August 2018 Tooth Eruption Pathophysiology of Oral Cancer Sleep Physiology JournaCALIFORNIA DENTAL ASSOCIATION

CRANIOFACIAL PHYSIOLOGY:Y WHAT MAKES US TICK? DanielDaniele N. N Jenkins, Jenkins DDSDDS, CDE C “I was convinced from my first order. The savings are very impressive!”

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DEPARTMENTS

473 The Editor/I’ll Drink to That

475 Letters to the Editor

479 Impressions

519 RM Matters/In Doubt About How To Handle a Situation? Err on the Side of Caution

523 Regulatory Compliance/Employee Injury Reporting and Records

527 Ethics/Write, Maintain Up-To-Date Patient Records

530 Tech Trends 479

FEATURES

485 Craniofacial Physiology in Dentistry An introduction to the issue. Daniel N. Jenkins, DDS, CDE

487 Lessons Learned as a Student of Craniofacial Biology: What This Might Mean for Orthodontic Professional Education and Clinical Practice in the 21st Century This reprint from Orthodontic Waves discusses the genesis of craniofacial biology from conception to present maturity to future prospects. Harold C. Slavkin, DDS

497 Inhibition of Collagen Crosslinking Produces Significant Retardation of Impeded and Unimpeded Eruption Rates This manuscript provides a summary on the eruption of teeth including additional review of the cogent advances made in cell and matrix studies by cell and oral biologists. Norman R. Thomas, PhD, DDS, MB, BSc, and Daniel N. Jenkins, DDS, CDE

507 Pathophysiology of Oral Cancer: An Overview The purpose of this article is to provide an overview of the pathophysiology of oral squamous cell carcinoma including the role of genetics and epigenetics based on the review of literature. Anupama Grandhi, BDS, DDS

513 Understanding Normal Sleep, Respiration and Circulation This paper is designed to give the reader an understanding of the normal physiology of sleep. Anne-Maree Cole, BDSc, MScMed

AUGUST 2018 471 CDA JOURNAL, VOL 46, Nº8

Volume 46, Number 8 JournaCALIFORNIA DENTAL ASSOCIATION August 2018 CDA Classifieds.

Free postings. published by the Editorial Production Manuscript California Kerry K. Carney, DDS, CDE Val B. Mina Submissions EDITOR-IN-CHIEF SENIOR GRAPHIC DESIGNER Priceless results. Dental Association www.editorialmanager. 1201 K St., 14th Floor [email protected] com/jcaldentassoc Sacramento, CA 95814 Randi Taylor SENIOR GRAPHIC DESIGNER 800.232.7645 Ruchi K. Sahota, DDS, CDE ASSOCIATE EDITOR cda.org Letters to the Editor Upcoming Topics www.editorialmanager. Brian K. Shue, DDS, CDE September/Evidence-Based com/jcaldentassoc CDA Offi cers ASSOCIATE EDITOR Dentistry Natasha A. Lee, DDS PRESIDENT Gayle Mathe, RDH October/Periodontics Subscriptions SENIOR EDITOR [email protected] November/General Topics Subscriptions are available only to active members of R. Del Brunner, DDS Daniel N. Jenkins, DDS, CDE Advertising the Association. The PRESIDENT-ELECT GUEST EDITOR subscription rate is $18 and Sue Gardner is included in membership [email protected] ADVERTISING SALES Andrea LaMattina, CDE dues. Nonmembers can PUBLICATIONS MANAGER [email protected] Richard J. Nagy, DDS view the publication online 916.554.4952 VICE PRESIDENT at cda.org/journal. [email protected] Kristi Parker Johnson EDITORIAL SPECIALIST Permission and Manage your subscription Judee Tippett-Whyte, DDS Reprints online: go to cda.org, log in SECRETARY Blake Ellington and update any changes to Andrea LaMattina, CDE TECH TRENDS EDITOR your mailing information. [email protected] PUBLICATIONS MANAGER Email questions or other [email protected] Steven J. Kend, DDS Jack F. Conley, DDS changes to membership@ 916.554.5950 TREASURER EDITOR EMERITUS cda.org. [email protected] CDA classifiedsclassifieds wworkork harder to Robert E. Horseman, DDS HUMORIST EMERITUS bbringring you resuresults.lts. SeSellinglling a practice Craig S. Yarborough, DDS, MBA or a piece ooff equipment? Now you SPEAKER OF THE HOUSE [email protected] Stay Connected cda.org/journal can include photos to help buyers Clelan G. Ehrler, DDS see the potential. IMMEDIATE PAST PRESIDENT [email protected]

And if you’re hiring, candidates Journal of the California Dental Association (ISSN 1043–2256) is published monthly by the Management California Dental Association, 1201 K St., 14th Floor, Sacramento, CA 95814, 916.554.5950. anywhere can apply right from Periodicals postage paid at Sacramento, Calif. Postmaster: Send address changes to Journal Peter A. DuBois of the California Dental Association, P.O. Box 13749, Sacramento, CA 95853. the site. Looking for a job? You can EXECUTIVE DIRECTOR post that, too. And the best part— The California Dental Association holds the copyright for all articles and artwork published Jennifer George herein. The Journal of the California Dental Association is published under the supervision of it’s free to all CDA members. CHIEF MARKETING OFFICER CDA’s editorial staff . Neither the editorial staff , the editor, nor the association are responsible for any expression of opinion or statement of fact, all of which are published solely on the authority Carrie E. Gordon of the author whose name is indicated. The association reserves the right to illustrate, reduce, All of these features are designed to CHIEF STRATEGY OFFICER revise or reject any manuscript submitted. Articles are considered for publication on condition help you get the results you need, that they are contributed solely to the Journal. Alicia Malaby faster than ever. Check it out for COMMUNICATIONS Copyright 2018 by the California Dental Association. All rights reserved. DIRECTOR yourself at cda.org/classifieds.

472 AUGUST 2018 Editor CDA JOURNAL, VOL 46, Nº8

I’ll Drink to That Kerry K. Carney, DDS, CDE

ince the Boston Tea Party, our country has had an interesting relationship with taxes. When So now there is a new war: The sugar-sweetened we do pay taxes, we want value beverage industry’s war on public health. And Big and a return on our money. Soda is taking a page out of Big Tobacco’s game plan. SThat is why taxes levied on the leading source of a public health crisis and targeted at reducing that public health problem make sense. And that’s why I’m proud to support our association and other health The fi lm was very direct and very Dr. Glantz taught our class to critically care groups in the fi ght against Big Soda moving. It was aired on Thames analyze the quality and interpretation of and its bully tactics. Tobacco serves as a TV in Great Britain, stimulating an data. He showed us that evidence and paradigm for this. There is good evidence immediate response. The clear message data are not necessarily the same. He that the two actions that produce a was that cigarette smoking had made showed us the meaning of evidence-based reduction in tobacco use are a signifi cant the Marlboro man sick. This was a dentistry before we had even heard that cost increase (through an item-specifi c brand disaster. “Death in the West” term. We could use the critical skills sales tax) and restrictions on where tobacco was a direct indictment of the brand he illustrated, but like so many things, may be used. When tobacco is affordable the tobacco industry had spent so my appreciation of the importance of and ubiquitous, the only brake on its use much time and money building. those skills, that documentary and of is public education and understanding. The tobacco industry decided to the bravery and dedication of Dr. Glantz Education and understanding, though play hardball. They did everything they did not really register for several years. necessary, are not suffi cient to produce could to stub out the burning embers that In 1994, Dr. Glantz received boxes signifi cant reductions in tobacco use. The threatened a confl agration of consumer containing 4,000 documents leaked addictive aspects of tobacco add another ill will. After three years of injunctions from the third largest U.S. cigarette insidious dimension to the equation. and litigation, Phillip Morris Tobacco manufacturer, Brown & Williamson. These Tobacco use has a long and Company was able to effectively kill were the basis for the “Cigarette Papers,” storied history in civilization. Modern the documentary. The fi lm was never which showed that the tobacco industry countermeasures and battles with the to be shown again — all fi lm, tapes had known for decades that nicotine was tobacco industry are sources of the and video were to be surrendered. addictive and that smoking caused cancer.2 dramatic theater we have experienced However, using so much muscle to The “Cigarette Papers” played signifi cantly on the big screen, on the page and in the stamp something out can backfi re … in the state and national litigation that tiny theaters of our personal tragedies. and it did. has been described as the Tobacco Wars. “Death in the West” was a 1976 In 1982, Stanton Glantz, PhD, was So now there is a new war: The documentary that included the fi rst an associate professor of the University sugar-sweetened beverage industry’s war recorded admission by a tobacco industry of California, San Francisco, School of on public health. And Big Soda is taking executive that “cancer-causing agents are Medicine. He also taught biostatistics a page out of Big Tobacco’s game plan. found in cigarettes.”1 The fi lm interspersed in the dental school. He had been an But let’s go back and review the Marlboro cigarette ads and interviews anti-tobacco activist for some time and chess moves that led us to the game with tobacco industry leaders with found himself in possession of a copy board positions we observe today. interviews of six cowboys. The cowboys of “Death in the West.” (Things had a According to the CDC, “Sugar- matched the portrayals in the tobacco way of showing up on his doorstep.) He sweetened beverages (SSBs) or sugary ads of manly, cigarette-smoking men. screened “Death in the West” in many drinks are leading sources of added These cowboys had been heavy smokers venues and worked with colleagues to sugars in the American diet. Frequently and were at the time of the fi lming develop companion classes for the fi lm’s drinking sugar-sweetened beverages is dying of emphysema or lung cancer. presentation in the public school system. associated with weight gain/obesity,

AUGUST 2018 473 AUG. 2018 EDITOR

CDA JOURNAL, VOL 46, Nº8

Type 2 diabetes, heart disease, kidney SSBs to fi ght obesity and fund children’s It is a clash between California voters’ diseases, nonalcoholic liver disease, tooth health. So the beverage industry has right to protect our children’s well-being decay and cavities and gout, a type of resorted to a cynical form of arm-twisting. and the soda conglomerates’ protection arthritis. Limiting the amount of SSB They have threatened (in the form of profi t margins. CDA is part of the intake can help individuals maintain a of a statewide initiative) the ability of coalition that will not be intimidated healthy weight and have a healthy diet.” local municipalities to levy taxes with but stands up to the beverage industry’s Mexico implemented a tax on sugar- a simple majority vote of its citizens. coercion and asks, “You want to play sweetened beverages on Jan. 1, 2014. They are reacting to a future set in hardball? Does the beverage industry Studies show an average reduction in motion by the decision of the citizens really want to risk the sort of calamitous purchases of taxed beverages of 7.6 percent of one California city to assess a tax of damage that tobacco suffered over their compared to the projected spending based 1 cent per ounce. Though that was just a years of playing with a similarly signifi cant on previous purchases of SSBs. They drop in the bucket, the beverage industry threat to public health?” It makes me also showed an increase in purchases is hearing the sound of one drop after very proud to be a member of CDA. So of untaxed beverages of 2.1 percent. another as each mounted local defense proud, I will drink to that (with a glass of In November 2014, Berkeley, Calif., falls. It must sound like the dripping of a nonsugar-sweetened beverage of course). ■ became the fi rst city in the United States to leaky roof before the whole thing gives pass a sugar-sweetened beverage tax. (San way in a national movement. With this REFERENCES Francisco’s effort failed in that election threat of a limitation on the ability of the 1. “’Death in the West’ to be resurrected.” The Herald. May cycle.) Research found that one year after local communities to tax themselves for 11, 1982 p. 6. Accessed July 7, 2018. 2. Glantz S, et al. “The Cigarette Papers.” University of the SSB tax was introduced, SSB sales fell anything, the beverage industry was able California Press. in Berkeley by 9.6 percent and sales of water to leverage a huge concession from the 3. Get the Facts: Sugar-Sweetened Beverages and jumped by 15.6 percent. The average cost California state government. The state Consumption. www.cdc.gov/nutrition/data-statistics/sugar- sweetened-beverages-intake.html. of transactions for the consumer remained agreed to ban localities from passing new 4. Silver LD, Ng SH, Ryan-Ibarra S, Taillis LS, Miles DR, Poti the same and the tax cost was usually passed taxes on SSBs for the next 12 years and the JM, Popkin BM. Changes in prices, sales, consumer spending, through to the consumer. The fi ndings of beverage industry withdrew its initiative. and beverage consumption one year after a tax on sugar- sweetened beverages in Berkeley, California, U.S.: A before- the study suggest that SSB taxes may be But here’s where it gets inspiring. and-after study. PLoS Med 2017 Apr 18;14(4):e1002283. effective in shifting consumers to purchase Instead of wringing hands and doi: 10.1371/journal.pmed.1002283. eCollection 2017 Apr. healthier beverages without causing undue lamenting the cynical actions of the economic hardship and while raising beverage industry, the California The Journal welcomes letters 4 revenue for social objectives. The Berkeley Medical Association and the We reserve the right to edit all tax raised 1.5 million dollars for health California Dental Association formed communications. Letters should discuss and nutrition programs in its fi rst year. a coalition to counterattack. an item published in the Journal within Since then, Philadelphia and the The CDA and CMA plan for a the last two months or matters of general California cities of San Francisco, 2020 ballot initiative that, if approved, interest to our readership. Letters must be Oakland and Albany have implemented would create a statewide tax on sugar- no more than 500 words and cite no more SSB taxes. Internationally, France, sweetened drinks, raise at least $1.7 than fi ve references. No illustrations will Hungary, Ireland and the United billion for health programs and write Kingdom are following Mexico’s lead localities’ power to enact similar taxes be accepted. Letters should be submitted and instituting measures aimed at into California’s Constitution. They at editorialmanager.com/jcaldentassoc. By discouraging people from drinking SSBs. went on to say, “Big Soda may have won sending the letter, the author certifi es that The beverage industry is not sitting a cynical short-term victory, but for the neither the letter nor one with substantially still for these attempts to reduce SSB sake of our children’s health, we cannot similar content under the writer’s authorship consumption. They have consistently out- and will not allow them to undermine has been published or is being considered spent the public health activists in every California’s long-term commitment to for publication elsewhere, and the author battle. This war by attrition does not have health care and disease prevention.” acknowledges and agrees that the letter and a good prospect for SSBs. Some polls show The analogies between this confl ict all rights with regard to the letter become the 57 percent of the public support taxes on and the tobacco wars are easy to draw. property of CDA.

474 AUGUST 2018 Letters CDA JOURNAL, VOL 46, Nº8

May 2018 Medication-Related Osteonecrosis Treating MRONJ With Ozone Mixed-Dentition Orthodontics Clinical Judgement JournaCALIFORNIA DENTAL ASSOCIATION

This is in regard to an article in the The Authors Respond

MAKING eHEALTH RELEVANT TO THE PRACTICE OF DENTISTRY: May 2018 issue, “Medication-Related The Journal describes itself as follows: A PROPOSED STRATEGY Osteonecrosis of the Jaw: Update and “This award-winning peer-reviewed Future Possibilities” by James L. Borke, scientifi c publication keeps dentists MS, PhD, et al. I was quite surprised to up to date about scientifi c advances, read their comments toward the end business management strategies and of the article under the section “Future new products. It also features thought- Possibilities for Treatment” related to ozone. provoking editorials, practice support, From what I’ve heard, the only risk management and regulatory success that I’ve come across treating compliance articles and technological N Vol 46 o this osteonecrosis has been using ozone. trends that affect dentistry.” 5 Two things surprised me. The fi rst is In this description, it is clear that, in that you mentioned ozone at all. That part, the Journal exists to provoke thought is a major leap away from politically and present trends that affect dentistry. correct and toward examining scientifi c Whether the topic of ozone therapy results of an ambitious intervention studies, which, given ozone’s history in is politically correct or not does not deserve program with the goal of improving this country related to people talking consideration in scientifi c discourse. As the oral health and nutritional status about it, is actually quite courageous. you mentioned in your letter, data exists of 586 Vietnamese children. My compliments. The second surprise suggesting this may have positive future The intervention consisted is that you also mentioned its use in implications for MRONJ and is thus worthy of oral health screenings, mouth carious lesions, ulcerations, extraction of inclusion in the section of our report pain evaluation, fl uoride varnish sockets, herpetic lesions, root canals and entitled “Future Possibilities for Treatment.” applications and oral health and periodontal pockets. The surprise here Presentation of this information nutrition education delivered through is that these things weren’t necessarily requires no courage whatsoever. preschools twice a year for two years. related to the subject matter of the article Those with a genuine interest in ozone The purpose of the research was stated so mentioning them at all was surprising. therapy or any other topic presented as being “to complete a descriptive A suggestion here. Each of these uses are encouraged to dig deeper into the evaluation of changes over time” of the is quite effective, and there have been literature and formulate their own position intervention on the oral health and studies published in other countries on the topic. This article was not designed nutrition in Vietnamese childhood. related to these things, with Edward to be an exhaustive review of ozone There is limited research published Lynch, currently dean at the Warwick therapy; however, we would encourage you regarding the relationship between School of Dentistry just north of London, or any other reader to write such a review, early childhood oral health status previously at Queens, being the most as we are sure many — including ourselves in Vietnam, and your project of prolifi c author and publisher. These need — would fi nd it thought provoking. intervention and research serve well greater attention in this country and you Thank you for your interest. in this regard. Oral health status as an might consider going into these areas in JAMES L . BORKE, PHD outcome measurement is appropriate greater depth and backing up what you JEFFREY A . ELO, DDS, MS because the goal is to improve oral say with some studies. You are on the Pomona, Calif. health in Vietnamese childhood. right track. But as they’re doing research, Oral health status may vary on the a researcher should be documenting Improving Oral Health in Early presence or absence of plaque, but his statements more, especially when Childhood also vary due to the presence of caries documentation is available and I read with great interest the risk and decayed teeth. Caries risk is readers are generally unaware of it. article “Improving Early Childhood considered a multifactorial disease. Thank you for the article; I was surprised Oral Health in Vietnam: Results of Nutritional habits are important, to read what you said, but did appreciate it. a Two-Year Intervention Study” that but caries risk is also infl uenced by JOHN LICKING, DDS appeared in the November 2017 issue microorganisms, time, oral hygiene, Sunnyvale, Calif. of the Journal. The authors discuss the fl uoride and saliva among other factors.

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The authors mention that the subjects World Health Organization (WHO) REFERENCES received applications of fl uoride varnish, criteria. The plaque index was recorded 1. Bica I, Cunha M, Reis M, Costa P, Costa J, Albuquerque C. Educational Intervention for Oral Health. Procedia Soc Behav oral hygiene instructions and education, based on the classifi cation criteria of Greene Sci 2015 Jan 16;171:613–9. toothbrushes and toothpaste for them and Vermillion. As a way to validate oral 2. World Health Organization. Promoting Oral Health in Africa. and their families and twice-annual hygiene status data over time, in my humble Prevention and control of oral diseases and noma as part of essential non-communicable disease interventions. dental screenings. In their article titled opinion, I think that a plaque index should ALEJANDRO ESPEZÚA, DENTAL STUDENT “Educational Intervention of Oral Health” be registered as well for future assessments STEFANY CABALLERO- GARCÍA, MSC published in 2015, Bica et al.1 evaluated and research of oral health status because the Universidad Peruana de Ciencias Aplicadas the oral health risk of 200 adolescents by WHO considers tooth decay, periodontal Lima, Peru a questionnaire phase assessing variables disease and others as priority oral diseases.2 such as personal background, diet, control I appreciate and recognize your interest of plaque and motivation for proper oral in working to improve oral health in early health, among others. During the clinical childhood and the effort made to research phase, assessment of the oral cavity was the factors that could deteriorate oral done using the DMFT index based on health status in Vietnamese childhood.

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476 AUGUST 2018 Give health, hope and happiness.

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It Is Better To Give David W. Chambers, EdM, MBA, PhD

Here is a paradox: We often have more positive attitudes toward those we help than those who help us. This was a popular sentiment during the 18th century. In his autobiography, Benjamin Franklin said, “This is another instance of the truth of an old maxim I had learnt, which says, he that has once done you a kindness will be more ready to do you another, than he whom you yourself have obliged.” His contemporary, the Scottish philosopher David Hume, expressed it this way: “We attach ourselves more by the services we perform than by those we receive.” We tend to discount our indebtedness to those who help us. We dislike being dependent. In 2015, Americans spent roughly $118 billion on dental care. Let’s imagine something very dramatic: Let’s cap this at $47 billion, total, for all dentists. Dentists could perform as much dentistry as they felt that the public needed, but less than half of what was formerly paid for would be compensated. Patients only pay about $40 of every $100 from their The nub: own pockets. About 45 percent comes from benefi ts programs (mistakenly called “insurance”) and 15 percent 1. Help, particularly unasked-for from the government. Although external sources have assistance, is often resented. allowed dentistry to be performed at a much higher level than it was about a half-century ago when the payment mix 2. We all have our threshold for started to change, I know very few dentists who publically what we think is fair. sing the praises of insurance or government. The general sentiment is to grouse, almost to the point of ingratitude. 3. Pro bono work promotes good I have mentioned the Ultimatum Game before. In feelings about the underserved. the game, Player A is given a sum of money free, usually equivalent to a day’s wages. For convenience we will say $100. Player A can share any amount up to $100 with Player B, a stranger who has no claim on the money. If Player B David W. Chambers, EdM, MBA, PhD, is a professor accepts the offer, the amount is split as agreed. If Player B of dental education at the University of the Pacifi c, Arthur A. Dugoni School of Dentistry, San Francisco, and the editor declines the offer, neither A or B get anything. Both insurance of the American College of Dentists. and the income tax system come to mind as examples. The Ultimatum Game has been played innumerable times in countries and social classes all over the world. Even in one- off exchanges, an offer of about $30 of the $100 is accepted while offers of less are usually rejected. The receiving party would rather have nothing than an amount he or she considers “unfair.” Dentists often say things like this with regard to insurance or government-supported care, but most accept the offer. Presumably, current compensation arrangements meet the grumble threshold but are better than the deal threshold. We are committed to advance the interests of those whom we help, not those who have given us a hand up. Ask any dentists who have volunteered at a CDA Cares event or a mission to an underdeveloped country. ■

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CDA JOURNAL, VOL 46, Nº8

Research Examines Geographic, Health System Correlates of Interprofessional Oral Health Practice A study published recently in the journal Family Medicine and Community Health found that physicians are more likely to provide fluoride varnish if they 1 in 5 Deaths of Young have proper training, have access to patient data to determine eligibility, have Adults Is Opioid-Related access to dentists to whom they can refer patients and are engaged by leadership in the decision to provide the services. One out of every fi ve deaths Researchers from The DentaQuest Institute in Massachusetts and Medical among young adults in the United University of South Carolina examined unknown correlates of oral health prevention States is related to opioids, suggests a and intervention at geographic, organizational and system levels relating to the study led by researchers in Canada. impact of referral mechanisms and systems as well as health information technology The study, published in the on fluoride varnish administration and risk-based oral evaluations. JAMA Network Open and led by With caries activity being one of the most common diseases of childhood, St. Michael’s Hospital in Toronto, prevention/intervention by primary care teams can positively impact patient results, Ontario, found that the percentage of deaths attributable to opioids in according to the study. Research evidence supports the clinical and cost-effectiveness the U.S. increased by 292 percent of primary care-based oral health risk assessments and fluoride varnish applications. from 2001 to 2016, with one in Many studies have demonstrated the successful adoption of interprofessional every 65 deaths related to opioid use oral health practices at the clinic, system and state levels. But while the personal by 2016. Men represented nearly attributes and opinions of individual physicians and pediatricians have been 70 percent of all opioid deaths by explored, few studies have examined the organization and system characteristics 2016, and the highest burden was that enable or facilitate use of fluoride varnish or oral health risk assessments. among young adults aged 24 to 35. The business case for oral health interprofessional practice was presented in “Despite the amount of attention that a single state study that demonstrated its has been placed on this public health cost-efficiency albeit with diminishing returns issue, we are increasingly seeing the depending on reimbursement levels. devastating impact that early loss of life Read more of this study in Family from opioids is having across the United Medicine and Community Health (2018); States,” said Tara Gomes, PhD, MHSc, a doi.org/10.15212/FMCH.2018.0104. scientist in the Li Ka Shing Knowledge Institute of St. Michael’s. “In the absence of a multidisciplinary approach to this issue that combines access to treatment, harm reduction and education, this crisis will impact the U.S. for generations.” related deaths was seen in those aged 24 “These numbers show us the Researchers reviewed all deaths that to 35. By 2016, 20 percent of all deaths dramatic impact of opioid-related occurred in the U.S. between 2001 in this age group were related to opioid harms across all demographics in and 2016 using the Centers for Disease use — up from only 4 percent in 2001. the U.S.,” Dr. Gomes said. “We Control and Prevention WONDER Dr. Gomes and her team found that know this is not an isolated public Multiple Cause of Death online a total of 1,681,359 years of life were health issue — it is one that database. This record captures mortality lost prematurely to opioid-related causes spans across North America.” and population estimates across the in 2016, which exceeds the years of life Read more of this study in the JAMA U.S. by age and sex. The most dramatic lost each year from hypertension, HIV/ Network Open (2018); doi:10.1001/ increase in illicit and prescribed opioid- AIDS and pneumonia in the U.S. jamanetworkopen.2018.0217.

