As the gateway to the body, the mouth is challenged by a constant barrage of invaders—bacteria, viruses, parasites, fungi. Thus infectious diseases, notably dental caries and periodontal diseases, predominate among the ills that can compromise oral health. Injuries take their toll as well, with the face and head particularly vulnerable to sports injuries, motor vehicle crashes, violence, and abuse. Less common but very serious are oral and pharyngeal cancers, with a 5-year survival rate of hardly better than 50 percent (Kosary et al. 1995). Birth defects and developmental disorders frequently affect the craniofacial complex. These appear most commonly as isolated cases of cleft lip or palate, but clefting or other craniofacial defects can also be part of complex hereditary diseases or syndromes. Additionally, acute and chronic pain can affect the oral-facial region, particularly in and around the temporomandibular (jaw) joint, and accounts for a disproportionate amount of all types of pain that drive individuals to seek health care.
Many systemic diseases such as diabetes, arthritis, osteoporosis, and AIDS, as well as therapies for systemic diseases, can directly or indirectly compromise oral tissues. The World Health Organization's International Classification of Diseases and Stomatology currently lists more than 120 specific diseases, distributed in 10 or more classes, that have manifestations in the oral cavity (WHO 1992).
This chapter concentrates on six major oral disease categories: dental and periodontal infections; mucosal disorders; oral and pharyngeal cancers; developmental disorders; injuries; and a sampling of chronic and disabling conditions, including Sjögren's syndrome and oral-facial pain. back to top
DENTAL AND PERIODONTAL INFECTIONS
The most common oral diseases are dental caries and the periodontal diseases. Individuals are vulnerable to dental caries throughout life, with 85 percent of adults aged 18 and older affected. Periodontal diseases are most often seen in maturity, with the majority of adults experiencing some signs and symptoms by the mid-30s. Certain rare forms of periodontal disease affect young people. The major oral health success story of the past half century is that both caries and periodontal diseases can be prevented by a combination of individual, professional, and community measures.back to top
The word caries derives from the Latin for rotten, and many cultures early on posited a tooth worm as the cause of this rottenness. By the twentieth century, caries came to describe the condition of having holes in the teeth—cavities. This description, although not incorrect, is misleading. In actuality, a cavity is a late manifestation of a bacterial infection.
The bacteria colonizing the mouth are known as the oral flora. They form a complex community that adheres to tooth surfaces in a gelatinous mat, or biofilm, commonly called dental plaque. A cariogenic biofilm at a single tooth site may contain one-half-billion bacteria, of which species of mutans streptococci are critical components. These bacteria are able to ferment sugars and other carbohydrates to form lactic and other acids. Repeated cycles of acid generation can result in the microscopic dissolution of minerals in tooth enamel and the formation of an opaque white or brown spot under the enamel surface (Mandel 1979). Frequency of carbohydrate consumption (Gustafsson et al. 1954), physical characteristics of food (e.g., stickiness), and timing of food intake (Burt and Ismail 1986) also play a role.
The essential role of bacteria in caries initiation was established in landmark experiments in the 1950s. Investigators observed that germ-free animals fed high-sugar diets remained caries-free until the introduction of mutans streptococci (a particular group of bacterial strains having a number of common characteristics, and which adhere tightly to the tooth). Later experiments demonstrated the transmissibility of the bacteria from mother to litter and from caries-infected to uninfected cage-mates (Fitzgerald and Keyes 1960). Species of Lactobacillus, Actinomyces, and other acid-producing streptococci within the plaque may also contribute to the process (Bowden 1990).
If the caries infection in enamel goes unchecked, the acid dissolution can advance to form a cavity that can extend through the dentin (the component of the tooth located under the enamel) to the pulp tissue, which is rich in nerves and blood vessels. The resulting toothache can be severe and often is accompanied by sensitivity to temperature and sweets. Treatment requires endodontic (root canal) therapy. If untreated, the pulp infection can lead to abscess, destruction of bone, and spread of the infection via the bloodstream.
Dental caries can occur at any age after teeth erupt. Particularly damaging forms can begin early, when developing primary teeth are especially vulnerable. This type of dental caries is called early childhood caries (ECC). Some 6 out of 10 children in the United States have one or more decayed or filled primary teeth by age 5 (U.S. Department of Health and Human Services, National Center for Health Statistics 1997). ECC may occur in children who are given pacifying bottles of juice, milk, or formula to drink during the day or overnight. The sugar contents pool around the upper front teeth, mix with cariogenic bacteria, and give rise to rapidly progressing destruction (Ripa 1988). Other risk factors for ECC include arrested development of tooth enamel, chronic illness, altered salivary composition and volume (resulting from the use of certain medications or malnourishment), mouth breathing, and blockage of saliva flow in a bottle-fed infant (Bowen 1998, Seow 1998).
Although there have been continuing reductions in dental caries in permanent teeth among children and adolescents over the past few decades, caries prevalence in the primary dentition may have stabilized or increased slightly in some population groups (Petersson and Bratthall 1996, Rozier 1995). Reductions in caries in permanent teeth also have been proportionately greater on the smooth surfaces rather than on the pit-and-fissure surfaces characteristic of chewing surfaces. The gingival tissues tend to recede over time, exposing the tooth root to cariogenic bacteria that can cause root caries. An important risk factor for root caries in older people is the use of medications that inhibit salivary flow, leading to dry mouth (xerostomia).
Saliva contains components that can directly attack cariogenic bacteria, and it is also rich in calcium and phosphates that help to remineralize tooth enamel. Demineralization of enamel occurs when pH levels fall as a result of acid production by bacteria. It can be reversed at early stages if the local environment can counteract acid production, restoring pH to neutral levels. Remineralization can occur through the replacement of lost mineral (calcium and phosphates) from the stores in saliva. Fluoride in saliva and dental plaque and the buffering capacity of saliva also contribute to this process. Indeed, it is now believed that fluoride exerts its chief caries-preventive effect by facilitating remineralization. Several studies have demonstrated that remineralization results in an increase in tooth hardness and mineral content, rendering the tooth surface more resistant to subsequent acid attack (Larsen 1987, Linton 1996, Retief 1983, Shannon 1978, Vissink et al. 1985, White 1988).
Overt caries lesions develop when there is insufficient time for remineralization between periods of acidogenesis, or when the saliva production is compromised. Over 400 medications list dry mouth as a side effect, notably some antidepressants, antipsychotics, antihistamines, decongestants, antihypertensives, diuretics, and antiparkinsonian drugs (Sreebny et al. 1992). The effects of xerostomia may be particularly severe in cancer patients receiving radiation to the head or neck because the rays can destroy salivary gland tissue rather than simply inhibiting salivary secretion.
The professional application of dental sealants (plastic films coated onto the chewing surfaces of teeth) is an important caries-preventive measure that complements the use of fluorides. The films prevent decay from developing in the pits and fissures of teeth, channels that are often inaccessible to brushing and where fluoride may be less effective.
The rate of caries progression through enamel is relatively slow (Berkey 1988, Ekanayake 1987, Shwartz et al. 1984) and may be slower in patients who have received regular fluoride treatment or who consume fluoridated water (Pitts 1983, Shwartz et al. 1984). Because a large percentage of enamel lesions remain unchanged over periods of 3 to 4 years, and because progression rates through dentin are comparably slow (Craig et al. 1981, Emslie 1959, Kolehmainen and Rytömaa 1977), the application of infection control and monitoring procedures to assess caries risk status, lesion activity status, evidence of lesion arrest, and evidence of lesion remineralization over extended periods of time is recommended.
Experts believe that the earlier mutans streptococci are acquired in infancy, the higher the caries risk. Most studies indicate that infants are infected before their first birthday, around the time the first incisors emerge. However, one study found the median age of acquisition to be 26 months, coinciding with the emergence of the primary molars (Bowen 1998, Caufield et al. 1993, Seow 1998). DNA fingerprinting has demonstrated that the source of transmission is usually the mother (Caufield et al. 1993).
It is not clear why some individuals are more susceptible and others more resistant to caries. Genetic differences in the structure and biochemistry of enamel proteins and crystals (Slavkin 1988), as well as variations in the quality and quantity of saliva and in immune defense mechanisms are among the factors under study. Analysis of mutans streptococci genomes may also shed light, indicating which species are particularly virulent and which genes contribute to that virulence.
Even the most protective genetic endowment and developmental milieu are unlikely to confer resistance to decay in the absence of positive personal behaviors. These include sound dietary habits and good oral hygiene, including the use of fluorides, and seeking professional care. There are indications, however, that some destructive oral habits are on the rise, such as the use of smokeless (spit) tobacco products by teenage boys. Although the chief concern here lies in the long-term risk for oral cancers, spit tobacco that contains high levels of sugar is also associated with increased levels of decay of both crown and root surfaces (Tomar and Winn 1998).back to top
Like dental caries, the periodontal diseases are infections caused by bacteria in the biofilm (dental plaque) that forms on oral surfaces. The basic division in the periodontal diseases is between gingivitis, which affects the gums, and periodontitis, which may involve all of the soft tissue and bone supporting the teeth. Gingivitis and milder forms of periodontitis are common in adults. The percentage of individuals with moderate to severe periodontitis, in which the destruction of supporting tissue can cause the tooth to loosen and fall out, increases with age.
Gingivitis is an inflammation of the gums characterized by a change in color from normal pink to red, with swelling, bleeding, and often sensitivity and tenderness. These changes result from an accumulation of biofilm along the gingival margins and the immune system's inflammatory response to the release of destructive bacterial products. The early changes of gingivitis are reversible with thorough toothbrushing and flossing to reduce plaque. Without adequate oral hygiene, however, these early changes can become more severe, with infiltration of inflammatory cells and establishment of a chronic infection. Biofilm on tooth surfaces opposite the openings of the salivary glands often mineralizes to form calculus or tartar, which is covered by unmineralized biofilm—a combination that can exacerbate local inflammatory responses (Mandel 1995). A gingival infection may persist for months or years, yet never progress to periodontitis.
Gingival inflammation does not appear until the biofilm changes from one composed largely of gram-positive streptococci (which can live with or without oxygen) to one containing gram-negative anaerobes (which cannot live in the presence of oxygen). Numerous attempts have been made to pinpoint which microorganisms in the supragingival (above the gum line) plaque are the culprits in gingivitis. Frequently mentioned organisms include Fusobacterium nucleatum, Veillonella parvula, and species of Campylobacter and Treponema. But as Ranney (1989) notes, "The complexity of the results defies any attempt to define a discrete group clearly and consistently associated with gingivitis."
Gingival inflammation may be influenced by steroid hormones, occurring as puberty gingivitis, pregnancy gingivitis, and gingivitis associated with birth control medication or steroid therapy. The presence of steroid hormones in tissues adjacent to biofilm apparently encourages the growth of certain bacteria and triggers an exaggerated response to biofilm accumulation (Caton 1989). Again, thorough oral hygiene can control this response.
Certain prescription drugs can also lead to gingival overgrowth and inflammation. These include the antiepileptic drug phenytoin (Dilantin); cyclosporin, used for immunosuppressive therapy in transplant patients; and various calcium channel blockers used in heart disease. Treatment often requires surgical removal of the excess tissue followed by appropriate personal and professional oral health care.
A form of gingivitis common 50 years ago but relatively rare today is acute necrotizing ulcerative gingivitis, also known as Vincent's infection or trench mouth. This aggressive infection is characterized by destruction of the gingiva between the teeth, spontaneous bleeding, pain, and oral odor. People under extreme stress have an increased susceptibility. Spirochetes and other bacteria have been found in the connective tissue of those affected. An association between smoking and this type of gingivitis is well recognized and was demonstrated as early as 1946 (Pindborg 1947, 1949). This condition has been seen in some HIV-positive patients (Murray 1994). Treatment requires a combination of professional periodontal treatment and antibacterial therapy along with professional smoking cessation assistance as appropriate.
The most common form of adult periodontitis is described as general and moderately progressing; a second form is described as rapidly progressing and severe, and is often resistant to treatment. The moderately progressive adult form is characterized by a gradual loss of attachment of the periodontal ligament to the gingiva and bone along with loss of the supporting bone. It is most often accompanied by gingivitis (Genco 1990). It is not necessarily preceded by gingivitis, but the gingivitis-related biofilm often seeds the subgingival plaque. The destruction of periodontal ligament and bone results in the formation of a pocket between the tooth and adjacent tissues, which harbors subgingival plaque. The calculus formed in the pocket by inflammatory fluids and minerals in adjacent tissues is especially damaging (Mandel and Gaffar 1986).
The severity of periodontal disease is determined through a series of measurements, including the extent of gingival inflammation and bleeding, the probing depth of the pocket to the point of resistance, the clinical attachment loss of the periodontal ligament measured from a fixed point on the tooth (usually the cemento-enamel junction), and the loss of adjacent alveolar bone as measured by x-ray (Genco 1996). Severity is determined by the rate of disease progression over time and the response of the tissues to treatment.
