Identification of gum disease genes may speed quest for compounds to treat severe periodontitis

Identification of the genes represents a vital step toward developing compounds that can be used in targeted, individualized treatment of severe periodontitis, before loss of teeth and supportive bone occurs.

Findings of the study were published recently in the Journal of Dental Research.

In gene expression studies, investigators find those genes that are most commonly expressed in either healthy or diseased tissue. But such studies cannot identify a causal link between these genes and the disease, and often miss genes that affect a larger number of genetic pathways, which may have a large impact on the disease process.

In this study, a team led by Panos N. Papapanou, DDS, PhD, professor and chair of oral, diagnostic and rehabilitation sciences at the College of Dental Medicine at CUMC, “reverse-engineered” the gene expression data to build a map of the genetic interactions that lead to periodontitis and identify individual genes that appear to have the most influence on the disease. “Our approach narrows down the list of potentially interesting regulatory genes involved in periodontitis,” says Dr. Papapanou. “This allows us to focus on the handful of genes that represent the most important players in the process rather than the whole transcriptome.”

To identify the genes, Dr. Papapanou partnered with CUMC investigators including Ryan Demmer, PhD, assistant professor of epidemiology, at the Mailman School of Public Health, and researchers in Systems Biology who had previously developed algorithms to identify regulatory genes that fuel cancer growth. The researchers examined RNA from healthy and diseased gum tissues of 120 patients with periodontitis. They applied one algorithm to study the interactions among the genes and used another algorithm to identify genes that disrupt healthy tissue and drive the disease process.

Many of the genes identified by Dr. Papapanou and his team are implicated in immune and inflammatory pathways, confirming laboratory and clinical observations of the development of periodontal disease.

Identification of the master regulator genes will allow investigators to test compounds that interrupt their action, creating treatments that stop periodontal disease at its source. “Now it’s important to do the downstream work of validating these master regulators in the lab before we can test these genes in experimental models,” says Dr. Papapanou.

Researchers find byproducts from gum disease incite deadly oral cancer growth

Researchers from Case Western Reserve University have discovered how byproducts in the form of small fatty acids from two bacteria prevalent in gum disease incite deadly oral cancer growth (the growth of deadly Kaposi’s sarcoma-related (KS) lesions and tumors in the mouth).

The discovery could lead to early saliva testing for the bacteria, which, if found, could be treated and monitored for signs of cancer before it develops into a malignancy, researchers say.

“These new findings provide one of the first looks at how the periodontal bacteria create a unique microenvironment in the oral cavity that contributes to the replication the Kaposi’s sarcoma Herpesvirus (KSHV) and development of KS,” said Fengchun Ye, the study’s lead investigator from Case Western Reserve School of Dental Medicine’s Department of Biological Sciences.

The discovery is described in The Journal of Virology article, “Short Chain Fatty Acids from Periodontal Pathogens Suppress HDACs, EZH2, and SUV39H1 to Promote Kaposi’s Sarcoma-Associated Herpesvirus Replication.”

The research focuses on how the bacteria, Porphyromonas gingivalis (Pg) and Fusobacterium nucleatum (Fn), which are associated with gum disease, contribute to cancer formation.

Ye said high levels of these bacteria are found in the saliva of people with periodontal disease, and at lower levels in those with good oral health—further evidence of the link between oral and overall physical health.

The deadly oral cancer growth KS impacts a significant number of people with HIV, whose immune systems lack the ability to fight off the herpesvirus and other infections, he said.

“These individuals are susceptible to the cancer,” Ye said.

Deadly oral cancer growth KS first appears as lesions on the surface of the mouth that, if not removed, can grow into malignant tumors. Survival rates are higher when detected and treated early in the lesion state than when a malignancy develops.

Also at risk are people with compromised immune systems: those on medications to suppress rejection of transplants, cancer patients on chemotherapies and the elderly population whose immune systems naturally weaken with age.

The researchers wanted to learn why most people never develop this form of cancer and what it is that protects them.

The researchers recruited 21 patients, dividing them into two groups. All participants were given standard gum-disease tests.

The first group of 11 participants had an average age of 50 and had severe chronic gum disease. The second group of 10 participants, whose average age was about 26, had healthy gums, practiced good oral health and showed no signs of bleeding or tooth loss from periodontal disease.

The researchers also studied a saliva sample from each. Part of the saliva sample was separated into its components using a spinning centrifuge. The remaining saliva was used for DNA testing to track and identify bacteria present, and at what levels.

