cells. The oral cavity and palatine tonsils appear to resist infection and transfer to susceptible lymphoid cells in the lamina propria by local anti-HIV-1 mechanisms. In some cases, expression of these antiviral mechanisms increases after exposure to HIV-1. During primary exposure and before seroconversion, based on limited in vitro and primate data, a window of opportunity for capture of HIV-1 by the oral epithelium may exist. After seroconversion, the risk of infectious HIV-1 appearing in saliva is negligible. This report considers evidence that oral epithelium has the potential both to enable and to resist infection by HIV-1.
Dynamics of Cell Interactions and Communications during Melanoma Development
Authors: Li G. , Satyamoorthy K. , Herlyn M.
Published: January 2009

Melanoma development not only involves genetic and epigenetic changes that take place within the cell, but also involves processes determined collectively by micro-environmental factors, including cell-cell interactions and communications. During the transition from normal cells to benign and malignant lesions, and subsequently to metastatic cancer, stepwise changes in intercellular communications provide tumor cells with the ability to overcome cell-cell adhesion and micro-environmental controls from the host and to invade surrounding tissues and disperse to distant locations. Cadherins are major cell–cell adhesion molecules involved in the development and maintenance of skin. E-cadherin expressed in normal melanocytes mediates growth and invasion control by keratinocytes. Progressive loss of E-cadherin and gain of N-cadherin during melanoma development not only free melanoma cells from control by keratinocytes, but also provide new adhesion properties, resulting in switched partnerships with fibroblasts and vascular endothelial cells. The cadherin subtype switching also dictates gap junctional specificity in melanocytic cells during tumor development. This selective intercellular communication may contribute to the regulation of cell growth, differentiation, apoptosis, and migration of melanocytic cells in both physiologic and pathologic conditions. Abnormal up-regulation of the immunoglobin repeat-containing cell adhesion molecules Mel-CAM and L1-CAM potentiates invasion and migration of melanoma. Thus, abnormal expression of intercellular adhesion receptors and dysregulated intercellular communication underlies melanoma development and progression.
Cysteine Peptidases of Mammals: Their Biological Roles and Potential Effects in the Oral Cavity and Other Tissues in Health and Disease
Authors: Dickinson D.P.
Published: January 2009

Cysteine peptidases (CPs) are phylogenetically ubiquitous enzymes that can be classified into clans of evolutionarily independent proteins based on the structural organization of the active site. In mammals, two of the major clans represented in the genome are: the CA clan, whose members share a structure and evolutionary history with papain; and the CD clan, which includes the legumains and caspases. This review focuses on the properties of these enzymes, with an emphasis on their potential roles in the oral cavity. The human genome encodes at least (but possibly no more than) 11 distinct enzymes, called cathepsins, that are members of the papain family C1A. Ten of these are present in rodents, which also carry additional genes encoding other cathepsins and cathepsin-like proteins. Human cathepsins are best known from the ubiquitously expressed lysosomal cathepsins B, H, and L, and dipeptidyl peptidase I (DPP I), which until recently were considered to mediate primarily “housekeeping” functions in the cell. However, mutations in DPP I have now been shown to underlie Papillon-Lefèvre syndrome and pre-pubertal periodontitis. Other cathepsins are involved in tissue-specific functions such as bone remodeling, but relatively little is known about the functions of several recently discovered enzymes. Collectively, CPs participate in multiple host systems that are active in health and in disease. They are involved in tissue remodeling and turnover of the extracellular matrix, immune system function, and modulation and alteration of cell function. Intracellularly, CPs function in diverse processes including normal protein turnover, antigen and proprotein processing, and apoptosis. Extracellularly, they can contribute directly to the degradation of foreign proteins and the extracellular matrix. However, CPs can also participate in proteolytic cascades that amplify the degradative capacity, potentially leading to pathological damage, and facilitating the penetration of tissues by cancer cells. We know relatively little regarding the role of human CPs in the oral cavity in health or disease. Most studies to date have focused on the potential use of the lysosomal enzymes as markers for periodontal disease activity. Human saliva contains high levels of cystatins, which are potent CP inhibitors. Although these proteins are presumed to serve a protective function, their in vivo targets are unknown, and it remains to be discovered whether they serve to control any human CP activity.
Nutrition as a Mediator in the Relation between Oral and Systemic Disease: Associations between Specific Measures of Adult Oral Health and Nutrition Outcomes
Authors: Ritchie Christine S. , Joshipura Kaumudi , Hung Hsin-Chia , Douglass Chester W.
Published: January 2009