Adult periodontitis often begins in adolescence but is usually not clinically significant until the mid-30s. Prevalence and severity increase but do not accelerate with age (Beck 1996). One view proposes that destruction occurs at a specific site during a defined period, after which the disease goes into remission (Socransky et al. 1984). The current view is that the disease process may not be continuous but rather progresses in random bursts in which short periods of breakdown of periodontal ligament and bone alternate with periods of quiescence. These episodes occur randomly over time and at random sites in the mouth. Part of the difficulty in determining the pattern of progression reflects variation in the sensitivity of the instruments used to measure the loss of soft tissue and bone. The latest generation of probes finds evidence of both continuous and multiple-burst patterns of loss in different patients and at different times (Jeffcoat and Ready 1991).
Most researchers agree that periodontitis results from a mixed infection but that a particular group of gram-negative bacteria are key to the process and markedly increase in the subgingival plaque. The bacteria most frequently cited are Porphyromonas gingivalis, Prevotella intermedia, Bacteroides forsythus, Treponema denticola, and Actinobacillus actinomycetemcomitans (Genco 1996). Their role in disease initiation and progression is determined in part by their "virulence factors." These include the ability to colonize subgingival plaque, generate products that can directly injure tissues, and elicit an inflammatory or immune response. The potentially noxious bacterial products include hydrogen sulfide, polyamines, the fatty acids butyrate and propionate, lipopolysaccharide (also known as endotoxin), and a number of destructive enzymes. The interaction of this arsenal with the host response is at the core of periodontal pathology (Genco 1992, Socransky and Haffajee 1991, 1992). Sequencing of the genomes of several key periodontal pathogens is under way and should provide further insight into these pathogens as well as catalyze new treatment approaches.
Delicate Balances. Neutrophils (a type of white blood cell) and antibodies are the major immune defenses against bacterial attack. Neutrophils move to the site of infection, where they engulf bacteria and elaborate antibacterial agents and enzymes to destroy bacteria. Although stimulation of the immune system to attack the offending bacteria is generally protective, immune hyperresponsiveness and hypersensitivity can be counterproductive, leading to the destruction of healthy tissue. Nevertheless, the neutrophil/antibody axis is critical for full protection against periodontal diseases (Genco 1992).
Also important is the release of certain potent molecules called cytokines and prostaglandins, especially prostaglandin E2 (PGE2) which can contribute to tissue destruction. Cytokines are proteins secreted by immune cells that help regulate immune responses and also affect bone, epithelial, and connective tissues. Most prominent in periodontal diseases are interleukin 1 (IL-1), tumor necrosis factor alpha (TNF-gamma), and interferon gamma (IFN-gamma). These cytokines mediate the processes of bone resorption and connective tissue destruction.
Susceptibility and Resistance. PGE2 may play a central role in the tissue destruction that occurs in periodontal diseases. Levels of PGE2 in periodontal tissue are low or undetectable in health, increase in gingivitis, and rise significantly in periodontitis. Now there is increasing evidence that the level of PGE2 produced in response to bacterial challenge (especially by endotoxin) can be used as a measure of susceptibility (Offenbacher et al. 1993).
Presumably, the level of PGE2 production is subject to genetic influence. Studies of identical and fraternal twins, either reared together or apart, provide evidence that genetic factors may indeed influence susceptibility or resistance to the common adult form of periodontitis (Michalowicz 1994). Recently, a commercial test for a genetic marker of susceptibility has been introduced. The marker is associated with increased production of a particular form of interleukin 1-beta (IL-1-beta) when stimulated by periodontopathic bacteria (Kornman et al. 1997). Newman (1996) found that nonsmoking adults who are positive for the marker are 6 to 19 times more likely to develop severe periodontitis.
Susceptibility to adult periodontitis has also been explored in relation to a variety of behavioral and demographic variables as well as to the presence of other diseases. One of the strongest behavioral associations is with tobacco use. The risk of alveolar bone loss for heavy smokers is 7 times greater than for those who have not smoked (Grossi et al. 1995). Cigarette smoking also may impair the normal host response in neutralizing infection (Seymour 1991), resulting in the destruction of healthy periodontal tissues adjacent to the site of infection (Lamster 1992). Smokers also have decreased levels of salivary and serum immunoglobulins to Prevotella intermedia and Fusobacterium nucleatum (Bennet and Reade 1982, Haber 1994) and depressed numbers of helper T cells as well (Costabel et al. 1986). Finally, smoking alters the cells that engulf and dispose of bacteria—neutrophils and other phagocytes—affecting their ability to clear pathogens (Barbour et al. 1997).
Epidemiologic studies have found that such additional factors as increasing age, infrequent dental visits, low education level, low income, co-morbidities, and inclusion in certain racial or ethnic populations are associated with increased prevalence of periodontitis (Page 1995). It is important that epidemiologic studies also take into consideration the fact that tobacco use, oral hygiene, professional prophylaxis, and routine dental care are correlated to socioeconomic status, as are race and ethnicity. Sex is another factor. Males tend to have higher levels of periodontal diseases, presumably because of a history of greater tobacco use and differences in personal care and frequency of dental visits. However, female hormones may play a protective role (as they do in protecting against osteoporosis) (Genco 1996).
Certain systemic diseases heighten susceptibility. Epidemiological studies have confirmed that patients with diabetes mellitus, both type 1 and type 2, are more susceptible to periodontal diseases (Genco 1996). Measures such as the gingival index, pocket depth, and loss of attachment are more severe if the diabetic patients are smokers (Bridges et al. 1996). The likelihood of periodontal disease increases markedly when diabetes is poorly controlled. In contrast, periodontal diseases respond well to therapy and can be managed successfully in patients with well-controlled diabetes. Such therapy can result in improvements in the diabetic condition itself (Mealey 1996) (see Chapter 5).
There is some evidence that osteoporosis may be a risk factor for periodontal disease. More clinical attachment loss and edentulousness have been reported in osteoporotic than in nonosteoporotic women (Jeffcoat and Chestnut 1993). Two studies in 1996 showed that estrogen replacement therapy in postmenopausal women not only gives protection against osteoporosis, but also results in fewer teeth lost to periodontal disease (Grodstein et al. 1996, Jacobs et al. 1996).
The less common rapidly progressive form of adult periodontitis typically affects people in their early 20s and 30s. It is characterized by severe gingival inflammation and rapid loss of connective tissue and bone. Many patients have an inherent defect in neutrophil response to infection. Several systemic diseases have been associated with this form of periodontal disease, including type 1 diabetes, Down syndrome, Papillon-Lefevre syndrome, Chediak-Higashi syndrome, and HIV infection (Caton 1989). Specific bacteria associated with rapidly progressive disease include Porphyromonas gingivalis, Prevotella intermedia, Eikenella corrodens, and Wolinella recta (Scheutz et al. 1997). Most recently, mutations in the cathepsin C gene have been associated with the Papillon-Lefevre syndrome (Hart et al. 1999) and how the defect can result in periodontal disease (Toomers et al. 1999).
Refractory Periodontitis. Refractory periodontitis is not a specific form of disease, but refers to cases in which patients continue to exhibit progressive disease at multiple sites despite aggressive mechanical therapy to remove biofilm and calculus, along with the use of antibiotics. Refractory sites exhibit elevated levels of a number of different bacteria, with the dominant species different in different subjects. It is not known whether variations in pathogenicity of the bacteria, defects in the subject's defense systems, or combinations of these factors are responsible for the refractory nature of the disease (Haffajee et al. 1988). The adoption of new diagnostic technology to detect predominant bacterial species, followed by selective antibiotic treatment, may help resolve infection and disease in these patients.
The forms of periodontitis occurring in adolescents and young adults generally involve defects in neutrophil function (Van Dyke et al. 1980). Localized juvenile periodontitis (LJP) mainly affects the first molar and incisor teeth of teenagers and young adults, with rapid destruction of bone but almost no telltale signs of inflammation and very little supragingival plaque or calculus. Actinobacillus actinomycetemcomitans has been isolated at 90 to 100 percent of diseased sites in these patients, but is absent or appears in very low frequency in healthy or minimally diseased sites (Socransky and Haffajee 1992). It is possible that the bacteria are transmitted among family members through oral contacts such as kissing or sharing utensils, because the same bacterial strain appears in affected family members. However, evidence of a neutrophil defect argues for a genetic component. Another organism frequently associated with LJP is Capnocytophaga ochracea. Neither of these bacteria dominate in the generalized adult form of the disease, where Porphyromonas gingivalis is considered of greatest significance (Schenkein and Van Dyke 1994).
Prepubertal periodontitis is rare and can be either general or localized. The generalized form begins with the eruption of the primary teeth and proceeds to involve the permanent teeth. There is severe inflammation, rapid bone loss, tooth mobility, and tooth loss. The localized form of the disease is less aggressive, affecting only some primary teeth. The infection involves many of the organisms associated with periodontitis, but the mix may differ somewhat, with Actinobacillus actinomycetemcomitans, Prevotella intermedia, Eikenella corrodens, and several species of Capnocytophaga implicated (Caton 1989). Defects in neutrophil function noted in both forms of the disease (Schenkein and Van Dyke 1994) may explain why patients are highly susceptible to other infections as well (Suzuki 1988).back to top
SELECTED MUCOSAL INFECTIONS AND CONDITIONS
Like the skin, the mucosal lining of the mouth serves to protect the body from injury. This lining is itself subject to a variety of infections and conditions, ranging from benign canker sores to often fatal cancers. back to top
Chronic hyperplastic candidiasis is a red or white lesion that may be flat or slightly elevated and may adhere to soft or hard tissue surfaces, including dental appliances. It is caused by species of Candida, especially Candida albicans, the most common fungal pathogen isolated from the oral cavity. Normally, the fungi are present in relatively low numbers in up to 65 percent of healthy children and adults and cause no harm (McCullough et al. 1996). Problems arise when there is a change in oral homeostatis—the normal balance of protective mechanisms and resident oral flora that maintain the health of the oral cavity—so that defense mechanisms are compromised (Scully et al. 1994). Under these circumstances the fungal organisms can overgrow to cause disease. A primary disruption in homeostasis occurs with the use of antibiotics and corticosteroids, which can markedly change the composition of the oral flora. Deficiencies in the immune and endocrine systems are also important. Indeed, the diagnosis of candidiasis in an otherwise seemingly healthy young adult may be the first sign of HIV infection. Other causes of candidiasis include cancer chemotherapy or radiotherapy to the head and neck, xerostomia resulting from radiation to the head and neck, medications, chronic mucosal irritation, certain blood diseases, and other systemic conditions. Also, tobacco use has been identified as a cofactor.
Candidiasis often causes symptoms of burning and soreness as well as sensitivity to acidic and spicy foods. Patients may complain of a foul taste in the mouth. However, it can also be asymptomatic. Genomic analysis of the Candida albicans genome is helping investigators identify numerous genes that code for virulence factors, including enzymes that can facilitate adhesion to and penetration of mucous membranes. At the same time, researchers are exploring novel gene technologies to increase production of a family of native salivary proteins, the histatins, that have known anticandidal and other antimicrobial effects.
The most common form of oral candidiasis is denture stomatitis. It occurs when tissues are traumatized by continued wearing of ill-fitting or inadequately cleaned dental appliances and is described as chronic erythematous candidiasis. Another form, candidal angular cheilosis, occurs in the folds at the angles of the mouth and is closely associated with denture sore mouth (Tyldesley and Field 1995). Other common forms of Candida infection are pseudomembranous candidiasis (thrush), which may affect any of the mucosal surfaces, and acute erythematous candidiasis, a red and markedly painful variant commonly seen in AIDS patients.
In most cases, Candida infection can be controlled with antifungal medications used locally or systemically. Control is difficult, however, in patients with immune dysfunction, as in AIDS, or other chronic debilitating diseases. Often the organisms become resistant to standard therapy, and aggressive approaches are necessary (Tyldesley and Field 1995). The spread of oral candidiasis to the esophagus or lungs can be life-threatening and is one of the criteria used to define frank AIDS (Samaranayake and Holmstrup 1989).back to top
Herpes Simplex Virus Infections
In any given year, about one-half-million Americans will experience their first encounter with the herpes simplex virus type 1 (HSV-1), the cause of cold sores. That first encounter usually occurs in the oral region and may be so mild as to go unnoticed. But in some people, particularly young children and young adults, infection may take the form of primary herpetic stomatitis, with symptoms of malaise, muscle aches, sore throat, and enlarged and tender lymph nodes, prior to the appearance of the familiar cold sore blisters. These blisters usually show up on the lips, but any of the mucosal surfaces can be affected. Bright-red ulcerated areas and marked gingivitis may also be seen (Tyldesley and Field 1995).
Herpes viruses also cause genital infections, which are transmitted sexually. Both HSV-1 and HSV-2 have been found in oral and genital infections, with HSV-1 predominating in oral areas and HSV-2 in genital areas (Wheeler 1988). Herpes viruses have also been implicated as cofactors in the development of oral cancers. Crowded living conditions can result in greater contact with infected individuals, which aids in transmission of HSV (Whitley 1992).