480 AUGUST 2018 CDA JOURNAL, VOL 46, Nº8

Postsurgery Opioid Prescribing Can Lead to Addiction Greater coordination is needed which are most likely to prescribe opioids between surgeons and physicians when for the fi rst time to postoperative patients. prescribing pain-relieving opioid drugs His research was published in the Journal following surgery in order to help identify of General Internal Medicine in June 2018. patients who are at risk of becoming Exposure to opioids is pervasive addicted to the drugs, according to in surgical care in the U.S., and Michael Klueh, MD, of the University of overprescribing is a common occurrence medication can lead to addiction. A Michigan, who led a retrospective review following operations. This has its recent study showed that up to 7 percent of medical specialty areas to fi nd out drawbacks, as the long-term use of such of all patients who were prescribed such painkillers following surgery developed a persistent habit, according to the study. “Millions of Americans each year are continuing opioid use beyond the New Material Could Regenerate Dental Enamel normal recovery period of 90 days after Researchers at Queen Mary University of London have developed a new a surgical procedure,” Dr. Klueh said. way to grow mineralized materials that could regenerate hard tissues such as Researchers analyzed a national dataset dental enamel and bone. of insurance claims fi led by patients aged 18 to 64 who had undergone surgical Unlike other tissues of the body, enamel cannot regenerate once it is lost, which can procedures between 2008 and 2014. All lead to pain and tooth loss. These problems affect more than 50 percent of the world’s had received opioid drugs as a form of pain population, so finding ways to recreate enamel has been a major need in dentistry. relief for the fi rst time in their lives. In all, The study, published in Nature Communications, showed that this new the researchers identifi ed 5,276 patients approach can create materials with remarkable precision and order that look who had developed persistent drug habits and behave like dental enamel. and continued fi lling opioid prescriptions The materials could be used for a wide variety of dental complications three to six months after their operations such as the prevention and treatment of tooth decay or tooth sensitivity — also had taken place — well past the stage known as dentin hypersensitivity. that the use of such medication is The mechanism that has been developed is based on a specific protein deemed normal. Dr. Klueh’s team also material that is able to trigger and guide the growth of apatite nanocrystals at noted which medical practitioners had multiple scales — similarly to how these crystals grow when dental enamel provided them with the prescriptions. develops in our body. This structural organization is critical for the outstanding The researchers found that surgeons physical properties exhibited by natural dental enamel. (69 percent) wrote most prescriptions Enabling control of the mineralization process opens the possibility to create in the three months following surgery, materials with properties that mimic different hard tissues beyond enamel such as followed by primary care physicians (13 bone and dentin. As such, the work has the potential to be used in a variety of percent), emergency medicine personnel applications in regenerative medicine. In addition, the study also provides insights (2 percent) and physical medicine and into the role of protein disorder in human physiology and pathology. rehabilitation staff (1 percent). All other Learn more about this research in Nature specialties accounted for 15 percent of Communications (2018); doi.org/10.1038/ such prescriptions. In contrast, nine to s41467-018-04319-0. 12 months after surgery, the majority of opioid prescriptions were provided by primary care physicians (53 percent) Close-up of the enamel-like material. (Credit: Alvaro Mata) followed by surgeons (11 percent). Learn more about this study in the Journal of General Internal Medicine (2018); doi.org/10.1007/s11606-018-4463-1.

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Film Helps Dental Retainers, Aligners Fight Bacteria More than 5 million people seek orthodontic treatments each year, according to the American Association of Orthodontists. These procedures include braces and aligners, which are sets of plastic pieces that shift the teeth slightly over time in an attempt to fix crowded jaws, overbites and Drinking Alcohol Aff ects underbites and improperly aligned teeth. Mouth Bacteria Linked Clear aligners or retainers, known collectively as clear overlay appliances (COAs), are made by taking a dental cast and using pressure or heat on a to Diseases plastic sheet. But bacteria frequently build up on COAs as difficult-to-treat When compared with nondrinkers, biofilms, and the plastics easily wear down. So a group of researchers men and women who had one or developed a film to prevent bacteria from growing on the appliances. Their more alcoholic drinks per day had research was published in ACS Applied Materials and Interfaces in May 2018. an overabundance of oral bacteria Drawing inspiration from superhydrophilic antibacterial coatings on linked to gum disease, some cancers other medical devices, the researchers wanted to see if they could make and heart disease but fewer bacteria something similar for COAs in the unique oral environment. They took a known to check the growth of other polymer sheet made of polyethylene terephthalate that was modified with harmful germs, according to a study glycol (PETG) and layered films of carboxymethyl cellulose and chitosan led by NYU School of Medicine on it. This layered film created a superhydrophilic surface, or a surface researchers. Their fi ndings were that loves water, that prevented bacteria from adhering. When PETG with published online in the journal the film was compared to the bare material, bacterial growth was reduced Microbiome in April 2018. by 75 percent. The coated plastic also was stronger and more durable, “Our study offers clear evidence even when tested with artificial saliva and that drinking is bad for maintaining various acidic solutions. a healthy balance of microbes in Read more of this study in ACS the mouth and could help explain why drinking, like smoking, leads Applied Materials and Interfaces (2018); to bacterial changes already tied to doi:10.1021/acsami.8b04433. cancer and chronic disease,” said Jiyoung Ahn, PhD, an epidemiologist and the study’s senior investigator. In the study, Dr. Ahn and her research team offered evidence that rebalancing some of the 700 types ongoing national cancer trials. All Researchers noted that while their of bacteria in the mouth, or oral were healthy when they enrolled in study was large enough to capture microbiome, could potentially reverse either study and provided mouthwash differences between bacteria among or prevent some health problems samples of their oral microbiome along drinkers and nondrinkers, more people tied to drinking. She said roughly with detailed information about their would be needed to assess any microbiome 10 percent of American adults are alcohol consumption. Laboratory differences among those who consumed estimated to be heavy drinkers, which testing was then used to genetically sort only wine, beer or liquor. Some 101 experts defi ne as consumption of one and quantify the oral bacteria among wine-only drinkers were involved in the or more drinks per day for women and the 270 nondrinkers, 614 moderate latest study, in addition to 39 who drank two or more drinks per day for men. drinkers and 160 heavy drinkers. only beer and 26 who drank only liquor. The study involved 1,044 Results were plotted on graphs to Learn more about this study mostly white participants between determine which bacteria in drinkers in Microbiome (2018); doi.org/ the ages of 55 and 87 from two stood out more than in nondrinkers. 10.1186/s40168-018-0448-x.

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Most Toddlers Consume Large Amounts of Added Sugar A new study suggests that children in percent of a representative sample of U.S. the U.S. begin consuming added sugar at toddlers aged 19–23 months consumed a very young age and that many toddlers’ an average of just over seven teaspoons of sugar intake exceeds the maximum added sugar on a given day — more than amount recommended for adults. the amount of sugar found in a Snickers The study, led by author Kirsten candy bar. Sixty percent of children were A. Herrick, PhD, MSc, a nutritional found to consume added sugar before age 1. and toddlers 6–23 months old who epidemiologist at the Centers for Disease For the study, Dr. Herrick analyzed participated in the 2011–2014 National Control and Prevention, found that 99 data from more than 800 infants Health and Nutrition Examination Survey, a research study that is representative of the American population. Parents were asked to record every item their child consumed Graphene Flakes Can Kill Bacteria on Implants during a 24-hour period. To assess added sugar, researchers counted any A tiny layer of graphene flakes becomes a deadly weapon and kills bacteria, calorie-containing sugars that were stopping infections during procedures such as implant surgery, according to added to a food item, including cane research from Chalmers University of Technology, Sweden, published in the sugar, high-fructose corn syrup, honey journal Advanced Materials Interface in early 2018. and other forms of sugar. The study Operations for surgical implants, such as hip and knee replacements or did not include artifi cial zero-calorie dental implants, have increased in recent years. However, in such procedures, sweeteners or the sugars that occur there is always a risk of bacterial infection. In the worst case scenario, this can naturally in fruits, vegetables and milk. cause the implant to not attach to the skeleton. The results indicated that 85 percent Bacteria travel around in fluids, such as blood, looking for a surface to cling of infants and toddlers consumed to. Once in place, they start to grow and propagate, forming a protective layer added sugar on a given day and added- known as a biofilm. The Chalmers research team has shown that a layer of vertical sugar consumption rose with age. Just graphene flakes forms a protective surface that makes it impossible for bacteria to over 60 percent of babies aged 6–11 attach. Instead, bacteria are sliced apart by the sharp graphene flakes and killed. months consumed added sugar on a Coating implants with a layer of graphene flakes can therefore help protect the given day, averaging just under one patient against infection, eliminate the need for antibiotic treatment and reduce the teaspoon. Among those aged 12–18 risk of implant rejection, according to the study. Additionally, the osseointegration — months, 98 percent consumed added the process by which the bone structure grows to attach the implant — is not disturbed. sugar, averaging 5.5 teaspoons. By 19–23 months, 99 percent of children “We discovered that the key parameter is to orient the graphene vertically. If consumed an average of just over it is horizontal, the bacteria are not harmed” said Ivan Mijakovic, PhD, professor seven teaspoons of added sugar on a at the Chalmers department of biology and biological engineering. given day, according to the study. Learn more about this study in Advanced Materials Interface (2018); Among children aged 12–23 months, doi.org/10.1002/admi.201701331. added sugar consumption was highest among non-Hispanic black children Vertical graphene flakes form a protective and lowest among non-Hispanic white surface that makes it impossible for bacteria children, Dr. Herrick said. There were no to attach. (Credit: Yen Strandqvist/ differences in added sugar consumption Chalmers University of Technology) by race among infants aged 6–11 months. Dr. Herrick presented this research at the American Society for Nutrition annual meeting during Nutrition 2018 held June 9–12, 2018, in Boston.

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Craniofacial Physiology in Dentistry

Daniel N. Jenkins, DDS, CDE

GUEST EDITOR

Daniel N. Jenkins, DDS, entists spend a lot of time For many dentists, the name Harold CDE, received his dental learning how to repair C. Slavkin, DDS, brings up thoughts degree from the Loma pathological and traumatic of a genius dentist who ran the dental Linda University, School of Dentistry in 1975 and conditions of the craniofacial section of the National Institute of is in private practice as a components. Besides Health for many years. He was the satellite dentist focusing on Dlearning chemistry, anatomy, aesthetics, main impetus behind the renaming of TMD and sleep disorders. psychology and sociology, it is important that section as the National Institute He has been the editor to understand how the craniofacial system of Craniofacial Studies. We received for the Tri-County Dental Society for 16 years and is works when it is operating properly. permission to reprint one of his articles the current editor-in-chief of This aids in determining how to repair recently published in Orthodontic the American Association the pathologies. If the dentist does not Waves. The background of modern of Dental Editors and consider the physiology involved in craniofacial research will give readers Journalists. He was treating patients, they are, once again, an understanding of how much effort awarded the Distinguished Editor Award for 2017 by as they were considered in the Middle has gone into developing craniofacial 1 the ADA. Ages — a technician in the mouth. physiology research to where it is today. Confl ict of Interest In this issue are four articles Norman R. Thomas, PhD, DDS, Disclosure: None reported. regarding the physiology involved in MB, BSc, has more degree “initials” after the craniofacial system. Of course, his name than most of us have letters in there are many more areas that could our name. His research over the years be included. However, to involve has ventured deeply into the physiology more would limit the depth of study of the craniomandibular system. One in each area of physiology of the amazing thing is that at 80 years old he craniofacial system. I should state that still remembers what he studied over all this issue is not intended to entertain of his years — as those of us who have the reader — rather, it is intended been tutored by him can attest. He still to challenge and provide knowledge. practices dentistry, with a physiological Some of the information may not, emphasis on TMJ and sleep disorders, at fi rst read, seem applicable to the with his sons in Edmonton, Canada. operatory. However, I encourage you I have been honored to work with to reread and study something that Dr. Thomas on this paper and other does not come to you at fi rst blush. research over our years of association.

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I feel the need, and honor, to prepare Recently, it was announced that My wish for you, my fellow dental Journal readers for studying Dr. Thomas’ cancer cases were decreasing — except professional, in reading the articles in this and my paper, as, traditionally, the topic for oral cancer.2 While cancer is usually issue on craniofacial physiology is to renew of tooth eruption is not covered often — thought of as an interference of the your interest in how our amazing bodies and is probably not that interesting to the physiology of the body, I asked Anupama work. We are learning more and more of masses. In fact, you may wonder what, Grandhi, BDS, DDS, from the Loma how the mouth is not isolated from the if any, clinical application there is for Linda University, School of Dentistry head and the head is not isolated from this paper. While the paper involves the to discuss the physiology of cancer itself the rest of the body. By understanding descriptions and reasons for proper tooth to help us understand how it operates. the physiology of our body, it makes eruption, it provides the dental practitioner With the rise of human papillomavirus it less diffi cult to determine when and with information that can help parents and (HPV) cancers, it is useful for dentists what is wrong and then the best way to caretakers of children who are at tooth- to keep the physiology of the “enemy treat that physiological malfunction. ■ erupting age to assure a better result for to life” in their minds as they provide REFERENCES their dentition. If the teeth do not erupt regular oral cancer screenings for their 1. Garant PR. The Long Climb: From Barber-Surgeons to properly, their jaws will not grow properly patients — and are asked questions Doctors of Dental Surgery. 1st ed. Quintessence Pub Co. and the chance of a diminished vertical about it when someone in a social Hanover Park, Ill. 2013:25. 3 2. Cronin KA, et al. Annual Report to the Nation on the Status dimension of the jaws could lead to other setting asks about oral cancer. of Cancer, Part 1: National Cancer Statistics. Cancer May 22, craniofacial disorders. This may even I encourage all dental professionals 2018. doi.org/10.1002/cncr.3155. lead to limited tongue space causing sleep to sign up frequently for continuing 3. HPV-Related Oropharyngeal Cancers Have Increased. ADA Morning Huddle, May 29, 2018. disorders such as sleep apnea or more. education on the topic of cancer. This paper shows how carbohydrates The American Dental Association in the diet can affect the proper eruption C.E. website provides oral cancer of teeth. Therefore, it is important to courses that are available 24/7. impart this knowledge, sometimes in Courses can be accessed at ebusiness. simple terms, to the parents and caregivers ada.org/education/CourseCatalog. of children so they will take to heart the aspx#q=cancer&sort=relevancy. responsibility to minimize the intake of Sleep has now become a very hot topic sweets, sodas and other high-carbohydrate in dentistry. All of us receive notifi cations foods. There are “big” words in this paper of C.E. programs on how to treat sleep that dental professionals will likely have to disorders. As with many subjects, it is simplify for the average patient — such as best to know how things are supposed gubernaculum. Many of us have not used to work before further studying how to those words since basic science classes in correct disorders. Anne-Maree Cole, dental school. However, if the dentist uses BDSc, MScMed, is one of our fellow the word gubernaculum, they can point practicing dentists who has completed to the radiolucent area on a radiograph her master’s degree in sleep medicine. She above an unerupted tooth and say to the shares her knowledge with other dental child’s caregiver, “That is the soft tissue professionals both in the United States that connects the erupting tooth to the and her homeland of Australia. For this gum!” This should help them realize that paper, I requested her to limit the sharing the sugary foods may cause more long- of her knowledge to the physiology of term damage to their child than cavities sleep itself. For example, what is normal in their teeth. Thus, if the practitioner sleep? She assures me she will submit observes a small child with caries, it an additional paper in the future on would be a good time to point out the the pathology and treatment of sleep lifelong effects in the development of their disorders, as she feels it involves more craniofacial anatomy and physiology. than just a sleep appliance or CPAP.

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Lessons Learned as a Student of Craniofacial Biology: What This Might Mean for Orthodontic Professional Education and Clinical Practice in the 21st Century

Harold C. Slavkin, DDS

AUTHOR

Harold C. Slavkin, DDS, Abstract change for the Institute to become is dean emeritus and a The National Institute of Dental the National Institute of Dental and professor at the Herman Research (NIDR) supported the Craniofacial Research (NIDCR) to better Ostrow School of Dentistry of USC. From 1995 to international symposium “Congenital refl ect our scientifi c portfolio. Today I ask 2000, he served as director Anomalies of the Face and Associated how craniofacial biology evolved from of the National Institute of Structures” led by Professor Sam teratology to neural crest cell mapping, to Dental and Craniofacial Pruzansky and members of the fi rst Dental experimental embryology, to correlating Research within the National Study Section in 1959. The plan was single gene mutations to phenotype(s), Institutes of Health in Bethesda, Md. One of his unique in that it examined the human and knowledge of gene functions. Now accomplishments there face as a biological continuum, from in the 21st century, craniofacial biology was the completion of conception through postnatal growth contributes to genomics and epigenetics the fi rst surgeon general’s and development, to maturity in terms in animal models and human soft and report to focus exclusively of functions, structures, and behavior. hard tissue diseases and disorders. For on craniofacial, oral and dental health published in The symposium forged foundations for the near future, biomedical scientists and 2000. He is a member of what we now term “craniofacial biology.” clinical scholars seek to understand how the National Academy of In tandem, the fi rst grant by NIDR was human and microbial genomics impact Medicine, a fellow of the funded in 1957 to Dr. Herbert K. Cooper, diseases, how to use gene editing to treat American Association for orthodontist, for his landmark animal diseases, how to employ precision dentistry the Advancement of Science and a member of a number and human studies of cleft lip and cleft and medicine, and how to advance of scientifi c and dental palate. What followed were decades of major revisions in professional health organizations. multidisciplinary studies in embryology, education and interprofessional clinical Confl ict of Interest anatomy, and physiology coupled with practice. As in the past, orthodontists Disclosure: None reported. diagnostics, therapeutics, biomaterials, and many other disciplines will continue imaging, speech pathology, and studies to play key roles involving critical of human behaviors to promote health thinking and sound clinical acumen to and health literacy. In 1998, as Director improve the quality and precision of of the NIDR, I championed a name craniofacial-oral-dental health care.

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TABLE 1 Craniofacial Biology Highlights: 3.62 Million Sites in 0.32 Seconds From Google Search March 2018

Vertebrate fossils show craniofacial birth defects Aristotle and biological observations (frog embryology) “The most beautiful discoveries are Charles Darwin “On The Origin of Species” (1859) and “The Expression of the Emotions of Man” (1872) made not so much by men as by the period. fi rst used term “craniofacial;” fi rst PubMed citation Thomas Huxley (1876) with evolutionary biology They mature in the course of time, just Creation of National Association of Teachers of Speech in 1925 as fruit falls from the tree at the same Synthesis of genetics, biochemistry and embryology to become “evo-devo” time in different gardens.” Goethe Hans Spemann receives Nobel Prize in 1935 (studies in craniofacial biology) And with this quotation from Goethe, Professor Sam Pruzansky of the University Herbert Cooper creates fi rst craniofacial team (1938) of Illinois and as Chairman for the fi rst World War II and ultrasound, antibiotics, anesthesiology and surgery Dental Study Section of the NIDR opened Vannevar Bush and creation of the NIH (cancer, dental and heart) in 1948 a conference “Congenital Anomalies of NIDR creates “fi rst” genetics section at entire NIH (1950) the Face and Associated Structures” held NIDR fi rst grants for craniofacial in 1957 to Lancaster at Mountain View Hotel in Gatlinburg, Tennessee on December 6, 1959.1 Pruzansky Landmark conference Dec. 6–9, 1959, called “Gatlinburg Conference” or “Congenital Anomalies of the and his Study Section colleagues Lucien A. Face and Associated Structures” (Pruzansky, editor) Bavetta (University of Southern California Paul Tessier, John Converse, Peter Randal, Poul Fogh-Andersen (surgeons), Bob Gorlin, Carl Witkop, and one of my mentors), Gerrit Bevelander F. Clark Fraser, Michael Cohen Jr., Marilyn Jones (genetics), Sam Pruzansky, R. Bruce Ross, Ross Long (New York University), Gerald J. Cox (orthodontist), Duane Spriestersbach, Betty Jane McWilliams and Don Warren all exemplars of clinical (University of Pittsburgh) and Robert Hill scholars (late 1960s–1980s and beyond) (Executive Secretary of the Dental Study Creation of American Speech-Language-Hearing Association (ASHA) in 1978 Section) invited and hosted 125 scientists Basic, translational and clinical research in craniofacial diseases and disorders and clinicians from all parts of the nation, Joseph Murray plastic/craniofacial surgeon receives Nobel Prize in 1990 and from abroad, to assess what is known NIDR “name” changed to NIDCR in 1998 (budget doubles) “50 year anniversary” and what were the scientifi c opportunities NIDCR sponsors “Face Base Initiative” 2004–present in congenital craniofacial diseases and disorders.1 This conference was a major Gordon Conferences “Craniofacial Morphogenesis and Tissue Engineering” (2004–present) benchmark for what was soon to follow. High-defi nition, Precision craniofacial-oral-dental medicine and dentistry That historic period contained teratology CRISPR and gene editing (2014–present) and experimental embryology in animals, the “thalidomide epidemic,” radiation induced birth defects, gene-environment It was for me a thrilling event in San communication, and cooperation between interactions, the structure and function of Francisco. Featured speakers at this fi rst anatomists, physical anthropologists, deoxyribonucleic acid (DNA), and major meeting of the Craniofacial Biology embryologists, physiologists, biochemists, funding from the National Institutes of Interest Group included Sam Pruzansky genetics, pharmacology, microbiology Health (NIH) and the March of Dimes. and Bob Gorland. In turn, Herbert and immunology, coupled with A few years later, Craniofacial biology K. Cooper, also an orthodontist, who audiology, dentistry (pediatrics, oral and was the term coined by Sam Pruzansky, an earlier created the fi rst craniofacial team maxillofacial surgery, orthodontists, and orthodontist who served as the Director of in Lancaster, Pennsylvania in 1938, prosthodontics), dental hygiene, medicine Craniofacial Anomalies at the University inspired Pruzansky and many others to (surgery, pediatrics, adolescent pediatrics, of Illinois in Chicago.2 At that time, create interprofessional, multidisciplinary primary care), nursing, pharmacy, my postdoctoral mentor Lucien Bavetta craniofacial teams including orthodontists radiology, speech therapy and social sponsored me to attend that fateful to address diagnosis and treatment services — all asking patient-centered evening at the International Association of cleft lip and palate and related questions and advancing investigations for Dental Research (IADR) being held congenital as well as acquired craniofacial of basic, translational, clinical, outcomes in March 1968. My postdoctoral studies malformations. Both men realized that and implementation scientifi c research included developmental biology of teeth, there was a unique opportunity to organize of the craniofacial–oral–dental complex. classical biochemistry and immunology craniofacial biology as a fi eld of study Pruzansky became “the father of related to collagens and enamel proteins. that required elaborate collaboration, craniofacial biology” while many of us

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TABLE 2 From Chromosome to High-Definition, Precision Oral Health Care