The researchers were interested in Pg’s and Fn’s byproducts of lipopolysaccharide, fimbriae, proteinases and at least five different short-chain fatty acids (SCFA): butyric acid, isobutryic acid, isovaleric acid, propionic acid and acetic acid.

After initially testing the byproducts, the researchers suspected that the fatty acids were involved in replicating KSHV. The researchers cleansed the fatty acids and then introduced them to cells with quiescent KSHV virus in a petri dish for monitoring the virus’s reaction.

After introducing SCFA, the virus began to replicate. But the researchers saw that, while the fatty acids allowed the virus to multiple, the process also set in motion a cascade of actions that also inhibited molecules in the body’s immune system from stopping the growth of KSHV.

“The most important thing to come out of this study is that we believe periodontal disease is a risk factor for Kaposi sarcoma tumor in HIV patients,” Ye said.

With that knowledge, Ye said those with HIV must be informed about the importance of good oral health and the possible consequences of overlooking that area.

The research was supported by a career development grant at Center for AIDS Research at Case Western Reserve University, and a National Institute of Dental and Craniofacial Research grant.

Contributing to the study were Case Western Reserve University researchers Abdel-Malek Shahir and Nabil Bissada, from the Department of Periodontics; Xiaolan Yu, Jingfeng Sha, Zhimin Feng, Betty Eapen, Stanley Nithianantham, and Aaron Weinberg, from the dental school’s Department of Biological Sciences; and Biswajit Das and Jonathan Karn, from the Department of Molecular Biology & Microbiology at the School of Medicine.

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This article deals with practical oral care for people with intellectual disability. Providing oral care to people with intellectual disability requires adaptation of the skills you use every day. In fact, most people with mild or moderate intellectual disability can be treated successfully in the general practice setting. This article will help you make a difference in the lives of people who need professional oral care.

Intellectual disability is a disorder of mental and adaptive functioning, meaning that people who are affected are challenged by the skills they use in everyday life. Intellectual disability is not a disease or a mental illness; it is a developmental disability that varies in severity and is usually associated with physical problems. While one person with intellectual disability may have slight difficulty thinking and communicating, another may face major challenges with basic self-care and physical mobility.

Data indicate that people with intellectual disability have more untreated caries and a higher prevalence of gingivitis and other periodontal diseases than the general population.

Health challenges in intellectual disability and strategies for care

Many people with intellectual disability also have other conditions such as cerebral palsy, seizure or psychiatric disorders, attention deficit/hyperactivity disorder, or problems with vision, communication, and eating. Though language and communication problems are common in anyone with intellectual disability, motor skills are typically more affected when a person has coexisting conditions.

Before the appointment, obtain and review the patient’s medical history. Consultation with physicians, family, and caregivers is essential to assembling an accurate medical history. Also, determine who can legally provide informed consent for treatment.

Mental challenges

People with intellectual disability learn slowly and often with difficulty. Ordinary activities of daily living, such as brushing teeth and getting dressed, and understanding the behaviour of others as well as their own, can all present challenges to a person with intellectual disability.

• Set the stage for a successful visit by involving the entire dental team–from the receptionist’s friendly greeting to the caring attitude of the dental assistant in the operatory. All should be aware of your patient’s mental challenges.
• Reduce distractions in the operatory, such as unnecessary sights, sounds, or other stimuli, to compensate for the short attention spans commonly observed in people with intellectual disability.
• Talk with the parent or caregiver to determine your patient’s intellectual and functional abilities, then explain each procedure at a level the patient can understand. Allow extra time to explain oral health issues or instructions and demonstrate the instruments you will use.
• Address your patient directly and with respect to establish a rapport. Even if the caregiver is in the room, direct all questions and comments to your patient.
• Use simple, concrete instructions and repeat them often to compensate for any short-term memory problems. Speak slowly and give only one direction at a time.
• Be consistent in all aspects of oral care, since long-term memory is usually unaffected. Use the same staff and dental operatory each time to help sustain familiarity. The more consistency you provide for your patients, the more likely they will cooperate.
• Listen actively, since communicating clearly is often difficult for people with intellectual disability. Show your patient whether you understand. Be sensitive to the methods he or she uses to communicate, including gestures and verbal or nonverbal requests.