Normally, the immune system mounts a successful attack on the viruses, with symptoms abating by the time neutralizing antibodies appear in the bloodstream, in about 10 days. However, herpes viruses are notorious for their ability to avoid immune detection by taking refuge in the nervous system, where they can remain latent for years. In oral herpes the virus commonly migrates to the nearby trigeminal ganglion, the cluster of nerve cells whose fibers branch out to the face and mouth. In about 20 to 40 percent of people who are virus-positive, the virus may reactivate, with infectious virus particles moving to the oral cavity to cause recurrent disease (Scott et al. 1997).
The usual site of a recurrent lesion is on or near the lips. Recurrences are rarely severe, and lesions heal in 7 to 10 days without scarring (Higgins et al. 1993). The recurrences may be provoked by a wide range of stimuli, including sunlight, mechanical trauma, and mild fevers such as occur with a cold. Emotional factors may play a role as well.
back to top
Oral Human Papillomavirus Infections
There are more than 100 recognized strains of oral human papillomavirus (HPV), a member of the papovavirus family, implicated in a variety of oral lesions (Regezi and Sciubba 1993). Most common are papillomas (warts) found on or around the lips and in the mouth. HPV is found in 80 percent of these oral squamous papillomas (de Villiers 1989). The virus has also been identified in 30 to 40 percent of oral squamous cell carcinomas (Chang et al. 1990) and has been implicated in cervical cancer as well. Whether a cancer or nonmalignant wart develops may depend on which virus is present or on which viral genes are activated.
Oral warts are most often found in children, probably as a result of chewing warts on the hands. In adults, sexual transmission from the anogenital region can occur (Franchesi et al. 1996).
In general, viral warts spontaneously regress after 1 or 2 years. The immune system normally keeps HPV infections under control, as evidenced by the increased prevalence of HPV-associated lesions in HIV-infected patients and others with immunodeficiency.
back to top
Recurrent Aphthous Ulcers
Recurrent aphthous ulcers (RAU), also referred to as recurrent aphthous stomatitis, is the technical term for canker sores, the most common and generally mild oral mucosal disease. Between 5 and 25 percent of the general population is affected, with higher numbers in selected groups, such as health professional students (Axéll et al. 1976, Embil et al. 1975, Ferguson et al. 1984, Kleinman et al. 1991, Ship 1972, Ship et al. 1967).
The disease takes three clinical forms: RAU minor, RAU major, and herpetiform RAU. The minor form accounts for 70 to 87 percent of cases. The sores are small, discrete, shallow ulcers surrounded by a red halo appearing at the front of the mouth or the tongue. The ulcers, which usually last up to 2 weeks, are painful and may make eating or speaking difficult. About half of RAU patients experience recurrences every 1 to 3 months; as many as 30 percent report continuous recurrences (Bagan et al. 1991).
RAU major accounts for 7 to 20 percent of cases and usually appears as 1 to 10 larger coalescent ulcers at a time, which can persist for weeks or months (Bagan et al. 1991). Herpetiform RAU has been reported as occurring in 7 to 10 percent of RAU cases. The ulcers appear in crops of 10 to 100 at a time, concentrating in the back of the mouth and lasting for 7 to 14 days (Bagan et al. 1991, Rennie et al. 1985).
RAU can begin in childhood, but the peak period for onset is the second decade (Lehner 1968). About 50 percent of close relatives of patients with RAU also have the condition (Ship 1965), and a high correlation of RAU has been noted in identical but not fraternal twins. Associations have been found between RAU and specific genetic markers (Scully and Porter 1989).
RAU has also been associated with hypersensitivities to some foods, food dyes, and food preservatives (Woo and Sonis 1996). Nutritional deficiencies—especially in iron, folic acid, various B vitamins, or combinations thereof—have also been reported, and improvements noted with suitable dietary supplements (Nolan et al. 1991).
The two factors that have been found to have the strongest association with RAU are immunologic abnormality, possibly involving autoimmunity, and trauma (Lehner 1968, Ship 1996, Woo and Sonis 1996).
Volunteers with and without a history of RAU were studied for their reaction to the trauma of a needle prick to the inner cheek tissue. No ulcers developed in non-RAU subjects, but nearly half of those prone to canker sores had a recurrence (Wray et al. 1981).
RAU also can occur in a number of systemic diseases, including HIV infection, ulcerative colitis, Crohn's disease, and Behçet's disease (Ship 1996). In general, people who are immunocompromised are more susceptible to RAU, as are people with a variety of blood diseases.
RAU itself does not give rise to other illnesses but is uncomfortable. Symptomatic treatment includes topical analgesics, antibacterial rinses, topical corticosteroids, and a new prescription medication that reduces pain and healing time (Khandwala et al. 1997, Ship 1996).
back to top
ORAL AND PHARYNGEAL CANCERS AND PRECANCEROUS LESIONS
In 2000, oral or pharyngeal cancer will be diagnosed in an estimated 30,200 Americans and will cause more than 7,800 deaths (Greenlee et al. 2000). Over 90 percent of these cancers are squamous cell carcinomas—cancers of the epithelial cells. The most common oral sites are on the tongue, the lips, and the floor of the mouth. Oral cancer is the sixth most common cancer in U.S. males and takes a disproportionate toll on minorities; it now ranks as the fourth most common cancer among African American men (Kosary et al. 1995). The prominent role of tobacco use, especially in combination with alcohol, in causing these cancers is a major incentive to develop effective health promotion and disease prevention efforts.
back to top
Heightening the Risk
Oral cancer develops as a clone from a single genetically altered cell (Solt 1981). It generally has a long latency period and invariably develops from a precancerous lesion on the oral mucosa, such as a white leukoplakia, or more commonly, a reddish erythroplakia (Mashberg 1978, Shklar 1986). Both kinds of lesions are usually induced by tobacco use alone or in combination with heavy use of alcohol. The development of squamous cell carcinoma from initial erythroplakia lesions has been well demonstrated experimentally. Silverman (1998) reported rates of malignant transformation for leukoplakias of between 0.13 and 17.5 percent. However, there is considerable debate as to the actual malignant potential of the leukoplakia lesion associated with the use of smokeless (spit) tobacco. Meaningful data for determining a specific malignant transformation rate or relative risk of oral cancer due to smokeless tobacco use are difficult to obtain because of the confounding effects of other habits such as concurrent smoking and alcohol consumption and because of the variations in smokeless (spit) products and how they are used.
Another oral precancerous lesion that has received attention is submucous fibrosis. It is commonly seen in India and Southeast Asia and is related to betel nut use (Canniff et al. 1986).
Early epidemiologic studies identified behaviors such as smoking and environmental factors such as exposure to solar radiation and x-rays as causes of intraoral and lip cancers (Pindborg 1977). Researchers then sought experimentally to explain the mechanisms of initiation. In the 1980s and 1990s, investigators exploited the techniques of molecular biology and genetics to probe what was going on deep inside the cell. These studies revealed an abundance of systemic and local factors, including viral and fungal infections, that affect cell behavior. Some factors stimulate cell division and others inhibit it—even to the point of initiating a program of cell "suicide," called apoptosis. How a given cell behaves at any given time in its life cycle is the net result of the signals it receives from neighboring cells and molecules, from circulating factors in the blood or immune system, and from its own internal controls. The following sections provide a brief description of these factors and how they may participate in enhancing the risk for the development of oral cancers.
Tobacco and Alcohol
Tobacco and alcohol are the major risk factors for oral cancers, and their effects have been studied for many years (Rothman and Keller 1972, Decker and Goldstein 1982). Tobacco contains substances that are frankly carcinogenic or act as initiators or promoters of carcinogenesis. Among these are N-nitrosonornicotine, 4-nitroquinoline-N-oxide, and benzpyrene. The most damaging carcinogens are found in the tars of tobacco smoke, but many forms of smokeless (spit) tobacco, including snuff, have been implicated in the development of mouth cancer (Advisory Committee to the Surgeon General 1986, International Agency for Research on Cancer 1985, Winn 1984). Other habits that have been related to oral cancer include chewing betel nut in the presence of tobacco, as is done primarily in Southeast Asia (Hirayama 1966, Mehta et al. 1981), and, more recently, using marijuana (Donald 1986).
The role of alcohol in oral carcinogenesis has been demonstrated experimentally (Wight and Ogden 1998) and appears to be related to its damaging effect on the liver. Major metabolites of alcohol, such as acetaldehyde—a known carcinogen in animals—may also be important. Alcohol is also thought to act as a solvent that facilitates the penetration of tobacco carcinogens into oral tissues. That observation may partly explain why the combined use of tobacco and alcohol produces a greater risk for oral cancer than use of either substance alone. Indeed, tobacco and alcohol, working in tandem, are thought to account for 75 to 90 percent of all oral and pharyngeal cancers in the United States (Blot et al. 1988).
The role of viruses in causing cancer in animals was established early in the century when Rous showed that a virus, later named the Rous sarcoma virus (RSV), caused tumors in chickens. The issue of whether viruses could cause cancer in humans remained unexplored until the mid-1970s, when Varmus and Bishop showed that RSV had a special gene, which they called src (for sarcoma), that could transform the cell it infected into a malignant cell (Bishop et al. 1978). It was an oncogene, or cancer-causing gene. The researchers subsequently, and surprisingly, discovered that src was not native to the virus, but had been picked up by some ancestor virus from a chicken cell's own genome, where src had presumably played a role in the chicken cell's normal growth and development. Somehow RSV was able to subvert src when it infected a chicken cell to cause the cell to divide uncontrollably. Varmus and Bishop called the normal cellular src gene a proto-oncogene, meaning that it had the potential to be converted to an oncogene. Subsequent research led to the discovery of other viruses that could cause tumors in animals and revealed the presence of proto-oncogenes in birds and mammals. These genes could also be converted to oncogenes, behaving exactly like those carried by cancer viruses. In 1982 an oncogene isolated from a human bladder cancer turned out to be virtually identical to ras, the oncogene found in a rat sarcoma virus (Parada et al. 1982).
Viruses that have been implicated in oral cancer include herpes simplex type 1 and human papillomavirus. Epstein-Barr virus, also a herpes virus, is now accepted as an oncogenic virus responsible for Burkitt's lymphoma, occurring primarily in Africa, and nasopharyngeal carcinoma, occurring primarily in China. HPV is a major etiologic agent in cervical cancer (Howley 1991), and has been found in association with oral cancer as well (Sugerman and Shillitoe 1997). HPV DNA sequences have been found in oral precancerous lesions as well as in squamous cell carcinomas (Adler-Storthz et al. 1986, Syrjanen et al. 1988), and experimental evidence has shown that HPV-16 can be an important cofactor in oral carcinogenesis (Park et al. 1991, 1995). Herpes simplex type 1 antibodies were demonstrated in patients with oral cancer, and herpes was found to induce dysplasia (abnormal cellular changes) in the lips of hamsters when combined with the application of tobacco tar condensate (Park et al. 1986).
More recently, human herpes virus 8, a newly identified member of the herpes virus family, has been found in Kaposi's sarcoma, an otherwise rare cancer occurring in patients with AIDS. These tumors often appear initially within the oral cavity (Epstein and Scully 1992). Other uncommon oral malignant tumors, such as Hodgkin's lymphoma and non-Hodgkin's lymphoma, can also occur in the mouths of AIDS patients.
In addition to viruses, infection with strains of the fungus Candida albicans has been linked to the development of oral cancers via the fungal production of nitrosamines, which are known carcinogens.
Of the more than 50 known oncogenes, many have been reported to be present in oral cancer, and multiple oncogenes have been reported in oral and pharyngeal cancer (Spandidos et al. 1985). Some of these are Bcl-1, c-erb-B2, c-myc, ins-2, and members of the ras family (Berenson et al. 1989, Bos 1989, Riviere et al. 1990, Somers et al. 1990, 1992).
The genetic derangements that can give rise to oral cancer, including many mutations associated with the transformation of proto-oncogenes, have received notable attention (Sidransky 1995, Wong et al. 1996). In some instances a change in a single nucleotide base—a point mutation—in a gene encoding a proto-oncogene is enough to transform it into an oncogene. Cancerous changes may also involve alterations, deletions, and break points in chromosomes that affect the position of genes.
Mutations that disarm the cell's DNA repair mechanisms, as well as mutations in tumor suppressor genes, which inhibit abnormal cell growth, play a major role in cancer development. If an individual inherits or acquires a mutation in one or more tumor-suppressor genes, for example, the loss of this protective mechanism reduces the number of other deleterious changes needed for cancer to develop.