To karyotyping (1930s–1970s) To genomics to “the post-genomic era” (2004–present) Discoveries by Drs. Cooper, Pruzansky chromosome, and refers to the entire To the transcriptome to proteomics and Bavetta That Inspired and Shaped set of genetic instructions found within To metabolomics to “the diseaseome” My Career every somatic cell. Signifi cantly, it was a To pharmacogenomics and systems approaches I directly learned from Herb Cooper dentist scientist, Norman Simmons, who in biology and Sam Pruzansky in the late 1960s and fi rst isolated and purifi ed DNA in 1952 early 1970s the value of multidisciplinary that enabled Rosalind Franklin to utilize To biomimetics and tissue engineering research as well as for providing health care the fi rst X-ray crystallography images To tissue and organ regeneration and for patients and their families.1–14 These of DNA from Simmons’ preparation. nanobioinformatics men were true clinical scholars with strong The Franklin images led James Watson, To phenomics, precision medicine, high-defi nition, convictions and dedication to advancing Francis Crick and Maurice Wilkins to precision health care, gene editing (CRISPR), the fi eld of craniofacial biology. They predict the structure in 1953.17 In Wilkins’ and beyond … modeled communication, cooperation, acceptance speech for the Nobel Prize collaboration, and coordination as critical in physiology and medicine in 1962, served as “midwives” for the birth of features within craniofacial clinics and of isolating DNA and thereby helping craniofacial biology. Here was the origin of laboratories. Further, Lucien Bavetta, a great many workers, including us.”16 craniofacial biology and “interprofessional biochemist and my mentor, modeled Simmons received a bachelor’s degree in patient-centered health care.”1–11 the importance of critical thinking, science in 1935 from the City College of Over the following fi ve plus decades, oral and writing skills, imagination New York; a doctor of dental medicine craniofacial biology became a mature and the scientifi c method, especially degree in 1939 from Harvard, and a doctor trans-professional, multidisciplinary, as applied to studies of craniofacial of philosophy degree in 1950 from the and international coalition working to developmental and molecular biology. University of Rochester, Rochester, New unravel craniofacial developmental biology York. Thereafter, he joined Rosalind and clinical problems associated with Linkage of Dentistry and Genomics Franklin, then part of Maurice Wilkin’s congenital birth defects, head and neck The craniofacial–oral–dental laboratory in England, also occupied trauma, and a host of chronic degenerative scientifi c biomedical research community by James Watson and Francis Crick. diseases and disorders, as well as forging the contributed to signifi cant advances Simmons was nominated for the molecular biology foundations for human in molecular biology and genetics by Nobel Prize in Physiology or Medicine in and microbial genomics and regenerative mapping and deciphering the nucleotide 1972 in recognition of his fundamental craniofacial-oral-dental health care.5–14 letters of the human genome and by studies of changes in light absorption The progression of craniofacial biology describing the proteome, the information associated with conformational changes is quite remarkable in breadth and depth that comprises all the coding genes and within proteins and polypeptides: the (TABLE 1). The reader is encouraged to their encoded proteins that make us so-called “Cotton effects” (named after explore the author’s latest book “Birth unique and individual humans.7–11,15,16 Aimé Cotton).18 Thereafter, his work in of a Discipline: Craniofacial Biology” This resulted in precise risk assessment nuclear medicine and oral biology in the published in 2012, as well as his earlier assays using an array of biomarkers and School of Dentistry at the University text “Craniofacial Developmental Biology” gene-based, saliva-based diagnostic tests of California, Los Angeles (UCLA), published in 1979 with a Forward by Dr. for improvements in patient treatment as well as his studies of the isolation of Sam Pruzansky,5,6 and several relatively related to skeletal dysmorphogenesis, tobacco mosaic virus DNA and RNA, recent reviews of the scientifi c basis for head and neck trauma, and in oral cancer served as the foundation that led to the dentistry in the United States.7–10,12–14 and several periodontal diseases.5–15 development of numerous nucleic acid The genetics, embryology, physiology, One extraordinary scientifi c discovery and polypeptide biomarkers for gene-based cell and molecular biology of craniofacial- was elucidating chromosomes and the diagnostics as today used in congenital oral-dental development has been structure and possible functions of DNA and acquired craniofacial malformations. profoundly advanced in understanding (TABLE 2). Curiously, the genome is a Another dental clinical scholar was and in many clinical applications for term coined in 1920 by the German Robert Gorlin who earned a bachelor’s diagnosis, treatment, biomaterials, botanist Hans Winkler and likely degree from Columbia University, New wound healing and regeneration.5–14 intended as a portmanteau of gene and York City, and a dental degree in 1947

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from Washington University School of imperfect) and dentine (dentinogenesis Research Foundation at Georgetown Dentistry, St. Louis. He joined the faculty imperfect), oral mucosal pigmentation University in Washington D.C., he at the University of Minnesota School of disorders and pigment metabolism. joined with Margaret Oakley Dayhoff Dentistry, which served as his academic Over time, his program found synergy and created the fi rst computer-assisted home for the second half of the 20th with NIDR investigations in congenital biological databases. They discovered century. Gorlin was known for his ability craniofacial malformations.5,7–11,14,20–22 and developed computer-assisted to deftly integrate his encyclopedic By the end of the 20th century, tomography and also founded the fi eld knowledge of birth defects with clinical researchers had begun to identify the of bioinformatics.23–25 It is important observations, phenotypic traits and specifi c role of a modest number of to realize that Professor Ledley and specifi c genotypes. One of Gorlin’s genes in various craniofacial–oral– his team further fostered “big data” pioneering contributions was the ability dental diseases and disorders; this was, and the promise to transform health to discriminate between syndromic and in no small measure, the result of the care with the widespread capture of nonsyndromic birth defects. His memory remarkable sensitivity and specifi city electronic patient records and high- of craniofacial anomalies was almost as derived from developmental and volume streams from sources ranging extraordinary as was his clinical prowess; from insurance claims and registries both dentists and physicians consulted to personal genomics, microbial him for his diagnostic expertise. genomics, and biosensors. Recently, Gorlin’s diagnostic skills became known Knowing the biochemical artifi cial intelligence and machine- internationally through his lectures, and immunological features of the learning predictive algorithms are book chapters, books and peer-reviewed dominant enamel protein led to becoming the “keys” to unlock the data publications.19,20 From esoteric to that can precisely inform real-time mainstream diseases and disorders, he the isolation, characterization and decisions in health care. Machine- was considered an expert in diagnosing clinical application of the major learning methods are already suited birth defects. The key to his success was enamel gene: amelogenin. to diagnoses as well as prognoses. his ability to see, to understand, and to Knowing the biochemical and integrate an array of seemingly disparate immunological features of the dominant types of information. He could envision enamel protein led to the isolation, the body in terms of “systems biology” molecular biology and a renaissance in characterization and clinical application when others saw only derangements sophisticated instrumentation and dental of the major enamel gene: amelogenin. of its parts. Gorlin became one of the and medical devices for applications to The collaboration of an interdisciplinary leading geneticists in the world and clinical dentistry and medicine.5,7–10,12 team from Baylor College of Medicine was the recipient of numerous awards, For example, we learned that Papillon- led by Professor Savio Woo, and the including the Award for Excellence in Lefèvre syndrome, an autosomal recessive author’s research team at the University Human Genetics Education from the disorder characterized by periodontal of Southern California, enabled the American Society for Human Genetics.19 disease and palmoplantar keratosis, dental gene to be cloned.26 Mapping The creation of the fi rst Intramural diagnosed mainly by dentists, is caused by this gene to the X- and Y-chromosomes Genetics Section within the NIH a mutation in the cathepsin C gene.21,22 of human and mouse27 provided a Campus in Bethesda, Maryland, in 1957 A major contribution was the strategy forensic tool to discriminate the was designed to address genetic diseases and implementation of computer- corporal remains of males versus females and disorders of the craniofacial– oral– assisted big databases that covered and provided the basis for advancing dental complex led by Carl Witkop.14 nucleic acids as well as proteins made our understanding of the Mendelian Witkop received his DDS degree from by Robert Ledley, a dentist graduate inheritance of enamel birth defects.28 the University of Minnesota in 1949 from the New York University School of Yet another advance was the discovery and his MS degree in Oral Pathology Dentistry in 1948, and a Master’s Degree by Mary MacDougall that a gene on in 1950. He then pursued his interests in physics from Columbia University chromosome 4 generates three different within the NIDR Intramural Program in 1950. In the 1960s and 1970s, gene products by alternative splicing: focusing on enamel (amelogenesis working at the National Biomedical dentin phosphoprotein, dentin sialoprotein

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Phenotype (examples) Genotype + epigenetics

■ Cleft lip and/or cleft palate (CLP). ■ Unilateral versus bilateral, ethnicity. ■ Male versus female (gender). biology. The future holds enormous ■ Chromosomal, Mendelian, complex and opportunities for the pursuit of one or teratogenic; syndromic and nonsyndromic. more genetic mutations in one or several ■ CLP aff ects 1/700 live births with wide genes that result in clinical phenotypes variability across geography, racial and ethnic within craniofacial dysmorphology.5–15 groups SES and environmental exposures. New methods and instrumentation for ■ See ncbi.nlm.nih.gov/omim. high-throughput genotyping now enable ■ See Michael Dixon, Mary Marazita, Terri patient genotypes to be completed for less Beatty and Jeff Murray (2011) Cleft Lip and than $1,000 per patient and the new era Palate: Synthesizing. of precision dentistry and medicine.31–34 ■ Genetic and Environmental Infl uences. Another use of genetic science is Nature Review Genetics 12(3):167–178. somatic stem cell and gene therapies to ■ See nidcr.nih.gov. treat human disease.5,7–11 Researchers within the NIDCR Intra- and FIGURE 1. Phenotype + genotype + epigenetics = phenomics: from single nucleotide polymorphisms to Extramural programs are moving genes patient, family and population craniofacial phenotypes. from the laboratory to chairside to treat salivary gland diseases.5,7–12,15 It and dentin glycoprotein.29 Mutations in is considered clinically distinct from Pfeiffer also may be possible to transfer genes genes encoded within chromosome 4 syndrome, yet each is caused by point to readily accessible salivary glands are causal to dentinogenesis imperfecta. mutations in the same gene — FGFR2. In and use them as “biofactories” or as a The molecular cloning and mapping of fact, these two syndromes, as well as Beare- source of proteins to treat diseases or the gene for ameloblastin, the second Stevenson, Jackson-Weiss and Antley- disorders caused by defi cient glycol- and most abundant enamel-forming protein, Bixler syndromes, each represents different mucoproteins biosynthesis found within also was accomplished.28 Furthermore, point mutations in the extracellular domain saliva (xerostomia). As craniofacial- investigators linked the human genome of the transmembrane protein FGFR2.30 oral-dental health professionals, we and proteome at the level of teeth, Mimi Jabs and her team made a remarkable appreciate that the mouth is readily extending our understanding of normal discovery. Jabs discovered that different accessible and that oral soft tissues and abnormal formation of the dentin and point mutations in the same gene resulted may provide a relatively easy route for enamel extracellular matrix tissues.26–29 in differing arrays of phenotype features introducing genes to prevent or treat a The astute clinician who exercises or traits yet each syndrome-contained variety of oral and systemic diseases.5–15 experience, knowledge of human growth craniosynostosis in common. This was not and development, and critical thinking only a brilliant and critical analysis of the Genomics and 21st Century Health Care aligned with the emerging human genetic amino acid sequence data for FGFR2 gene Norman Simmons isolated and and phenotypic datasets heralds the future mutations representing slightly different purifi ed adenoviral DNA with Rosalind (FIGURE 1). For example, based on the clinical phenotypes, but it also celebrates Franklin and thereafter the DNA model NIDCR-supported research studies of Mimi that signifi cance of critical clinical construct and analyses were published in Jabs at Johns Hopkins, we learned that phenotype analyses by a group of clinicians. April 1953.16–18 These discoveries led to members of the fi broblast growth factor Enter the new fi eld of phenomics.5,7,12,30 discoveries demonstrating that the rules (FGFs) family binds to one of three cognate Phenomics is the use of large- for DNA structure and function were receptors (FGFRs) — FGFR1, FGFR2 and scale approaches to study how genetic relatively conserved throughout all living FGFR3.5,7,30 We further understand, based instructions from a single gene, gene cluster organisms albeit viral, bacterial, yeast, on engaging clinicians as well as molecular or the whole genome translate into the full plant or animal. This led to recombinant biologists in the mid-1990s, that many set of clinical phenotypic traits of a patient, DNA technology and questions such as different clinical phenotypes are associated family or population.31,32 Mutations in the what is the language of genetics and is it with allelic dominant mutations in FGFRs, extracellular domain of the transmembrane conserved amongst living creatures? Is there and that these mutations act through FGFR2 are a superb model for genotype a “genetic code” and what is that code? different mechanisms. Crouzon’s syndrome to phenotype variations in craniofacial How is a code within DNA transcribed

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Basic and Clinical Implementation translational ▲ research ▲ research research Following these discoveries suggests that naming cancers after tissues or organs no longer informs diagnosis or Synergies among three concepts: precision oral health care, implementation treatment. This has been described for a science and the learning oral health care system number of liver, lung, and breast cancers. Such an approach will impact redefi ning within the heterogeneity of periodontal FIGURE 2. The future for craniofacial-oral-dental research, education and health care. diseases as well as head and neck cancers. Further, metagenome-wide association studies (MWAS) now enable the high- into information of utility? How does that approximately 1 million non-coding resolution investigations of associations transcription become translated into a fi nal RNAs. There are >3 million regulatory between the human microbiome and gene product? Can specifi c microorganisms regions and 15 million transcription factor a number of complex human diseases synthesize recombinant human insulin for recognition elements. This emerging including Type 2 diabetes, obesity, liver the treatment of Type 2 diabetes? And, database enables clinicians to defi ne cirrhosis, colorectal cancer, rheumatic more recently, how is the information the precise gene mutation(s) associated arthritis, and periodontal diseases. within DNA regulated and orchestrated with a specifi c intracellular molecular MWAS not only identifi ed the more or to become cells, tissues, organs, and organ pathway (e.g., tumor suppressor gene less abundant microbial taxa, but also systems in health or disease? Sustained mutations that effect the regulation of includes the identifi cation of bacterial government and foundation fi nancial DNA synthesis and the cell cycle) that functions that are enriched or less support enables fundamental scientifi c cause birth defects, neoplastic diseases, abundant. MWAS is rapidly becoming investigation leading to risk assessment, and a host of other diseases and disorders an investigative technology that informs diagnostic and therapeutic advances, (dental caries, periodontal diseases, the prevention, diagnosis and treatment and to health promotion and disease temporomandibular dysfunction, chronic of diseases including craniofacial-oral- prevention interventions5–10,12–14 (TABLE 3). orofacial pain, and autoimmune disorders). dental diseases and disorders.7–11 Beginning in 1988, the Human Mendelian inherited gene mutations Genome Project (HGP) was created as are rare, yet these genetic disorders occur Opportunities for Oral Health a “big science” international coalition to at a rate of 82 per 1,000 live births. Professional Education in Genomics identify and sequence the human genome Epidemiology studies show that if all and Clinical Practice to reveal “the parts list” of being human. congenital anomalies (e.g., adontia, A number of excellent conferences, Twelve years later the 95 percent complete cleft lip, cleft palate, and craniofacial workshops and scientifi c and education- drafts of the human genome were syndromes) are considered as part of the directed publications encourage all published and by 2003 the entire human human genetic load, then approximately health professions to prepare students genome was disclosed.5,7–12,35,36 In tandem, 8 percent of persons are identifi ed as and graduates for “the genomic era.”37–61 also in the 1980s, the link between having a genetic disorder before reaching All health professional students must altered chromatin protein structure and adulthood or 3 million American people. be knowledgeable in the relationships gene activation and/or deactivation were Knowing the specifi c gene(s) between genotype, phenotype, discovered as epigenomic events. Native mutation(s) also provides a precise environmental factors, epigenetics, gene regulatory elements were marked opportunity to design patient-specifi c and the patters of craniofacial–oral– by altered chromatin structure that in therapy using a pharmacogenomics dental diseases and disorders — so- turn resulted from the methylation of database. Further, specifi c gene called “phenomics.”36–60 We also nucleotides cytosine (C) or guanosine (G). mutations in a specifi c intracellular need to acknowledge that above and More than 300 such regulatory elements molecular pathway during embryonic beyond basic science backgrounds were mapped as of early 21st century. and fetal development or during is the requirement to understand Each human being possesses 60,000 postnatal development also may how to make scientifi c advances genes including 21,000 traditional coding reveal a comparable gene mutation relevant to all Americans of all ages genes, 40,000 non-coding genes, and in a neoplastic disease process. and reduce health disparities.37,41–56

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TABLE 3 Opportunities in Craniofacial-Oral- Dental and Behavioral Research To Improve Human Health

Fundamental science Health promotion Medicine” announced in his State of the periodontium. The available of the Union Address on January 20, epidemiology suggests that 10 percent Disease prevention 2015. In tandem, I had earlier written to 15 percent of the general adult U.S. Risk assessment a paper “From Phenotype to genotype: population develop severe, destructive Diagnostics, treatments and cures enter genomics and the transformation forms of periodontal diseases. Further, of primary health care around the the oral microfl ora bacteria are world,” published in 2014, anticipating implicated as well as socioeconomic In this context, the NIH defi nition the president’s announcement. factors in the severity of disease. We of implementation science is the This primer complements an now have the tools to link phenotype study of “strategies to adopt and excellent publication “Personalized with genotype with environmental integrate evidence-based health Oral Health Care” edited by Dean factors to better identify people at interventions and change practice Emeritus Peter J. Polverini from the risk for periodontal diseases and, in patterns within specifi c settings.”56 University of Michigan.57–61 In that some situations, with systemic chronic Ideally, implementation science publication a number of invited infl ammatory diseases such as Type 2 answers questions, “Why do evidence- diabetes. Recently, sequence genetic based interventions lose effectiveness variants in the gene SLC16A11 were over time in real-world settings?” found to be a common risk factor for and “How do interventions need We now have the tools Type 2 diabetes in large populations to be applied to various settings to of Hispanic people from Mexico and maintain clinical effectiveness?” When to link phenotype with Latin American countries.62 The interventions shown to be effi cacious in genotype with environmental genetic expression of SLC16A11 the controlled environment of clinical factors to better identify people alters lipid metabolism causing an trials are applied to the real-world where increase in intracellular triacylglycerol there is greater population variability at risk for periodontal diseases. metabolism levels. This approach with and the inability to maintain control sample sizes of many thousands of over environment and patient responses, people (i.e., 3,848 Type 2 diabetes and it becomes enormously important to 4,366 controls) provides the potential evaluate for clinical effectiveness. Future chapters explore the utilization of to even illuminate pathophysiology, research, education and patient health genomics to prevention, diagnosis, health disparities, and even the care will benefi t enormously from the oral cancer therapy, diagnosis and population genetic origins of diabetes synergy between basic, clinical, and stratifi cation of periodontal disease and periodontal disease alleles.59–61 implementation sciences (FIGURE 2). patients, metabolomics and oral As I conclude my refl ections of A primer from the National disease diagnosis, genomics and dental craniofacial biology, I would be remiss Academy of Medicine (NAM) caries risk assessment, personalized not to also highlight the emerging was published as “Applying an oral medicine, chronic orofacial pain, signifi cance of epigenetic differences Implementation Science Approach to and preparing the next generation that arise during the lifetime of Precision Medicine.”56 This Workshop of oral health care professionals for a monozygotic twins (identical twins Summary focused on how to utilize precision oral health care environment. with identical genotypes at birth) and implementation science to provide There are now many important the future prospects from gene editing. an essential background and best implications for genomics and Even though monozygotic twins practices for all health professionals in genomic technology for the diagnosis, share a common genotype at birth, contemporary genomics to enhance risk treatment and management of as they advance in the lifespan they assessment, diagnosis, and treatments diseases. Periodontal diseases are a increasingly demonstrate phenotypic for precision health care. In no heterogeneous group of pathologies discordances such as differences in small measure, this NAM-sponsored that share many clinical signs and susceptibilities to acute and chronic workshop evolved from President symptoms (phenotype or traits); chiefl y diseases, cancers, dementia as well Barak Obama’s “Initiative of Precision chronic infl ammation and destruction as a wide range of anthropomorphic

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features. The phenotypic discordance human genomes and, for the fi rst REFERENCES result from global and locus-specifi c time in history, offers the opportunity 1. Pruzansky S, editor. Congenital anomalies of the face and associated structures. Springfi eld, Ill.: Charles C. Thomas, 66 differences in DNA methylation and to control evolution. CRISPR is publisher; 1961. histone acetylation found from studies the acronym for “clustered regularly 2. Pruzansky S. What is craniofacial biology? J Dent Res of a large cohort of identical twins.63 interspaced short palindromic repeats” 1968;47 (6):931–3. 3. Cooper HK. Integration of services in the treatment of Specifi cally, differences in genomic fi rst discovered in bacterial DNA. cleft lip and palate. J Am Dent Assoc 1953;47:27–35. distribution of 5-methyl-cytosine CRISPR/Cas9 genome editing allows 4. Cooper HK. Historical perspectives and philosophy DNA and histone acetylation affected researchers to create precise deletion of treatment. 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The evolution of America’s scientifi c advancements in dentistry in the past 150 years. J Am Dent even in the genomic era, it is not enjoyed revisiting the genesis of Assoc 2009;140(9 Suppl):8S–15S. human genes alone but the interplay our discipline from conception to 14. Harris RR. Dental science in a new age: A history of of multiple genes, epigenetics, present maturity to future prospects. the National Institute of Dental Research. Rockville, Md.: ■ Montrose Press; 1989. the microbial genome and their The best is yet to come! 15. Wong DTW. Salivaomics. J Am Dent Assoc interactions with oral hygiene, diet, 2012;143(10 Suppl):19s–24s. ACKNOWLEDGMENTS 16. Wilkins MHF. The molecular confi guration of nucleic exercise, and substance abuses that I wish to thank my formal mentors Lucien Bavetta (University of acids. Nobel lecture. Dec. 11, 1926. www.nobelprize.org/ infl uence the type and severity of Southern California), Dick Greulich (University of California at nobel_prizes/medicine/laureates/1962/wilkins-lecture.pdf. 46–52,54,55,59,65 Los Angeles), and Sam Pruzansky (University of Illinois, Chicago periodontal diseases. As 17. Watson JD, Crick FH. Molecular structure of nucleic Medical Campus) for getting me off on “the right foot” with acids. A structure for deoxyribose nucleic acid. Nature you refl ect on what you have read, ask admiration for originality, ideas, innovations, and the importance 1953;171: 737–8. yourself if we are approaching what of words. I also thank my colleagues at the National Institutes of 18. Simmons NS, Blout ER. The structure of tobacco Health (1995–2000) and the administration, faculty, staff and Malcolm Gladwell described as the mosaic virus and its components: Ultraviolet optical rotary student colleagues associated with the Center for Craniofacial dispersion. Biophys J 1960;1(1):55–62. “Tipping Point” that now requires Molecular Biology (CCMB) at the University of Southern 19. Cohen Jr MM. Robert J Gorlin, 1923–2006: major revisions in health professional California (1968–2014), and the many visiting Japanese A remembrance. Am J Med Genet A 2006 60 scholars (spending months to many years with us at CCMB) education and clinical practices? Dec1;140(23):2516–20. from whom so much was learned, enjoyed, and savored. Finally, consider a new scientifi c 20. Gorlin RJ, Slavkin HC. Embryology of the face. In: discovery and technology termed Tewfi k TL, Der Kaloustian VM, eds. Congenital anomalies of REPRINT the ear, nose and throat. New York: Oxford University Press; CRISPR which enables gene editing Reprinted from Orthodontic Waves, vol. 77, issue 1, March 1997. pp 287–96. of microbial, plant, animal and 2018, pp 1–9, copyright 2018, with permission from Elsevier. 21. Hart TC, Hart PS, Michalec MD, Zang Y, Firatli E, van

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Dyke TE, et al. Haim-Munk syndrome and Papillon-Lefevre world. Lancet 2010;376:1923–58. 58. Wright JT. Genomics of dental caries and caries risk syndrome are allelic mutations in cathepsin C. J Med Genet 38. Kopel H, ed. The teaching of human genetics in dental assessment. In: Polverini PJ, ed. Personalized oral health 2000;37: 88–9. education. Los Angeles: University of Southern California care: from concept design to clinical practice. Switzerland: 22. Hart TC, Hart PS, Bowden DW, Michalec MD, Callison Press; 1979. Springer International Publishing; 2015. pp 87–98. SA, Walker SJ, et al. Mutations of the cathepsin C gene are 39. Sanger R, editor. Guidelines for the teaching of human 59. Garaicoa-Pazmino C, Decker AM, Polverini PJ. responsible for Papillon-Lefevre syndrome. J Med Genet genetics in dental education. Denver: University of Colorado Personalized medicine approaches to the prevention, 1999;36:881–7. Press; 1979. diagnosis and treatment of chronic periodontitis. 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Inborn 1):3–10s. 66. Doudna JA, Sternberg SH. A crack in creation: Gene errors of development. New York: Oxford University Press; 49. Collins FS, Tabak LA. A call for increased education editing and the unthinkable power to control evolution. 2004. pp. 380–409. in genetics for dental health professionals. J Dent Educ Boston, New York: Houghton Miffl in Harcourt; 2017. 31. Bilder RM, Sabb FW, Cannon TD, London ED, Jentsch 2004;68:807–8. JD, Parker DS, et al. Phenomics: The systematic study 50. Giannobile WV, Kornman KS, Williams RC. THE AUTHOR, Harold C. Slavkin, DDS, can be reached at of phenotypes on a genome-wide scale. Neuroscience Personalized medicine enters dentistry: What might [email protected]. 2009;164(1):30–42. this mean for clinical practice? J Am Dent Assoc 32. Pendergrass SA, Brown-Gentry K, Dudek SM, 2013;144:874–6. Torstenson ES, Ambite JL, Avery CL, et al. The use of 51. Kornman KS, Duff GW. 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Switzerland: Springer education to strengthen health systems in an interdependent International Publishing; 2015.