Behaviour challenges

While most people with intellectual disability do not pose significant behaviour problems that complicate oral care, anxiety about dental treatment occurs frequently. People unfamiliar with a dental office and its equipment and instruments may exhibit fear. Some react to fear with uncooperative behaviour, such as crying, wiggling, kicking, aggressive language, or anything that will help them avoid treatment. You can make oral health care a better experience by comforting your patients and acknowledging their anxiety.

• Talk to the caregiver or physician about techniques they have found to be effective in managing the patient’s behaviour.
• Schedule patients with intellectual disability early in the day if possible. Early appointments can help ensure that everyone is alert and attentive and that waiting time is reduced.
• Keep appointments short and postpone difficult procedures until after your patient is familiar with you and your staff.
• Allow extra time for your patients to get comfortable with you, your office, and the entire oral health care team. Invite patients and their families to visit your office before beginning treatment.
• Permit the parents or caregiver to come into the treatment setting to provide familiarity, help with communication, and offer a calming influence by holding your patient’s hand during treatment. Some patients’ behaviour may improve if they bring comfort items such as a stuffed animal or blanket.
• Reward cooperative behaviour with compliments throughout the appointment.
• Consider nitrous oxide/oxygen sedation to reduce anxiety and fear and improve cooperation. Obtain informed consent from the legal guardian before administering any kind of sedation.
• Use immobilization techniques only when absolutely necessary to protect the patient and staff during dental treatment–not as a convenience. There are no universal guidelines on immobilization that apply to all treatment settings. Before employing any kind of immobilization, it may help to consult available guidelines on federally funded care, your State department of mental health/disabilities, and your State Dental Practice Act. Guidelines on behaviour management published by the American Academy of Paediatric Dentistry may also be useful. Obtain consent from your patient’s legal guardian and choose the least restrictive technique that will allow you to provide care safely. Immobilization should not cause physical injury or undue discomfort.

People with intellectual disability often engage in perseveration, a continuous, meaningless repetition of words, phrases, or movements. Your patient may mimic the sound of the suction, for example, or repeat an instruction over and again. Avoid demonstrating dental equipment if it triggers perseveration, and note this in the patient’s record.

Physical challenges

Intellectual disability does not always include a specific physical trait, although many people have distinguishing features such as orofacial abnormalities, scoliosis, unsteady gait, or hypotonia due to coexisting conditions. Countering physical challenges requires attention to detail.

• Maintain clear paths for movement throughout the treatment setting. Keep instruments and equipment out of the patient’s way.
• Place and maintain your patient in the centre of the dental chair to minimize the risk of injury. Placing pillows on both sides of the patient can provide stability.
• If you need to transfer your patient from a wheelchair to the dental chair, ask the patient or caregiver about special preferences such as padding, pillows, or other things you can provide to ease the transition. The patient or caregiver can often explain how to make a smooth transfer.
• Some patients cannot be moved into the dental chair but instead must be treated in their wheelchairs. Some wheelchairs recline or are specially moulded to fit people’s bodies. Lock the wheels, then slip a sliding board (also called a transfer board) behind the patient’s back to provide support for the head and neck during care.

Cereal palsy occurs in one-fourth of those who have intellectual disability and tends to affect motor skills more than cognitive skills. Uncontrolled body movements and reflexes associated with cerebral palsy can make it difficult to provide care.

• Place and maintain your patient in the centre of the dental chair. Do not force arms and legs into unnatural positions, but allow your patient to settle into a position that is comfortable and will not interfere with dental treatment.
• Observe your patient’s movements and look for patterns to help you anticipate direction and intensity. Trying to stop these movements may only intensify the involuntary response. Try instead to anticipate the movements, blending your movements with those of your patient or working around them.
• Softly cradle your patient’s head during treatment. Be gentle and slow if you need to turn the patient’s head.
• Help minimize the gag reflex by placing your patient’s chin in a neutral or downward position.
• Stay alert and work efficiently in short appointments.
• Exert gentle but firm pressure on your patient’s arm or leg if it begins to shake.
• Take frequent breaks or consider prescribing muscle relaxants when long procedures are needed. People with cerebral palsy may need sedation, general anaesthesia, or hospitalization if extensive dental treatment is required.

Cardiovascular anomalies such as heart murmurs and damaged heart valves occur frequently in people with intellectual disability, especially those with Down syndrome or multiple disabilities. Consult the patient’s physician to determine if antibiotic prophylaxis is necessary for dental treatment.

Seizures are common in this population but can usually be controlled with anticonvulsant medications. The mouth is always at risk during a seizure: Patients may chip teeth or bite the tongue or cheeks. Persons with controlled seizure disorders can easily be treated in the general dental office.