Recent associations between oral health and systemic disease have led to renewed interest in the mouth and its contribution to health outcomes. Many pathways for this relationship have been postulated, among them the potential mediating role of nutrition. The link between various nutrients and systemic disease has been established, but relatively little work has been done in relating oral conditions with nutrition. We searched MEDLINE, from 1966 to July, 2001, to identify articles relating specific oral measures to nutrition outcomes. We included original articles written in English with a sample size greater than 30 that used objective oral health measures. We reviewed a total of 56 articles. Only a small proportion of these studies were methodologically sound. Although many studies were small and cross-sectional, the literature suggests that tooth loss affects dietary quality and nutrient intake in a manner that may increase the risk for several systemic diseases. The impact of tooth loss on diet may be only partially compensated for by prostheses. To date, there is little information relating periodontal disease and oral pain and nutrition. A few studies suggest poorer nutrition among individuals with xerostomia and altered taste. Further, impaired dentition may contribute to weight change, depending on age and other population characteristics. There is a paucity of well-designed studies addressing oral health and nutrition. Before we can acquire a better understanding of how nutrition and oral health interrelate, however, more studies will be required to confirm these associations—preferably longitudinal studies with larger sample sizes and better control of important confounders.
Cellular, Molecular, and Genetic Determinants of Tooth Eruption
Authors: Wise G.E. , Frazier-Bowers S. , D’Souza R.N.
Published: January 2009

Tooth eruption is a complex and tightly regulated process that involves cells of the tooth organ and the surrounding alveolus. Mononuclear cells (osteoclast precursors) must be recruited into the dental follicle prior to the onset of eruption. These cells, in turn, fuse to form osteoclasts that resorb alveolar bone, forming an eruption pathway for the tooth to exit its bony crypt. Some of the molecules possibly involved in the signaling cascades of eruption have been proposed in studies from null mice, osteopetrotic rodents, injections of putative eruption molecules, and cultured dental follicle cells. In particular, recruitment of the mononuclear cells to the follicle may require colony-stimulating factor-one (CSF-1) and/or monocyte chemotactic protein-1 (MCP-1). Osteoclastogenesis is needed for the bone resorption and may involve inhibition of osteoprotegerin transcription and synthesis in the follicle, as well as enhancement of receptor activator of NFκB ligand (RANKL), in the adjacent alveolar bone and/or in the follicle. Paracrine signaling by parathyroid-hormone-related protein and interleukin -1α, produced in the stellate reticulum adjacent to the follicle, may also play a role in regulating eruption. Osteoblasts might also influence the process of eruption, the most important physiologic role likely being at the eruptive site, in the formation of osteoclasts through signaling via the RANKL/OPG pathway. Evidence thus far supports a role for an osteoblast-specific transcription factor, Cbfa1 (Runx2), in molecular events that regulate tooth eruption. Cbfa1 is also expressed at high levels by the dental follicle cells. This review concludes with a discussion of the several human conditions that result in a failure of or delay in tooth eruption.
The Pathogenesis of Oral Lichen Planus
Authors: Sugerman P.B. , Savage N.W. , Walsh L.J. , Zhao Z.Z. , Zhou X.J. , Khan A. , Seymour G.J. , Bigby M.
Published: January 2009

Both antigen-specific and non-specific mechanisms may be involved in the pathogenesis of oral lichen planus (OLP). Antigen-specific mechanisms in OLP include antigen presentation by basal keratinocytes and antigen-specific keratinocyte killing by CD8+ cytotoxic T-cells. Non-specific mechanisms include mast cell degranulation and matrix metalloproteinase (MMP) activation in OLP lesions. These mechanisms may combine to cause T-cell accumulation in the superficial lamina propria, basement membrane disruption, intra-epithelial T-cell migration, and keratinocyte apoptosis in OLP. OLP chronicity may be due, in part, to deficient antigen-specific TGF-β1-mediated immunosuppression. The normal oral mucosa may be an immune privileged site (similar to the eye, testis, and placenta), and breakdown of immune privilege could result in OLP and possibly other autoimmune oral mucosal diseases. Recent findings in mucocutaneous graft- versus-host disease, a clinical and histological correlate of lichen planus, suggest the involvement of TNF-α, CD40, Fas, MMPs, and mast cell degranulation in disease pathogenesis. Potential roles for oral Langerhans cells and the regional lymphatics in OLP lesion formation and chronicity are discussed. Carcinogenesis in OLP may be regulated by the integrated signal from various tumor inhibitors (TGF-β1, TNF-α, IFN-γ, IL-12) and promoters (MIF, MMP-9). We present our recent data implicating antigen-specific and non-specific mechanisms in the pathogenesis of OLP and propose a unifying hypothesis suggesting that both may be involved in lesion development. The initial event in OLP lesion formation and the factors that determine OLP susceptibility are unknown.
Supragingival Calculus: Formation and Control
Authors: Jin Ye , Yip Hak-Kong
Published: January 2009