Tumor suppressor genes suspected to be mutated in oral and pharyngeal cancers include those for Rb, p16 (MTS1, CDKN2, or IN4a), and p53. Todd et al. (1995) recently reported a novel oral tumor suppressor gene, named "deleted in oral cancer-1 (doc-1)." Of the group of tumor suppressor genes, that coding for p53 is considered of major importance, with mutations in the p53 gene detected in many types of cancer (Greenblatt et al. 1994, Hollstein et al. 1991), including oral and pharyngeal cancer (Langdon and Partridge 1992, Somers et al. 1992). The p53 gene has been called the "guardian of the genome" (Lane 1992) because of its ability to recognize damage to a cell's DNA and stop the process of growth and division until the damage is repaired. If repair is not possible, p53 can trigger apoptosis. Mutations in the p53 gene in oral cancer have been linked to smoking and alcohol use (Brennan et al. 1995).
Loss of Immunosurveillance and Control
The immune system can, as first noted by Paul Ehrlich in 1909, seek and destroy initial clones of transformed cancer cells (Ehrlich 1957). Ehrlich called this process immunosurveillance, and it has been confirmed in experimental animals (Burnet 1970, Shklar et al. 1990) and in humans with induced immunosuppression (Penn 1975).
One mechanism of immunosurveillance involves stimulating cytotoxic macrophages and lymphocytes to migrate to the tumor site and release tumor necrosis factors alpha and beta (Shklar and Schwartz 1988). Another mechanism operative in oral cancer appears to be stimulation of Langerhans cells, a special group of immune cells, in the oral mucosa (Schwartz et al. 1985). Other immune cells implicated in tumor rejection are natural killer cells and lymphokine-activated killer cells (Reif 1997).
There is an increased incidence of cancer in patients with AIDS or other immunodeficient conditions or with induced immunosuppression prior to organ transplantation.
In addition, there is evidence that smoking depresses the immune system (Chretien 1978), and this may be one of the ways in which smoking acts as a major risk factor in oral cancer.
Immune cells are potent generators of growth factors and other molecules that can stimulate other cells to migrate and proliferate. This capacity is important in normal cell growth and turnover, in wound healing, and in coping with infection. Unfortunately, the release of growth factors can contribute to oral cancer by stimulating keratinocyte (oral epithelial cell) proliferation (Aaronson 1991, Issing et al. 1993, Wong 1993). Increased levels of transforming growth factor alpha (TGF-alpha) and epidermal growth factor have been found in oral and pharyngeal cancers and therefore could serve as markers for malignancy (Grandis and Tweardy 1993). Nicotine at high doses stimulates the release of growth hormones, among other endocrine effects (Pomerleau and Pomerleau 1984, Seyler et al. 1984, 1986).
back to top
Prevention and Management
Studies of experimental carcinogenesis are elucidating the role of micronutrients in tumor development and progression. Alpha tocopherol (vitamin E) also has been studied as an antioxidant in nutritional approaches to the prevention or control of oral cancer. Antioxidants can trap free radicals, the highly reactive molecules that build up in cells and can damage DNA. The control of oral cancer and precancerous lesions has been demonstrated experimentally using a variety of antioxidant micronutrients, such as retinoids, carotenoids, and glutathione, as well as alpha tocopherol. For example, it was found that alpha tocopherol inhibited tumor development and tumor angiogenesis (blood vessel formation) in hamsters, as well as the expression of TGF-alpha, a potent angiogenesis stimulator (Shklar and Schwartz 1996). Animal research and tissue culture studies using animal- and human-derived cancer cell lines have shown combinations of micronutrients to be more effective than single micronutrients and to work synergistically. The nutrients not only were able to inhibit experimental carcinogenesis, but also could completely prevent tumor development and cause established squamous cell carcinomas to regress (Shklar and Schwartz 1993). The mechanisms of cancer control by micronutrients are gradually becoming clarified and involve common pathways of activity at the molecular level (Shklar and Schwartz 1994). Clinical studies in humans have shown an inhibitory effect on oral leukoplakia (Benner et al. 1993, Blot et al. 1993, Garewal 1993, Garewal et al. 1990, Hong et al. 1986), suggesting a potential role for nutrients in the overall prevention and management of early oral cancer and precancerous leukoplakia. However, a recommendation to employ such approaches clinically at this time is premature.
back to top
The importance of the face as the bearer of identity, character, intelligence, and beauty is universal. Craniofacial birth defects, which can include such manifestations as cleft lip or palate, eyes too closely or widely spaced, deformed ears, eyes mismatched in color, and facial asymmetries, can be devastating to the parents and child affected. Surgery, dental care, psychological counseling, and rehabilitation may help to ameliorate the problems but often at great cost and over many years.
Although each developmental craniofacial disease or syndrome is relatively rare, the number of children affected worldwide is in the millions. In addition, craniofacial defects form a substantial component of many other developmental birth defects, largely because they occur very early in gestation, when many of the same genes that orchestrate the development of the brain, head, face, and mouth are also directing the development of the limbs and many vital internal organs, such as the heart, lungs, and liver.
By about the third week after fertilization, the three germ layers of the embryo—the ectoderm, endoderm, and mesoderm—have formed, as well as the first of four sets of paired swellings—the branchial arches—that appear at the sides of the head end of the embryo. (See Chapter 2 for more details on this process.) Some craniofacial defects result from failure of the arches to complete their morphogenetic development. Other craniofacial defects are the result of the abnormal differentiation of cells derived from the ectoderm and endoderm or from ectomesenchyme cells, which originate in a part of the ectoderm (the neural crest), in interaction with future connective tissue (the mesenchyme).
back to top
Craniofacial Anomalies Caused by Altered Branchial Arch Morphogenesis
Cleft Lip/Palate and Cleft Palate
The most common of all craniofacial anomalies—and among the most common of all birth defects—are clefts of the lip with or without cleft palate and cleft palate alone; these occur at a rate of 1 to 2 out of 1,000 births, resulting in over 8,000 affected newborns every year. Cleft lip/palate and cleft palate are distinct conditions with different patterns of inheritance and embryological origins (Lidral et al. 1997, Murray et al. 1997). The male to female ratio of cleft lip/palate is 2:1; the ratio for cleft palate alone is just the reverse, 1:2.
These anomalies result from the failure of the first branchial arches to complete fusion processes (Murray 1995, Robert et al. 1996). Clefting can occur independently or as part of a larger syndrome that may include mental retardation and defects of the heart and other organs. Not all cases of clefting are inherited; a number of teratogens (environmental agents that can cause birth defects) have been implicated, as well as defects in essential nutrients such as folic acid. Smoking by the mother during pregnancy also increases the risk. It is becoming increasingly evident that most diseases and disorders, not just craniofacial anomalies, result from interactions involving multiple genes and environmental factors.
Infants with clefts have difficulty with vital oral functions such as feeding, breathing, speaking, and swallowing. They are also susceptible to repeated respiratory infections. As these children grow, they must cope with the social consequences of a facial deformity, delayed and altered speech, frequent illness, and repeated surgeries that may persist through late adolescence.
Current molecular epidemiology investigations have examined both syndromic and nonsyndromic (isolated) cleft lip/palate and cleft palate. Linkage studies have identified a number of candidate genes (Lewanda and Jabs 1994), including MSX1, RAR, an X-linked locus, and the genes for TGF-beta-3 and TGF-alpha. The pattern of inheritance in cleft lip/palate and cleft palate suggests that between 2 and 20 genes may be involved, with one gene representing a major component in the development of the cleft. One of the common syndromic forms of cleft lip/palate, the Van der Woude syndrome, is caused by an autosomal dominant form of inheritance at a locus on chromosome 1 (Sander et al. 1995). Future molecular genetic studies will be needed to provide the information necessary for prenatal diagnosis, calculation of risk, and potential gene therapy.
The Treacher Collins Syndrome—Mandibulofacial Dysostosis
Children with the Treacher Collins syndrome have downward-sloping eyelids; depressed cheekbones; a large fishlike mouth; deformed ears with conductive deafness; a small, receding chin and lower jaw; a highly arched or cleft palate; and severe dental malocclusion (Dixon 1996). These defects result from defective cranial neural crest cell differentiation, migration, and proliferation (see Chapter 2). Consequently, the first branchial arch structures are deficient, and all derivative craniofacial components are affected.
The underdeveloped facial structures can contribute to airway blockage and repeated upper respiratory infections, either of which can be fatal. The faulty development of the ears leads to a conductive deafness. The severe facial deformities exacerbate the psychological difficulties these youngsters face.
Investigators have identified the gene involved in an autosomal dominant form of the syndrome (Wise et al. 1997). The function of the gene is not yet known, but its identity will provide opportunities for prenatal diagnosis, gene therapy, and further understanding of craniofacial development.
The Pierre Robin Syndrome
Deficient development of the first-branchial-arch-derived mandibular portion results in the lower jaw's being set far back in relation to the forehead. As a result, the tongue is set back and may obstruct the posterior airway, compromising respiration (Elliott et al. 1995, Tomaski et al. 1995) and, in severe cases, leading to inadequate aeration and failure to thrive. The infant is also at risk for the development of cor pulmonale, an enlargement of the right ventricle of the heart that occurs secondarily to a chronic lung condition. Cleft palate may be another consequence.
The DiGeorge/Velocardiofacial Syndrome
The primary defect in the DiGeorge syndrome results from altered development of the fourth branchial arch and the third and fourth pharyngeal pouches (Goldmuntz and Emanuel 1997). Deficiencies affecting the thymus, parathyroid glands, and the great vessels that derive from these structures result. The facial features are subtle and include a squared-off nasal tip, small mouth, and widely spaced eyes. Similar facial features, along with heart defects, are seen in the velocardiofacial syndrome. Both syndromes are associated with deletions on the long arm of chromosome 22 (22q11) (Gong et al. 1997, Gottlieb et al. 1997). Further characterization of this chromosomal deletion region will provide information on the specific gene(s) affected and its function in craniofacial development.
The thymus defects severely compromise cellular immunity, depriving the body of thymus-derived T cells and paving the way for severe infectious disease. Inadequate or missing parathyroid glands cause severe hypocalcemia (low blood calcium levels) and seizures. The great vessel abnormalities alter cardiac output and lead to compromised circulation to heart tissues.
back to top
Cranial Bone and Dental Anomalies
Defects in the timing of developmental events can cause premature fusion of cranial bones. Impairments of tooth development can result from interruptions of the developmental sequence at several different stages.
Some craniofacial anomalies are associated with so-called master genes that orchestrate a program by which the embryo assumes its basic shape. Craniosynostosis, which occurs in approximately 1 out of 3,000 births, is one such anomaly. It results in the premature fusion of the cranial sutures, a dangerous condition that puts pressure on the developing brain. A number of diseases and syndromes, including Crouzon's, Apert's, Boston-type craniosynostosis, Pfeiffer's, and Saethre-Chotzen, share this anomaly, but differ in other features, which can include structural defects such as webbing of the hands and feet as well as mental retardation. Boston-type craniosynostosis has been linked to MSX2, one of the master genes. Several of the other syndromes involve point mutations at one or another locus in genes that code for fibroblast growth factor receptors (FGFR 1, 2, and 3) (Howard et al. 1997, Meyers et al. 1996). Collectively, these genes are associated with cell regulation, either through mediating growth factor effects or by serving as transcription factors (Cohen 1997).
Hereditary Hypodontia or Anodontia
Conditions of underdeveloped teeth (hypodontia) or their complete absence (anodontia) have been correlated with specific genes, such as MSX1 and LEF1. The complete absence of teeth alters the bony development of the mandible and maxilla.
Amelogenesis Imperfecta and Dentinogenesis Imperfecta
Amelogenesis imperfecta and dentinogenesis imperfecta are linked to defects in structural genes that code for proteins essential to the development of tooth enamel (amelogenesis imperfecta) or dentin (dentinogenesis imperfecta). The teeth are weak and extremely sensitive to temperature and pressure. The ordinary forces of chewing are painful and can lead to further wear and pain.
The enamel matrix genes include tuftelin, ameloblastin, and amelogenin; researchers have begun to link mutations in these genes with amelogenesis imperfecta. Similarly, genes labeled DSP and DPP have been characterized for dentin matrix and are associated with the inheritance of dentinogenesis imperfecta.
back to top
Craniofacial Defects Secondary to Other Developmental Disorders
A number of genetic diseases occur in which craniofacial defects are secondary to a more generalized structural or biochemical defect.
Inherited mutations of collagen genes lead to a number of "brittle bone" diseases characterized by defects in mineralized tissues that form from a collagen-rich matrix. Osteogenesis imperfecta presents a spectrum of deficiencies that includes fragile bones, clear or blue sclera, deafness, loose ligaments, and painful dentinogenesis imperfecta-like changes in the teeth.
Epidermolysis Bullosa—Recessive Dystrophic Type
The gene defect in epidermolysis bullosa—recessive dystrophic type—manifests as blisters or bullae that appear shortly after birth on skin areas following minor trauma. Mutations in keratin genes that contribute to the epithelial cell cytoskeleton have been correlated with this condition.
The oral manifestations include both mucosal bullae and altered teeth. Altered teeth with hypoplastic enamel develop and exhibit an increased susceptibility to caries. Oral bullae develop from even the slightest mucosal trauma. The condition is painful and dangerous because of the constant risk that the bullae will become infected.
back to top
Craniofacial Manifestations of Single-Gene Defects
In many craniofacial defects, mutations within a single gene manifest as complex syndromes with varied organ and limb defects as well as facial anomalies.