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CDA JOURNAL, VOL 46, Nº8

Inhibition of Collagen Crosslinking Produces Signifi cant Retardation of Impeded and Unimpeded Eruption Rates

Norman R. Thomas, PhD, DDS, MB, BSc, and Daniel N. Jenkins, DDS, CDE

ABSTRACT From observations on tooth development in man and animals generally it is postulated that tooth eruption is due to tractional force exerted by collagen and its effect on cell differentiation in the periodontium. The hypothesis was tested on limited eruption of molars and continuously erupting incisors in rats. Collagen formation alone did not satisfy the hypothesis. Specifi cally, collagen crosslink inhibitors aminoacetonitrile/beta aminopropionitrile in the drinking water markedly reduced tooth eruption as well as tooth support.1

AUTHORS

Norman R. Thomas, PhD, Daniel N. Jenkins, DDS, he most controversial area The original hypothesis cites collagen DDS, MB, BSc, attended CDE, received his dental in oral biology and clinical generation and crosslinkage as the prime the University of Bristol from degree from the Loma dentistry is the development mover or tractional force of eruption in 1951–57 and obtained Linda University, School his degree in dentistry with of Dentistry in 1975 and and physiology of the dental the dental follicle, gubernaculum and 6–12 honors and distinctions. is in private practice as a occlusion — otherwise known as periodontal ligament (PDL). The He was appointed satellite dentist focusing on Tthe bite. It was a privilege to be entrusted removal of the apical or odontogenic professor of oral biology TMD and sleep disorders. with the presentation of the fi nal chapter, region (root resection) of the unimpeded at the University of Alberta, He has been the editor “Collagen as the Generator of Tooth right lower incisor was produced in 16 Canada, from 1968 to for the Tri-County Dental 1977 while he continued Society for 16 years and is Eruption,” in 1975 at the University adult male Wistar rats (Berkovitz and specialist pathology training the current editor-in-chief of of Bristol, U.K., Colston Symposium Thomas 1969). The unimpeded condition at the Medical College of the American Association No. 27 “The Eruption and Occlusion of is where the tooth is coronally cut down Virginia. In 1990, he was of Dental Editors and Teeth.” Regrettably that reference is now to the gingival margin so that it does not awarded professor emeritus Journalists. He was out of print, as are most of the Colston suffer from occlusal force and attrition. status in dental science at awarded the Distinguished the University of Alberta. Editor Award for 2017 by papers, and I take this opportunity to The left incisor is the impeded tooth Dr. Thomas is chancellor of the ADA. thank the California Dental Association and measures the eruption of a tooth the International College Confl ict of Interest for inviting me to present a summary that is subjected to occlusal forces and of Craniomandibular Disclosure: None reported. of my original paper on the eruption of attrition. In 11 of the rats, the unimpeded Orthopedics. teeth including additional review of the eruption attained control levels four Confl ict of Interest Disclosure: None reported. cogent advances made in cell and matrix to seven days after operation and this studies by cell and oral biologists.2–6 level was attained in approximately

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12 days when, as the base of the tooth ■ The cushioned hammock ligament tooth eruption to increase, whereas in the approached the level of the alveolar theory. This theory depends upon later studies concentrated glutaraldehyde crest, the unimpeded rate decreased. a vital pulp that is absent from (0.5%) fi xed the tendon so that further The following extant theories did not resected teeth. Histology failed response to saline infusion failed. When appear essential to the eruptive process: to reveal the existence of an mean systolic blood pressure is reduced ■ Root elongation. This process is organized tissue beneath the tooth by 20 percent (in vivo), it had no effect prevented by root resection. that resembled the description of on unimpeded eruption rate. As for ■ Pulp cell proliferation and dentine a cushioned hammock ligament. cell proliferation theory, demecolcine formation. Histological examination The tentative conclusion drawn from rapidly retards eruption indicative of shows that the pulp is destroyed the root resection experiment is that if cell involvement in eruption. Thus the following root resection. it is as well-known that the theory of eruption process is a complex of tractional ■ Fundic bone deposition. Macroscopic unspecifi ed pressure forces per se cannot factors producing the eruptive force. As for and microscopic examinations be ascribed an eruptive function, then the effect of lysyl oxidase, recent literature reveal that fundic bone immediately tractional pull forces appear probable shows that lysyl oxidase oxidation not adjacent to the resected tooth only crosslinks collagen but also produces base did not keep pace with tooth oxidation of membranes of mesodermal eruption and a “space” developed or blast stem cells of the ECM, including beneath the base of the tooth. Cell chemotaxis, diff erentiation collagen forming fi broblasts, vascular ■ Tissue fl uid pressure. This hypothesis and migration act concurrent smooth muscle cells, monocytes, etc., to depends upon pressure within an to the stiff ening eff ect of evoke fi broblast differentiation. Thus, cell enclosed system. The alveolar wall chemotaxis, differentiation and migration at the base was removed at the collagen crosslinking by act concurrent to the stiffening effect time of root resection and later a lysyl oxidase on the of collagen crosslinking by lysyl oxidase second wall was breached through periodontal ligament ECM. on the periodontal ligament ECM.7–14 the exposed pulp chamber by the Most recently, an extracellular necessity to maintain an unimpeded matrix molecule, Periostin, has been eruption. These openings remained identifi ed as osteoblast-specifi c-2 in the patent during the subsequent encouraging the fullest investigation. periosteum and various formative dental normal eruption. There was neither It is conceded that the collagenous tissues, including PDL, in cell-to-cell and macroscopic nor histological tissue incorporates within its structure cell-to-matrix interaction with adhesive evidence of organized tissue or fi brin mucopolysaccharides and glycoproteins properties. It has also been defi ned with blocking the pulpal exposure or that exert osmotic pressures within the the composition of lysyl oxidase (LOX) sealing the resected tooth apex. collagen framework, which thereby adds crosslinker, bone morphogenic protein ■ Pressure within the periodontal to increase the stiffening tension of the (BMP1), collagen protease and fi bronectin ligament. Pressure per se due to extracellular matrix (ECM). Indeed, in (FN) adherence factor as the source of an cell proliferation, formation of the Colston Symposium it was shown eruptive force in collagenous tissues.15–17 extracellular constituents, tissue fl uid by Thomas and Tyler in transducer Hence, polymerization and or any other unspecifi ed pressure studies on rat tail tendon, rat incisor crosslinkage of collagen in conjunction in the periodontal ligament are and dog canine that ECM tensions were with LOX, FN and BMP1 has been inadequate to account for continued developed when noradrenaline, tolazoline, given the status of a supramaximal eruption because the vector of hydroxytryptamine, glutaraldehyde, molecule acting as the prime mover such pressures would only serve Ringer’s solution and saline were added of tooth eruption among other ECM to push the resected tooth back into a blood vessel or water bath in functions of formative signifi cance in the into the socket or space beneath which they were incubated with results development of the dental occlusion. the erupting tooth given that the consistent with the tractional hypothesis. Micropatterning of cell-matrix interaction basal diameter of a rodent incisor is In dilute solution, glutaraldehyde (.05%) has been detected by fl uorescent greater than its coronal diameter. caused rat tail tendon to contract and microscopy in conjunction with force

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spectroscopy mapping at molecular noncovalent interactions of the collagen sarcoplasmic triads, which together with levels ~20 nanometers. These have been chains in a head-to-tail and laterally ~ATP results in muscle contraction from used to identify cell and matrix receptor quarter-staggered pentagonal arrangement myosin actin cross bridges. In the case ligand adhesion domains of integrins in to form the collagen microfi bril. The of collagen, there is no motor end plate conjunction with fi bronectin that allow latter is neither stable nor well-oriented as such but there are cell-to-matrix and cell adherence to its surroundings and but free to slide over each other in matrix-to-cell interactions, durotaxis, in the differentiation of fi broblasts.18,19 their salt soluble-liquid-like state.23 involving a wide range of integrins acting It is well-known that collagen However, following assembly, on intracellular actin-myosin.25,26 polymerization is primarily a reaction covalent crosslinking, by the enzyme According to Eastwood et al. and in which liquid monomer is held in LOX and to some extent by glycation Jenkins et al., it was shown with a solution until converted into an insoluble and nitration, stabilizes the fi brils culture force monitor that there is at fi rst form by crosslinking. Furthermore, conferring the high tensile strength collagen polymerization and crosslinkage Kalamajski et al. recently showed that characteristic of mature fi brils. Thus the enhanced by integrin-directed fi broblast fi bromodulin provides collagen stiffening crosslinks act as a stiffening isometric differentiation with an isotonic in a temporary quarter stagger alignment contraction and fi nally an equilibrium until lysyl oxidase crosslinking ensues. phase. Though this was undertaken in Consisting of a family of proteins, the vitro, Thomas and Tyler showed that type 1 collagen fi bril is the dominating The crosslinks act as a when a crosslinker glutaraldehyde in form in tissues requiring tensile strength stiff ening isometric tensile diluted form is added to a rat tail tendon, such as ECM, dermis, myofascia, agent that converts soluble contraction was immediate as indeed was tendon, fi brous periosteum, dura the case when dilute glutaraldehyde was mater, periodontal and joint ligaments uncrosslinked collagen into added to a water bath containing a rat including the temporomandibular insoluble collagen both incisor. There was an appreciable eruption ligament, bone and tooth cementum. in vivo and in vitro. of the tooth similarly when injected into In addition to enzymatic LOX as a the periodontal artery of a dog incisor.27–29 serial crosslinker, advanced glucation Movement of a tooth toward bone end products (AGEs) glucose crosslinks was demonstrated in vitro by Bellows et collagen in a nonserial alignment in the tensile agent that converts soluble al. It is important to stress that in these glucosepane in unsatisfactory excessive uncrosslinked collagen into insoluble and other in vitro and in vivo shrinkage dietary carbohydrate intake.20,21 collagen both in vivo and in vitro.24 studies, contraction of the collagen of The basic monomeric unit of a This stiffening is the development the ECM is assisted by the differentiation collagen microfi bril is procollagen about of an isometric tension due to increased of mesodermal stem cells by durotactic 3000A in length and 15A wide with a resistance to fi bril rotation. In vitro and chemotactic stimulation into central right-handed triple helix region contraction of gel collagen occurs by migratory contractile myofi broblasts.30 of three alpha polypeptide chains and two mechanisms at cell membranes The tractional theory of tooth eruption terminal short nonhelical telopeptides. subsequently by noncovalent chemical now argues that if there is fi rst assembly of According to the Hodge-Petruska model, reactions that are independent of cells. extracellular collagen by noncovalent and the collagen molecules line up — in In vivo isotonic contraction of the covalent polymerization by crosslinkage parallel quarter-staggered side-by-side tensile collagenous tissue may or may it reaches a threshold isometric level of arrangement — to form hydrated fi brils not occur due to its fi xed attachments stiffness tension to trigger mesodermal of tropocollagen molecules 3000A in to relatively static bone or tooth. This cell differentiation of the accompanying length consisting of four periods or is somewhat analogous to that observed stem cells. Subsequently it is argued that 680A banding formation with gaps when skeletal muscle actin and myosin as a result of the obliquity of the PDL containing nonhelical peptides.22 are activated by a nerve-generated ECM including differentiated cells and In the extracellular environment, these action potential at the motor end plates. collagen fi ber contraction, the tooth tropocollagen molecules self-assemble The action potential sweeps over the is pulled into occlusion. In summary, according to electrostatic and hydrophobic muscle liberating calcium from the the fi brous connective collagenous

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TABLE 1 Normal Rat First Molar Growth and Eruption Measured From Tetracycline Marker Studies

Age (days) Root growth Fundic bone Alveolar bone Eruption microns growth microns growth (mean of three (initial resorption microns methods*) tissue in the periodontal ligament is 88 microns) microns initially in a state of isometric tone 12–19 954 54 203 880 until crosslinks stiffen the collagen to 19–26 640 51 163 701 the threshold essential for fi broblast differentiation into myofi broblast that, 26–33 402 45 166 450 under the further infl uence of integrins 33–40 108 48 168 154 and fi bronectin, it undergoes enhanced *Methods of measuring eruption: 1. Alveolar crest tetracycline marker to cementoenamel junction. 2. Fundic bone plus root growth. ECM contraction. The contraction 3. Interradicular bone growth from day 14. depends on noncovalent electrostatic TABLE 2 charge along the collagen molecules as well as the covalent crosslinks between Aminoacetonitrile Bisulfate (0.1%), Effect on Unimpeded Eruption Rates lysine-lysine and hydroxylysine amino Days Height of Length of Eruption Fundic bone Alveolar crest groups of collagen peptides. The latter crown in mm r o o t i n m m (CEJ) in mm in mm in mm are enzymatically produced by LOX 7 1.2 0.0 0.0 –0.10 1.25 and to a lesser extent nonenzymatically 12 1.3 0.24 0.04 –0.30 1.47 by glycation and nitration.31 The isotonic/isometric tension 14 1.3 0.36 0.45 0.09 1.55 of collagen polymer occurs in ECM 21 1.27 1.13 1.30 0.14 1.85 generally, whether from heart, 25 1.26 1.35 1.53 0.18 2.05 tendon or skin, and specifi cally in 35 1.20 1.62 1.84 0.23 2.15 periodontium when the tooth actually 42 1.14 1.80 2.05 0.27 2.25 erupts. In this collagen polymerization, collagen crimping contributes recoil 49 1.10 1.91 2.04 0.32 2.30 force when the load is removed.32 56 1.05 2.01 2.40 0.36 2.34 Thus, alternation between isometric 63 1.01 2.10 2.51 0.40 2.40 and isotonic contraction phases is cell 70 0.95 2.16 2.60 0.43 2.45 dependent — which migrates as the 77 0.92 2.20 2.68 0.46 2.50 collagen polymerizes and packs by end- 84 0.90 2.25 2.73 0.48 2.52 to-end and lateral aggregation.33–36 These biochemical and biophysical 91 0.87 2.31 2.83 0.52 2.55 entities are observed in histologically 98 0.85 2.34 2.91 0.54 2.60 identifi ed maturing collagen in the 105 0.85 2.40 2.99 0.58 2.62 dental follicle, periodontal ligament 112 0.85 2.43 3.05 0.61 2.65 (PDL), cervical loop and root sheath 119 0.84 2.46 3.09 0.63 2.68 of rat and mouse incisors and molars. Thomas defi nes them as the source 126 0.84 2.49 3.14 0.66 2.72 of tooth eruption stages of the dental 133 0.84 2.51 3.17 0.69 2.75 follicle, intraosseous formative root stage 140 0.84 2.53 3.23 0.71 2.77 of periodontal ligament, gubernaculum breach of the oral epithelium, intraoral pre-occlusal and post-occlusal In the physiological in vivo situation, While the increased tensile strength plane. These have been recognized enzymic lysyl oxidase collagen crosslinking during collagen polymerization and as stages where recent researchers is predominant but can be partially crosslinkage is now designated as a stiffening claim that the expression patterns of replaced in pathological and aging by of the ECM, matrix stiffness acting in the a molecular complex consisting of glyoxylate crosslinks as in mitochondrial effect of actinomyosin evoked cell tension Periostin, LOX, BMP1 and FN have a hypoxia of excessive dietary carbohydrate following stem cell proliferation. Mih et signifi cant role in fi brillogenesis.37,38 or in the diabetic condition.39–41 al. show that cells residing in a soft matrix

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TABLE 3

Measurements From Cephalometric Radiographs of the Pups of Nursing Mothers and Weanlings on 0.3% AANB* Supplied in Drinking Water

Experimental group — days of age Control group — days of age 19 26 33 40 19 26 33 40 Upper diastema (A–B) (mm) 7.0 8.0 8.5 9.25 7.75 8.5 9 9.75 Lower diastema (C–D) (mm) 4.8 4.95 5.0 5.1 5.0 5.0 5.0 5.1 Distance between occlusal surfaces of the fi rst lower 1.8 1.95 2.2 2.5 2.5 2.7 2.9 3.1 molar and lingual alveolar bone (E–F) (mm) Extra alveolar length of lower incisor (C–G) (mm) 3.0 3.8 4.8 5.1 3.7 4.5 5.0 5.7 Extra alveolar length of upper incisor (A–K) (mm) 1.8 2.7 3.2 3.2 2.1 3.0 3.3 3.8 Mandibular length (mm) 16.2 16.5 18.8 19.8 16.7 17.2 18.8 20.7

*AANB: Aminoacetonitrile bisulfate (0.1%). exhibit reduced proliferation or growth Taverne debates that while accepting Thomas provided a soft diet in place of arrest. There is also down regulation in the that lathyrogen does decrease eruption the traumatic hard pellets that traumatize soft matrices in terms of cell-spreading, rates, on fi nding that the turnover rate of gingival tissue and occlusal stability.48 migration, traction leading to cytoplasmic lathyrogen collagen does not change, infers TABLE 1 presents the data for rat fi rst tensegrity — including myosin light that this “makes it doubtful that collagen molar eruption. Over the fi rst 12 days of chain phosphorylation and focal adhesion could be responsible for eruption.”46 Again root growth, the root grows apically 88 assembly. Their results demonstrate a failure on the part of that worker to microns resorbing fundic bone before that matrix stiffness is a critical trigger understand that it is not the amount of taking off and erupting 2,185 microns among a wide range of differentiating collagen that sets a threshold for fi broblast as it totally grows 2,104 microns. Thus fi broblast functions. It therefore comes differentiation but rather the level of the tooth does move coronally toward as no surprise that Berkovitz et al. found crosslinked collagen as found in the the occlusion i.e., the tooth does move that inhibition of collagen crosslinkage pumping power of the heart by Lopez et al.47 coronally through and above the alveolar by lathyrogen beta-amino proprionitrile It cannot be over-emphasized that bone by 701 microns. Thus because the (BAPN) has no signifi cant effect on the dietary counseling to reduce sugar, refi ned tooth is at fi rst covered over by alveolar unimpeded eruption rates because there carbohydrate, intake is in order in the bone, eruption consists of the summation is concomitant action of fi bromodulin, case of neuromuscular treatment of the of both active eruption, bodily movement which was not known until recently. patient with neuromuscular fatigue with and passive eruption — where the Their graph of unimpeded versus control evidence of weakness of PDL, tendon, overlying bone and epithelium is resorbed. tooth eruption shows that from the myofascial and joint ligament due to Thus relatively fi xed markers must be used second to the eighth day there is a 20 glyoxylate collagen crosslinking replacing for accuracy. Here tetracycline markers percent decrease in mean eruption rate. highly ordered LOX crosslinked collagen. were used and the bony, gingival and But subsequently there is no difference Not to do so is counterproductive to occlusal plane must be interpreted thereby. in eruption rates. Despite these facts of the prognosis of temporomandibular TABLE 2 shows that studies were temporary fi xation, they showed the disorder treatment. The case for the continued to 20 weeks (140 days) and easy extraction of lathyritic teeth with signifi cance of CCL whether to tooth used as controls against experimental reduced resistance to eruption.42,43 eruption, dental arch formation, occlusal rats given aminoacetonitrile lathyritic Moxham and Berkovitz fi ndings interferences or mechanical force of studies. Eruption slowed as the teeth explain the difference in older animals. the heart all are based on the specifi c came into occlusion. Similarly, studies Their comparison of experimental property of ECM in collagen turnover and undertaken on human deciduous teeth fi ndings with controls indicates that crosslinking in which the timing of the were made using the inferior dental canal, while resistance of a lathyritic PDL to LOX switch in development is critical. which showed no resorptive alterations extrusion is markedly reduced, it follows Michaeli et al. confi rmed Thomas. between 0 and 6 years of age. Fundic that “while eruption rates can appear to The basal jaw bone and external alveolar bone was used as a measure of eruption be unchanged it does not preclude an bone of adult rats is in a relative state TABLE 3 provides the data of effect of the drug on the eruptive force.” of completion compared with younger measurements made on cephalometric (See for example Silver et al.)44,45 pups. They correctly point out that radiographs comparing molar and

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TABLE 4 Comparison of Eruption of Impeded and Unimpeded Eruption of Control and Experimental Rats

Mean eruption Control Control Experimental Experimental Day Impeded mm Unimpeded mm Impeded mm Unimpeded mm incisor teeth eruption (impeded) under 1 .57 .85 .56 .85 control and experimental conditions. 2 1.13 1.79 1.17 1.9 Note the gingival margins and occlusal 3 1.72 2.81 1.81 2.75 planes are unreliable as fi xed points particularly those in lathyrism. 4 2.53 3.70 2.21 3.51 TABLE 4 compares unimpeded and 5 3.11 4.58 2.55 4.08 impeded eruption of the incisors. Note 6 3.61 5.45 2.84 4.81 that experimental impeded eruption 7 4.23 6.47 3.12 5.35 (lathyrism) is virtually arrested within 8 4.78 7.19 3.36 5.81 eight days — the impeded greater than the unimpeded. The impeded 9 5.38 8.21 3.61 6.12 rate decreased from 12.18 to 4.8 10 6.12 9.31 3.82 6.70 mm i.e., by 61 percent over 20 days. 11 6.58 9.95 3.95 6.75 The unimpeded rate decreased from 12 7.21 10.86 4.12 6.90 18.13 to 7.93 mm i.e., by 57 percent, 13 7.79 11.71 4.24 7.05 which was supportive of the tractional 14 8.38 12.69 4.41 7.28 theory of collagen crosslinking. 15 9.12 13.53 4.521 7.45 In TABLE 5, for reliability, statistical measurements were compared for 16 9.58 14.31 4.681 7.65 older control (12) and experimental 17 10.17 15.10 4.760 7.72 rats (12) on 0.1% BAPN lathyrogen 18 10.81 16.20 4.81 7.81 in the drinking water using amalgam 19 11.38 17.07 4.80 7.91 fi xed points against occlusal and gingival points. There is a very 20 12.18 18.13 4.80 7.93 signifi cant reduction (p < 0.001 cf p > 0.05) in impeded and unimpeded TABLE 5 eruption rates over a period of 17 Mean Total Eruption of Control and Lathyritic Rats Over 17 Days days. The control impeded rate decreased from 11.42 mm to 9.78 mm Eruption rate Using occlusal plane (mm) Amalgam pellet (mm) Diff erence cf from 10.57 to 8.08 over 17 days. Lathyritic — unimpeded 16.24 (SD=1.19) 13.75 (SD=0.635) 2.49 In conclusion, the fi ndings are Control — unimpeded 17.01 (SD=1.13) 15.37 (SD=0.38) 1.64 confi rmatory for lathyrogen retarded Diff erence 0.77 (4.5%) + 1.62 (10.4%)* eruption. Michaeli et al. agreed with Lathyritic — impeded 10.57 (SD=1.4) 8.08 (SD=0.08) 2.49 Thomas’ conclusions and obtained similar results as Thomas by cutting the Control — impeded 11.42 (SD=1.2) 9.78 (SD=0.76) 1.64 unimpeded tooth out of occlusion once Diff erence .85 (7.4%) + 1.7 (17%)* only on day 20 and using the higher * Statistically signifi cant p < 0.001. The diff erence between results using the occlusal plane and amalgam pellets is explained as dose level of 0.3% BAPN utilizing underestimation in the former due to the intrusion of the impeded teeth. the same Bryer reference markers.1

Discussion agents that retard or accelerate contractile packing, tensile strength and contractile The fi ndings demonstrate that properties of ECM. It is also clear that properties. A notable fi nding in the collagen crosslinking is signifi cant as an young animals are more sensitive to present study is that the absolute decrease eruptive force as well as for providing a the effects of lathyrism. The fi ndings of in mean eruption rate of impeded and supportive property to the ECM. The this study are consistent with known in unimpeded incisors is comparable evidence also shows that a reliable vivo and in vitro effects of inhibition when the less potent lathyrogen BAPN reference is essential in assessing effects of of crosslinking of collagen on its is given in the drinking water.

