Biological Events in Periodontal Ligament and Alveolar Bone Associated with Application of Orthodontic Forces.

Orthodontic force-induced stresses cause dynamic alterations within the extracellular matrix and within the cytoskeleton of cells in the periodontal ligament and alveolar bone, mediating bone remodelling, ultimately enabling orthodontic tooth movement. In the periodontal ligament and alveolar bone, the mechanically induced tensile strains upregulate the expression of osteogenic genes resulting in bone formation, while mechanically induced compressive strains mediate predominantly catabolic tissue changes and bone resorption. In this review article we summarize some of the currently known biological events occurring in the periodontal ligament and in the alveolar bone in response to application of orthodontic forces and how these facilitate tooth movement.

Periodontal Biological Events Associated with Orthodontic Tooth Movement: The Biomechanics of the Cytoskeleton and the Extracellular Matrix.

The mechanical stimuli generated by orthodontic forces cause deformation of extracellular matrices and cells, vascular changes, inflammation, and the release of active biological agents generating a complex multifactorial sequence of biological events culminating in bone remodelling enabling orthodontic tooth movement. Orthodontic forces on the teeth generate stresses in periodontal tissues according to a number of variables including the type (continuous, interrupted, or intermittent), magnitude, direction, and frequency of the applied load. Whether the strain is compressive or tensile determines whether bone deposition or bone resorption will occur. The mechanically induced strains mediate structural changes in extracellular matrices and in cells, consequently affecting cellular gene expression and function. In the extracellular matrix, mechanosensing molecules integrated into the structure of various proteins can be activated upon load-induced protein unfolding. These specialized molecules have the capacity to sense and then to convert microenvironmental biomechanical stimuli into intracellular biochemical signals that interact to generate a coordinated tissue response. It is also possible that the applied force may directly cause nuclear deformation with configurational changes in chromatin, thus influencing gene expression. In this review article we summarize the current general concepts of mechanotransduction influencing the remodelling of periodontal tissues thus enabling tooth movement in response to applied orthodontic loads.

Oral candidosis in relation to oral immunity.

Symptomatic oral infection with Candida albicans is characterized by invasion of the oral epithelium by virulent hyphae that cause tissue damage releasing the inflammatory mediators that initiate and sustain local inflammation. Candida albicans triggers pattern-recognition receptors of keratinocytes, macrophages, monocytes and dendritic cells, stimulating the production of IL-1ß, IL-6 and IL-23. These cytokines induce the differentiation of Th17 cells and the generation of IL-17- and/or IL-22-mediated antifungal protective immuno-inflammatory responses in infected mucosa. Some immune cells including NKT cells, γδ T cells and lymphoid cells that are innate to the oral mucosa have the capacity to produce large quantities of IL-17 in response to C. albicans, sufficient to mediate effective protective immunity against C. albicans. On the other hand, molecular structures of commensal C. albicans blastoconidia, although detected by pattern-recognition receptors, are avirulent, do not invade the oral epithelium, do not elicit inflammatory responses in a healthy host, but induce regulatory immune responses that maintain tissue tolerance to the commensal fungi. The type, specificity and sensitivity of the protective immune response towards C. albicans is determined by the outcome of the integrated interactions between the intracellular signalling pathways of specific combinations of activated pattern-recognition receptors (TLR2, TLR4, Dectin-1 and Dectin-2). IL-17-mediated protective immune response is essential for oral mucosal immunity to C. albicans infection.

Noma (cancrum oris) in the South African context.

Noma (cancrum oris) is a destructive necrotising disease affecting orofacial tissues predominantly of malnourished young children. It is characterised by a rapid acute onset which usually starts in the mouth, spreads intra-orally destroying soft tissue and bone and progresses to perforate the facial skin, causing disfigurement. Polybacterial anaerobic infection is critical too, but is not alone sufficient for the initiation of noma. Cofactors, first and foremost malnutrition, but also systemic viral and bacterial infections are crucial to the development of noma. A patient with necrotising stomatitis or noma must be admitted to hospital for antibiotic treatment, fluid and electrolytes as well as nutritional supplementation and general supportive treatment. The epidemiology of noma in the South African population is unknown, and the clinicopathological features are poorly characterised. Although worldwide there is no evidence that HIV infection is a strong risk factor for noma, HIV infection may play a substantial role in the pathogenesis of noma in South Africa.

Oral medicine case book 65: Necrotising stomatitis.