The ectodermal dysplasias (EDs) are a family of hereditary diseases first observed by Charles Darwin over a century ago. They involve defects in two or more tissues derived from the ectoderm—skin, hair, teeth, nails, and sweat glands. The ectodermal structures fail to differentiate properly owing to altered epithelial-mesenchymal signaling. A gene, EDA, at an X-linked locus has been linked to the syndrome, and ongoing research is aimed at determining the function of the gene and the molecular mechanism of the syndromes (Kere et al. 1996, Zonana et al. 1994). More recently, investigators have discovered genes linked to autosomal (i.e., non-sex-linked) forms of ED, displaying both dominant and recessive inheritance (Monreal et al. 1999).
Oral manifestations of the ectodermal dysplasias are associated with the teeth. Alterations in tooth development can include hypodontia, anodontia, and conically shaped teeth.
The Waardenburg Syndrome
The Waardenburg syndrome has been subdivided into several types. All involve a variety of abnormalities in the position and appearance of the nose and eyes, with pigment changes that may cause one eye to differ in color from the other. Other signs include deafness, a mildly protruding jaw, cleft lip and palate, and skeletal deformities (Reynolds et al. 1995). The syndrome is inherited in an autosomal dominant manner with complete penetrance and variable expression. Specific genes associated with this syndrome are members of the homeobox family that regulate the transcription of other genes: Waardenburg type 1 with PAX3; Waardenburg type 2 with MITF, 3q14.1; and Waardenburg type 3 with PAX3, 2q35 (Asher et al. 1996).
The inheritance of a regulatory gene defect in cleidocranial dysplasia leads to features that include delayed tooth eruption, supernumerary teeth, altered or missing collarbones, short stature, and possible failure of cranial suture closure. The exact mechanism of the associated gene, CBFA1, located on chromosome 6, has not been determined but appears to be essential for bone development.
back to top
The common perception is that injuries are random occurrences that are unpredictable and hence unpreventable. In actuality, experts in the field make the point that there are no basic scientific distinctions between injury and disease (Haddon and Baker 1981). Injuries have been categorized as "intentional" and "unintentional." People identified as being at risk for certain injuries, as well as the causes of those injuries, can be targeted for appropriate prevention strategies. Such an approach is broadly applicable to sports, falls, and motor vehicle injuries (unintentional) as well as to injuries caused by abusive and violent behaviors (intentional).
Injuries are a major public health problem, outranking cancer and heart disease as a leading cause of death in some age groups of the population (Kraus and Robertson 1992). Cranial injuries in particular are a leading cause of mortality. Oral-facial injuries can bring disfigurement and dysfunction, greatly diminishing the quality of life and contributing to social and economic burdens (Reisine et al. 1989).
The leading causes of oral and craniofacial injuries are sports, violence, falls, and motor vehicle collisions (Kraus and Robertson 1992). Oral cavity injuries may also be caused by foreign objects in food (Hyman et al. 1993).
back to top
Craniofacial sports injuries occur not only in contact sports, but also in individual activities such as bicycling, skating, and gymnastics, especially on trampolines. Each sport predisposes its participants to a specific array of extrinsic risk factors (Pinkham and Kohn 1991). These include physical contact, projectiles such as balls and pucks, and the quality of the playing field and equipment. In contact sports the absence of protective equipment such as headguards and mouthguards is a major risk factor. In a recent survey of school-aged children in organized sports, football was the only sport in which the majority of participants used mouthguards and headgear (Nowjack-Raymer and Gift 1996).
There are intrinsic risk factors as well, relating to characteristics of the individual participant. These include age, sex, injury history, body size, aerobic fitness and muscle strength, central motor control, and general mental ability (Taimela et al. 1990).
back to top
Falls are a major cause of trauma to teeth, primarily to incisors. Unlike bone fractures, fractures of the crowns of the teeth do not heal or repair, and affected teeth often have an uncertain prognosis. Problems may develop later due to damage to the pulp.
back to top
Motor Vehicle Collisions
The effects of motor vehicle collisions may range from minor and reversible effects to long-term medical, surgical, and rehabilitative consequences. Post-traumatic headaches and chronic oral-facial pain can occur. Neuromuscular and glandular damage may cause short- or long-term problems with chewing, swallowing, and tearing or result in facial tics or paralysis.
back to top
The family is the single most frequent locus of violence in Western society. Domestic violence includes child abuse, spousal and elder abuse, and abuse of the disabled. Child abuse is of particular concern to the oral health community because 65 percent of cases involve head and oral-facial trauma (Mathewson 1993, Needleman 1986) and dentists are required to report suspected cases of child abuse. In the young child, head injury is the most common cause of death. Psychological trauma from abuse can result in sleep disturbances, eating disorders, developmental growth failure in young children, and nervous habits such as lip and fingernail biting and thumb sucking. Effects may also include chronic underachievement in school and poor peer relationships (Mathewson 1993). In abusive families, physical neglect is commonplace, with inadequate provision of basic needs, including medical and oral health care (Mathewson 1993).
back to top
SELECTED CHRONIC AND DISABLING CONDITIONS
Oral, dental, or craniofacial signs and symptoms play a critical role in autoimmune disorders such as Sjögren's syndrome and in a number of chronic and disabling pain conditions.
back to top
Sjögren's syndrome is one of several autoimmune disorders in which the body's own cells and tissues are mistakenly targeted for destruction by the immune system. Like other autoimmune conditions, Sjögren's syndrome is more prevalent among women. The ratio of females to males affected is 9:1, with symptoms usually developing in middle age. There are an estimated 1 to 2 million individuals in the United States with Sjögren's syndrome (Talal 1992).
The disease occurs in two forms. Primary Sjögren's involves the salivary and lacrimal (tear) glands. In secondary Sjögren's the glandular involvement is accompanied by the development of a connective tissue or collagen disease, most often rheumatoid arthritis, lupus erythematosis, scleroderma, or biliary cirrhosis.
The glandular involvement causes a marked reduction in fluid secretion, resulting in xerostomia and xerophthalmia (dry eyes). The constant oral dryness causes difficulty in speaking, chewing, and swallowing; the dry eyes often itch and feel gritty. There is no cure for Sjögren's, and patients often carry eyedrops and water bottles or saliva substitutes in an attempt to provide symptomatic relief. Clinically, the reduction in salivary flow changes the bacterial flora, which, in addition to the reduction in salivary protective components, increases the risk of caries and candidiasis (Daniels and Fox 1992). Recent studies have indicated that there is a reduction in masticatory function (Dusek et al. 1996) and an increased prevalence of periodontal disease (Najera et al. 1997). In advanced stages the salivary glands may swell because of obstruction and infection or lymphatic infiltration. In both forms of the disease, other systems may eventually become affected. Nasal, laryngeal, and vaginal dryness may occur, as well as abnormalities in internal organs (Oxholm and Asmussen 1996).
Diagnosis is difficult in the early stages, and women often report that it took many years and consultations with many specialists before they received the correct diagnosis. Diagnosis involves demonstration of specific antibodies in the blood characteristic of an autoimmune disorder, a labial (minor) salivary gland biopsy, and a series of eye tests to measure flow rate and tissue characteristics. Confirmatory tests include an evaluation of salivary flow and chemistry.
Patients with Sjögren's syndrome are at some risk of developing diseases such as non-Hodgkin's lymphoma; clinical data indicate that such lymphomas develop in 5 percent of patients with Sjögren's syndrome (Moutsopoulos et al. 1978).
Histological examination shows that immune cells infiltrate the glands and cluster around the secretory elements, resulting in a breakdown of the normal structure of the gland. The mechanisms by which this occurs involve immune-cell-mediated inflammation and stimulation of the salivary gland cells themselves to produce tissue-destructive molecules such as cytokines. Another hypothesis is that a viral infection of the glands may trigger the immune response that leads to autoimmunity, whereas genetic or regulatory alterations might lead to abnormalities in apoptosis (Fox and Speight 1996).
In addition to saliva substitutes and artificial tears, some medications, such as pilocarpine and cevimeline, are prescribed to increase salivary flow from the residual healthy gland tissue, again providing symptomatic relief only. The problems that develop in the other organ systems are also treated symptomatically. At advanced stages, steroids are employed intermittently to alleviate problems.
back to top
Acute and Chronic Oral-Facial Pain
Since the nineteenth century, when two dentists, Horace Wells and Frederick Morton, demonstrated the analgesic powers of nitrous oxide and ether, oral health investigators have been recognized leaders in the field of pain management worldwide. Their analyses of the cells, pathways, and molecules involved in the transmission and modulation of pain have given rise to a growing variety of medications, often combined with other approaches, that can control acute and chronic pain. Pain researchers today stress that chronic pain can become a disease in itself, causing long-term detrimental changes in the nervous system. These changes may affect resistance to other diseases as well as effectively destroy quality of life. Most people have experienced acute pain involving teeth and the oral tissues at one time or another.
Atypical Facial Pain
Atypical facial pain is characterized by a continuous dull ache on one or both sides, most frequently in the region of the maxilla (the upper jaw). The pain tends to be episodic and is aggravated by fatigue, worry, or emotional upset. It is often accompanied by pain elsewhere in the body and depression. Once a dental cause can be ruled out, pain resolution depends on the successful use of antidepressants, psychotherapy, or both (Tyldesley and Field 1995).
The oral-facial region is also subject to pain that can be paroxysmal or continuous along a distinct nerve distribution. The most frequently encountered of these oral facial neuralgias is tic douloureux, or trigeminal neuralgia, a disease of unknown etiology affecting one, two, or all three branches of the trigeminal nerve. The pain is highly intense and of a stabbing nature, and lasts for a few seconds. This transient attack may be repeated every few minutes or several hours. There may be no precipitating factor, or it may occur in response to a gentle touch or a breeze wafting across the face—a condition experts call allodynia, the feeling of pain in response to a normally nonpainful stimulus. On other occasions, there may be a specific trigger zone. Although spontaneous remission for weeks or months may occur, it is rarely permanent. Given the unknown, unpredictable nature of tic douloureux, it is not surprising that fear of pain comes to dominate these patients' lives, as they avoid doing anything that might trigger an attack.
Trigeminal neuralgia generally occurs in later life, but also occurs in younger individuals affected by multiple sclerosis, where it is assumed to be associated with lesions (multiple sclerosis "plaques") in the brain stem. Medical treatment depends largely on the use of a drug that has become a virtual specific, the antiepileptic drug carbamazepine. For those patients with no consequential adverse effects, it can control the disease. An alternative for chronic sufferers is the surgical removal of a small vein or artery that may be exerting pressure on the nerve root or the selective destruction of the nerve fibers themselves using chemical or electrical methods. In many cases, these procedures can produce complete relief from pain (Tyldesley and Field 1995).
back to top
Various etiological factors, including trauma, can give rise to pain and dysfunction in the temporomandibular joint and surrounding muscles, conditions collectively called temporomandibular disorders (TMDs). The pain may be localized or radiate to the teeth, head, ears, neck, and shoulders. Abnormal grating, clicking, or crackling sounds, known as crepitus, in the joint often accompany localized pain. Pain is also found in response to clinical palpation of the affected structures. TMDs are common, occurring in as many as 10 million Americans. Although surveys indicate that both sexes are affected, the majority of individuals seeking treatment are women of childbearing age, a phenomenon suggesting that hormonal influences should be investigated.
Several factors can contribute to the onset or exacerbation of TMD symptoms. These factors include certain developmental anomalies; injury to the jaw from accidents or abuse; oral habits that greatly stress the joint and musculature, such as tooth grinding (bruxism); jaw manifestations of systemic diseases such as fibromyalgia and arthritic diseases; and some irreversible treatments for initial signs and symptoms.
The multiplicity of factors that may cause or contribute to TMDs has unfortunately led to a multiplicity of treatments. Most of these treatments have not been tested in randomized controlled clinical trials. During the 1970s and 1980s, many individuals underwent surgery, which proved unsuccessful in many cases.
Leading investigators have proposed standardized research diagnostic criteria to clarify the kinds of pathology that can give rise to TMDs and to classify the most common forms of TMDs. Such criteria could be used in designing clinical trials and could ultimately lead to better diagnostics, treatments, and prevention. The criteria use two dimensions or axes: axis I delineates various forms of joint or muscle pathology; axis II explores pain-related disability and psychological status. The approach requires detailed clinical examinations and patient histories (Dworkin and LeResche 1992).
back to top
A MIRROR, A MODEL, AND A BETTER UNDERSTANDING OF DISEASES AND DISORDERS
Studying the diseases and disorders that affect craniofacial tissues can provide scientists with models of systemic pathology. Because some craniofacial tissues, such as bones, mucosa, muscles, joints, and nerve endings, have counterparts in other parts of the body and these tissues are often more accessible to research analysis than deeper-lying tissues, researchers studying craniofacial tissues can gain valuable insights into how cancer develops, the role of inflammation in infection and pain, the effects of diet and smoking, the consequences of depressed immunity, and the changes that can arise from a mutated gene.