Dental calculus is composed of inorganic components and organic matrix. Brushite, dicalcium phosphate dihydrate, octacalcium phosphate, hydroxyapatite, and whitlockite form the mineral part of dental calculus. Salivary proteins selectively adsorb on the tooth surface to form an acquired pellicle. It is followed by the adherence of various oral micro-organisms. Fimbriae, flagella, and some other surface proteins are essential for microbial adherence. Microbial co-aggregation and co-adhesion enable some micro-organisms, which are incapable of adhering, to adhere to the pellicle-coated tooth surface. Once organisms attach to the tooth surface, new genes could be expressed so that mature dental plaque can form and biofilm bacteria assume increased resistance to antimicrobial agents. Supersaturation of saliva and plaque fluid with respect to calcium phosphates is the driving force for plaque mineralization. Both salivary flow rate and plaque pH appear to influence the saturation degree of calcium phosphates. Acidic phospholipids and specific proteolipids present in cell membranes play a key role in microbial mineralization. The roles of crystal growth inhibitors, promoters, and organic acids in calculus formation are discussed. Application of biofilm culture systems in plaque mineralization is concisely reviewed. Anti-calculus agents used—centering on triclosan plus polyvinyl methyl ether/maleic acid copolymer, pyrophosphate plus polyvinyl methyl ether/maleic acid copolymer, and zinc ion—in commercial dentifrices are also discussed in this paper.
The Fate of the Terminally Differentiated Chondrocyte: Evidence for Microenvironmental Regulation of Chondrocyte Apoptosis
Authors: Adams Christopher S. , Shapiro Irving M.
Published: January 2009

Chondrocytes contained within the epiphyseal growth plate promote rapid bone growth. To achieve growth, cells activate a maturation program that results in an increase in chondrocyte number and volume and elaboration of a mineralized matrix; subsequently, the matrix is resorbed and the terminally differentiated cells are deleted from the bone. The major objective of this review is to examine the fate of the epiphyseal chondrocytes in the growing bone. Current studies strongly suggest that the terminally differentiated epiphyseal cells are deleted from the cartilage by apoptosis. Indeed, morphological, biochemical, and end-labeling techniques confirm that death is through the apoptotic pathway. Since the induction of apoptosis is spatially and temporally linked to the removal of the cartilage matrix, current studies have examined the apoptogenic activity of Ca2+-, Pi-, and RGD-containing peptides of extracellular matrix proteins. It is observed that all of these molecules are powerful apoptogens. With respect to the molecular mechanism of apoptosis, studies of cell death with Pi as an apoptogen indicate that the anion is transported into the cytosol via a Na+/Pi transporter. Subsequently, there is activation of caspases, generation of NO, and a decrease in the thiol reserve. Finally, we examine the notion that chondrocytes transdifferentiate into osteoblasts, and briefly review evidence for, and the rationale of, the transdifferentiation process. It is concluded that specific microenvironments exist in cartilage that can serve to direct chondrocyte apoptosis.
Cementum and Periodontal Wound Healing and Regeneration
Authors: Grzesik Wojciech J. , Narayanan A.S.
Published: January 2009

The extracellular matrix (ECM) of cementum resembles other mineralized tissues in composition; however, its physiology is unique, and it contains molecules that have not been detected in other tissues. Cementum components influence the activities of periodontal cells, and they manifest selectivity toward some periodontal cell types over others. In light of emerging evidence that the ECM determines how cells respond to environmental stimuli, we hypothesize that the local environment of the cementum matrix plays a pivotal role in maintaining the homeostasis of cementum under healthy conditions. The structural integrity and biochemical composition of the cementum matrix are severely compromised in periodontal disease, and the provisional matrix generated during periodontal healing is different from that of cementum. We propose that, for new cementum and attachment formation during periodontal regeneration, the local environment must be conducive for the recruitment and function of cementum-forming cells, and that the wound matrix is favorable for repair rather than regeneration. How cementum components may regulate and participate in cementum regeneration, possible new regenerative therapies using these principles, and models of cementoblastic cells are discussed.
Analysis of Pulpal Reactions to Restorative Procedures, Materials, Pulp Capping, and Future Therapies
Authors: Murray Peter E. , Windsor L. Jack , Smyth Thomas W. , Hafez Abeer A. , Cox Charles F.
Published: January 2009

Every year, despite the effectiveness of preventive dentistry and dental health care, 290 million fillings are placed each year in the United States; two-thirds of these involve the replacement of failed restorations. Improvements in the success of restorative treatments may be possible if caries management strategies, selection of restorative materials, and their proper use to avoid post-operative complications were investigated from a biological perspective. Consequently, this review will examine pulp injury and healing reactions to different restorative variables. The application of tissue engineering approaches to restorative dentistry will require the transplantation, replacement, or regeneration of cells, and/or stimulation of mineralized tissue formation. This might solve major dental problems, by remineralizing caries lesions, vaccinating against caries and oral diseases, and restoring injured or replacing lost teeth. However, until these therapies can be introduced clinically, the avoidance of post-operative complications with conventional therapies requires attention to numerous aspects of treatment highlighted in this review.
TGF-β Signaling and its Functional Significance in Regulating the Fate of Cranial Neural Crest Cells
Authors: Chai Y. , Ito Y. , Han J.
Published: January 2009

Members of the transforming growth factor-β (TGF-β) superfamily regulate cell proliferation, differentiation, and apoptosis, and control the development and maintenance of most tissues. TGF-β signal is transmitted through the phosphorylation of Smad proteins by TGF-β receptor serine/threonine kinase. During craniofacial development, TGF-β may regulate the fate specification of cranial neural crest cells. These cells are multipotent progenitors and capable of producing diverse cell types upon differentiation. Here we summarize evidence that TGF-β ligands and their signaling intermediates have significant roles in patterning and specification of cranial neural crest cells. The biological function of TGF-β is carried out through the regulation of transcriptional factors during embryogenesis.
Glucan-binding Proteins of the Oral Streptococci
Authors: Banas J.A. , Vickerman M.M.
Published: January 2009