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Immunohistochemical localisation of periostin in tooth 43. Berkovitz BKB, Migdalski A, Solomon M. The effect and occlusal contact in the physiology of the rat incisor: IX. and its surrounding tissues in mouse mandibles during of the lathyritic agent aminoacetonitrile on the unimpeded Impeded and unimpeded eruption in lathyritic rats. J Dent development. Anat Record A Discov Mol Cell Evol Biol eruption rate. Arch Oral Biol 1972 Dec;17(12):1755– Res 1975 Jul–Aug;54(4):891–896. 2004 Dec;281(2):1264–1275. 1763. 49. Pischon N, Babakhanlou-Chase H, Darbois L, Ho WB, 39. Gucliucci A, Glycation as the glucose link to 44. Moxham B, Berkovitz BKB. A capacitance transducer to Brenner MC, Kessler E, Palamakumbra AH, Trackman PC. diabetic complications. J Am Osteopath Assoc 2000 monitor the effect of extrusive loads of 0.01-0.1N applied Regulation of collagen deposition and lysyl oxidase by Oct;100(10):621–634. to the lathyritic mandibular incisors of rabbits compared tumor necrosis factor alpha in osteoblasts. J Biol Chem 40. Brownlee M. The pathobiology of diabetic with their controls. Arch Oral Biol 1984;29:773–778. 2004;279:30060–65. complications — a unifying mechanism. Diabetes 2005 45. Silver FH, Freeman JW, Seehra GP. Collagen self- 50. Trackman PC. Diverse biological functions of Jun;54(6):1615–1625. assembly and the development of tendon mechanical extracellular collagen processing enzymes. J Cell Biochem 41. Kosanam H, Thai K, Zhang Y, Advani A, Conelli KA, properties. J Biomech 2003 Oct;36(10):1529–53. 2005, Dec 1; 96(5):927–37. doi: 10.1002/jcb.20605. Diamandis EP, Gilbert RE. Diabetes induces acetylation of 46. Tavern AA. Lathyrism and the half-life of collagen. Aust intermediary metabolism enzymes in the kidney — invokes Orthod J 1991 Oct;12(2):110–5. THE CORRESPONDING AUTHOR, Norman R. Thomas, PhD, DDS, acetylation of lysine. Diabetes 2014 Jul;63(7):2432– 47. Lopez B, Querejeta R, Arantxa G, Larman M, MB, BSc, can be reached at [email protected]. 2439. doi: 10.2337/db12-1770. Epub 2014 Mar 27. Diez J. Collagen crosslinking (CCL) but not collagen 42. Mih DJ, Marinkovic A, Liu F, Sharif AS, Tschumperlin amount associates with elevated filling pressures DJ. Matrix stiffness reverses the effect of actomyosin tension in hypertensive patients with stage C heart failure. on cell proliferation. J Cell Sci 2012 Dec 15;125(Pt Hypertension 2012 Sep;60:677–683. doi: 10.1161/ 24):5974–5983. doi: 10.1242/jcs.108886. Epub 2012 hypertensionaha.112.196113. Epub 2012 Jul 23. Oct 24. 48. Michaeli P, Zajicek G, Weinreb MM. Role of attrition

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TOTOGEG THT ERR WEW ARER LIL MIM TLTLESESS oral cancer

CDA JOURNAL, VOL 46, Nº8

Pathophysiology of Oral Cancer: An Overview

Anupama Grandhi, BDS, DDS

ABSTRACT Oral cancer is a common malignancy in the United States with a high mortality rate. The purpose of this article is to provide an overview of the pathophysiology of oral squamous cell carcinoma including the role of genetics and epigenetics based on the review of literature.

AUTHOR

Anupama Grandhi, ead and neck cancer is the sixth Several environmental risk BDS, DDS, is an assistant most common malignancy factors are linked to the occurrence professor in the department in the world,1,2 comprising of OSCC, including most commonly of oral and maxillofacial 3,4 surgery at the Loma 6 percent of all cancers. tobacco, alcohol and viral infections 11–14 Linda University School Head and neck squamous (e.g., human papillomavirus). of Dentistry and the Hcell carcinoma (HNSCC) has an annual department of pathology incidence of approximately 615,000 cases.1 Hallmarks of Cancer and human anatomy at Oral squamous cell carcinoma (OSCC) is According to Hanahan and the Loma Linda University 4–6 School of Medicine. She the predominant subtype of HNSCC. Weinberg, six essential alterations in is a fellow of the American OSCC is the eighth most common cancer cell physiology collectively dictate Academy of Oral and among males and the 14th most common the growth of malignancy: Maxillofacial Pathology cancer among females worldwide.7 In ■ Self-suffi ciency in growth signals, and a diplomate of the United States, the annual estimated for example mutations, the American Board of Oral and Maxillofacial incidence of oral and oropharyngeal cancer chromosomal translocations,

Pathology. is about 51,540 new cases, and nearly 10,030 retroviral insertions Confl ict of Interest patients die from the disease every year.8 The or amplifi cation of oncogenes. Disclosure: None reported. overall fi ve-year survival rate of OSCC is ■ Insensitivity to antigrowth low despite signifi cant progress in the fi eld of (growth-inhibitory) signals, cancer biology, prevention and treatment.6,9 for example inactivation of tumor suppressor genes. Pathophysiology of Oral Cancer ■ Evasion of programmed Carcinogenesis, or the formation cell death (apoptosis). of cancer, is a multifactorial, multistep ■ Limitless replicative potential process that is mediated by either (cellular immortality). environmental factors, immunologic ■ Sustained angiogenesis (develop- factors and/or sequential accumulation ment of new blood vessels). of genetic and epigenetic defects.3,6,10 ■ Tissue invasion and metastasis.10,15,16

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Genetic Alterations Aneuploidy cycle regulators, for example cyclin D1; There are numerous genetic and In OSCC, with the measurement of or those involved in the inhibition of epigenetic abnormalities that may nuclear DNA content,21 50–60 percent apoptosis, for example bcl-2, bax.15 be associated with the growth of oral of patients demonstrated aneuploidy In normal cells, receptor tyrosine squamous cell carcinoma. According and some were diploid. Aneuploidy is kinases (RTKs) are activated by growth to the literature, these anomalies may frequently considered to be the outcome factors such as epidermal growth factor affect chromosomes, alleles, oncogenes, of alterations in genomic stability (EGF), fi broblastic growth factor tumor suppressor genes or nucleotides due to accumulation of mutations.18 (FGF),26 insulin growth factor (IGF) and the type of anomaly may include and vascular endothelial growth factor polymorphism, point mutations, Epigenetics (VEGF), etc., which in turn activate deletions, amplifi cation or other Epigenetics refers to heritable the cell-signaling protein molecules, alterations.6,7,16–18 According to Ha et al., changes in the gene expression without the ras and PI3K. Active ras activates the common regions of chromosomal modifi cations in the DNA sequence.6,18,20,22 PI3K by binding to p110a, a subunit of loss are at 1p, 3p, 4p, 5q, 8p, 10p, 11q, DNA methylation is considered the PI3K. It also sets off downstream effector 13q and 18q, with gains at 1q, 3q, 5p, most common epigenetic alteration in pathways, such as Ras/Raf/mitogen- 7q, 8q, 9q, 11q, 12p, 14q and 15q.19 OSCC.6,16,18,22–24 It is unclear if there is an activated protein (MAP) kinase and the association between DNA methylation phosphatidyl inositol-3 kinase (PI3K/ Loss of Heterozygosity and environmental risk factors AKT) signaling pathways.9,14,18,27,28 The Loss of heterozygosity (LOH) is the responsible for OSCC.23 Histone covalent ras is regulated by gene modulators process where an allelic imbalance occurs modifi cations and posttranscriptional like microRNAs, for example let-7 due to loss of chromosomal regions gene regulations by noncoding RNA microRNA.28,29 The transduction of containing a gene in either the maternal are also considered to be key processes cell signaling, which controls cell or paternal allele.14,18 This process may in epigenetic regulation.6,14,22 Histones growth, differentiation and survival, impair the tumor suppressor function are structural proteins that are packaged is mediated by proteins that are of the genes that are present in the with DNA and the activity of histone encoded by the ras oncogene.28 In oral affected region.16 LOH has been reported acetyl transferases (HATs) and histone squamous cell carcinoma, oncogenes at regions on chromosomes 3p, 8p, 9p deacetylases (HDACs) infl uences the such as EGFR, ras, PIK3CA, etc., (p16), 13q and 17p (p53 locus).14,16,20 histone acetylation status.2,6 HATs are are genetically deregulated, with the enzymes that function as both oncogenes ras being one of the most commonly Allelic Loss and Allelic Polymorphisms and tumor suppressor genes.22 mutated and activated oncogene.21,27,28 In advanced stages of carcinoma Mutations of H-ras, a member of the and in poorly differentiated carcinomas, Oncogenes and Tumor Suppressor Genes ras oncogene family, has been identifi ed allelic losses at 5q21–22, 22q13, 4q, Oncogenes, which are seen secondary as being more prevalent, especially 11q, 18q and 21q have also been to alteration of normal cellular proto- in Asia, when compared to K-ras and reported.16 Allelic polymorphisms in oncogenes,25 are able to promote N-ras.9,27,28 The expression of nuclear the genes HLA and MICA (major uncontrolled cell proliferation and factor-kappa B, a nuclear transcription histocompatibility complex-class-I- tumor formation.7 Several mechanisms factor that plays a role in infl ammatory chain-related gene A) have also been may drive inappropriate proliferation and immune responses, has also been recognized in some studies.16,21 Single of cancer cells, either through growth found to be upregulated in OSCC.15 nucleotide polymorphisms are areas factors or growth factor receptors, for The normal function of tumor around the genome with altered DNA example hst-1, int-2, EGFR/erbB1, erbB2/ suppressor genes is to maintain the sequences that may or may not lead to Her-2, sis, which play a role in cell homeostasis of cell growth including alterations in the amino acid sequences.19 proliferation, differentiation, adhesion, regulation of cell cycle, programmed The DNMT3B gene may demonstrate migration, tumor invasion and apoptosis;7 cell death, adhesion of cells and repair three single nucleotide polymorphisms intracellular signal transducers, for of DNA.19 Chromosomal deletions have in the promoter region that may play a example ras, raf, stat-3; transcription been reported at 2q21–24, 2q33–35 and role in the development of OSCC.16,21 factors, for example myc, fos, jun; cell- 2q37 affecting tumor suppressor genes,

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including, LRP1B, CASP8, CASP10, Minichromosome Maintenance Proteins of cells.14,21 Cellular immortality in BARD1, ILKAP, PPP1R7 and ING5.16,21 Minichromosome maintenance HNSCC may also be acquired through Aberrant expression of at least one of proteins play a role in the initiation genetic and epigenetic inactivation the members of the retinoblastoma of DNA replication; however, of p16 and mutations in p53.9 (pRb) family of growth suppressor their role in oral squamous cell proteins has been identifi ed in oral carcinoma is still unknown.30 Tumor Microenvironment carcinomas. TP53 is considered another The cellular and extracellular important tumor suppressor gene and Heat Shock Proteins and Toll-Like matrix microenvironment of the host maps on chromosome 17p13.1.2,6,14,16,19 Receptors controls the behavior of the tumor Mutations in the TP53 sequence Heat shock proteins (HSPs) are cells, supplies nutrients to tumor cells may cause aberrant p53 protein intracellular proteins that play a role in by angiogenesis and creates a path for activity7 and genetic polymorphisms the regulation of apoptosis.30 During oral metastasis through the vasculature.30 in the p53 pathway affect formation carcinogenesis, HSPs promote growth and progression of a tumor.7 and survival of tumor cells, however, Tumor-Associated Macrophages and they also play a role in promotion of Interleukins Cyclin Dependent Kinases tumor immunity through stimulation In OSCC, tumor-associated Cyclin dependent kinases (CDKs) of innate immunity.32 HSP70, HSP27, macrophages (TAMs) may be a factor in usually become active after binding to HSP90 and HSP60 are some of the heat tumor progression and metastasis. They cyclins,30 and these play a role in the shock proteins that have been studied also enable angiogenesis, invasion and regulation of cellular proliferation. Two in OSCC.30,32 Several studies have suppression of antitumor response.14,36 CDK inhibitors, p16 and p14, are encoded demonstrated increased expression of TAMs in conjunction with OSCC by the genes that are present in the region HSP70 in OSCC.32 Toll-like receptors cells induce expression of matrix of 9p21 and are frequently inactivated (TLRs) are proteins whose interaction metalloproteinases (MMP) MMP-9 and by promoter hypermethylation.2,6,16,22,31 with HSP family molecules mediates MMP-13 via interleukins (IL) IL-1β/ Allelic imbalance at 9p21 (also known presentation of tumor antigens to IL-1R that cause migration and invasion as CDKN2A locus) has been described antigen presenting cells to induce of tumor cells.36 IL-4 and IL-1 are useful in the majority of carcinomas and immunogenic effect.33 TLRs are not only for activation of TAMs.36 Angiogenesis in may be considered an early event in involved in innate and adaptive immune OSCC is mediated through IL-8.15,36 The oral carcinogenesis.7,16,31 In OSCC, defense, they also play a role in both cellular response of IL-8 is mediated by cell CCND1 is an important oncogene that progression and inhibition of cancer.34 surface receptors CXCR1 and CXCR2, encodes the protein cyclin D1,14 which which are examples of chemokine receptors is amplifi ed in the chromosome band Cellular Senescence that play a role in the growth of a tumor.15 11q13 along with other genes located at The mechanism by which normal cells Cyclooxygenase 2 (COX-2) is an enzyme the same region, such as fi broblast growth lose the ability to divide is called cellular that is produced secondary to secretion factors 3 (FGF3) and 4 (FGF4), protein senescence. This is a tumor suppressive of IL-1β by tumor cells.37 It has been phosphatase 1 catalytic subunit alpha mechanism, however, malignant cells associated with the inhibition of apoptosis, (PPP1CA) or oral cancer overexpressed can escape this and become immortal modulation of angiogenesis and invasiveness 1 (ORAOV1, also known as TAOS1).31 by lengthening of telomere (repetitive in OSCC.15 VEGF plays an essential role tandem DNA sequences complexed in normal and pathological angiogenesis; Survivin with telomere-binding proteins at the however, fi ndings regarding any association Survivin is a protein that regulates distal end of chromosomes) due to with OSCC have been inconsistent.4,15 cell proliferation, apoptosis and telomerase activity.3,14,15,18,35 In early oral angiogenesis.22 Upregulation of carcinogenesis, there is an increase in Tumor-Associated Fibroblasts the protein has been described in the expression of the human telomerase In OSCC, tumor-associated fi broblasts some cancers.30 In OSCC, promoter reverse transcriptase (hTERT) protein (TAFs) are the most important cell type and hypomethylation of the BIRC5 gene that leads to dysregulation of cell are associated with epithelial mesenchymal that encodes survivin has been noted.22 cycle and uncontrolled proliferation transition, invasion, local recurrence,

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angiogenesis, metastasis and poor WNT Signaling Pathway microRNA and Long Noncoding RNA survival.37,38 TGFβ-1 promotes modifi cation The WNT signaling pathway Most studies in the literature have of stromal cells into TAFs.37 Signals from controls normal processes and evaluated the role of protein coding cancer cells stimulate TAFs to produce functions such as cellular proliferation, genes in carcinogenesis, however, pro-invasive molecules, such as hepatocyte differentiation and survival. The the role of noncoding sequences is growth factor (HGF), insulin-like growth signaling may be mediated either still unclear.42 Noncoding RNAs are factor 2 (IGF2), bone morphogenic through the β-catenin-dependent comprised of microRNAs (miRNAs), protein 4 (BMP4) and chemokine ligand pathway (canonical WNT pathway) long noncoding RNAs (lncRNAs), 7 (CCL7) and proteases, that can digest or the β-catenin-independent pathway small interfering RNAs (siRNAs), matrix metalloproteases thereby facilitating (noncanonical WNT pathway). enhancer RNAs (eRNAs) and promoter- tumor invasion.37 Senescence of TAFs Dysregulation of the pathway promotes associated RNAs (PARs).22,43–45 is thought to be a distinctive feature of oral carcinogenesis and progression. Two types of small RNA molecules, genetically unstable and aggressive OSCC.39 OSCC development is mediated microRNA and small interfering RNA, through DNA methylation and initiate RNA interference (RNAi), Tumor-Infi ltrating Lymphocytes histone modifi cations, which play which is an RNA-dependent gene- Tumor-infi ltrating lymphocytes a role in the epigenetic silencing silencing process that is also controlled (TILs) are mononuclear immune of WNT-related genes.22,40 by the RNA-inducing silencing complex cells that are present in the stroma of (RISC).3,46 RNAi regulates gene OSCC.33 This infi ltrate is composed Notch Signaling Pathway expression at posttranscriptional levels predominantly of CD4+ cells that have The Notch signaling pathway is through RISC in a normal cell.3,42,47 been recognized as forkhead box-P3 involved in the mechanism of cell- The microRNAs (miRNAs) play (FoxP3)+ regulatory T cells (Treg) and to-cell communication. Notch can a role in direct interfacing with gene few NK cells.33 These (FoxP3)+ Tregs are act either as an oncogene or tumor promoters as well as epigenetic regulation responsible for preservation of immune suppressor gene. In OSCC, NOTCH1 and of DNA methylation and histone homeostasis in normal situations and intracellular NOTCH domain (NICD) modifi cations, thereby participating in their presence in OSCC is considered expression were found to be high.14,35 functions such as cell differentiation, to curtail antitumor immune response proliferation, apoptosis, survival, leading to the advancement of cancer.33 Mesenchymal-Epithelial Transition motility, invasion and metastasis.2,6,22,48 Factor They are 21–23 nucleotide long Epithelial-Mesenchymal Transition The mesenchymal-epithelial transition single-stranded noncoding RNA Epithelial-mesenchymal transition factor (c-MET) is a receptor tyrosine molecules.2,3,14,46 In HNSCC, microRNA (EMT) is a process in which epithelial cells kinase located on the epithelium,41 profi ling studies reported upregulation change from an epithelial phenotype into which when stimulated through its of approximately 264 miRNAs and a motile mesenchymal phenotype.14,15,17 hepatocyte growth factor/scatter factor downregulation of 168 miRNAs.3 EMT plays an important role in the (HGF/SF) ligand leads to angiogenesis, Approximately 109 miRNAs are initiation, progression and spread of proliferation, invasion and metastasis expressed in OSCC.2,6,49 OncomiRs are cancer.3,17 Transforming growth factor beta in OSCC along with upregulation of upregulated and downregulated miRNAs (TGFβ), WNT, Notch, interleukin-like matrix metalloproteinases (MMP) that demonstrate tumor suppressor or EMT-inducer, hepatocyte growth factor, MMP-1 and MMP-9.19,41 FGF2 stimulates oncogenic function by regulating the epidermal growth factor receptor and fi broblasts and matrix metalloproteinases genes that stimulate formation of a platelet-derived growth factor are important to produce HGF and TGF-β, which tumor. MiR-23a, miR-98, miR-155, factors for epithelial-mesenchymal play a role in tumor invasion.26 Many miR-130b, miR-31, miR-223, miR-34b, transition.17 EMT is characterized matrix metalloproteinases (e.g., MMP-2, miR-24, miR-184, miR-211 and miR-214 by down-regulation of cell adhesion MMP-3, MMP-10 and MMP-11 etc.), a are some examples of microRNA that molecules like E-cadherin and gain of family of zinc metalloenzymes involved in are upregulated in HNSCC4,6,22,29,46,49 and N-cadherin, vimentin and fi bronectin, extracellular remodeling, appear to play miR-17, miR-20a, miR-29, miR-100, which are mesenchymal markers.4,14,15,37 a role in the progression of OSCC.15 miR-99a, miR-125b, miR-375, miR-155,