Other craniofacial tissues—teeth, gingiva, tongue, salivary glands, and the organs of taste and smell—are unique to the craniofacial complex. Study of the diseases affecting these tissues has revealed a wealth of information about their special nature as well as the molecules and mechanisms that normally operate for the protection, maintenance, and repair of all the oral, dental, and craniofacial tissues. When factors perturb these nurturing elements, the oral health scale can tip toward disease. When those factors stem from systemic diseases or disorders, the mouth can sometimes mirror the body's ill health. Similarly underscoring the connection between oral and general health are studies suggesting that poor dental health, mainly due to chronic dental infections, may heighten the risk for both cardiovascular disease and stroke independently of factors such as social class and established cardiovascular risk factors (Grau et al. 1997). The interplay between craniofacial and systemic health and disease has become a lively focus of interest and research, as discussed in Chapter 5.
Current research on developmental disorders and diseases affecting the craniofacial complex is facilitating and complementing the intense effort of the Human Genome Project to map and sequence all 100,000 genes. This goal should be accomplished early in the twenty-first century and should begin to yield information on the genetic program that governs morphogenesis, organ development, and disease etiology and pathogenesis, with the potential for interventions that can correct errors in the program. The continued sequencing of the genomes of microbial pathogens involved in oral diseases also should lead to new diagnostic and preventive approaches.
back to top
- Microbial infections, including those caused by bacteria, viruses, and fungi, are the primary cause of the most prevalent oral diseases. Examples include dental caries, periodontal diseases, herpes labialis, and candidiasis.
- The etiology and pathogenesis of diseases and disorders affecting the craniofacial structures are multifactorial and complex, involving an interplay among genetic, environmental, and behavioral factors.
- Many inherited and congenital conditions affect the craniofacial complex, often resulting in disfigurement and impairments that may involve many body organs and systems and affect millions of children worldwide.
- Tobacco use, excessive alcohol use, and inappropriate dietary practices contribute to many diseases and disorders. In particular, tobacco use is a risk factor for oral cavity and pharyngeal cancers, periodontal diseases, candidiasis, and dental caries, among other diseases.
- Some chronic diseases, such as Sjögren's syndrome, present with primary oral symptoms.
- Oral-facial pain conditions are common and often have complex etiologies.
back to top
Aaronson SA. Growth factors and cancer. Science 1991 Nov 22;254(5035):1146-53.
Adler-Storthz K, Newland JR, Tessin BA, Yeudall WA, Shillitoe EJ. Human papillomavirus type 2 DNA in oral verrucous carcinoma. J Oral Pathol 1986 Oct;15(9):472-5.
Advisory Committee to the Surgeon General. The health consequences of using smokeless tobacco. Chapter 2, Carcinogenesis associated with smokeless tobacco use. Bethesda (MD): Public Health Service; 1986. NIH Pub. no. 86-2874.
Asher JH Jr, Harrison RW, Morell R, Carey ML, Friedman TB. Effects of PAX3 modifier genes on craniofacial morphology, pigmentation, and viability: a murine model of Waardenburg syndrome variation. Genomics 1996 Jun;34(3):285-98.
Axéll T, Mörnstad H, Sundström B. The relation of the clinical picture to the histopathology of snuff dipper's lesions in a Swedish population. J Oral Pathol 1976;5(4):229-36.
Bagan JV, Sanchis JM, Milian MA, Penarrocha M, Silverstein FJ. Recurrent aphthous stomatitis. A study of the clinical characteristics of lesions in 93 cases. J Oral Pathol Med 1991;20:395-7.
Barbour SE, Nakashima K, Zhang JB, Tangada S, Hahn CL, Schenkein HA, Tew JG. Tobacco and smoking: environmental factors that modify the host response (immune system) and have an impact on periodontal health. Crit Rev Oral Biol Med 1997;8(4):437-60.
Beck JD. Periodontal implications: older adults. Ann Periodontol 1996;7(1):322-57.
Benner SE, Winn RJ, Lippman SM, Poland J, Hansen KS, Luna MA, Hong WK. Regression of oral leukoplakia with alpha-tocopherol: a community clinical oncology program chemopreventative study. J Natl Cancer Inst 1993 Jan 6;85(1):44-7.
Bennet KR, Reade PC. Salivary immunoglobulin A levels in normal subjects tobacco smokers, and patients with minor aphthous ulceration. Oral Surg Oral Med Oral Pathol 1982 May;53(5):461-5.
Bishop JM, Baker B, Fujita D, McCombe P, Sheiness D, Smith K, Spector DH, Stehelin D, Varmus HE. Genesis of a virus-transforming gene. Natl Cancer Inst Monogr 1978 May;(48):219-23.
Berenson JR, Yang J, Mickel RA. Frequent amplification of the bcl-1 locus in head and neck squamous cell carcinomas. Oncogene 1989 Sep;4(9):1111-6.
Berkey CS, Douglass CW, Valachovic RW, Chauncey HH. Longitudinal radiographic analysis of carious lesion progression. Community Dent Oral Epidemiol 1988;16:83-90.
Blot WJ, McLaughlin JK, Winn DM, Austin DF, Greenberg RS, Preston-Martin S, Bernstein L, Schoenberg JB, Stemhagen A, Fraumeni JF Jr. Smoking and drinking in relation to oral and pharyngeal cancer. Cancer Res 1988;48:3282-7.
Blot WJ, Li JY, Taylor PR, Guo W, Dawsey S, Wang GQ, Yang CS, Zheng SF, Gail M, Li GY, et al. Nutrition intervention trials in Linxian, China: supplementation with specific vitamin/mineral combinations, cancer incidence, and disease-specific mortality in the general population. J Natl Cancer Inst 1993 Sep;85(18):1483-91.
Bos JL. ras oncogenes in human cancer: a review. Cancer Res 1989 Sep;49(17):4682-9.
Bowden GH. Microbiology of root surface caries in humans. J Dent Res 1990;69:1205-10.
Bowen WH. Response to Seow: biological mechanisms of early childhood caries. Community Dent Oral Epidemiol 1998;26(Suppl 1):28-31.
Brennan JA, Boyle JO, Koch WM, Goodman SN, Hruban RH, Eby YJ, Couch MJ, Forastiere AA, Sidransky D. Association between cigarette smoking and mutation of the p53 gene in squamous-cell carcinoma of the head and neck. N Engl J Med 1995 Mar;332(11):712-7.
Bridges RB, Anderson JW, Saxe SR, Gregory K, Bridges SR. Periodontal status of diabetic and non-diabetic men: effects of smoking, glycemic control, and socioeconomic factors. J Periodontol 1996;67:1185-92.
Burnet F. The concept of immunologic surveillance. Prog Exper Tumor Res 1970;13:1-20.
Burt BA, Ismail AI. Diet, nutrition and food cariogenicity. J Dent Res 1986;65(SI):1475-84.
Canniff JP, Harvey W, Harris M. Oral submucous fibrosis: its pathogenesis and management. Br Dent J 1986 Jun;160(12):429-34.
Caton J. Periodontal diagnosis and diagnostic aids. In: Proceedings of the World Workshop in Clinical Periodontics; 1989 July 23-27. Princeton (NJ): American Academy of Periodontology; 1989. p. I-1-22.
Caufield PW, Cutter GR, Dasanayake AP. Initial acquisition of mutans streptococci by infants: evidence for a discrete window of infectivity. J Dent Res 1993;72:37-45.
Chang F, Syrjanen S, Nuutinen J, Karja J, Syrjanen K. Detection of human papilloma virus (HPV) in oral squamous cell carcinomas by in situ hybridization and polymerase chain reaction. Arch Dermatol Res 1990;282(8):493-7.
Chretien PB. The effects of smoking on immunocompetence. Laryngoscope 1978 Jan;88(1 Pt 2 Suppl 8):11-3.
Cohen MM Jr. Transforming growth factor beta s and fibroblast growth factors and their receptors: role in structural biology and craniosynostosis. J Bone Miner Res 1997 Mar;12(3):322-31.
Costabel U, Bross KJ, Reuter C, Ruhle KH, Mathys H. Alterations in immunoregulatory T-cell subsets in cigarette smokers. A phenotypic analysis of bronchoalveolar and blood lymphocytes. Chest 1986;90:39-44.
Craig GG, Powell CR, Cooper MH. Caries progression in deciduous molar teeth: 24-month results from a minimal treatment programe. Community Dent Oral Epidemiol 1981;9:260-5.
Daniels TE, Fox PC. Salivary and oral components of Sjögren's syndrome. Rheum Dis Clin North Am 1992;18:571-89.
Decker J, Goldstein JC. Risk factors in head and neck cancer. N Engl J Med 1982 May;306(19):1151-5.
de Villiers EM. Papilloma viruses in cancers and papillomas of the aerodigestive tract. Biomed Pharmacother 1989;43:31-6.
Dixon MJ. Treacher Collins syndrome. Hum Mol Genet 1996;5(Spec No):1391-6.
Donald PJ. Marijuana smoking—possible cause of head and neck carcinoma in young patients. Otolaryngol Head Neck Surg 1986 Apr;94(4):517-21.
Dusek M, Simmons J, Buschang PH, Al-Hashimi I. Masticatory function in patients with xerostomia. Gerodontology 1996;13(1):3-6.
Dworkin SF, LeResche L. Research diagnostic criteria for temporomandibular disorders: review, criteria, examinations, and specifications: critique. J Craniomandib Disord 1992;6(4).
Ehrlich P. Collected papers. In: Himmelweit F, editor. Vol. 2. New York: Pergamon Press; 1957. p. S50.
Ekanayake LS, Sheiham A. Reducing rates of progression of dental caries in British schoolchildren. Br Dent J 1987;163:265-9.
Elliott MA, Studen-Pavlovich DA, Ranalli DN. Prevalence of selected pediatric conditions in children with Pierre Robin sequence. Pediatr Dent 1995 Mar-Apr;17(2):106-11.
Embil JA, Stephens RG, Manuel FR. Prevalence of recurrent herpes labialis and aphthous ulcers among young adults on six continents. Can Med Assoc J 1975 Oct 4;113(7):627-30.
Emslie RD. Radiographic assessment of approximal caries. J Dent Res 1959;38:1225-6.
Epstein JB, Scully C. Neoplastic diseases in the head and neck of patients with AIDS. Int J Oral Maxillofac Surg 1992 Aug;21(4):219-26.
Ferguson MM, Carter J, Boyle P. An epidemiological study of factors associated with recurrent aphthae in women. J Oral Med 1984 Oct-Dec;39(4):212-7.
Fitzgerald RJ, Keyes PH. Demonstration of the etiologic role of streptococci in experimental caries in the hamster. J Am Dent Assoc 1960;61:9-19.
Fox PC, Speight PM. Current concepts of autoimmune exocrinopathy: immunologic mechanisms in the salivary pathology of Sjögren's syndrome. Crit Rev Oral Biol Med 1996;7(2):144-58.
Franchesi S, Munoz N, Bosch XF, Sniojers PJ, Walboomers JM. Human papillomavirus and cancers of the upper aerodigestive tract: a review of epidemiological and experimental evidence. Cancer Epidemiol Biomarkers Prev 1996;5:567-75.
Garewal HS. Beta-carotene and vitamin E in oral cancer prevention. J Cell Biochem 1993;17F(Suppl):262-9.
Garewal HS, Meyskens FL Jr, Killen D, Reeves D, Kiersch TA, Elletson H, Strosberg A, King D, Steinbronn K. Response of oral leukoplakia to beta-carotene. J Clin Oncol 1990 Oct;8(10):1715-20.
Genco R. Classification of clinical and radiographic features of periodontal diseases. In: Genco R, Goldman H, Cohen W, editors. Contemporary periodontics. St. Louis: CV Mosby; 1990. p. 63-81.
Genco RJ. Host responses in periodontal disease: current concepts. J Periodontol 1992 Apr;63(4 Suppl):338-55.
Genco RJ. Current view of risk factors for periodontal diseases. J Periodontol 1996 Oct;67(10 Suppl):1041-9.
Goldmuntz E, Emanuel BS. Genetic disorders of cardiac morphogenesis. The DiGeorge and velocardiofacial syndromes. Circ Res 1997 Apr;80(4):437-43.
Gong W, Emanuel BS, Galili N, Kim DH, Roe B, Driscoll DA, Budarf ML. Structural and mutational analysis of a conserved gene (DGSI) from the minimal DiGeorge syndrome critical region. Hum Mol Genet 1997 Feb;6(2):267-76.
Gottlieb S, Emanuel BS, Driscoll DA, Sellinger B, Wang Z, Roe B, Budarf ML. The DiGeorge syndrome minimal critical region contains a goosecoid-like (GSCL) homeobox gene that is expressed early in human development. Am J Hum Genet 1997 May;60(5):1194-201.
Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res 1993 Aug;53(15):3579-84.