The synthesis of extracellular glucan is an integral component of the sucrose-dependent colonization of tooth surfaces by species of the mutans streptococci. In investigators’ attempts to understand the mechanisms of plaque biofilm development, several glucan-binding proteins (GBPs) have been discovered. Some of these, the glucosyltransferases, catalyze the synthesis of glucan, whereas others, designated only as glucan-binding proteins, have affinities for different forms of glucan and contribute to aspects of the biology of their host organisms. The functions of these latter glucan-binding proteins include dextran-dependent aggregation, dextranase inhibition, plaque cohesion, and perhaps cell wall synthesis. In some instances, their glucan-binding domains share common features, whereas in others the mechanism for glucan binding remains unknown. Recent studies indicate that at least some of the glucan-binding proteins modulate virulence and some can act as protective immunogens within animal models. Overall, the multiplicity of GBPs and their aforementioned properties are testimonies to their importance. Future studies will greatly advance the understanding of the distribution, function, and regulation of the GBPs and place into perspective the facets of their contributions to the biology of the oral streptococci.
The Biochemistry and Physiology of Metallic Fluoride: Action, Mechanism, and Implications
Authors: Li Liang
Published: January 2009

Fluoride is a well-known G protein activator. Activation of heterotrimeric GTP-binding proteins by fluoride requires trace amounts of Al3+ or Be2+ ions. AlFx mimics a γ-phosphate at its transition state in a G α protein and is therefore able to inhibit its GTPase activity. AlFx also forms complexes with small GTP-binding proteins in the presence of their GTPase-activating proteins (GAP). As phosphate analogs, AlFx or BeFx affect the activity of a variety of phosphoryl transfer enzymes. Most of these enzymes are fundamentally important in cell signal transduction or energy metabolism. Al3+ and F- tend to form stable complexes in aqueous solution. The exact structure and concentration of AlFx depend on the pH and the amount of F- and Al3+ in the solution. Humans are exposed to both F and Al. It is possible that Al-F complexes may be formed in vivo, or formed in vitro prior to their intake by humans. Al-F complexes may play physiological or pathological roles in bone biology, fluorosis, neurotoxicity, and oral diseases such as dental caries and periodontal disease. The aim of this review is to discuss the basic chemical, biochemical, and toxicological properties of metallic fluoride, to explore its potential physiological and clinical implications.
Yeasts in Apical Periodontitis
Authors: Waltimo T.M.T. , Sen B.H. , Meurman J.H. , Ørstavik D. , Haapasalo M.P.P.
Published: January 2009

Microbiological reports of apical periodontitis have revealed that yeasts can be isolated from approximately 5-20% of infected root canals. They occur either in pure cultures or together with bacteria. Almost all isolated yeasts belong to the genus Candida, and the predominant species is C. albicans. Pheno- and genotypic profiles of C. albicans isolates show heterogeneity comparable with those of isolates from other oral sites. C. albicans expresses several virulence factors that are capable of infecting the dentin-pulp complex, including dentinal tubules. This causes, consequentially, an inflammatory response around the root apex, which suggests a pathogenic role for this organism in apical periodontitis. Yeasts are particularly associated with persistent root canal infections that do not respond favorably to conservative root canal therapy. This may be due to the resistance of all oral Candida species against a commonly used topical medicament, calcium hydroxide. However, other antimicrobial agents may offer alternative therapeutic approaches and improve the treatment of these persistent cases of apical periodontitis.
Biomechanical Behavior of the Temporomandibular Joint Disc
Authors: Tanaka Eiji , van Eijden Theo
Published: January 2009

The temporomandibular joint (TMJ) disc consists mainly of collagen fibers and proteoglycans constrained in the interstices of the collagen fiber mesh. This construction results in a viscoelastic response of the disc to loading and enables the disc to play an important role as a stress absorber during function. The viscoelastic properties depend on the direction (tension, compression, and shear) and the type of the applied loading (static and dynamic). The compressive elastic modulus of the disc is smaller than its tensile one because the elasticity of the disc is more dependent on the collagen fibers than on the proteoglycans. When dynamic loading occurs, the disc is likely to behave less stiffly than under static loading because of the difference of fluid flow through and out of the disc during loading. In addition, the mechanical properties change as a result of various intrinsic and extrinsic factors in life such as aging, trauma, and pathology. Information about the viscoelastic behavior of the disc is required for its function to be understood and, for instance, for a suitable TMJ replacement device to be constructed. In this review, the biomechanical behavior of the disc in response to different loading conditions is discussed.
OralHelicobacter pylori: Can We Stomach It?
Authors: Dowsett S.A. , Kowolik M.J.
Published: January 2009