Necrotising stomatitis is a fulminating anaerobic polybacterial infection affecting predominantly the oral mucosa of debilitated malnourished children or immunosuppressed HIV-seropositive subjects. It starts as necrotising gingivitis which progresses to necrotising periodontitis and subsequently to necrotising stomatitis. In order to prevent the progression of necrotising stomatitis to noma (cancrum oris), affected patients should be vigorously treated and may require admission to hospital. Healthcare personnel should therefore be familiar with the signs and symptoms of necrotising gingivitis/necrotising periodontitis, of their potential sequelae and of the need for immediate therapeutic intervention.

Osseointegration: biological events in relation to characteristics of the implant surface.

Osseointegration of titanium implants is a complex biological process involving interactions between immuno-inflammatory responses, angiogenesis and osteogenesis, all of which are influenced by the physical and chemical characteristics of the implant surface. An implant surface with moderately rough topography and high surface energy influences cellular activities, enhancing peri-implant bone wound healing. Primary mechanical stability of the implant is essential for osseointegration. In this article we review some of the more important biological events of peri-implant bone wound healing in the process of osseointegration, and discuss how the biophysical properties of implant surfaces influence cellular responses.

Oral HIV-associated Kaposi sarcoma.

Kaposi sarcoma (KS), an AIDS defining condition, remains one of the most commonly HIV-associated neoplasms. While the use of highly active antiretroviral therapy (HAART) has brought about a dramatic decrease in the prevalence and incidence of AIDS-KS worldwide, this has not been the case in resource-poor sub-Saharan African countries, where HIV has reached epidemic proportions and human herpesvirus-8 infection is endemic. Oral involvement is a common manifestation of AIDS-associated KS and may be an early presenting finding of HIV infection. The clinical manifestation of oral KS can vary and may have an unpredictable course ranging from mild to fulminant. Rapidly progressive facial lymphoedema associated with extensive advanced oral KS portends a poor prognosis. Oral KS may regress with antiretroviral therapy or may flare up as part of the immune reconstitution inflammatory syndrome. The oral lesions of AIDS-KS are best managed with HAART together with systemic chemotherapy. This article provides a review of contemporary knowledge of the biology, pathology, clinical features and management of oral AIDS-KS.

Alcohol and oral squamous cell carcinoma.

Alcohol is a risk factor for oral squamous cell carcinoma. It enhances the permeability of the oral epithelium, acts as a solvent for tobacco carcinogens, induces basal-cell proliferation, and generates free radicals and acetaldehyde, which have the capacity to cause DNA damage. Alcohol-associated malnutrition and immune suppression may further promote carcinogenesis. However, acetaldehyde, the first metabolite of ethanol, is the critical agent by which prolonged and excessive consumption of alcoholic beverages increases the risk of oral squamous cell carcinoma. Alcohol also acts synergistically with the products of tobacco combustion in the pathogenesis of oral squamous cell carcinoma.

Alveolar ridge preservation immediately after tooth extraction.

Ridge preservation procedures immediately after tooth extraction, are commonly used with a view to minimising remodelling and shrinkage of the alveolar ridge, associated with socket healing. These procedures may sometimes be effective, but they cannot completely prevent reduction in dimension of the ridge. Certain biomater als used may actually hamper normal deposition of bone within the healing socket, reducing bone trabeculae that can integrate with the implant surface. However, in extraction sockets in alveolar ridges of low bone density, particles of implanted bone substitute incorporated in the healing bone, may enhance the mechanical support for the implant, provided by normal healed bone of low trabecular density alone. This paper reviews biological rationales and procedures for ridge preservation immediately after extraction and comments on their clinical use.

Peri-implant mucositis and peri-implantitis: clinical and histopathological characteristics and treatment.

Osseointegrated dental implants are used routinely in dentistry in the confidence of predictable success. However, if the implant surfaces become colonised by pathogenic bacteria, the plaque-induced inflammation around the implants may cause peri-implant tissue destruction. Peri-implant mucositis is a reversible, plaque-induced inflammatory lesion confined to the peri-implant soft tissue unit and clinically is characterised by redness, swelling and bleeding on gentle probing. Peri-implantitis is an extension of peri-implant mucositis to involve the bone supporting the implant: it is characterised by loss of osseointegration of the coronal part of the implant, by increased probing depth and by bleeding and/or suppuration on probing. Established peri-implantitis does not respond predictably to treatment. The best management of plaque-induced peri-implant inflammatory diseases is prevention. Regular personal and professional cleaning of the implant is mandatory to minimise bacterial load. Despite our best efforts, plaque-induced peri-implant inflammatory diseases will occur frequently, and as these diseases respond best to early treatment, early detection of peri-implant mucositis by regular assessment will permit timely treatment. Peri-implant mucositis is readily treated non-surgically. Peri-implantitis is more difficult to treat largely because of the problem of decontamination of the roughened, threaded surfaces of exposed implants. As a rule, surgical treatment will be necessary, and even then success is not assured.