Grau AJ, Buggle F, Ziegler C, Schwarz W, Meuser J, Tasman AJ, Buhler A, Benesch C, Becher H, Hacke W. Association between acute cerebrovascular ischemia and chronic and recurrent infection. Stroke 1997;28(9):1724-9.
Greenblatt MS, Bennett WP, Hollstein M, Harris CC. Mutations in the p53 tumor suppressor gene: clues to cancer etiology and molecular pathogenesis. Cancer Res 1994 Sep;54(18):4855-78.
Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin 2000;50:7-33.
Grodstein F, Colditz GA, Stampfer MJ. Post-menopausal hormone use and tooth loss. A prospective study. J Am Dent Assoc 1996;127:370-7.
Grossi SG, Genco RJ, Machtei EE, Ho AW, Koch G, Dunford R, Zambon JJ, Hausmann E. Assessment of risk for periodontal disease. II. Risk indicators for alveolar bone loss. J Periodontol 1995;66(1):23-9.
Gustafsson BE, Quensel CE, Lanke US, Lundquist F, Grahnen H, Bonow BE, Krasse B. The Vipeholm dental caries study. The effect of different levels of carbohydrate intake on caries activity in 436 individuals observed for five years. Acta Odontol Scand 1954;11:232-364.
Haber J. Cigarette smoking: a major risk factor for periodontitis. Compendium Cont Educ Dent 1994;15:1002-14.
Haddon W Jr, Baker SP. Injury control. In: Clark DW, MacMahon B, editors. Preventive and community medicine. 2nd ed. Boston: Little, Brown; 1981. p. 109-40.
Haffajee AD, Socransky SS, Dzink JL, Taubman MA, Ebersole JL. Clinical, microbiological and immunological features of subjects with refractory periodontal diseases. J Clin Periodontol 1988;15(6):390-8.
Hart TC, Hart PS, Bowden DW, Michalec MD, Callison SA, Walker SJ, Zhang Y, Firatli E. Mutations of the cathepsin C gene are responsible for Papillon-Lefevre syndrome. J Med Genet 1999 Dec;36(12):881-7.
Higgins CR, Schofield JK, Tatnall FM, Leigh IM. Natural history, management and complications of herpes labialis. J Med Virol 1993;1(Suppl):22-6.
Hirayama T. An epidemiological study of oral and pharyngeal cancer in Central and South-East Asia. Bull World Health Organ 1966;34(1):41-69.
Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science 1991 Jul;253(5015):49-53.
Hong WK, Endicott J, Itri LM, Doos W, Batsakis JG, Bell R, Folonoff S, Byers R, Atkinson EN, Vaughan C, et al. 13-cis-retinoic acid in the treatment of oral leukoplakia. N Engl J Med 1986 Dec;315(24):1501-5.
Howard TD, Paznekas WA, Green ED, Chiang LC, Ma N, Ortiz de Luna RI, Garcia Delgado C, Gonzalez-Ramos M, Kline AD, Jabs EW. Mutations in TWIST, a basic helix-loop-helix transcription factor, in Saethre-Chotzen syndrome. Nat Genet 1997 Jan;15(1):36-41.
Howley PM. Role of the human papillomaviruses in human cancer. Cancer Res 1991 Sep;51(18 Suppl):5019s-22s.
Hyman FN, Klontz KC, Tollefson L. Eating as a hazard to health: preventing, treating dental injuries caused by foreign objects in food. J Am Dent Assoc 1993;124(11):65-9.
International Agency for Research on Cancer. IARC monograph on the evaluation of the carcinogenic risk of chemicals to humans: tobacco habits other than smoking; betel-quid and areca-nut chewing; and some related nitrosamines. Vol. 37. Lyons, France: International Agency for Research on Cancer; 1985.
Issing WJ, Wustrow TP, Heppt WJ. Oncogenes related to head and neck cancer. Anticancer Res 1993 Nov-Dec; 13(6B):2541-51.
Jacobs R, Ghyselen J, Koninckx P, van Steenberghe D. Long-term bone mass evaluation of mandible and lumbar spine in a group of women receiving hormone replacement therapy. Eur J Oral Sci 1996; 104:10-6.
Jeffcoat MK, Chestnut C. Systemic osteoporosis and oral bone loss: evidence shows increased risk factors. J Am Dent Assoc 1993;124:49-56.
Jeffcoat MK, Ready MS. Progression of probing attachment loss in adult periodontitis. J Periodontol 1991;62:185-91.
Kere J, Srivastava AK, Montonen O, Zonana J, Thomas N, Ferguson B, Munoz F, Morgan D, Clarke A, Baybayan P, et al. X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat Genet 1996 Aug;13(4):409-16.
Khandwala A, Van Inwegan RG, Alfano MC. 5% amlexanox oral paste, a new treatment for recurrent minor aphthous ulcers. I. Clinical demonstration of acceleration of healing and resolution of pain. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83(2):222-30.
Kleinman DV, Swango PA, Niessen LC. Epidemiologic studies of oral mucosal conditions—methodologic issues. Community Dent Oral Epidemiol 1991 Jun;19(3):129-40.
Kolehmainen L, Rytömaa I. Increment of dental caries among Finnish dental students over a period of 2 years. Community Dent Oral Epidemiol 1997;5:140-4.
Kornman KS, Crane A, Wang HY, di Giovine FS, Newman MG, Pirk FW, Wilson TG Jr, Higginbottom FL, Duff GW. The interleukin-1 genotype as a severity factor in adult periodontal disease. J Clin Periodontol 1997;24:72-7.
Kosary CL, Ries LA, Miller BA, Hankey BF, Harras A, Edwards BK, editors. SEER cancer statistics review. 1973-1992 tables and graphs. Bethesda (MD): National Cancer Institute; 1995 Dec. p.17, 34, 542, 355, 361. NIH Pub. no. 96-2789.
Kraus JF, Robertson LS. Injuries and the public health. In: Last JM, Wallace RB, editors. Public health and preventive medicine. 13th ed. East Norwalk (CT): Appleton and Lange; 1992. p. 1021-34.
Lamster IB. The host response in gingival crevicular fluid. Potential applications in periodontitis clinical trials. J Periodontol 1992;63:1117-23.
Lane DP. Cancer. p53, guardian of the genome. Nature 1992 Jul;358(6381):15-6.
Langdon JD, Partridge M. Expression of the tumour suppressor gene p53 in oral cancer. Br J Oral Maxillofac Surg 1992 Aug;30:214-20.
Larsen MJ, Fejerskov O. Chemical and structural challenges in remineralization of dental enamel lesions. Scand J Dent Res 1987;97:285-96.
Lehner T. Autoimmunity in oral diseases with special reference to recurrent oral ulcerations. Proc R Soc Med 1968;61:515-24.
Lewanda AF, Jabs EW. Genetics of craniofacial disorders. Curr Opin Pediatr 1994 Dec;6(6):690-7.
Lidral AC, Murray JC, Buetow KH, Basart AM, Schearer H, Schiang R, Naval A, Layda E, Magee K, Magee W. Studies of the candidate genes TGFB2, MSX1, TGFA, and TGFB3 in the etiology of cleft lip and palate in the Philippines. Cleft Palate Craniofac J 1997 Jan;34(1):1-6.
Linton JL. Quantitative measurements of remineralization of incipient caries. Am J Orthod Dentofacial Orthop 1996 Dec;110(6):590-7.
Mandel ID. Dental caries. Am Sci 1979;67:680-8.
Mandel ID. Calculus update: prevalence, pathogenicity and prevention. J Am Dent Assoc 1995 May;126:573-80.
Mandel ID, Gaffar A. Calculus revisited. J Clin Periodontol 1986;13:249-57.
Mashberg A. Erythroplasia: the earliest sign of asymptomatic oral cancer. J Am Dent Assoc 1978 Apr;96(4):615-20.
Mathewson RJ. Child abuse and neglect: the dental profession's responsibility. Compendium 1993 May;14(5):658-62.
McCullough MJ, Ross BC, Reade PC. Candida albicans: a review of its history, taxonomy, epidemiology, virulence attributes, and methods of strain differentiation. Int J Oral Maxillofac Surg 1996;25:136-44.
Mealey BL. Periodontal implications: medically compromised patients. Ann Periodontol 1996 Nov;1(1):256-321.
Mehta FS, Gupta PC, Pindborg JJ. Chewing and smoking habits in relation to precancer and oral cancer. J Cancer Res Clin Oncol 1981;99(1-2):35-9.
Meyers GA, Day D, Goldberg R, Daentl DL, Przylepa KA, Abrams LJ, Graham JM Jr, Feingold M, Moeschler JB, Rawnsley E, et al. FGFR2 exon IIIa and IIIc mutations in Crouzon, Jackson-Weiss, and Pfeiffer syndromes: evidence for missense changes, insertions and a deletion due to alternative RNA splicing. Am J Hum Genet 1996 Mar;58(3):491-8.
Michalowicz BS. Genetic and heritable risk factors in periodontal disease. J Periodontol 1994;65(5 Suppl):479-88.
Monreal AW, Ferguson BM, Headon DJ, Street SL, Overbeek PA, Zonana J. Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ecotodermal dysplasia. Nat Genet 1999 Aug;22(4):366-9.
Moutsopoulos HM, Kassan SS, Gardy M. Sjögren's syndrome: an update and overview. Am J Med 1978;64(5):732-41.
Murray JC. Face facts: genes, environment and clefts. Am J Hum Genet 1995 Aug;57(2):227-32.
Murray JC, Daack-Hirsch S, Buetow KH, Munger R, Espina L, Paglinawan N, Villanueva E, Rary J, Magee K, Magee W. Clinical and epidemiologic studies of cleft lip and palate in the Philippines. Cleft Palate Craniofac J 1997 Jan;34(1):7-10.
Murray PA. Periodontal diseases in patients infected by human immunodeficiency virus. Periodontol 2000 1994;6:50-67.
Najera MP, Al-Hashimi I, Plemons JM, Rivera-Hidalgo F, Rees TD, Haghighat N, Wright JM. Prevalence of periodontal disease in patients with Sjögren's syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997 Apr;83(4):453-7.
Needleman HL. Orofacial trauma in child abuse: types, prevalence, management and the dental profession's involvement. Pediatr Dent 1986 May;8(1 Spec No):71-80.
Newman HN. Focal infection. J Dent Res 1996 Dec;75(12):1912-9.
Nolan A, McIntosh WB, Allan BF, Lamey PJ. Recurrent aphthous ulceration: Vitamin B1, B2, B6 status and response to replacement therapy. J Oral Pathol Med 1991;20:389-91.
Nowjack-Raymer RE, Gift HC. Use of mouthguards and headgear in organized sports by school-aged children. Public Health Rep 1996;30(1):82-6.
Offenbacher S, Heasman PA, Collins JG. Modulation of host PGE2 secretion as a determinant of periodontal disease expression. J Periodontol 1993;64:432-44.
Oxholm P, Asmussen K. Primary Sjögren's syndrome: the challenge for classification of disease manifestations. J Intern Med 1996;239:467-74.
Page RC. Critical issues in periodontal research. J Dent Res 1995;74:1118-28.
Parada LF, Tabin CJ, Shih C, Weinberg RA. Human EJ bladder carcinoma oncogene is homologue of Harvey sarcoma virus ras gene. Nature 1982 Jun 10;297(5866):474-8.
Park NH, Sapp JP, Herbosa EG. Oral cancer induced in hamsters with herpes simplex infection and simulated snuff dipping. Oral Surg Oral Med Oral Pathol 1986 Aug;62(2):164-8.
Park NH, Min BM, Li SL, Huang MZ, Cherick HM, Doniger J. Immortalization of normal human oral keratinocytes with type 16 human papillomavirus. Carcinogenesis 1991 Sep;12(9):1627-31.
Park NH, Gujuluva CN, Back JH, Cherrick HM, Shin KH, Min BM. Combined oral carcinogenicity of HPV-16 and benzo(a)pyrene: an in vitro multistep carcinogenesis model. Oncogene 1995 Jun;10(11):2145-53.
Penn I. Immunosuppression and cancer. Importance in head and neck surgery. Arch Otolaryngol 1975 Nov;101(11):667-70.
Petersson HG, Bratthall D. The caries decline: a review of reviews. Eur J Oral Sci 1996;104:436-43.
Pindborg JJ. Tobacco and gingivitis. I. Statistical examination of the significance of tobacco in the development of ulceromembranous gingivitis and in the formation of calculus. J Dent Res 1947;26:261-4.
Pindborg JJ. Tobacco and gingivitis. II. Correlation between consumption of tobacco, ulceromembranous gingivitis and calculus. J Dent Res 1949;28:460-3.
Pindborg JJ. Epidemiological studies of oral cancer. Int Dent J 1977 Jun 2;27(2):172-8.
Pinkham JR, Kohn DW. Epidemiology and prediction of sports-related traumatic injuries. Dent Clin North Am 1991;35(4):609-26.