Helicobacter pylori infection is one of the most common in man. The bacterium primarily resides in the human stomach, where it plays a significant role in gastric disease. If the spread of H. pylori is to be prevented, an understanding of the transmission process is essential. The oral cavity has been proposed as a reservoir for gastric H. pylori, which has been detected by culture and PCR in both dental plaque and saliva. This review will discuss the evidence for the role of the oral cavity in the transmission of gastric H. pylori. Moreover, the difficulties encountered in addressing this topic, possible directions for future research, and the implications for the dental profession are discussed.
Implants in the Medically Compromised Patient
Authors: Beikler Thomas , Flemmig Thomas F.
Published: January 2009

Dental clinicians are confronted with an increasing number of medically compromised patients who require implant surgery for their oral rehabilitation. However, there are few guidelines on dental implant therapy in this patient category, so that numerous issues regarding pre- and post-operative management remain unclear to the dental clinician. Therefore, the aim of the present review is to offer a critical evaluation of the literature and to provide the clinician with scientifically based data for implant therapy in the medically compromised patient. This review presents the current knowledge regarding the influence of the most common systemic and local diseases on the outcome of dental implant therapy, e.g., abnormalities in bone metabolism, diabetes mellitus, xerostomia, and ectodermal dysplasias. Specific pathophysiologic aspects of the above-mentioned diseases as well as their potential implications for implant success are critically appraised. In line with these implications, guidelines for pre- and post-operative management that may assist in the successful implant-supported rehabilitation of this patient category are proposed.
Erratum: Paracoccidioidomycosis of the Mouth: an Emerging Deep Mycosis
Authors: Almeida Oslei Paes , Jacks Jorge , Scully Crispian
Published: January 2009

Oral fungal infections (mycoses) have come into particular prominence since the advent of infection with Human Immunodeficiency Virus (HIV), and recognition of the Acquired Immune Deficiency Syndrome (AIDS), as well as the phenomenal increase in world travel with increased exposure to infections endemic in the tropics. Paracoccidioidomycosis is a rare mycosis worldwide but common in Brazil and some other areas in Latin America. It can be life-threatening and can manifest with a spectrum of clinical presentations, including frequent oral lesions. This paper reviews the more recent information on Paracoccidioidomycosis, emphasizing those areas most relevant in dental science.
The Biofilm Concept: Consequences for Future Prophylaxis of Oral Diseases?
Authors: Scheie Anne Aamdal , Petersen Fernanda Cristina
Published: January 2009

Biofilm control is fundamental to oral health. Existing oral prophylactic measures, however, are insufficient. The main reason is probably because the micro-organisms involved organize into complex biofilm communities with features that differ from those of planktonic cells. Micro-organisms have traditionally been studied in the planktonic state. Conclusions drawn from many of these studies, therefore, need to be revalidated. Recent global approaches to the study of microbial gene expression and regulation in non-oral micro-organisms have shed light on two-component and quorum-sensing systems for the transduction of stimuli that allow for coordinated gene expression. We suggest interference with two-component and quorum-sensing systems as potential novel strategies for the prevention of oral diseases through control of oral biofilms. Information is still lacking, however, on the genetic regulation of oral biofilm formation. A better understanding of these processes is of considerable importance.
New Molecules in the Tumor Necrosis Factor Ligand and Receptor Superfamilies with Importance for Physiological and Pathological Bone Resorption
Authors: Lerner Ulf H.
Published: January 2009

Osteoclasts are tissue-specific polykaryon bone-resorbing cells derived from the monocyte/macrophage hematopoietic lineage with specialized functions required for the adhesion of the cells to bone and the subsequent polarization of the cell membrane, secretion of acid to dissolve mineral crystals, and release of proteolytic enzymes to degrade the extracellular matrix proteins. Most pathological conditions in the skeleton lead to loss of bone due to excess osteoclastic bone resorption, including periodontal disease, rheumatoid arthritis, and osteoporosis. In rare cases, most of them genetic, patients with osteopetrosis exhibit sclerotic bone due either to a lack of osteoclasts or to non-functional osteoclasts. Mainly because of phenotypic findings in genetically manipulated mice or due to spontaneous mutations in humans, mice, and rats, several genes have been discovered as being crucial for osteoclast formation and activation. Recent breakthroughs in our understanding of osteoclast biology have revealed the critical roles in osteoclast differentiation played by RANKL, RANK, and OPG, three novel members of the tumor necrosis factor ligand and receptor superfamilies. The further study of these molecules and downstream signaling events are likely to provide a molecular basis for the development of new drugs for the treatment of diseases with excess or deficient osteoclastic bone resorption.
Neuropeptides and Neurogenic Mechanisms in Oral and Periodontal Inflammation
Authors: Lundy F.T. , Linden G.J.
Published: January 2009