• Consult your patient’s physician. Record information in the chart about the frequency of seizures and the medications used to control them. Determine before the appointment whether medications have been taken as directed. Know and avoid any factors that trigger your patient’s seizures.
• Be prepared to manage a seizure. If one occurs during oral care, remove any instruments from the mouth and clear the area around the dental chair. Attaching dental floss to rubber dam clamps and mouth props when treatment begins can help you remove them quickly. Do not attempt to insert any objects between the teeth during a seizure.
• Stay with your patient, turn him or her to one side, and monitor the airway to reduce the risk of aspiration.

Visual impairments, most commonly strabismus (crossed or misaligned eyes) and refractive errors, can be managed with careful planning.

• Determine the level of assistance your patient requires to move safely through the dental office.
• Use your patients’ other senses to connect with them, establish trust, and make treatment a good experience. Tactile feedback, such as a warm handshake, can make your patients feel comfortable.
• Face your patients when you speak and keep them apprised of each upcoming step, especially when water will be used. Rely on clear, descriptive language to explain procedures and demonstrate how equipment might feel and sound. Provide written instructions in large print (16 point or larger).

Hearing loss and deafness can also be accommodated with careful planning. Patients with a hearing problem may appear to be stubborn because of their seeming lack of response to a request.

• Patients may want to adjust their hearing aids or turn them off, since the sound of some instruments may cause auditory discomfort.
• If your patient reads lips, speak in a normal cadence and tone. If your patient uses a form of sign language, ask the interpreter to come to the appointment. Speak with this person in advance to discuss dental terms and your patient’s needs.
• Visual feedback is helpful. Maintain eye contact with your patient. Before talking, eliminate background noise (turn off the radio and the suction). Sometimes people with a hearing loss simply need you to speak clearly in a slightly louder voice than normal. Remember to remove your facemask first or wear a clear face shield.

Record in the patient’s chart strategies that were successful in providing care. Note your patient’s preferences and other unique details that will facilitate treatment, such as music, comfort items, and flavour choices

Oral health problems in intellectual disability and strategies for care

In general, people with intellectual disability have poorer oral health and oral hygiene than those without this condition. Data indicate that people who have intellectual disability have more untreated caries and a higher prevalence of gingivitis and other periodontal diseases than the general population.

Periodontal disease

Medications, malocclusion, multiple disabilities, and poor oral hygiene combine to increase the risk of periodontal disease in people with intellectual disability.

• Encourage independence in daily oral hygiene. Ask patients to show you how they brush, and follow up with specific recommendations on brushing methods or toothbrush adaptations. Involve your patients in hands-on demonstrations of brushing and flossing.
• Some patients cannot brush and floss independently due to impaired physical coordination or cognitive skills. Talk to their caregivers about daily oral hygiene. Do not assume that all caregivers know the basics; demonstrate proper brushing and flossing techniques. A power toothbrush or a floss holder can simplify oral care. Also, use your experiences with each patient to demonstrate sitting or standing positions for the caregiver. Emphasize that a consistent approach to oral hygiene is important–caregivers should try to use the same location, timing, and positioning.
• Some patients benefit from the daily use of an antimicrobial agent such as chlorhexidine. Recommend an appropriate delivery method based on your patient’s abilities. Rinsing, for example, may not work for a patient who has swallowing difficulties or one who cannot expectorate. Chlorhexidine applied using a spray bottle or toothbrush is equally efficacious.
• If use of particular medications has led to gingival hyperplasia, emphasize the importance of daily oral hygiene and frequent professional cleanings.

Dental caries

People with intellectual disability develop caries at the same rate as the general population. The prevalence of untreated dental caries, however, is higher among people with intellectual disability, particularly those living in noninstitutionalised settings.

• Emphasize non-cariogenic foods and beverages as snacks. Advise caregivers to avoid using sweets as incentives or rewards.
• Advise patients taking medicines that cause xerostomia to drink water often. Suggest sugar-free medicine if available and stress the importance of rinsing with water after dosing.
• Recommend preventive measures such as fluorides and sealants.

Malocclusion

The prevalence of malocclusion in people with intellectual disability is similar to that found in the general population, except for those with coexisting conditions such as cerebral palsy or Down syndrome. A developmental disability in and of itself should not be perceived as a barrier to orthodontic treatment. The ability of the patient or caregiver to maintain good daily oral hygiene is critical to the feasibility and success of treatment.