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miR-181a, miR-133a, miR-133b, miR- Cancer Stem Cells and Neck Squamous Cell Carcinoma. Int Rev Cell Mol Biol 137, miR-193a, miR-503, miR-15a and Recent evidence has shown that 2013;303:357–385. 4,6,42,46,48–51 4. Irani S. miRNAs Signature in Head and Neck Squamous Cell miR-222 are downregulated. cancer stem cells (CSCs) are a rare Carcinoma Metastasis: A Literature Review. J Dent (Shiraz) 2016 MiR-21 is frequently upregulated in subset of cells that form the bulk of Jun;17(2):71–83. OSCC2,4,6,22,29,42,46,48 and is involved the tumor in HNSCC. The American 5. Rai V, Mukherjee R, Ghosh AK, Routray A, Chakraborty 52 C. “Omics” in Oral Cancer: New Approaches for Biomarker in cellular proliferation, apoptosis, Association for Cancer Research Discovery. Arch Oral Biol 2017 Dec 8;87:15–34. epithelial-mesenchymal transition Workshop on Cancer Stem Cells 6. Mascolo M, Siano M, Ilardi G, Russo D, Merolla F, De Rosa G, and invasion. It also regulates the defi nes CSCs as cells within a tumor Staibano S. Epigenetic Disregulation in Oral Cancer. Int J Mol Sci 40 2012;13(2):2331–2353. WNT/β-catenin signaling. The that possess the capacity to self-renew 7. da Silva SD, Ferlito A, Takes RP, Brakenhoff RH, Valentin MD, downregulation of miR-138 has been and generate heterogeneous lineages Woolgar JA, Bradford CR, Rodrigo JP, Rinaldo A, Hier MP, consistently observed in HNSCC and of cancer cells that comprise the Kowalski LP. Advances and Applications of Oral Cancer Basic 3,29,42 53 Research. Oral Oncol 2011;47(9):783–791. OSCC. The metastasis of cancer tumor. They can develop either due 8. Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2018. cells is dependent on cytoskeleton to genomic instability and mutation in CA Cancer J Clin 2018 Jan;68(1):7–30. doi: 10.3322/ remodeling that is essential for cell normal stem cells or from mutations caac.21442. Epub 2018 Jan 4. 53 9. 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Epidemiology, Aetiopathogenesis, Diagnosis and Prognostication. 39. Parkinson EK, James EL, Prime SS. Senescence-Derived Oral Oncol 2008;44:103–108. Extracellular Molecules as Modulators of Oral Cancer 22. Castilho RM, Squarize CH, Almeida LO. Epigenetic Development: A Mini-Review. Gerontology 2016;62(4):417– Modifi cations and Head and Neck Cancer: Implications for Tumor 424. doi: 10.1159/000440954. Epub 2015 Dec 3. Progression and Resistance to Therapy. Int J Mol Sci 2017 Jul 40. Shiah SG, Shieh YS, Chang JY. The Role of Wnt Signaling in 12;18(7). Squamous Cell Carcinoma. J Dent Res 2016 Feb;95(2):129–134. 23. González-Ramírez I, García-Cuellar C, Sánchez-Pérez Y, 41. Szturz P, Budíková M, Vermorken JB, Horová I, Gál B, Granados-García M. DNA Methylation in Oral Squamous Cell Raymond E, de Gramont A, Faivre S. Prognostic Value of c-MET in Carcinoma: Molecular Mechanisms and Clinical Implications. Head and Neck Cancer: A Systematic Review and Meta-Analysis Oral Dis 2011 Nov;17(8):771–8. of Aggregate Data. Oral Oncol 2017 Nov;74:68–76. 24. Malik UU, Zarina S, Pennington SR. Oral Squamous Cell 42. Kolokythas A, Miloro M, Zhou X. Review of MicroRNA Carcinoma: Key Clinical Questions, Biomarker Discovery, and the Deregulation in Oral Cancer. Part I. J Oral Maxillofac Res 2011 Role of Proteomics. Arch Oral Biol 2016 Mar;63:53–65. Jul 1;2(2):e1. 25, Sarode GS, Sarode SC, Maniyar N, Anand R, Patil S. Oral 43. Gomes CC, de Sousa SF, Calin GA, Gomez RS. The Cancer Databases: A Comprehensive Review. J Oral Pathol Med Emerging Role of Long Noncoding RNAs in Oral Cancer. 2017 Nov;1–10. Oral Surg Oral Med Oral Pathol Oral Radiol 2017 26. Xie X, Wang Z, Chen F, Yuan Y, Wang J, Liu R, Chen Q. Roles of February;123(2):235–241. FGFR in Oral Carcinogenesis. Cell Prolif 2016 Jun;49(3):261–269. 44. Salyakina D, Tsinoremas NF. Non-Coding RNAs Profi ling in 27. Murugan AK, Munirajan AK, Tsuchida N. Ras Oncogenes Head and Neck Cancers. NPJ Gen Med 2016 Jan 13;1. in Oral Cancer: The Past 20 Years. Oral Oncol 2012 45. Momen-Heravi F, Bala S. Emerging Role of Non-Coding May;48(5):383–392. RNA in Oral Cancer. Cell Signal 2018 Jan;42:134–143. doi: 28. Murugan AK, Munirajan AK, Alzahrani AS. MicroRNAs: 10.1016/j.cellsig.2017.10.009. Epub 2017 Oct 19. Modulators of the Ras Oncogenes in Oral Cancer. J Cell Phys 46. Chen D, Cabay RJ, Jin Y, Wang A, Lu Y, Shah-Khan M, Zhou 2016 Jul;231(7):1424–1431. X. MicroRNA Deregulations in Head and Neck Squamous Cell 29. Gorenchtein M, Poh CF, Saini R, Garnis C. MicroRNAs in an Carcinomas. J Oral Maxillofac Res 2013 Apr 1;4(1):e2. Oral Cancer Context — from Basic Biology to Clinical Utility. J Dent 47. Karatas OF, Oner M, Abay A, Diyapoglu A. MicroRNAs in Res 2012 May;91(5):440–446. Human Tongue Squamous Cell Carcinoma: From Pathogenesis to 30 Taghavi N, Yazdi I. Prognostic Factors of Survival Rate in Oral Therapeutic Implications. Oral Oncol 2017 Apr;67:124–130. Squamous Cell Carcinoma: Clinical, Histologic, Genetic and 48. Jamali Z, Aminabadi NA, Attaran R, Pournagiazar F, Molecular Concepts. Arch Iranian Med 2015 May;18(5):314– Oskouei SG, Ahmadpour F. MicroRNAs as Prognostic Molecular 319. Signatures in Human Head and Neck Squamous Cell Carcinoma: 31. Ramos-García P, Gil-Montoya JA, Scully C, Ayén A, González- A Systematic Review and Meta-Analysis. Oral Oncol 2015 Ruiz L, Navarro-Triviño FJ, González-Moles MA. An Update on the Apr;51(4):321–331. Implications of Cyclin D1 in Oral Carcinogenesis. Oral Dis 2017 49. Janiszewska J, Szaumkessel M, Szyfter K. microRNAs Are Oct;23(7):897–912. Important Players in Head and Neck Carcinoma. Crit Rev Oncol 32. Bablani Popli D, Sircar K, Chowdhry A, Rani V. Role of Heat Hematol 2013 Dec;88(3):716–728. Shock Proteins in Oral Squamous Cell Carcinoma: A Systematic 50. Yu X, Li Z. MicroRNA Expression and Its Implications for Review. Biomed Pap Med Fac Univ Palacky Olomouc Czech Diagnosis and Therapy of Tongue Squamous Cell Carcinoma. J Repub 2015 Sep;159(3):366–71. doi: 10.5507/bp.2015.004. Cell Mol Med 2016 Jan;20(1):10–6. Epub 2015 Feb 19. 51. Sannigrahi MK, Sharma R, Panda NK, Khullar M. Role of 33. Hussaini HM, Parachuru VPB, Seymour GJ, Rich AM. Non-Coding RNAs in Head and Neck Squamous Cell Carcinoma: Forkhead Box-P3+ Regulatory T Cells and Toll-Like Receptor 2 A Narrative Review. Oral Dis 2017 Sep 21:1–11. Co-Expression in Oral Squamous Cell Carcinoma. Acta Histochem 52. Kolokythas A, Miloro M, Zhou X. Review of MicroRNA 2017 Apr;119(3):205–210. Proposed Target Genes in Oral Cancer. Part II. J Oral Maxillofac 34. Mäkinen LK, Ahmed A, Hagström J, Lehtonen S, Mäkitie Res 2011 Jul 1;2(2):e2. AA, Salo T, Haglund C, Atula T. Toll-Like Receptors 2, 4, and 9 in 53. Sayed SI, Dwivedi RC, Katna R, Garg A, Pathak KA, Primary, Metastasized and Recurrent Oral Tongue Squamous Cell Nutting CM, Rhys-Evans P, Harrington KJ, Kazi R. Implications of Carcinomas. J Oral Pathol Med 2016 May;45(5):338–345. Understanding Cancer Stem Cell (CSC) Biology in Head and Neck 35. Ali J, Sabiha B, Jan HU, Haider SA, Khan AA, Ali SS. Genetic Squamous Cell Cancer. Oral Oncol 2011 Apr;47(4):237–243. Etiology of Oral Cancer. Oral Oncol 2017 Jul;70:23–28. 54. Costea DE, Tsinkalovsky O, Vintermyr OK, Johannessen 36. Petruzzi MN, Cherubini K, Salum FG, de Figueiredo MA. AC, Mackenzie IC. Cancer Stem Cells — New and Potentially Role of Tumour-Associated Macrophages in Oral Squamous Cells Important Targets for the Therapy of Oral Squamous Cell Carcinoma Progression: An Update on Current Knowledge. Diagn Carcinoma. Oral Dis 2006 Sep;12(5):443–454. Pathol 2017 Apr 5;12(1):32. 55. Papagerakis S, Pannone G, Zheng L, About I, Taqi N, Nguyen 37. Leef G, Thomas SM. Molecular Communication Between NP, Matossian M, McAlpin B, Santoro A, McHugh J, Prince ME, Tumor-Associated Fibroblasts and Head and Neck Squamous Cell Papagerakis P. Oral Epithelial Stem Cells — Implications in Normal Carcinoma. Oral Oncol 2013 May;49(5):381–386. Development and Cancer Metastasis. Exp Cell Res 2014 Jul 38. Lin NN, Wang P, Zhao D, Zhang FJ, Yang K, Chen 15;325(2):111–129. doi: 10.1016/j.yexcr.2014.04.021. Epub R. Signifi cance of Oral Cancer-Associated Fibroblasts in 2014 May 5. Angiogenesis, Lymphangiogenesis and Tumor Invasion in Oral Squamous Cell Carcinoma. J Oral Pathol Med 2017 THE AUTHOR, Anupama Grandhi, BDS, DDS, can be reached Jan;46(1):21–30. at [email protected].

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Understanding Normal Sleep, Respiration and Circulation

Anne-Maree Cole, BDSc, MScMed

ABSTRACT Far more than a reversible state of unconsciousness, it would be more accurate to consider sleep as “the work of sleep.” This paper is designed to give the reader an understanding of the normal physiology of sleep. Because with an appreciation of normal, one can recognize and discern the implications associated with sleep-disordered breathing.

AUTHOR

Anne-Maree Cole, BDSc, ince time immemorial, All animal species sleep. The duration MScMed, graduated sleep has been considered a and time within the 24-hour cycle vary. In from the University of “switching off from the outside general, the smaller the animal and the less Queensland, Australia, with 4 honors in dentistry in 1982. world,” a reversible state biologically mature, the more it sleeps. The 1 In 2014, she completed a of unconsciousness. A lot, cause is believed to be due to the higher master’s degree in sleep Showever, has been learned in the past metabolism rates of smaller animals, which medicine from the University century and it would be more accurate to incur a heavier free-radical load and the of Sydney. Her practice consider sleep to be “the work of sleep.” ontogenetic theory of rapid eye movement in Brisbane, Australia, is 5 limited to the treatment of Interruptions are highly impactful (REM) sleep that purports REM sleep patients with craniofacial on productivity in daily working life, to be integral to the development of pain, TMD, obstructive sleep and so it is with sleep. Bonnet (2003) neurologic pathways essential for full apnea and sleep-disordered has shown that periods of 10–20 function. During non-REM (NREM) sleep, breathing and the minutes of consolidated, uninterrupted metabolic rates decrease along with core prevention and treatment of these problems through sleep are needed to wake feeling body temperature creating the opportunity 2 various techniques including refreshed. This equates to three to for cellular, enzymatic and proteinaceous arch development and six arousals per hour. Physiologically, repair, replacement, recovery and renewal.4 orthopedic orthodontics it is normal to have arousals and even using a balanced to wake once or twice a night across a Sleep Drive physiologic approach. Dr. 3 Cole lectures nationally seven- to eight-hour sleep period. So From birth until death, life suspends and internationally on what is normal and what is not? This within a regular rhythm of only three sleep-disordered breathing, paper is designed to give the reader an physiologic states: wake, NREM sleep TMD and jaw development understanding of the normal physiology and REM sleep.3 Unconsciousness, a orthodontics. of sleep. By understanding normal, state uncommonly encountered, is not Confl ict of Interest Disclosure: None reported. one can then indeed recognize and physiologic. It is either pathologic or discern the implications associated medically induced, and as such, this article with sleep-disordered breathing. will not elaborate on it further. Humans

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are diurnal: active during the day and physiologically programmed to sleep at night. This cycle, however, can be selectively overridden, and modern society with its shift work, bright lights and screen time indeed has encroached upon this evolutionary template but not without consequence. There are two contributory drives that collaborate to maintain either 6 wakefulness or sleep (FIGURE 1). The fi rst 6 9 12 3 6 9 12 3 6 is the homeostatic drive to sleep, known as Process S. It is linearly related to the time frame since the prior sleep period. In other words, the longer you are awake, FIGURE 1. Physiologic drivers to sleep. Two complimentary physiologic processes interplay to maintain wakefulness the stronger the drive is to go to sleep. during the day and consolidate sleep during the night. Process H is the physiologic drive to go to sleep. It increases Physiologically this linear increase in sleep linearly with sleep debt. Process C is the internal circadian rhythm that competes with Process H to maintain wakefulness drive is related to the buildup of adenosine during the day and conversely maintains sleep during the night as Process H diminishes as sleep is achieved. There is a circadian drive to be in deep sleep in the early part of the night and to be in REM sleep in the latter half. through the breakdown of adenosine triphosphate to adenosine diphosphate and phosphate.7 The complementary process, commences with NREM sleep.3 NREM Following N3 sleep, there is a known as Process C, is the circadian rhythm sleep progressively deepens from N1 to N2 progressive lightening of sleep, up through for sleep and wakefulness. During the day and then N3 sleep. N1 is initial, light, sleep- N2 and N1 and then a change in state as the homeostatic drive for sleep increases, onset sleep. It briefl y materializes before to REM sleep. Brain wave frequency Process C offsets this drive to maintain progressing to N2 sleep or lightening back gradually increases until REM sleep vigilance.6 A dip in this offset occurs to wakefulness. It occupies approximately 5 emerges and brain wave activity resembles around 2 p.m. with many people fi ghting percent of the total sleep time and reappears the waking state.3 Neurologically, REM-on fatigue or succumbing to its pressure at this within the four to fi ve sleep cycles that cells herald the change in state.11 Brain time.8 As evening advances, the circadian occur across the night. N2 sleep populates waves are desynchronized. Blood fl ow to oscillations in hormonal levels including the majority of the sleep period (45–50 and metabolism of the brain increases melatonin release and minimal levels of percent). N3 sleep nomenclature exists as to at least the levels of wakefulness, cortisol9 along with the adenosine burden many other terms including deep sleep, slow albeit refl ective of the areas of increased result in the activation of sleep-on cells wave sleep and sleep stages 3 and 4. This or decreased functional activity during in the basal forebrain and sleep ensues.10 deep restorative sleep stage should occupy the specifi c sleep neuronal activity.12 Just as wakefulness increases the 20–25 percent of the total sleep time. Good Comparatively, a global drop in blood homeostatic drive to sleep, the function of quality, uninterrupted N3 sleep is imperative fl ow of up to 44 percent occurs in slow sleep itself diminishes it. The longer the for that feeling of “a good night’s sleep.” wave sleep.13 REM sleep is the period sleep period, the lower the homeostatic It is a period of profound cardiovascular of vivid dreaming, but its function goes drive becomes. Once again, the circadian stability and the time in which growth well beyond dreaming. REM sleep is rhythm of Process C steps in to hormone secretion materializes.9 NREM “for the brain.” Simultaneous with consolidate the sleep time.6 sleep is considered to be “for the body” the increased brain activity, the motor and REM sleep “for the brain.” During function of the body, all movement Sleep Architecture NREM sleep cortical activity is diminished except the eyes, is inhibited, resulting in The process of sleep is precisely curated and brain waves become synchronized. It an active brain within a disabled body.3 and deserves consideration as the “work of is a time during which cellular repair and Normal REM sleep proportion is 20–25 sleep.” It is not a constant state but follows recovery can occur, a period of metabolic percent of total sleep time. The fi rst REM a progressive rhythmic sleep architecture. maintenance. In contrast to REM sleep, period occurs 70–90 minutes after sleep In the normal healthy human, sleep the brain is idling within a movable body.4 onset. Its initial duration is short, but the

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100

90

80 these are known as the monoamines. They are highly active during wakefulness. 70 Their cessation of activity with REM sleep enables the cells’ rest and recovery period, 60 allowing restoration of normal function during wakefulness.4 Disruptions in the 50 monoamine pathways can result in multiple system dysfunctions including emotional 40 stability, cognitive processing, hormonal stability, circadian rhythms, appetite Hemoglobin Saturation (%)Hemoglobin Saturation 17 30 control and functional movement. REM sleep at the birth of full-term 20 infants occupies 50 percent of total sleep time, decreasing with age. Premature babies without consolidated high REM 10 sleep percentage are at greater risk of 0 developmental delays compared to preterm infants displaying quality REM 0 10 20 30 40 50 60 70 80 90 100 profi les.18 This consequence implies a Oxygen Pressure in Arteries (mmHg) vital role for REM sleep in ontogenetic development by constructing the FIGURE 2. Oxygen dissociation curve. The relationship between the arterial partial pressure of oxygen, which genetically programmed neural super is invasive to measure, and the arterial oxygen saturation, which is readily monitored. highways that enable mature function.19 REM sleep may have a role in memory span lengthens with subsequent REM early sleep segment from 9 p.m. to midnight consolidation, but the evidence is weak.20 periods.3 It is not uncommon to awaken appears driven toward deep restorative during the fi nal fourth or fi fth REM period sleep and in the latter part of the night Cardiovascular System and Sleep with an awareness of being in the middle of a is a circadian drive to be in REM sleep. The primary purpose of the dream. Erections are a natural phenomenon As a result, going to bed physiologically cardiovascular system is for gas exchange, during REM sleep. The sleep stages too late decreases the opportunity for which it achieves with great effi ciency, themselves bear infl uence from both the deep restorative sleep and the REM maintaining the blood gas levels within homeostatic and circadian drives. Deep N3 latency may be less than the usual 70–90 very tight physiologic confi nes.21 Within sleep is predominant in the fi rst part of the minutes. A short REM latency can be a the lung alveoli, carbon dioxide expires sleep period while REM sleep predominates sign of narcolepsy so understanding the and oxygen replenishes; the reverse in the latter portion of the night.14 Napping circadian drive and the time of sleep onset occurs within the tissue capillaries. Gas during the day reduces the homeostatic load is important in allaying that possibility.14 exchange only occurs at the capillary and may impact the quality and duration level. The heart acts as the pump, and of nocturnal deep sleep. In contrast, it The Role of REM Sleep the remainder of the larger blood vessels may have an overall benefi cial infl uence REM sleep plays a signifi cant role in serve simply as the delivery network.21 in instances of chronic sleep debt.15 emotional stability, and dysregulation may The majority of the oxygen is It is interesting to note that as Process S be a prodromal and perpetuating factor transported on hemoglobin molecules, diminishes with sleep, Process C steps in to in mood disorders such as depression.16 only releasing when the partial pressure consolidate the sleep period. This scenario The increased brain cell activity during of the free oxygen molecules within manifests through the maintenance of sleep REM sleep is broad-based except for a the plasma drops with gas exchange at despite heightened brain activity associated select group of cells that produce the the tissue capillaries. Measurement of with the prolongation of REM periods. neurotransmitters histamine, dopamine, blood gas levels is an invasive procedure; From a circadian rhythm perspective, the serotonin and noradrenaline. Collectively, however, a correlate, oxygen saturation

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is readily measured with a pulse the arterial system drops via pathologic a reduction in the sensitivity of the oximeter, which records the saturation mechanisms, oxygen is still present but chemoreceptors and a diminished lung of hemoglobin with oxygen within the the gradient diminishes so the tissues do capacity due to the recumbent position.3 arterial system.22 An oxygen dissociation not receive adequate oxygen exchange Differences between NREM and curve visually marries the relativity and become hypoxic metabolically, REM sleep also impact the cardiovascular of oxygen saturation with the partial a highly stressful phenomenon.21 system. Control of the automatic processes pressure (FIGURE 2). With replenishment Carbon dioxide gas exchange similarly of the body is by the autonomic nervous at the lungs, the partial pressure of oxygen occurs under a pressure gradient. At the system. It divides into two parts: The is 100 mmHg, and the arterial oxygen lungs, the high pressure of carbon dioxide parasympathetic nervous system, which saturation (SpO2) would correspond at within the pulmonary circulation causes has a calming effect on the body, and 97–100 percent. At the tissue capillaries, rapid dissolution out to the lung alveoli the sympathetic nervous system, which the high-pressure gradient causes rapid dropping the partial pressure from 45 mmHg initiates the fi ght-or-fl ight stress response. diffusion of the free oxygen to the to 40 mmHg.21 The reverse occurs in the With sleep onset, the voluntary input is hypoxic tissue, dropping the partial tissues. Note that carbon dioxide partial quiescent and survival depends entirely on pressure of oxygen to 40 mmHg.21 the autonomic systems. Sleep requires the As the oxygen pressure diminishes, the body to be in a parasympathetic state, and hemoglobin releases one oxygen molecule, this parasympathetic drive continues to leaving the remaining three molecules With sleep onset, several increase from N1 to N3 sleep along with bound securely to the hemoglobin and a corresponding decrease in sympathetic transported back to the lungs where the physiologic changes tone.26 This results in a lower heart rate oxygen decrement replenishes. Physiologic occur that cause a reset and cardiac output and a decrease in gas exchange in the tissues results in a of the homeostatic norms peripheral vascular resistance and blood venous oxygen saturation of 75 percent pressure. It is cyclic for the blood pressure due to the expenditure of one-quarter of of the wake state. to dip across the night. NREM sleep is the available oxygen. It is important to important for cardiovascular recuperation. note that the pulse oximeter only records N3 sleep is a decidedly stable period for the arterial oxygen saturation, not that within cardiovascular and respiratory systems.3 the venous blood. Concern is high if the pressure maintains much tighter boundaries REM sleep results in an even further

SpO2 drops below 90 percent. From the than oxygen. High carbon dioxide levels increase in parasympathetic tone with a oxygen dissociation curve, it is evident are a stronger respiratory driver than further lowering of the aforementioned that the partial pressure of oxygen drops lower oxygen pressures.24 Within the impacts. This amplifi cation of rapidly at this point, such that a small cardiovascular system, peripheral and parasympathetic nervous input, however, decrease in oxygen saturation corresponds central chemoreceptors act like taste buds, is interspersed with fl uctuating very high to a substantial drop in the pressure under continuously monitoring oxygen and sympathetic activity associated with the which oxygen transits within the system.21 carbon dioxide levels to ensure they stay actual bursts of rapid eye movements. A good analogy to help visualize within physiologic norms. Messages are The resultant is a period of cardiovascular this important concept is to think about sent directly to the respiratory center in variability and potential instability. The opening a bottle of soda.23 The high pressure the brainstem to regulate respiration to sympathetic activity can be twice as high within the vessel causes a very robust and maintain homeostasis, with rapidity.25 as in the awake state. REM sleep is capable rapid gas exchange upon opening. That With sleep onset, several physiologic of being a high-risk period for patients is what is happening in the lungs and the changes occur that cause a reset of the with poor cardiovascular function.27 tissue capillaries. The high-pressure gradient homeostatic norms of the wake state. enables effi cient gas exchange. Once Oxygen saturation drops 2 percent and Respiration and Sleep that soda has been left open for a while, carbon dioxide partial pressure rises 2–8 Unlike the heart, the stimulus to however, bubbles can still be seen fl oating mmHg, which is related to the loss of the breathe is not located within the pulmonary to the surface, but the effi ciency dissipates. wakefulness drive to breathe, a decrease tissue but at a distance in the respiratory Similarly, if the oxygen pressure within in basal metabolism, low muscle tone, center of the brainstem. A network of

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receptors, including pressure, stretch and with a decrease in tidal volume and an metabolism during sleep. Cerebrovasc Brain Metab Rev chemical receptors, provide neural feedback increase in frequency.29 Furthermore, there 1991;3(4):281–96. 14. Czeisler CA, Zimmerman JC, Ronda JM, Moore-Ede MC, to the respiratory center, which along with is a major reduction in chemoreceptor Weitzman ED. Timing of REM sleep is coupled to the circadian a built-in pacemaker drive the stimulus to sensitivity to changing blood gasses, rhythm of body temperature in man. Sleep 1980;2(3):329–46. breathe, the timing, rate and amplitude. dropping to as low as one-third of the 15. Faraut B, Andrillon T, Vecchierini MF, Leger D. Napping: A public health issue. From epidemiological to laboratory studies. The phrenic nerve directly stimulates the sensitivity during wakefulness. The postural Sleep Med Rev 2017 Oct;35:85–100. doi: 10.1016/j. diaphragm, the tone of which does not alter atonia, a cardinal indicator of REM smrv.2016.09.002. Epub 2016 Sep 13 2016. with REM sleep. Airway opening muscles, sleep, further adds to this vulnerability, 16. Palagini L, Baglioni C, Ciapparelli A, Gemignani A, Riemann D. REM sleep dysregulation in depression: State of the 30 in particular the genioglossus, are activated especially in the supine position. art. Sleep Med Rev 2013;17(5):377–90. just ahead of the phrenic nerve stimulation 17. Millan MJ. The role of monoamines in the actions of to provide structural resistance to collapse, Conclusion established and “novel” antidepressant agents: A critical review. Eur J Pharmacol 2004;500(1–3):371–84. offsetting the increased negative pressure Despite the adjustments within the 18. Arditi-Babchuk H, Feldman R, Eidelman AI. Rapid eye about to be encountered during inspiration. cardiovascular and respiratory systems with movement (REM) in premature neonates and developmental Depending on metabolic need or breathing sleep onset, these changes are inadequate to outcome at 6 months. Infant Behav Dev 2009;32(1):27–32. 19. Marks GA, Shaff ery JP, Oksenberg A, Speciale SG, habit, accessory muscles of inspiration cause airway collapse in normal individuals. Roff warg HP. A functional role for REM sleep in brain may also necessitate recruitment.21 It is a very different story though if obesity maturation. Behav Brain Res 1995;69(1–2):1–11. With sleep onset as mentioned above, or poor craniofacial development or other 20. Siegel JM. The REM sleep-memory consolidation hypothesis. Science 2001;294(5544):1058–63. there is a resetting of the homeostatic physiologic at-risk factors come into play. 21. West JB, Luks A. 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AUGUST 2018 517 Specializing in selling and appraising dental practices for over 40 years!