It is generally accepted that the nervous system contributes to the pathophysiology of peripheral inflammation, and a neurogenic component has been implicated in many inflammatory diseases, including periodontitis. Neurogenic inflammation should be regarded as a protective mechanism, which forms the first line of defense and protects tissue integrity. However, severe or prolonged noxious stimulation may result in the inflammatory response mediating injury rather than facilitating repair. This review focuses on the accumulating evidence suggesting that neuropeptides have a pivotal role in the complex cascade of chemical activity associated with periodontal inflammation. An overview of neuropeptide synthesis and release introduces the role of neuropeptides and their interactions with other inflammatory factors, which ultimately lead to neurogenic inflammation. The biological effects of the neuropeptides substance P (SP), calcitonin gene-related peptide (CGRP), vasoactive intestinal polypeptide (VIP), and neuropeptide Y (NPY) are summarized, and evidence for their involvement in the localized inflammatory lesions which characterize periodontitis is presented. In this context, the role of CGRP in bone metabolism is described in more detail. Recent research highlighting the role of the nervous system in suppressing pain and inflammation is also discussed.
The Role of Human Papillomavirus in Oral Carcinogenesis
Authors: Ha Patrick K. , Califano Joseph A.
Published: January 2009

Human papillomavirus (HPV) infection with high-risk types 16 and 18 has widely been reported as one of the prominent mechanisms behind the development of cervical squamous cell carcinoma. Links between HPV and oral cavity cancer have been suggested as well, based on epidemiologic and molecular means, though the association is less well-established. It is likely that HPV plays a role in oral cavity carcinogenesis, though only in a small subset of cases. The difficulty in providing true causal evidence of HPV’s role in oral cancer lies in our lack of understanding of the significance of mechanisms by which HPV leads to oral carcinogenesis, as well as limitations in the molecular analysis of HPV. Further studies are necessary for the contribution of HPV in oral cavity malignancy to be better demonstrated.
Adverse Drug Reactions in the Orofacial Region
Authors: Scully C. , Bagan J.-V.
Published: January 2009

A wide spectrum of drugs can sometimes give rise to numerous adverse orofacial manifestations, particularly dry mouth, taste disturbances, oral mucosal ulceration, and/or gingival swelling. There are few relevant randomized double-blind controlled studies in this field, and therefore this paper reviews the data from case reports, small series, and non-peer-reviewed reports of adverse drug reactions affecting the orofacial region (available from a MEDLINE search to April, 2003). The more common and significant adverse orofacial consequences of drug therapy are discussed.
Implantology and the Severely Resorbed Edentulous Mandible
Authors: Stellingsma C. , Vissink A. , Meijer H.J.A. , Kuiper C. , Raghoebar G.M.
Published: January 2009

Patients with a severely resorbed edentulous mandible often suffer from problems with the lower denture. These problems include: insufficient retention of the lower denture, intolerance to loading by the mucosa, pain, difficulties with eating and speech, loss of soft-tissue support, and altered facial appearance. These problems are a challenge for the prosthodontist and surgeon. Dental implants have been shown to provide a reliable basis for fixed and removable prostheses. This has resulted in a drastic change in the treatment concepts for management of the severely resorbed edentulous mandible. Reconstructive, pre-prosthetic surgery has changed from surgery aimed to provide a sufficient osseous and mucosal support for a conventional denture into surgery aimed to provide a sufficient bone volume enabling implants to be placed at the most optimal positions from a prosthetic point of view. The aim of this paper is to review critically the literature on procedures related to the severely resorbed edentulous mandible and dental implant treatment. The study includes the transmandibular implant, (short) endosseous implants, and reconstructive procedures such as distraction osteogenesis, augmentation of the mandibular ridge with autogenous bone, and bone substitutes followed by the placement of implants. The number of patients participating in a study, the follow-up period, the design of the study, the degree of mandibular resorption, and the survival rate of the dental implants all are considered evaluation parameters. Although numerous studies have described the outcome results of dental implants in the edentulous mandible, there have been few prospective studies designed as randomized clinical trials that compare different treatment modalities to restore the severely resorbed mandible. Therefore, it is not yet possible to select an evidence-based treatment modality. Future research has to be focused on long-term, detailed follow-up clinical trials before scientificaly based decisions in treating these patients can be made. This will contribute to a higher level of care in this field.
Smokeless Tobacco and Oral Cancer: A Review of the Risks and Determinants
Authors: Rodu Brad , Jansson Christer
Published: January 2009

Smokeless tobacco has been associated with oral cancer for many decades. The purpose of this article is to review research relevant to this association, including epidemiologic studies, studies of putative carcinogens such as tobacco-specific nitrosamines (TSNAs) and other contaminants, and possible cancer inhibitors. Epidemiologic studies addressing this issue primarily consist of case-control studies. They show that the use of chewing tobacco and moist snuff is associated with very low risks for cancers of the oral cavity and related structures (relative risks [RR] from 0.6 to 1.7). The use of dry snuff is associated with higher RRs, ranging from 4 to 13, while the RRs from smokeless tobacco, unspecified as to type, are intermediate (RR = 1.5 to 2.8). With regard to TSNAs, historical levels in American moist snuff products were higher than those in their Swedish counterparts, but levels in contemporary products are uniformly low. TSNA levels in chewing tobacco have always been low, but levels in dry snuff have been higher, including some very high levels in current products. In general, smokeless tobacco users are not exposed to significant levels of cadmium, lead, benzo(a)pyrene, polonium-210, and formaldehyde, when compared with concentrations of these compounds in foods. Finally, low oral cancer risk from smokeless tobacco use may be influenced by the presence of cancer inhibitors, mainly anti-oxidants, in smokeless tobacco products.
The Use of Enamel Matrix Derivative in the Treatment of Periodontal Defects: a Literature Review and Meta-analysis
Authors: Venezia E. , Goldstein M. , Boyan B.D. , Schwartz Z.
Published: January 2009