Peri-implant mucositis and peri-implantitis: bacterial infection.

Osseointegrated dental implants have a ong-term success rate of over 90%, but may be threatened by peri-implant mucostis and peri-implantitis, bacteria biofilm-induced inflammatory conditions. While peri-implant mucositis is a reversible inflammatory condition confined to the peri-implant soft-tissue unit, peri-implantitis is characterised by progressive inflammatory destruction of the crest of the alveolar bone supporting the implant, by increased peri-implant probing depths, and by bleeding and/or suppuration on probing. Effective treatment of peri-implant mucositis will prevent the development of peri-implantitis. Plaque accumulation on the implant/abutment surface juxtaposed to the junctional epithelium and to the connective tissue zone of the peri-implant soft-tissue unit induces the development of peri-implant mucositis which can subsequently progress to peri-implantitis. The aim of this paper is to review some aspects of bacterial infection of the tissue supporting dental implants, and to explore how to maintain the healthy peri-implant soft-tissue unit.

The peri-implant soft tissue unit: a literature review.

Restoration of the integrity of the dentition with endosseous implants is a treatment option made available to patients not only by specialists but increasingly also by non-specialist dental practitioners. Properly done implants at well-selected sites in suitable persons remain functionally and biologically sound for many years. An important factor n determining the success of implants s the integrity of the peri-implant soft tissue unit. Therefore, the implant placement protocol and the restorative protocol should be designed to favour the formation and maintenance of the peri-implant soft tissue unit. The purpose of this short review is to refresh the reader's knowledge of some important factors with regard to establishing and maintaining the integrity of the peri-implant soft tissue.

Discoid lupus erythematosus as it relates to cutaneous squamous cell carcinoma and to photosensitivity.

Lupus erythematosus is a chronic inflammatory autoimmune disease with diverse clinical manifestations ranging from an indolent chronic cutaneous form to a severe potentially life-threatening disease, systemic lupus erythematosus. Discoid lupus erythematosus is a subphenotype of chronic cutaneous lupus erythematosus, characterised by scaly disk-shaped plaques which may be localised or widespread, occurring predominantly on sun-exposed skin and which may rarely progress to squamous cell carcinoma. The pathogenesis of discoid LE comprises complex interactions between multiple susceptibility genes involved in immune responses and clearance of apoptotic cells on the one hand, and environmental factors on the other. Herein, we discuss some aspects of the pathogenesis of discoid lupus erythematosus in relation to ultraviolet radiation and malignant transformation.

Bisphosphonate-related osteonecrosis of the jaw.

Bisphosphonates are agents commonly used in the treatment of osteoporosis, and in the management of metastatic bone disease, and of hypercalcaemia of malignancy. Any oral surgical procedure or traumatic event exposing bone to bacterial infection may precipitate osteonecrosis of the jaw in subjects who have been treated with bisphosphonates which suppress bone turnover and inhibit the angiogenesis associated with healing. New guidelines for the treatment of bisphosphonate-related osteonecrosis of the jaw are emerging, but hitherto treatment has been empirically conservative.

HPV-associated oral warts.

Human papillomavirus (HPV) is strictly epitheliotropic, infecting stratified squamous cutaneous and mucosal epithelial cells. Oral HPV infection may be subclinical or putatively associated with benign or malignant oral neoplasms. The benign HPV-associated oral lesions, focal epithelial hyperplasia (Heck disease), oral squamous cell papilloma, oral verruca vulgaris (common wart) and oral condyloma acuminatum, are collectively referred to as oral warts. Oral warts are usually asymptomatic, may be persistent or uncommonly, may regress spontaneously. HPV-associated oral warts have a prevalence of 0.5% in the general population, occur in up to 5% of HIV-seropositive subjects, and in up to 23% of HIV-seropositive subjects on highly active antiretroviral therapy. This paper is a clinico-pathological review of HPV-associated oral warts.

Biological consequences of cancer radiotherapy in the context of oral squamous cell carcinoma.