Missing permanent teeth, delayed eruption and enamel hypoplasia

Missing permanent teeth, delayed eruption and enamel hypoplasia are more common in people with intellectual disability and coexisting conditions than in people with intellectual disability alone.

• Examine a child by his or her first birthday and regularly thereafter to help identify unusual tooth formation and patterns of eruption.
• Consider using a panoramic radiograph to determine whether teeth are congenitally missing. Patients often find this technique less threatening than individual films.
• Take appropriate steps to reduce sensitivity and risk of caries in your patients with enamel hypoplasia

Damaging oral habits

Damaging oral habits are a problem for some people with intellectual disability. Common habits include bruxism; mouth breathing; tongue thrusting; self-injurious behaviour such as picking at the gingiva or biting the lips; and pica, eating objects and substances such as gravel, cigarette butts, or pens. If a mouth guard can be tolerated, prescribe one for patients who have problems with self-injurious behaviour or bruxism

Trauma and injury

Trauma and injury to the mouth from falls or accidents occur in people with intellectual disability. Suggest a tooth-saving kit for group homes. Emphasize to caregivers that traumas require immediate professional attention and explain the procedures to follow if a permanent tooth is knocked out. Also, instruct caregivers to locate any missing pieces of a fractured tooth, and explain that radiographs of the patient’s chest may be necessary to determine whether any fragments have been aspirated.

Physical abuse often presents as oral trauma. Abuse is reported more frequently in people with developmental disabilities than in the general population. If you suspect that a child is being abused or neglected, State laws require that you call your Child Protective Services agency.

Making a difference in the oral health of a person with intellectual disability may go slowly at first, but determination can bring positive results–and invaluable rewards. By adopting the strategies discussed in this booklet, you can have a significant impact not only on your patients’ oral health, but on their quality of life as well.

Reproduced February 2017 from NIH Publication No. 09-5194

Periodontal Disease background 

Oral plaque (biofilm) contains a complex of multiple bacterial species that can lead to periodontitis or inflammation and, in its more advanced stages, deterioration of gums and tissues that surround the teeth (Periodontal Disease). Dental scaling and root planing removes plaque and tartar; however, these bacterial biofilms have been documented to redevelop in as little as two days post-cleaning. Recent molecular explorations of oral biofilm formation have examined colony formation of several bacterial species in supragingival (above the gum line) and subgingival (below the gum line) locations. Assuming that the order of bacterial succession may be important to periodontal health, the authors of the present report conducted a large-scale biofilm formation study, examining the temporal bacterial species formation in subjects with healthy periodontium and subjects with chronic periodontitis at supragingival and subgingival locations.

Advance in Periodontal Disease

Supragingival and subgingival plaque samples were taken from 28 sites at 1, 2, 4, and 7 days post-cleaning in healthy and periodontitis subjects (post-full mouth scaling and root planing). Plaque samples were analyzed for changes in bacterial proportions for 41 species of bacteria.

Supragingival plaque redevelopment was similar in both healthy and periodontitis samples, but the subgingival profiles were different between these two groups. Both supragingival colony succession order as well as colony proportion were comparatively similar for healthy and periodontal subjects. Subgingival biofilm, however, exhibited changes in colony development order and timing. Healthy individuals had increases in S. oralis and S. constellatus by day 1. Periodontitis subjects exhibited significant increases in C. gracilis, A. oris, P. intermedia and S. noxia by day 7. Proportions of more ‘classic’ periodontal pathogens did not significantly increase in either group; and, in fact, E. nodatum, P. gingivalis, T. forsythia and T. denticola decreased in periodontitis subjects, which with other reports suggest that these complexes may take longer to establish in part because they may require the presence of appropriate conditions provided by earlier colonizers.

Periodontal Disease public impact statement and significance

Results from this NIDCR-supported study suggest that the supragingival microenvironment for plaque redevelopment is similar for healthy and periodontal patients, but that bacterial recolonization is different in periodontal disease when examining subgingival biofilms. Understanding the sequence of microbial colonization may lead to more targeted approaches for controlling periodontal disease.

Publication citation

The work, published in the Journal of Periodontal Research in February 2012, was conducted by Teles FR, Teles RP, Uzel NG, Song XQ, Torresyap G, Socransky SS, and Haffajee AD at the Forsyth Institute and Harvard School of Dental Medicine​.

Reproduced February 2017 from NIH Publication No. 16-6288 July 2016