LOS ANGELES COUNTY ORANGE COUNTY RIVERSIDE & SAN BERNARDINO COUNTIES CARSON— Long established GP in a small shopping BREA— Beauful well established pracce located BANNING—LH & Equipment only! Consists of 3 eq center. Grossed $277K in 2017. Has 3 eq ops & 2 on a corner locaon. Has 8 equipped ops and 3 ops in a 925 st suite. Property ID #5184. plmbd not eq. Rering seller work 3 days/wk. Great chairs in open bay.SOLD Grossed $1.5M. On a busy street visibility. Property ID #5181. major street of the city. Property ID #5190. CHINO HILLS— GP in busy shopping center. Grossed $352K . NET $141K. PPO & Cash Only! Has 3 eq ops COMPTON— (GP + Real Estate) Established in 1982 COSTA MESA - Est. in 1952 in a sing bld w/ 3 eq w/ 4 eq ops / 3 plumbed not eq. Gross. $581K in ops. Cash & Delta Premier Only!! Proj. approx. and 1 plmbed op. EstablishedSOLD in 1992. Property ID 2017. Net $154K. Property ID # 5209. $373K for 2017. PropertySOLD #5202. #5219.

ENCINO - GP w/ 4 eq ops in a prof. bldg. w/ widow HUNTINGTON BEACH - LH & Equip only! 4 eq ops CORONA— Beauful GP w/ 6 eq ops / 4 plmbd not views to the mountain. Fee for service. Net $144K. and 1 plmbd not eq in a 2,100 sq suite. Located eq for expansion in a 3,700 sq office. Located on a Gross. $488K in 2017.SOLD Property ID #5210.0 in a 2 story professional building. Has been known one story free standing building next to a busy shop- as a icon in the community for 43 yrs. Prop. #5218. GLENDALE—Beauful office w/ 3 eq ops in a 850 sq ping center. Grossed $346K in 2017. Great potenal . LH & Equip Only! Great starter office. Near resi- IRVINE - Well established Cash Only GP w/ 5 eq for a full me denst. Property ID #5224. denal & commercialSOLD area. Property ID #5208. ops in a1,915 sq office . Grossed approx. $482K in 2017. Property ID #5193. DESERT HOT SPRINGS— GP + Real Estate! Two GLENDALE - GP located in a med bldg w/3 eq ops in partners one office. Consists of 4 eq ops / 1 plmbd a 1,123 sq ste. Ins & Cash Only! Est. in 1994. SOLD NEWPORT BEACH—Long established GP in mul not eq. Est. in 1986. Proj. approx. $802K for 2017. Grossed $473K in 2017. Prop. #5216. story bldg w/ great views to the coast. Has 3 eq ops SOLD Property ID #5198. MONTEREY PARK— GP in shopping center. Absen- and 2 plumbed not eq. Grossed approx. $560K in tee owner. Grossed approx. $636K in 2017. Net 2017. Net $241K. Property ID #5211. FONTANA— GP + Real Estate!! Premier office with $183K. 5 eq ops / 3 plumbed not eq ops. Property ID ORANGE— Est. in 1978 GP in one story free stand- 50 years of goodwill. In a 3,000 sq bldg with 8 eq #5201. ing duplex w/ 3 eq ops. Grossed approx. $386K in ops. Has the latest technology.SOLD Grossed approx. MOTEBELLO—Grossed approx. $1M in 2017, locat- 2017. Property ID #5213.SOLD $2.3M in 2016. Net of $968K. Property ID #5140. ed in a free standing bldg w/ 5 eq ops. Established in PLACENTIA— Turn-Key GP in one story medical PALM DESERT— Beauful GP located in a single 2002. Property ID #5168SOLD bldg w/ 2 eq ops & 2 plmbed not eq. Estab. in story corner building. Heavy traffic flow. Consists of PASADENA – 56 yrs of gdwll w/5 eq ops in a 2 story 2009. Grossed $129K in 2017. Property ID #5227. 4 eq ops in a 1,800 sq office. Reasonable rent. med/dent bldg. Fee for service. Proj. approx. $990K SANTA ANA— Well established pracce. PPO & Monthly revenues of $132K. Grossed $1.4M in 2017. for 2017. Net $217K.SOLD Great pracce. Prop. ID #5204. Cash only. Gross. approx. $500K. Prop. ID #5113. NET $383K. Property ID #5217. SANTA CLARITA—GP w/ 36 yrs of goodwill in prof. bldg. w/ 5 eq ops. Grossed approx. $449K in 2017. PALM SPRINGS – General pracce with 3 equipped Property ID #5207. ops located in a free standing bldg. Established in 2005. Suite is approx. 1,200. Seller work 5 days/wk. TARZANA - Established in 1929 w/ 5 eq ops in a SAN DIEGO COUNTY BUYER’S NET OF $115K. Property ID #4487. 1,552 sq suite. Delta Premier and Cash Only! Grossed $681K in 2017. Buyer’s Net $183K. Proper- LA JOLLA— 4 eq ops in 2 story med building. PPO RANCHO CUCAMONGA— GP established in 2004 in ty #5226. & Cash Only! Grossed approx. $1.1M in 2017. Property ID #5220. busy shopping center. Consists of 3 eq ops in a 1,200 KERN, VENTURA, & SAN LUIS OBISPO COUNTIES sq suite. Grossed $422K in 2017. Net $149K. Prop- LA MESA— Beauful GP office in shopping center erty ID #5169. FRESNO— GP 4 eq ops in a retail shopping center. w/ 5 eq ops & 1 plumbd not eq. Sees 80-100 new Grossed $448K in 2017. NET $202K. Prop. #5214. paents/mo. Grossed $1.5M in 2017. Net $368K. UPLAND—Pediatric dental pracce located in a Prop.#5228. medical bldg with 40 years of goodwill. Consists of 4 GOLETA—GP w/ 27 yrs of gdwll in a 2 story mix OCEANSIDE— Orthodonc pracce w/4 chairs in chairs in open with Alpha-DentSOLD soware. Grossed bldg. 4 eq ops. Grossed $572K. Prop. #5205. open bay in a 1,550 sq office. Grossed $263K in $271K in 2016. Property ID #5188. 2017. Property ID #5225. OXNARD—Est, in 1973 w/ 4 eq ops in a 1,100 sq suite. Grossed $585K Net $186K. Prop. #5206. SAN DIEGO— GP in med/dent bldg. w/ 3 eq ops. Fee for service. Estab. circa 1950. Grossed $301K SIMI VALLEY— GP + Real Estate. Pracce has 4 eq in 2017. Net $129K. Property ID # 5212. ops & 2 plmbd not eq ops. Net of $92K. ID #5185.

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CONTACT US FOR A FREE CONSULTATION WWW.CALPRACTICESALES.COM Phone: (800) 697-5656 CA BRE #00283209 RM Matters CDA JOURNAL, VOL 46, Nº8

In Doubt About How To Handle a Situation?

Err on the Side of Caution TDIC Risk Management Staff

he Risk Management Advice her again a few hours later and she Line is a complimentary reported that the bleeding had stopped. service of The Dentists “The likelihood of something The following day, the dentist was Insurance Company that has informed that the patient’s husband helped thousands of dentists happening is always observed she was snoring that evening, Tseeking guidance on handling diffi cult possible. Even though the but then later stopped breathing. Her situations in their offi ces. But not dentist took the right steps husband immediately began performing all callers are in the midst of a crisis. CPR after calling 911. The dentist Sometimes, they simply need reassurance to avoid potential problems, subsequently spoke with the patient’s that they’ve done the right thing. an incident occurred.” cardiologist, who informed him that Senior Risk Management analyst Taiba he did not believe the incident was Solaiman reports a situation in which a related to the dental treatment. dentist called the Advice Line about a 36-year-old patient who presented for an exam and evaluation of her third molars. The dentist recommended extracting all four because their supereruption had created an anterior open bite following the use of an occlusal guard. The patient noted on her medical You are not history form that she was taking a sales goal. magnesium supplements. She also noted a history of benign ventricular contractions. As a precautionary measure, the dentist consulted with the patient’s physician prior to treatment. He had an informed consent discussion with the patient and the patient signed the informed consent form prior to the extractions. After checking the patient’s vitals, the dentist proceeded with treatment You are a dentist deserving of an insurance company relentless using fi ve carpules of mepivacaine, in its pursuit to keep you protected. At least that’s how we see plain and nitrous oxide. The dentist it at The Dentists Insurance Company, TDIC. Take our Risk performed the extractions using an Management program. Be it seminars, online resources or our elevator and extraction forceps, as they Advice Line, we’re in your corner every day. With TDIC, were considered simple extractions. you are not a sales goal or a statistic. You are a dentist. The treatment was completed without incident and the patient was discharged with a prescription for pain medication. ® The dentist called the patient later Protecting dentists. It’s all we do. that evening for a postoperative check. 800.733.0633 | tdicinsurance.com | CA Insurance Lic. #0652783 The patient reported that the extraction sites were still oozing. The dentist called

AUGUST 2018 519 AUG. 2018 RM MATTERS

CDA JOURNAL, VOL 46, Nº8

Concerned over the incident, the patient and followed this with the written TDIC’s Risk Management Advice dentist contacted the Advice Line. The form. He checked her vitals prior to the Line provides confi dential, one-on-one analyst who answered advised him that he procedure and used a local anesthetic guidance on a number of issues, including followed the proper protocol, but she also that did not contain epinephrine (due employer-employee relations, record referred him to an attorney to determine to her reported heart condition). keeping and documentation, commercial whether he was obligated to report the “There were no issues with the property, online security and scope of incident to his state’s dental board, as some dentist’s protocol and treatment,” she practice. Callers do not need to be TDIC states require reporting of hospitalization said. “But the likelihood of something policyholders — the service is offered at following dental treatment. In this case, happening is always possible. Even though no cost to members of CDA, ADA or the attorney advised the dentist that he the dentist took the right steps to avoid any sponsoring dental association. When did not deem the incident reportable as potential problems, an incident occurred.” calling the Advice Line, it is important to the patient wasn’t transported directly Solaiman said this scenario illustrates have the following information on hand: to the hospital from the dental offi ce. that in risk management, it’s better to be ■ Policy number or fi rst Solaiman noted that this was a case of overly cautious than not cautious enough. and last name if you are a a dentist doing everything he was supposed “No matter how careful you are, TDIC policyholder. to. He consulted with the patient’s things can and do happen,” she said. ■ ADA number if you are not medical doctor prior to treatment. He had “We are always on hand to confi rm that a TDIC policyholder. an informed consent discussion with the you’ve followed the proper procedures.” ■ Patient chart if calling about a patient issue. ■ Employee fi le if calling about an employment issue. ■ Details on prior calls to the Advice Line if the issue is ongoing or recurring. ■ Correspondence and other documentation (if applicable) should the analyst have further questions. It is always prudent to err on the side of caution by calling the Advice Line. Not only can speaking to dedicated analysts set your mind at ease, it can ensure you’ve taken the necessary measures to protect your patients and your practice. ■

The Risk Management Advice Line is available Monday through Friday, 8 a.m. to 4 p.m., at 800.733.0633 or [email protected]. You can also request an appointment at a time convenient for you. Visit tdicinsurance.com/advice-line.

520 AUGUST 2018 CARROLL “Matching the Right Dentist to the Right Practice” V &COMPANY 4248 MENLO PARK FACILITY Remodeled, 930 sq. ft. dental facility with 4241 SF ENDO Seller transitioning into retirement and offering 41 year 2 fully equipped ops. and plumbed for 2 additional ops, reception area, practice in premier downtown building. 1,190 sq. ft. modern office. 4 doctor- doctor's office, sterilization, lab, storage and restroom. Medical/Dental days per week with seasoned & loyal staff and excellent referral sources. building in highly desirable location. Asking $200K. Asking $463K.

4192 REDWOOD CITY GP Profitable, established, general practice 4271 SOUTH SF DENTAL FACILITY Turnkey facility in well known available, now, in rapidly growing Redwood City. Over 1,000 active patients beautiful, professional building with dedicated parking lot. Incredible location & a 5 year average gross receipts of $890kIN net.G Beautiful re-modeled with EZ freeway access to Hwys 280, 380 and 101. Asking only $45K. ND handicap accessible office with 4P fully-equippedE ops. Asking $636K. 4198 PETALUMA DENTAL BUILDING Condominiumized dental office 4215 PALO ALTO ENDO Practice in prime Silicon Valley location with 40+ conveniently located close to Petaluma Valley Hospital and nearby shops, loyal referral sources. 900 square foot office in modern professional center with easy access to Highway 101 and with ample, dedicated parking. with 2 operatories. Averaging 20 new patients per month. Long term staff. Approximately 1,600+ square feet with five (5) fully-equipped operatories set 2017 gross receipts $603k. Asking $399k. up for right hand delivery. There is a reception area, business office, consult room, staff lounge, lab, sterilization area, private office and separate storage 4246 SUNNYVALE GP Retiring seller offering a well est. general practice area. Asking $495K. with loyal staff in organized office with 3 fully-euippedING ops. Located in highly ND desirable neighborhood. 2017 GrossPE Receipts $540K+. Asking $390K. 4178 SONOMA COUNTY PERIO Seller retiring from 21 year practice with trained, seasoned staff and great location. Exceptional 2,100 sq. ft. ample 4269 WEST SAN JOSE GP Well established practice offering 46 yrs of office with 6 fully equipped ops. Majority of equipment purchased in 2002. 4 goodwill. Excellent West San Jose location. 7ops, 5 fully equipped in 2,000 doctor-days & 3 hygiene days per week. Average gross receipts $1M+. sq. ft facility. Approx 3,000 active patients, all fee-for-service. 9 days of Asking $677K. hygiene/week. Outstanding staff. Average annual GR $1.3M with an adjusted net of $473K. Asking price $1,015,000. Potential to purchase 4191 SONOMA COUNTY ENDO Seller retiring from 38 year endodontic bldg interest, price to be determined. Owner willing to help in the transition. practice located in attractive ground floor office (remodeled in 2011) with updated modern equipment and cabinetry. Close to several regular referral 4217 WEST SAN JOSE GP Seller retiring, offering 35+ years of goodwill in sources. Doctor sees an average of 7-8 patients per day. 5 year average well-established practice with loyal staff and stable patient base. 10-15 new Gross Receipts $700K+. Asking $447K. patients a month. Excellent location on busyLD thoroughfare. Asking $509K. SO 4159 SANTA ROSA GP Dedicated practitioner retiring from practice with 4237 SAN JOSE GP Busy general practice in state-of-the-art 1,500 sq. ft. emphasis on Restorative care. 2,330 square foot office with 5 ops. 4 doctor- office with 5 fully-equipped operatories. Approx.ING 1,900 active patients and days per week and approximately 1,000 active patients and average Gross ND approx. 19 new patients per month.P AverageE Gross Receipts $1.3M+. Receipt of $733K+. Asking $557K. 4267 SAN JOSE GP 36-year established 4 op practice near Willow Glen 4225 EUREKA GP & BUILDING Established since 1981 in charming area grossing $650K average. 950+ active patients. Beautifully maintained Northern California port city. Retiring doctor is offering practice and building. and updated 1,450 sq. ft. facility. 3-day doctor week, 3 hygiene days. Practice has approximately 1,200 active patients with new patients accepted Asking $450K. on a selective basis. Average Gross Receipts of $765K+ with 61% average overhead. Beautiful 1,400 square foot office with four (4) fully-equipped 4230 MORGAN HILL GP Well-established GP offering 30+ years of operatories. Asking price for practice $468K. goodwill in very desirable suburb of Silicon Valley. Asking price $199K. 4216 SIERRA NEVADA FOOTHILLS 23 year practice located in the heart 4210 UNION CITY GP Retiring GP offering 40+ years of goodwill. 5 ops in of the Sierra Nevada foothills in modern building close to downtown area. 1,100 sq. ft. 350 active patients, all fee-for-service. 2 yr average GR 1,024 square foot office with 4 fully- equipped ops., upgraded major $177K. Asking $85K. equipment and digital radiography. Average Gross Receipts $890K+ with 56% average overhead. Asking price for practice $604K. Seller is offering 4219 SANTA CRUZ FACILITY Great dental facility close to several real estate for sale to the buyer of his practice. LD amenities and minutes to HWY 1, andSO HWY 17. Turnkey dental office in 1,200 square foot facility with 3 fully-equipped ops. Asking $50K. 4172 NAPA GP Amazing opportunity to own the practice of your dreams in one of the world’s premier wine destinations! Situated in a prime 4202 SANTA CRUZ COUNTY GP Retiring seller offering 40+ years of neighborhood close to many amenities. 1,200 square foot office with 4 fully- D goodwill with emphasis on restorative care.OL Asking $300K. equipped and updated operatories. Over 1,000 active patients. Average S annual gross receipts over $700K. Asking price for practice $484K. Building 4232 SF GP Seller offering 26+ year general practice in SF Financial district. available for purchase. Ground floor office with high volume foot traffic.G Approx. 1,200 sq. ft. facility DIN with 4 fully-equipped ops. $930K+ avg.EN annual GR. Seller willing to help for a smooth transition. Asking $640K. P Carroll & Company 2055 Woodside Road, Suite 160 4196 PACIFIC HEIGHTS SOLO GROUP Individual SP within established Redwood City, CA 94061 successful group in a modern fully-equipped office with well trained BRE #00777682 personnel. Approximately 1,400 active patients with an average of 10 new patients per month. Asking $423K. Mike Carroll Pamela Carroll-Gardiner Mary McEvoy Carroll

carroll.company [email protected] (650) 362-7004 (650) 362-7007 Making your transition a reality.

Dr. Lee Dr. Thomas Dr. Russell Jim Kerri Gina Jaci Steve -D\ Thinh Maddox Wagner Okihara Engel McCullough Miller Hardison Caudill +DUWHU Tran LIC #01801165 /,& /,& /,& /,& /,& /,& /,& /,& /,& (949) 675-5578                   