Approximately 50% of subjects with cancer have been treated with ionizing radiation (IR) either as a curative, adjuvant, neoadjuvant or as a palliative agent, at some point during the clinical course of their disease. IR kills cancer cells directly by injuring their DNA, and indirectly by inducing immunogenic cell killing mediated by cytotoxic T cells; but it can also induce harmful biological responses to non-irradiated neighbouring cells (bystander effect) and to more distant cells (abscopal effect) outside the primary tumour field of irradiation.Although IR can upregulate anti-tumour immune reactions, it can also promote an immunosuppressive tumour microenvironment. Consequently, radiotherapy by itself is seldom sufficient to generate an effective long lasting immune response that is capable to control growth of metastasis, recurrence of primary tumours and development of second primary cancers. Therefore, combining radiotherapy with the use of immunoadjuvants such as immune checkpoint inhibitors, can potentiate IR-mediated anti-tumour immune reactions, bringing about a synergic immunogenic cell killing effect.The purpose of this narrative review is to discuss some aspects of IR-induced biological responses, including factors that contributes to tumour radiosensitivity/radioresistance, immunogenic cell killing, and the abscopal effect.

Xeroderma pigmentosum: a case report and review of the literature.

Inherited molecular defects in nucleotide excision repair genes cause the autosomal recessive condition xeroderma pigmentosum. Xeroderma pigmentosum is characterized by photo-hypersensitivity of sun-exposed tissues, and by a several thousand-fold increase in the risk of developing malignant neoplasms of the skin and of the eyes. Mutations in xeroderma pigmentosum genes that regulate nucleotide excision repair, not only predispose persons with xeroderma pigmentosum to multiple malignancies, but also promote premature cutaneous and ocular ageing, and in some cases promote progressive neurodegenerative changes. This paper describes a case of xeroderma pigmentosum with advanced cutaneous squamous cell carcinoma, actinic cheilitis and ocular lesions in a 19-year-old black woman. The extensive ultraviolet radiation-induced skin and eye damage are evidence of neglect of sun-protection and lack of appropriate medical care from childhood.

Facial lymphoedema as an indicator of terminal disease in oral HIV-associated Kaposi sarcoma.

Rapidly progressive facial lymphoedema developing concurrently with, or immediately after rapid enlargment of oral Kaposi sarcoma (KS) in HIV-seropositive highly active antiretroviral treatment (HAART)-naïve subjects, foretokens death. We present here an unusual case of HIV-KS in an 11-year-old HIV-seropositive HAART-naïve boy. Our patient's KS disease had had a fulminant course characterised by rapidly progressing oral HIV-KS, resorption of the mandibular alveolar bone process beneath some of the HIV-KS lesions, and rapidly progressive facial lymphoedema. He died 3 weeks after the onset of facial lymphoedema.

HIV-associated Kaposi sarcoma in African children.

HIV-associated Kaposi sarcoma (HIV-KS) is common in African countries where HIV infection is pandemic and anti-retroviral medication is not readily available. Human herpesvirus-8 (HHV-8), which is the essential, but not the sole aetiological factor in KS, is endemic in sub-Saharan Africa and is substantially more prevalent in HIV-seropositive than in HIV-seronegative subjects. In children in sub-Saharan Africa, KS, whether it be HIV-KS or African endemic KS is much more prevalent than any other epidemiological forms of KS. In addition, in sub-Saharan children oral KS is common, and the life-expectancy of HIV-seropositive children with KS is short. Since generalized systemic KS is frequently associated with oral HIV-KS, it is advisable to introduce systemic cytotoxic chemotherapy early in the course of oral HIV-KS. Although the introduction of highly active antiretroviral therapy (HAART) brought about a decline in the incidence of HIV-KS worldwide, HIV-KS remains a significant problem in sub-Saharan Africa where the prevalence of HHV-8 infection is high and access to HAART is limited.

The pathobiology and mechanisms of infection of HPV.

There are more than 120 types of low-risk and high-risk human papillomaviruses, all of which are epitheliotropic. HPV infection may be latent, or active in a subclinical form or a symptomatic form, the latter manifesting as benign or malignant neoplasms. In basal cells with non-productive HPV infection some early HPV proteins are expressed independently of cell maturation: the productive cycle of HPV replication depends upon specific cellular factors of the maturation of the infected keratinocytes. In HPV-mediated oncogenesis, the combined pathobiological effects of E6 and E7 oncoproteins of high-risk HPV culminate in cellular genomic instability and transformation of persistently infected cells, that progress to the development of a malignant phenotype. In this article we provide insights into the stages of HPV infection, and into the viral genomic organization and replicative cycle.