Background—Periodontal disease results in the loss of the attachment apparatus. In the last three decades, an increasing effort has been placed on seeking procedures and materials to promote the regeneration of this tissue. The aim of this paper is to evaluate the effect of enamel matrix derivative (EMD) during regenerative procedures. In addition, a meta-analysis is presented regarding the clinical results during regeneration with EMD, to gain evidence as to what can be accomplished following treatment of intrabony defects with EMD in terms of probing depth reduction, clinical attachment level gain, defect fill (using re-entry studies), and radiographic parameters. Methods—The review includes in vitro and in vivo studies as well as human case reports, clinical comparative trials, and histologic findings. In addition, a meta-analysis is presented regarding the regenerative clinical results. For this purpose, we used 28 studies—including 955 intrabony defects treated with EMD that presented baseline and final data on probing depth, clinical attachment level (CAL) gain, or bone gain—to calculate weighted mean changes in the different parameters. The selected studies were pooled from the MEDLINE database at the end of May, 2003. Results—The meta-analysis of intrabony defects treated with EMD resulted in a mean initial probing depth of 7.94 ± 0.05 mm that was reduced to 3.63 ± 0.04 mm (p = 0.000). The mean clinical attachment level changed from 9.4 ± 0.06 mm to 5.82 ± 0.07 mm (p = 0.000). These results were significantly better than the results obtained for either open-flap debridement (OFD) or guided tissue regeneration (GTR). In contrast, histologically, GTR is more predictable than EMD in terms of bone and cementum formation. No advantage was found for combining EMD and GTR. Xenograft, or EMD and xenograft, yielded inferior results compared with EMD alone, but a limited number of studies evaluated this issue. Promising results were noted for the combination of allograft materials and EMD. Conclusions—EMD seems to be safe, was able to regenerate lost periodontal tissues in previously diseased sites based on clinical parameters, and was better than OFD or GTR. Its combination with allograft materials may be of additional benefit but still needs to be further investigated.
Stories of Pain and the Pursuit of Justice: Law, Violence, Experience and Jurisprudence
Authors: Skinner Stephen
Published: January 2009

Following Robert Cover's essay on law's “field of pain and death”, Austin Sarat and Thomas Kearns have presented the bases for a “jurisprudence of violence,” part of which requires including experiential accounts of (law's) violence in legal theory. This article explores these writers' understanding of violence, its relationships with law and the relevance of its experiential impact for jurisprudence, before focusing on two methodological issues. First, it argues that discussion of violence needs to be clearly situated and outlines a conceptual map as the basis for further analysis. Second, it questions the concept of experience in this context and addresses some key problems involved in articulating violent experience in textual discourse.
Essential role of spi-1–like (spi-1l) in zebrafish myeloid cell differentiation
Authors: Bukrinsky Alex , Griffin Kevin J. P. , Zhao Yan , Lin Shuo , Banerjee Utpal
Published: January 2009

The ETS protein Spi-1/Pu.1 plays a pivotal and widespread role throughout hematopoiesis in many species. This study describes the identification, characterization, and functional analysis of a new zebrafish spi transcription factor spi-1–like (spi-1l) that is expressed in primitive myeloid cells, erythro-myelo progenitor cells, and in the adult kidney. Spi-1l functions genetically downstream of etsrp, scl, and spi-1/pu.1 in myeloid differentiation. Spi-1l is coexpressed in a subset of spi-1/pu.1 cells and its function is necessary and sufficient for macrophage and granulocyte differentiation. These results establish a critical role for spi-1l in zebrafish myeloid cell differentiation.
Aberrant splicing of folylpolyglutamate synthetase as a novel mechanism of antifolate resistance in leukemia
Authors: Stark Michal , Wichman Chen , Avivi Irit , Assaraf Yehuda G.
Published: January 2009

Folylpoly-γ-gluatamate synthetase (FPGS) catalyzes the polyglutamylation and thus intracellular retention of folates and antifolates (eg, methotrexate; MTX) through the addition of multiple glutamate equivalents to their γ-carboxyl residue. Since polyglutamylation of antifolates is crucial for their pharmacological activity in leukemia, loss of FPGS function results in decreased cellular levels of polyglutamylation-dependent antifolates and consequent drug resistance. Whereas resistance to pulse exposure to antifolates is frequently associated with loss of FPGS activity, the underlying molecular mechanism remains elusive. Here we explored the molecular basis of antifolate resistance in human MTX-resistant leukemia cell lines displaying marked loss of FPGS activity. We demonstrate that these MTX-resistant cells exhibit impaired splicing of FPGS mRNA based on intron retention and/or exon skipping, thereby resulting in loss of FPGS function due to premature translation termination. Furthermore, analysis of FPGS transcripts in blood or bone marrow specimens from patients with acute lymphoblastic leukemia revealed exon 12 skipping, both at diagnosis and at relapse, the latter of which occurs after high-dose MTX-containing chemotherapy. These results constitute the first demonstration of the loss of FPGS function via aberrant mRNA splicing, thereby resulting in loss of antifolate retention and drug resistance. The clinical ramifications of these novel findings are discussed.
Plasma from stored packed red blood cells and MHC class I antibodies causes acute lung injury in a 2-event in vivo rat model
Authors: Kelher Marguerite R. , Masuno Tomhiko , Moore Ernest E. , Damle Sagar , Meng Xianzhong , Song Yong , Liang Xiayuan , Niedzinski Jerry , Geier Steven S. , Khan Samina Y. , Gamboni-Robertson Fabia , Silliman Christopher C.
Published: January 2009

Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion death. We hypothesize that TRALI requires 2 events: (1) the clinical condition of the patient and (2) the infusion of antibodies against MHC class I antigens or the plasma from stored blood. A 2-event rat model was developed with saline (NS) or endotoxin (LPS) as the first event and the infusion of plasma from packed red blood cells (PRBCs) or antibodies (OX18 and OX27) against MHC class I antigens as the second event. ALI was determined by Evans blue dye leak from the plasma to the bronchoalveolar lavage fluid (BALF), protein and CINC-1 concentrations in the BALF, and the lung histology. NS-treated rats did not evidence ALI with any second events, and LPS did not cause ALI. LPS-treated animals demonstrated ALI in response to plasma from stored PRBCs, both prestorage leukoreduced and unmodified, and to OX18 and OX27, all in a concentration-dependent fashion. ALI was neutrophil (PMN) dependent, and OX18/OX27 localized to the PMN surface in vivo and primed the oxidase of rat PMNs. We conclude that TRALI is the result of 2 events with the second events consisting of the plasma from stored blood and antibodies that prime PMNs.
Human erythrocytes bind and inactivate type 5 adenovirus by presenting Coxsackie virus-adenovirus receptor and complement receptor 1
Authors: Carlisle Robert C. , Di Ying , Cerny Anna M. , Sonnen Andreas F.-P. , Sim Robert B. , Green Nicola K. , Subr Vladimir , Ulbrich Karel , Gilbert Robert J. C. , Fisher Kerry D. , Finberg Robert W. , Seymour Leonard W.
Published: January 2009

Type 5 adenovirus (Ad5) is a human pathogen that has been widely developed for therapeutic uses, with only limited success to date. We report here the novel finding that human erythrocytes present Coxsackie virus-adenovirus receptor (CAR) providing an Ad5 sequestration mechanism that protects against systemic infection. Interestingly, erythrocytes from neither mice nor rhesus macaques present CAR. Excess Ad5 fiber protein or anti-CAR antibody inhibits the binding of Ad5 to human erythrocytes and cryo-electron microscopy shows attachment via the fiber protein of Ad5, leading to close juxtaposition with the erythrocyte membrane. Human, but not murine, erythrocytes also present complement receptor (CR1), which binds Ad5 in the presence of antibodies and complement. Transplantation of human erythrocytes into nonobese diabetic/severe combined immunodeficiency mice extends blood circulation of intravenous Ad5 but decreases its extravasation into human xenograft tumors. Ad5 also shows extended circulation in transgenic mice presenting CAR on their erythrocytes, although it clears rapidly in transgenic mice presenting erythrocyte CR1. Hepatic infection is inhibited in both transgenic models. Erythrocytes may therefore restrict Ad5 infection (natural and therapeutic) in humans, independent of antibody status, presenting a formidable challenge to Ad5 therapeutics. “Stealthing” of Ad5 using hydrophilic polymers may enable circumvention of these natural virus traps.
Clinical characterization of acute myeloid leukemia with myelodysplasia-related changes as defined by the 2008 WHO classification system
Authors: Weinberg Olga K. , Seetharam Mahesh , Ren Li , Seo Katie , Ma Lisa , Merker Jason D. , Gotlib Jason , Zehnder James L. , Arber Daniel A.
Published: January 2009

Although some studies have validated the 2001 World Health Organization (WHO) classification of acute myeloid leukemia (AML), including the importance of multilineage dysplasia, others have suggested that multilineage dysplasia correlates with unfavorable cytogenetics but has no independent impact on prognosis. In 2008, the revised WHO classification has expanded this category into “AML with myelodysplasia-related changes” (AML-MRC). We evaluated the clinical, pathologic, cytogenetic, and molecular features of 100 AML patients using the 2008 WHO criteria. Patients underwent genetic screening for NPM1, FLT3-ITD, FLT3-D835, and CEBPA mutations. Compared with patients with AML, not otherwise specified, patients with AML-MRC were significantly older (P = .014), presented with a lower hemoglobin (P = .044), more frequently expressed CD14 (P = .048), and exhibited a decreased frequency of CEBPA mutations (P = .001). Multivariate analysis indicated that patients with AML-MRC had a significantly worse overall survival, progression-free survival, and complete response compared with AML-not otherwise specified (all P < .001). These data support the clinical, morphologic, and cytogenetic criteria for this 2008 WHO AML category.