Pitts NB. Monitoring of caries progresion in permanent and primary posterior approximal enamel by bite-wing radiography. Community Dent Oral Epidemiol 1983;11:228-35.
Pomerleau OF, Pomerleau CS. Neuroregulators and the reinforcement of smoking: towards a biobehavioral explanation. Neurosci Biobehav Rev 1984 Winter;8(4):503-13.
Ranney RC. Criteria for efficacy of plaque control agents for periodontal disease: microbiology. J Dent Res 1989 June;68(Spec No):848-1052.
Regezi JA, Sciubba J. Oral pathology. Clinical-pathologic correlations. 2nd ed. Philadelphia: Saunders; 1993.
Reif AE. Cancer immunology. In: Encyclopedia of human biology. 2nd ed. San Diego: Academic Press; 1997.
Reisine ST, Fertig J, Weber J, Leder S. Impact of dental conditions on patients' quality of life. Community Dent Oral Epidemiol 1989;17:7-10.
Rennie JS, Reade PC, Hay KD, Scully C. Recurrent aphthous stomatitis. Br Dent J 1985 Dec 7;159(11):361-7.
Retief DH, Bradley EL, Holbrook M, Switzer P. Enamel fluoride uptake, distribution and retention from topical fluoride agents. Caries Res 1983;17:44-51.
Reynolds JE, Meyer JM, Landa B, Stevens CA, Arnos KS, Israel J, Marazita ML, Bodurtha J, Nance WE, Diehl SR. Analysis of variability of clinical manifestations in Waardenburg syndrome. Am J Med Genet 1995 Jul;57(4):540-7.
Ripa LW. Nursing caries: a comprehensive review. Pediatr Dent 1988;10:268-82.
Riviere A, Wilckens C, Loning T. Expression of c-erbB-2 and c-myc in squamous epithelia and squamous cell carcinomas of the head and neck and the lower female genital tract. J Oral Pathol Med 1990 Oct;19(9):408-13.
Robert E, Kallen B, Harris J. The epidemiology of orofacial clefts. 1. Some general epidemiological characteristics. J Craniofac Genet Dev Biol 1996 Oct-Dec;16(4):234-41.
Rothman K, Keller A. The effect of joint exposure to alcohol and tobacco on risk of cancer of the mouth and pharynx. J Chronic Dis 1972 Dec;25(12):711-6.
Rozier RG. The impact of recent changes in the epidemiology of dental caries on guidelines for the use of dental sealants: epidemiologic perspectives. J Public Health Dent 1995;55(SI):292-301.
Samaranayake LP, Holmstrup P. Oral candidiasis and human immunodeficiency virus infection. J Oral Pathol Med 1989;18:554-64.
Sander A, Murray JC, Scherpbier-Heddema T, Buetow KH, Weissenbach J, Zingg M, Ludwig K, Schmelzle R. Microsatellite-based fine mapping of the Van der Woude syndrome locus to an interval of 4.1 cM between D1S245 and D1S414. Am J Hum Genet 1995 Jan;56(1):310-8.
Schenkein HA, Van Dyke TE. Early onset periodontitis: systemic aspects of etiology and pathogenesis. Periodontol 2000 1994;6:7-25.
Scheutz F, Matee MI, Andsager L, Holm AM, Moshi J, Kagoma C, Mpemba N. Is there an association between periodontal condition and HIV infection? J Clin Periodontol 1997 Aug;24(8):580-7.
Schwartz JL, Frim Sr, Shklar G. RA can alter the distribution of ATPase-positive Langerhans cells in the hamster cheek pouch in association with DMBA application. Nutr Cancer 1985;7(1-2):77-84.
Scott DA, Couter WA, Lamey PJ. Oral shedding of herpes simplex virus type 1: a review. J Oral Pathol Med 1997;26(10):441-7.
Scully C, Porter CR. Recurrent aphthous stomatitis: current concepts of etiology, pathogenesis and management. J Oral Pathol Med 1989;18:21-7.
Scully C, el-Kabir M, Samaranayake LP. Candida and oral candidosis: a review. Crit Rev Oral Biol Med 1994;5(2):125-57.
Seow WK. Biological mechanisms of early childhood caries. J Public Health Dent 1998;26(Suppl 1):8-27.
Seyler LE Jr, Fertig J, Pomerleau O, Hunt D, Parker K. The effects of smoking on ACTH and cortisol secretion. Life Sci 1984 Jan 2;34(1):57-65.
Seyler LE Jr, Pomerleau OF, Fertig JB, Hunt D, Parker K. Pituitary hormone response to cigarette smoking. Pharmacol Biochem Behav 1986 Jan;24(1):159-62.
Seymour GJ. Importance of the host response in the periodontium. J Clin Periodontol 1991;18:421-6.
Shannon IL, Edmonds EL. Effect of fluoride concentration on rehardening of enamel by a saliva substitute. Int Dent J 1978;28:421-6.
Ship II. Inheritance of aphthous ulcers of the mouth. J Dent Res 1965;44:837-44.
Ship II. Epidemiologic aspects of recurrent aphthous ulceration. Oral Surg Oral Med Oral Pathol 1972;33(3):400-6.
Ship II, Brightman VJ, Laster LL. The patient with recurrent aphthous ulcers and the patient with recurrent herpes labialis: a study of two population samples. J Am Dent Assoc 1967 Sep;75(3):645-54.
Ship JA. Recurrent aphthous stomatitis: an update. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996 Feb;81(2):141-7.
Shklar G. Oral leukoplakia. N Engl J Med 1986;315(24):1544-6.
Shklar G, Schwartz J. Tumor necrosis factor in experimental cancer regression with alphatocopherol, beta-carotene, canthaxanthin, and algae extract. Eur J Cancer Clin Oncol 1988 May;24(5):839-50.
Shklar G, Schwartz J. Oral cancer inhibition by micronutrients. The experimental basis for clinical trials. Eur J Cancer B Oral Oncol 1993 Jan;29B(1):9-16.
Shklar G, Schwartz JL. A common pathway for the destruction of cancer cells: experimental evidence and clinical implications. Int J Oncol 1994;4:215-24.
Shklar G, Schwartz JL. Vitamin E inhibits experimental carcinogenesis and tumour angiogenesis. Eur J Cancer B Oral Oncol 1996 Mar;32B(3):114-9.
Shklar G, Schwartz JL, Trickler DP, Reid S. Prevention of experimental cancer and immunostimulation by vitamin E (immunosurveillance). J Oral Pathol Med 1990 Feb;19(2):60-4.
Shwartz M, Gröndahl H-G, Pliskin JS, Boffa J. A longitudinal analysis from bite-wing radiographs of the rate of progression of approximal carious lesions through human dental enamel. Arch Oral Biol 1984;29(7):529-36.
Sidransky D. Molecular genetics of head and neck cancer. Curr Opin Oncol 1995 May;7(3):229-33.
Silverman S. Oral cancer. 4th ed. Hamilton, Ontario: B.C. Decker; 1998.
Slavkin H. Gene regulation in the development of the oral tissues. J Dent Res 1988;67:1142-9.
Socransky SS, Haffajee AD. Microbial mechanisms in the pathogenesis of destructive periodontal diseases: a critical assessment. J Periodontol Res 1991 Apr;26:195-212.
Socransky SS, Haffajee AD. The bacterial etiology of destructive periodontal disease: current concepts. J Periodontol 1992 Apr;63(4 Suppl):322-31.
Socransky SS, Haffajee AD, Goodson JM, Lindhe J. New concepts of destructive periodontal disease. J Clin Periodontol 1984 Jan;11(1):21-32.
Solt DB. Localization of gamma-glutamyl transpeptidase in hamster buccal pouch epithelium treated with 7, 12-dimethylbenz[a]anthracene. J Natl Cancer Inst 1981 Jul;67(1):193-200.
Somers KD, Cartwright SL, Schechter GL. Amplification of the int-2 gene in human head and neck squamous cell carcinomas. Oncogene 1990 Jun;5(6):915-20.
Somers KD, Merrick MA, Lopez ME, Incognito LS, Schechter GL, Casey G. Frequent p53 mutations in head and neck cancer. Cancer Res 1992;52(21):5997-6000.
Spandidos DA, Lamothe A, Field JK. Multiple transcriptional activation of cellular oncogenes in human head and neck solid tumors. Anticancer Res 1985;5(2):221-4.
Sreebny LM, Yu A, Green A, Valdini A. Xerostomia in diabetes mellitus. Diabetes Care 1992 Jul;15(7):900-4.
Sugerman PB, Shillitoe EJ. The high risk of human papillomaviruses and oral cancer: evidence for and against a causal relationship. Oral Dis 1997;3:130-47.
Suzuki JB. Diagnosis and classification of the periodontal diseases. Dent Clin North Am 1988 Apr;32(2):195-216.
Syrjanen SM, Syrjanen KJ, Happonen RP. Human papillomavirus (HPV) DNA sequences in oral precancerous lesions and squamous cell carcinoma demonstrated by in situ hybridization. J Oral Pathol 1988 Jul;17(6):273-8.
Taimela S, Kujala UM, Osterman K. Intrinsic risk factors and athletic injuries. Sports Med 1990 Apr;9(4):205-15.
Talal N. Sjögren's syndrome: historical overview and clinical spectrum of disease. Rheum Dis Clin North Am 1992 Aug;18(3):507-15.
Todd R, McBride J, Tsuji T, Donoff RB, Nagai M, Chou MY, Chiang T, Wong DT. Deleted in oral cancer-1 (doc-1), a novel oral tumor suppressor gene. FASEB J 1995 Oct;9(13):1362-70.
Tomar SL, Winn DM. Coronal and root caries among U.S. adult users of chewing tobacco [abstract]. J Dent Res 1998;77(SI):256.
Tomaski SM, Zalzal GH, Saal HM. Airway obstruction in the Pierre Robin sequence. Laryngoscope 1995 Feb;105(2):111-4.
Toomers C, James J, Wood AJ, et al. Loss of function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat Genet 1999 Dec;22:421-4.
Tyldesley WR, Field AE. Oral medicine. 4th ed. Oxford: Oxford University Press; 1995.
U.S. Department of Health and Human Services, National Center for Health Statistics. National Health and Nutrition Examination Survey III, 1988-1994. CD-ROM series 11, no.1. Hyattsville (MD): National Center for Health Statistics, Centers for Disease Control and Prevention; 1997. Available from National Technical Information Service (NTIS), Springfield, VA.
Van Dyke TE, Horoszewicz HU, Cianciola LJ, Genco RJ. Neutrophil chemotaxis dysfunction in human periodontitis. Infect Immun 1980 Jan;27(1):124-32.
Vissink A, 's-Gravenmade EJ, Gelhard TB, Panders AK, Franken MH. Rehardening properties of mucin- or CMC-containing substitutes on softened human enamel. Effects of sorbitol, xylitol and increasing viscosity. Caries Res 1985;19(3):212-8.
Wheeler CE. The herpes simplex problem. J Am Acad Dermatol 1988;18(1 Pt 2):163-8.
White DJ. Reactivity of fluoride dentifrices with artificial caries; II. Effects on subsurface lesions, F uptake, surface hardening, and remineralization. Caries Res 1988;22:27-36.
Whitley RJ. Neonatal herpes simplex virus infections: pathogenesis and therapy. Pathol Biol (Paris) 1992 Sep;40(7):729-34.
Wight AJ, Ogden GR. Possible mechanisms by which alcohol may influence the development of oral cancer—a review. Oral Oncol 1998;34:441-7.
Winn DM. Tobacco chewing and snuff dipping: an association with human cancer. IARC Sci Publ 1984;(57):837-49.
Wise CA, Chiang LC, Paznekas WA, Sharma M, Musy MM, Ashley JA, Lovett M, Jabs EW. TCOF1 gene encodes a putative nucleolar phosphoprotein that exhibits mutations in Treacher Collins syndrome throughout its coding region. Proc Natl Acad Sci USA 1997 Apr 1;94(7):3110-5.
Wong DT. TGF-alpha and oral carcinogenesis. Eur J Cancer B Oral Oncol 1993 Jan;30B(4):3-7.
Wong DT, Todd R, Tsuji T, Donoff RB. Molecular biology of human oral cancer. Crit Rev Oral Biol Med 1996;7(4):319-28.
Woo SB, Sonis ST. Recurrent aphthous ulcers: a review of diagnosis and treatment. J Am Dent Assoc 1996 Aug;127(8):1202-13.
World Health Organization (WHO). World Health Organization's international classification of diseases and stomatology, IDC-DA. 3rd ed. Geneva: WHO; 1992.
Wray D, Graykowski EA, Notkins AL. Role of mucosal injury in initiating recurrent aphthous stomatitis. Br Med J (Clin Res Ed) 1981 Dec 12;283(6306):1569-70.
Zonana J, Jones M, Clarke A, Gault J, Muller B, Thomas NS. Detection of de novo mutations and analysis of their origin in families with X linked hypohidrotic ectodermal dysplasia. J Med Genet 1994 Apr;31(4):287-92.
back to top
Next: Chapter 4