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$"-*'03/*" SACRAMENTO: 1200 VI w/ 3 Ops, I/O GREATER LOS ANGELES PERIO 6287+25$1*(&2817<2SV camera & Patient Base software. Practice PRACTICE: Price Reduced! 5 Ops, 34 (TXLSSHG,QWUD2UDO&DPHUD'LJLWDO;UD\V &$03%(//1HZ/LVWLQJ3DUWQHUVKLS established 40+ years, owner retiring. #CA408 Yrs. Goodwill. Dentrix, Digital, Laser, great /DVHUDQG&DUL9X\UVJRRGZLOOZUHWLULQJ RSSRUWXQLW\%X\HUWRSXUFKDVHLQWHUHVWWR 6$&5$0(1721HZ/LVWLQJ9HU\HIILFLHQWO\ referral base, 201 GR $KZAdj. Net VHOOHU*5.KUVZN0RVW VKDUHSDWLHQWVUHYHQXHDQGH[SHQVHV2SV $K #CA173 VSHFLDOW\ZRUNUHIIHUHGRXW&$ VI&$ UDQSUDFWLFHZIXOO\HTXLSSHGRSHUDWRULHV 3UDFWLFH:HEVRIWZDUH,2&DPHUD'LJL;UD\ LAGUNA BEACH: 4 Ops, 3 Equipped, SOUTH PASADENA AREA: 5 Ops, 4 CHICO: 7 Ops, Digital, Dentrix, Pano. Estab. *50ZYHU\ORZRYHUKHDG&$ beautiful location. Dentrix G4, Dexis Digital equipped. 23 yUV Goodwill. Digital ;-rays. 60+ yrs 2 long-term owners 6 days Kyg/wk. GR X-rays, paperless. 201 GR $442K w Great corner shopping center on main street 6$&5$0(1721HZ/LVWLQJ2S332  . $757K. #CA402 Adj. Net #CA443 w/ signage. Great opportunity. #CA436 CLEARLAKE: 4 Ops. 1600 . Dentrix, SUDFWLFHLQDSSUR[VI(DJOHVRIW6FKLFN VI VHQVRUV,2FDPHUD*5. /$.($552:+($'6$1%(51$5',12 TUSTIN: 6 Ops, Pano, 5 yr. new equip., Dexis, Laser, Microscope, Pano, GR $650K. 07161HZ/LVWLQJ332))6SUDFWLFHZ PracticeWorks, 60+ years Goodwill. G5 Est. 2001. Seller retiring. #CA457 GD\ZN&$ 6$1-26(1HZ/LVWLQJ\UDYJUHYHQXH 2SV6RIW'HQW'H[LVGLJLWDO;UD\V,2FDPHUD $525K. #CA486 EL DORADO COUNTY: 1200 VI., 3 Ops, 0RYHU.$GM1HWRQGD\ZN 3DQRDQGODVHU6WURQJ+\JLHQHSURJUDPLQ VENTURA&2817<: 4 Ops, 1350 VI in Pano, EZ 2000 software 'H[LV ,2 FDPHUDV )HH)RU6HUYLFHZ2SVVI SODFHGD\VK\JZN*50Z busy retail center on main thoroughfare. 201GR$Kon3day/wk.4 &RQH%HDP,PDJLQJ6FKLFN6HQVRUV/DVHUV .$GM1HW%OGJLVDOVRIRUVDOH&$ Dentrix, Digital X-rays, I/O Camera, and FROOHFWLRQVRI.2ZQHUUHWLULQJ #CA39 DQGPRUH&$ LONG BEACH: 1700 VI practice + Real Pano. 4 days hyg/wk. 2017 GR $641K Z *5($7(53/$&(59,//(: 6HOOLQJIRUOHVV SONOMA COUNTY: 2016 GR $680K, 3 Estate, paperless Z 6 Ops, Dentrix, Dexis $257K Adj. Net. #CA504 WKDQRIFROOHFWLRQVRI.PLQ days/wk. 3 Ops, 960 sq. ft., Condo for sale or digital ;-rays, digital Pano and laser. 4 days WESTERN SAN FERNANDO VALLEY IURP(O'RUDGR+LOOV2ZQHUZDQWVWRUHWLUH lease. Pano X-ray, I/O Camera, Soft Tissue hyg/wk. 2017 GR of $492K #CA499 PEDO PRACTICE:3ULFH5HGXFHGLocated SULFHUHGXFHGIRUTXLFNVDOHVIRIILFH Laser, Datacon PMS. Owner retiring. #CA463 LOS ANGELES ENDO PRACTICE: 4 Ops, in upscale location, 4 Ops, EagleSoft, I/O 2SV'HQWUL[VRIWZDUH6FKLFNVHQVRUVQHZ SONOMA COUNTY MULTI-SPECIALTY 3 Equipped with Scopes and Digital X-rays,  Camera, Pano. 9 yrs Goodwill. #CA399 VHUYHU &38V&$ 27+ yrs. Goodwill. 2017 GR $692K Z $433 *5($7(5526(9,//(HTXLSSHG2SV PRACTICE: Established 16 yrs., 2016 GR 4"/
%*&(0 $1. M+ on 3 days/wk. 6 fully equipped Ops; Adj. Net. #CA485 2SV VIRIILFH'HQWUL['H[LVGLJL  ò CHULA VISTA/BONITA AREA: 8 Ops, LANAP, Digital Pano, Dexis & Dentrix.  ORANGE: 4 Ops, Dentrix, Dexis, near VHQVRUV  QHZFRPSXWHUV.LQHTXLS  hospitals, 30+ years Goodwill. 2017 GR $308K well-established practicein stand-alone WHFKSXUFKDVHGLQGD\VK\JZN Retiring periodontist selling practice and 2000 VI Condo. #CA470 Z $173K Adj. Net. #CA487 building near a busy section of Bonita Z *5.RQ'UKUVZN&$ excellent visibility and SDUNLQJ2IILFHRSHQ *5($7(5526(9,//(52&./,11HZ VALLEJO: 4 Ops, 1650 sI., Digital X-Ray, ORANGE COUNTY 3(5,2 PRACTICE: GD\VZGD\VK\Jwk. SoftDent,Dexis, Pano, /LVWLQJ2S332SUDFWLFHDSSUR[VI Digital Pan. 201 GR $K Eaglesoft PMS New Listing! 2SVGD\VK\JZN5HWLULQJ I/O cameras, and Laser. Patient base of FFS, 6RIWGHQWVRIWZDUH6XQLGLJLVHQVRUODVHU ,2 with Paperless Patient Charts. #CA469 VHOOHUKDVDSSUR[13PRZDVWURQJUHIHUUDO Indemnity, and PPO patients. Most specialty FDPHUD*5.GD\ZN&$ VALLEJO: 1HZ/LVWLQJ5HDO(VWDWH EDVH/RQJKLVWRU\RIFROOHFWLQJ0\U work referred out. #CA476 $GM1HW.RQGD\ZN&$ GREATER SACRAMENTO ORAL $YDLODEOHVIZHTXLS2SV(DJOHVRIW LA JOLLA:7 Ops, 6 Equipped, Dentrix, SURGERY PRACTICE: 5 Ops, 2282 VI. 306'LJLWDO;UD\DQG&$'&$0*5 ORANGE COUNTY ENDO PRACTICE: Digital, and I/O Camera. 4 days Hyg./wk. GR suite. Digital X-rays and Pano. 20 GR $0. .òGD\ZN2ZQHUFDQDVVLVWZLWK5HDO 2SV*OREDO,QFOLQDEOH%LQRFXODU6FRSH $738K Z $264K Adj. Net on 4 day/wk. 60 Selling doctor retiring. #CA438 (VWDWHILQDQFLQJLVUHWLULQJ&$ ILUHSODFHV*5.ZLWKVHOOHUVFDOLQJ years goodwill, 29 with current owner. Most EDFNVLJQLILFDQWO\LQ&$ GREATER SACRAMENTO: Approx. 2000 WATSONVILLE: Practice & Real Estate.  specialty procedures referred out. #CA477 ORANGE COUNTY: 4 Ops, 40+ yrs. VI., 6 Ops, I/O Camera, Digital X-ray, Laser, Stand-alone 2245 VI bOGJ 4 equipped Ops,  1257+&2817<,1/$1'3526 CEREC, & Eaglesoft software. 2016 GR Paperless, Dexis Digital X-ray, Planet DDS/ goodwill, OpenDental, Digital X-rays. 201 GR $ K $ K Adj. Net. #CA440 35$&7,&(1HZ/LVWLQJ2S'HQWUL[  $935K. #CA455 Denticon software. 2017 GR $552K.#CA494  Z  'LJLWDO;UD\VLQDEHDXWLIXOIDFLOLW\&XUEVLGH GREATER SACRAMENTO: 4 Ops, Pano, WOODLAND: 2SRIILFHin a 2100 sI. suite 3$6$'(1$2S*HQHUDOSUDFWLFH5( YLVLELOLW\DQGOR\DOUHIHUUDOVRXUFHVQHDUE\ digital ;-rays, Cerec. 2016 Collections $1.0M+. Z 22 yrs. goodwill available. Shopping center 3DSHUOHVVSUDFWLFHZLWK6RIW'HQW'LJLWDO;UD\V 6HOOHULVUHORFDWLQJ*5.Z. Stand-alone bldg. selling w practice. #CA479 location2017 GR of $769KSeller retiring, DQG,2&DPHUD*5.DQG. $GM1HW&$ potential for increased collections. #CA497 $GM1HWRQGD\ZNZLWKGD\VK\JZN 6$1',(*21HZ/LVWLQJ2SV(= GREATER SACRAMENTO PERIO &$ 'LJLWDO332))66PDPRXQWRI0HGL&DO PRACTICE: Well-established, 4 days/wk $&/53"-
$"-*'03/*" 5$1&+2&8&$021*$1HZ/LVWLQJ 6HOOHU5HWLULQJ([FHOOHQW2SSRUWXQLW\IRUD practice, digital ;-rays, laser, I/O camera. CENTRAL COAST ENDO PRACTICE: 3 Ops, Digital -rays, Paperless, Cone Beam CT, 2SVIUHHVWDQGLQJEXLOGLQJRQEXV\FRUQHU QHZGRFWRURUDQGRIILFHORFDWLRQ*5. Seller relocating, but will work with buyer for ; Z.$GM1HW&$ smooth transition. #CA480 and PBS Endo Software. 2016 GR of $925K 'HQWUL['H[LV'LJLWDO3DQRVHSDUDWHFKDLU w $561K Adj. Net. #CA489 RUWKRED\*5.Z.$GM1HW 6$1',(*22SV&XWWLQJHGJHSUDFWLFH *5($7(56$&5$0(1721HZ/LVWLQJ FRESNO: &$ GD\VK\JZN(DJOH6RIW6FKLFN'LJLWDO&RQH RSVLQDSSUR[VIRIILFHLQD 1HZ/LVWLQJ3HULR,PSODQW2SV ODUJHFRQIHUHQFHURRPIRUWHDFKLQJPHHWLQJV RIVERSIDE COUNTY: Turnkey 4 Op %HDP&(5(&/DVHUV,2&DPHUDV0RVW SURIHVVLRQDOEXLOGLQJRQPDMRUWKRURXJKIDUH practice in single story Prof.Bldg. with signage. VSHFLDOW\ZRUNUHIHUUHGRXW*50Z HTXLSSHGZGLJLWDO;UD\VGLJLWDO3DQ,2 \UVJRRGZLOO&ROOHFWLRQVRI. GD\VZNFDVKRQO\RIILFH&$ Dentrix, Digital, Paperless. 201 GR $K w .$GM1HW&$ FDPHUDODVHUDQG&$'&$06HOOHU $K Adj. Net Income. #CA471 UHORFDWLQJ&$ MODESTO: 1110 sq. ft., 3 Ops, Dentrix 6$1',(*2)$&,/,7<21/<7XUQ.H\ software, Dexis Digi X-Uay, Fiber Optics, Laser. SAN FERNANDO VALLEY MULTI- 2SIDFLOLW\LQWKH'HO0DU+LJKODQGVDUHD LOS ALTOS: Great location and 30 yr. 201 GR $K 4 day/wk. #CA451 SPECIALTY PRACTICE: 13 Ops plus open +LJKO\VRXJKWDIWHUORFDWLRQVI/HDVH history. 1520 VI practice, 6 Ops,3 equipped. bay Pedo room with 4 chairs, Full porcelain lab UDWHLQFO&$0PR([FHOOHQWORFDWLRQ Pano, I/O, Soft Tissue laser, Eaglesoft PMS. 9,6$/,$1HZ/LVWLQJ(IILFLHQWO\UXQSUDFWLFH on-site, EagleSoft, Digital Pano. 18 hyg. days/ IRU(QGRRU*33ULFHGWRVHOOTXLFNO\&$ Seller retiring. #CA496 2SV3UDFWLFH:HEVRIWZDUH,2&DPHUD'LJL wk. GR $3.6M+ with $952K Adj. Net. #CA488 ;UD\*50ZORZRYHUKHDG&$ 065
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$"-*'03/*" SANTA ANA: 4 Ops shopping center on busy MARIN COUNTY FACILITY: New Listing! CENTRAL OAHU, HAWAII:Family- 2013 build in new condition, 3 Ops, brightairy 4065)&3/
$"-*'03/*" corner w/ signage. PPO/Denti-Calpractice.  201 GR $4K Z $1K Adj. Net. #CA460 oriented rural practice w3 Ops, Digi X-Uays, spacious layout, Planmeca Digi Pano, Digi ARCADIA/PASADENA AREA: Sierra Madre Pano, Innova. Retiring seller, PPO, Medicaid. sensor, I/O Camera. Paperless w/ bonus of practice 3 Ops, 50+ yrs. JRRGZLOO\UV w 6$17$%$5%$5$&2817< RSVLQ 2016 GR $923K w $322K Adj. Net. #HI109 patients. Opportunity to merge or work in an retiring seller. Strong Hygiene. 201 GR $K D VI VXLWH  \UV JRRGZLOO DQGLQ est. facility to make GUHDPSUDFWLFH! #CA502 wroom to grow. #CA481 KRXVH VSHFLDOLVWV ))6 332 DQG KDV D &(175$/2$+8+$:$,,1HZ/LVWLQJ &RQYHQLHQWIDPLO\RULHQWHGSUDFWLFH2SV PITTSBURG: 3ractice & Real Estate. Stand- BAKERSFIELD: 6 Ops, 5 Equip, duplex bldg +02 &$3 FKHFN RI .PR (= 'HQWDO 'LJLWDO;UD\V,2&DPHUDDQG3DQR (T332))66HOOHUUHWLULQJ'LJLWDO,QQRYD alone 2324 VI. building, 7 Ops, 5 equipped, w signage. 2016 GR $509K w room to grow. *5.Z.$GM1HW+, Paperless, Dexis Digital X-ray, PlanetDDS/ Most specialty referred out. PPO/Denti-Cal. *50Z.$GM1HW&$ #CA459 6$17$021,&$1HZ/LVWLQJ2SVLQD +212/8/8+$:$,,1HZ/LVWLQJ Denticon software, Pano. 2017 GR $781K. 2SV,QQRYD$OOVSHFLDOW\SURFVHQWRXW332 #CA493 CHINO: 3 Ops, 40+ yrs.goodwill. Prof. bldg., FHQWUDOL]HGORFDWLRQZLWKJUHDWVWUHHWYLVLELOLW\ CareStream, 2½ days Hyg/wk. GR $344K w ZLWK&DUH6WUHDPDQGGLJLWDO;UD\V*5 ))66HOOHUUHWLULQJPRWLYDWHG+, 5('',1*1HZ/LVWLQJVIRIILFHZ $126K Adj. Net #CA484 .Z.$GM1HW&$ ($67(51:$6+,1*7211HZ/LVWLQJ 2SV,2FDPHUDGLJLWDO;UD\3DQR'HQWUL[ :HOOHVWDEOLVKHGSUDFWLFHVIRIILFH VRIWZDUH/RQJKLVWRU\RI*50&$ )2817$,19$//(<2SV(= 6$17$021,&$1HZ/LVWLQJ7XUQNH\ VRIWZDUH Z 'LJL ;UD\V ,2FDPHUD\U 2SV(TXLSSHGRQO\''6LQSURIHVVLRQDO 2SV(DV\'HQWDOVRIWZDUH,2&DPHUD  SACRAMENTO: VIRIILFHZ2SVI/ ROGHTXLSPHQW0RVWVSHFLDOW\UHIHUUHGRXW EXLOGLQJ2SHQ'HQWDO'LJLWDO3DSHUOHVV*5 2UWKRSDQWRPJUDSK*5.GD\ZN O, Dexis digital x-ray, Carestream software. URRPIRUJURZWK *5.Z. .Z.$GM1HW&$ :$ Est. 30+ years, 201 GR $5K #CA424 $GM1HW&$ SOUTH BAY, LOS ANGELES AREA- SACRAMENTO: VIRIILFHZHTXLS */(1'$/(2SV'HQWUL['H[LV,QWUD IMPLANT/ORAL SURGERY: 3 Ops1700 VI Ops, 2 add’l plumbed. DentalMate software. 2UDO&DPHUDDQGD/DVHU3UDFWLFHKDVGD\V in retail/prof center. Paperlesscomputerized w 2015 GR $110K #CA332 K\JZNDQGGRFWRUGD\VZN*5 WinDent OMS Software, Dexis digi;-rays, .Z.$GM1HW&$ Digital Pano, CBCT. 2017 GR $475K. #CA498 ќџѡѕђџћȱюљіѓќџћіюȱѓѓіѐђ ќѢѡѕђџћȱюљіѓќџћіюȱѓѓіѐђ 1.800.519.3458 www.henryscheinppt.com 1.888.685.8100 Ž—›¢ȱŒ‘Ž’—ȱ˜›™˜›ŠŽȱ›˜”Ž›ȱǛŖŗŘřŖŚŜŜ Regulatory Compliance CDA JOURNAL, VOL 46, Nº8

Employee Injury Reporting and Records CDA Practice Support

ederal Occupational Safety and occurring in a place of employment or Health Administration’s recent in connection with any employment. mandate that certain employers Be aware that whenever a fi re or electronically submit by July 1 A dental practice that police agency is called to respond their Form 300A, “Summary of has not received a written to a serious accident involving an FWork-Related Injuries and Illnesses,” employee, the agency will notify Cal/ raised questions about the mandate’s request to log injuries and OSHA immediately. “Immediately” applicability to dentistry and dentistry’s illness is not required to means as soon as practically possible overall obligation to record and report complete these two forms. but not longer than eight hours after injuries and illnesses to OSHA and the employer knows or with diligent Cal/OSHA. The mandate applies to inquiry would have known of the employers with 20 to 249 employees in all death or serious injury or illness. states, including states such as California that enforce their own occupational safety and health program. However, the mandate applies to industries with “historically high rates of occupational injuries and illnesses.”1 The mandate to submit Form 300A electronically is not applicable to dental establishments.

Is a dental practice required to complete Form 300A or Form 300, “Log of Work-Related Injuries and Illnesses?” It depends. Dentistry is classifi ed as a “partially exempt industry.” This means that if a dental practice has received a written request from OSHA, the Bureau of Labor Statistics, the California Department of Industrial Relations or one of their divisions to record injuries and illness on these forms, then the practice must do so for the period requested. A dental practice that has not received a written request to log injuries and illness is not required to complete these two forms.

Is a dental practice partially exempt from reporting injuries, too? No. Every California employer must immediately report to the nearest Cal/OSHA district offi ce any serious injury, illness or death of an employee

AUGUST 2018 523 AUG. 2018 REGULATORY COMPLIANCE

CDA JOURNAL, VOL 46, Nº8

Look to one of the required How is a needlestick or sharps Regulatory Compliance appears posters for locations and telephone injury recorded on the form? What are monthly and features resources about laws numbers of the Cal/OSHA district examples of other recordable injuries? that impact dental practices. Visit cda.org/ offi ces. When reporting the injury Any injury caused by a needle or sharp practicesupport for more than 600 practice or illness, the following information contaminated with another person’s blood support resources, including practice should be provided if available: or other potentially infectious material must management, employment practices, dental ■ Time and date of accident. be recorded on Cal/OSHA Form 300 as an benefi ts plans and regulatory compliance. ■ Employer’s name, address injury if the dental practice is required to log and telephone number. injuries. Do not enter the employee’s name ■ Name and job title of person on the form in order to protect the employee’s reporting the accident. privacy. Enter “privacy case” in the space ■ Address of site of normally used for the employee’s name. accident or event. A recordable injury includes a work- ■ Name of person to contact related cut, fracture, sprain or amputation. at site of accident. A recordable illness includes a work- ■ Name and address of related abnormal condition or disorder injured employee(s). or acute or chronic illness such as skin ■ Nature of injury. disease, respiratory disorder or poisoning. ■ Location where injured employee(s) was (were) moved to. If an employee asks not to have ■ List and identity of other law his or her name on the Form 300, enforcement agencies present may I agree to that request? at the site of accident. Yes, you may agree to that request. ■ Description of accident and Employee names also should not be listed whether the accident scene or in cases of injuries or illnesses that involve instrumentality have been altered. sexual assault, mental illness, any intimate body part or reproductive system, HIV Earlier this year I received a written infection, hepatitis, tuberculosis or injuries request from the Bureau of Labor from needles or sharps contaminated Statistics to complete Form 300. I have a with another person’s blood or other temporary employee. If she gets injured, potentially infectious material. Enter must I record her injury on the form? “privacy case” in the space normally used Any occupational illness or injury for the employee’s name. A separate, to any paid employee, including confi dential list of case numbers and executives, hourly, salaried, part time, employee names should be maintained. seasonal and any temporary employee who is supervised on a day-to-day Where can I fi nd more information basis must be recorded on the Cal/ about the requirements to report and record OSHA Form 300. If using a temporary occupational injuries and illnesses? employment agency, confi rm with the Cal/OSHA’s website is dir.ca.gov/ agency whether it or the dental practice dosh/etools/recordkeeping. ■ will record the injury. The injury should only be recorded once. Self- REFERENCE employed persons, sole proprietors or 1. U.S. Department of Labor, Occupational Safety and Health Administration, Injury Tracking Application, Electronic Submission partners are not considered employees of Injury and Illness Records. www.osha.gov/injuryreporting. for record-keeping purposes. Accessed June 1, 2018.

524 AUGUST 2018 Specialists in the Sale and Appraisal of Dental Practices Practices Serving California Dentists since 1966 How much is your practice worth?? Wanted Selling or Buying, Call PPS today!

NORTHERNNORT CALIFORNIA SOUTHERN CALIFORNIA (415) 899-8580 – (800) 422-2818 (714) 832-0230 – (800) 695-2732 Raymond and Edna Irving Thomas Fitterer and Dean George [email protected] [email protected] www.PPSsellsDDS.com www.PPSDental.com California DRE License 1422122 California DRE License 324962 6145 MARINRIN COUNTY’S COUNTY’SNO NOVATOVATO Excellent foundation in this ALTA LOMA Shopping Center. Absentee Owner. Grossing desirable family community. Best location. Beautiful office. Adec $700,000. Can do $1 Million. equipped throughout with everything new since 2014. 500-active BAKERSFIELD 3,000 sq.ft. building. Established 60-years. files. 2018 tracking $250,000. Change in owner’s life dictates sale. &DQdo $1 Million. FP $650,000 includes RE. 6144 SACRAMENTO AREA Deeply anchored in its community. BAKERSFIELD AREA Small City. Grosses $40/mRQWK Conservative philosophy. 14-days of Hygiene. 3,000 active patients. on2-days. 1,800 sq.ft. 5-ops with small apt. FXOOPULFH $330,000. 2017 collected $1.85 Million. Strong staff. 7-ops in 2,500 sq.ft. suite. BELLFLOWER Lady DDS doing $100,000. 3-ops. Full Price Great location. Condo optional purchase. $65,000. 6143 BERKELEY’S ALTA BATES MEDICAL VILLAGE CAPISTRANO BEACH Doing $200,000 part-time. Full Price Perfect opportunity for nearby Delta Premier Dentist to relocate their $150,000 practice into this stand-alone building on Webster Street. On 3-day COLTON Hispanic practice doing $350,000. Absentee Owner. week, collections totaled $550,000 in 2017. 4-days of Hygiene saw  1,558 hygiene appointments last 12-months. 4-ops. Hands-on Owner will do $500,000 first year. FXOOPULFH $285,000. DIAMOND BAR Korean / Chinese Shopping Center. Very busy 6142 OAKLAND’S PIEDMONT “Out-of-Network” practice averages 16 new patients per month. Great views. 3-ops and until 9 PM. Owner works 1-day. Does $450,000. Should do $1+ Planmeca ProMax. 2017 collected $667,000. Profits of $000. Million. FXOOPULFH$450,000. Successor should be proficient in ortho or willing to learn. Seller GLENDALE / BURBANK Absentee Owner grossing $840,000. DYDLODEOHWRSURYLGHan orderly transition. Beautiful corner building. Newly renovated. RHDO(VWDWHincludes 6141 NORTH NAPA VALLEY 3-day per week Delta PPO smallapDUWPHQW. $2 Million location. practice. 3-days of Hygiene. 2017 Collected $359,000. Attractive 3- INLAND EMPIRE 3,000 sq.ft. building. 7-Adec 2ps, Cone op office. 15 new patients per month. Full price $150,000. %HDP Grossing $1.3 Million. FP $2.5 Million includes 5eal (state. 6140 SAN RAFAEL Dentist retiring after long career. Delta PPO INLAND EMPIRE DentiCal. Grosses near $300,000. 4-ops. provider. Has averaged $390,000 in annual collections on 26.5-hour )XOO3ULFH150,000. week. $223,000+ in Profits in 2017. Full Price $125,000. IRVINE Female Owner grossing $1.2 Million. 5-ops. 6139 SF BAY AREA PROSTHODONTI&35$&7,&( Very LAKE FOREST Adec equipped. Female DDS grossing $325,000. strong pedigree. Well positioned for the future. Excellent platform Buyer shall do $500,000 first year. Option to purchase condo. for younger Prosthodontist. "Out-of-Network!" 2017 billed $1.2 LA MIRADA Hi identity shopping center. HMO pays rent. Like Million and collected $1.19 Million. 4-days of Hygiene. Owner can new 3-ops with 2-more available. Grossing $450,000. work back to help assist with transition. NORTH PASADENA Doing $1 Million. Beautiful. Includes 6138 SILICON VALLEY Phenomenal opportunity shall secure a 5eal (state. rewarding career. Best technology, perfectly designed suite and ORANGE COUNTY BEACH CITY Absentee Owner. Grossing optimum stage to practice your craft. 2017’s collections topped $550,000. Hands-on Owner will do $1+ Million first year.Valuable $900,000 with Profits of $420,000. Condo included. Perfect for RHDO(VWDWHpossible. skilled practitioner who seeks to create high-end brand. ORANGE COUNTY’S FASHION ISLAND Grossing $650,000. 6136 SAN RAMON Strong foundation. Collections for 2017 Rare opportunity. totaled $575,000. And this SOLDwas on a work schedule averaging PEDO – CHINESE / HISPANIC Grossing $450,000. Long 2.5-days a week. 3-ops. Seller can work back 1-day a week for established. FXOO3ULFH$285,000. transition. REDLANDS Long established. Has done $1 Million. Lots of 6135 SONOMA COUNTY’S ROHNERT PARK 2017 collected potential. Grossing over $400,000. $1,067,000 reflecting nice growth over 2016 which collected REDLANDS Rent only $1,250 per month. $940,000. Available Profits exceeded $500,000 for the second year in a row. Six days of Hygiene. There shall be no change in fees for RIALTO HMO 4-to-5 Cap checks per month. +DVGRQH$1 the Successor. New homes being built nearby. Great IDPLO\area Million. Asking $285,000 6129 FOSTER CITY Wish to infuse your practice with quality RIVERSIDE Grossing near $300,000. 3RSHUDWRULHV Full Price patients? “Out-of-Network” practice collected $500,000+ in 2017 $150,000. RQpart-time schedule. Seller and Hygienist shall relocate into SAN DIMAS Emergency Sale! Buyer’s practice to transition patients. Full Price $100,000. SANTA CLARITA Endowants to share RIILFHwith Perio or GP. 22 SANTA CLARA - STARBUCKS "LIKE" LOCATION! SANTA CLARITA 70,000 autos pass daily. 8-ops. Absentee Best exposure in beautiful strip center on El Camino Real. Office Owner. Full Price $250,000. just remodeled. 5-Ops. This Delta PPO practice is currently trending TEMECULA HMO Grossing $500,000. Hi Identity, 5 ops. FXOO $1+ Million in Collections on 4-days. Perfect platform to operate 6- PULFH285 days a week. Wants to do $1.5+ Million UNION PRACTICE Shall do $1 Million. Full Price $775,000. SELL YOUR PRACTICE ...... to the right buyer! Knowing how, means doing all of the following - with precision:

1. Valid practice appraisal.

2. Contract preparation and negotiations, including critical tax allocation consideration.

3. Bank financing or Seller financing, with proper agreements to adequately protect the Seller and make the deal close - realistically and expeditiously.

4. Performance of “due diligence” requirements, to prevent later problems.

5. Preparation of all documentation for stock sale, when applicable.

6. Lease negotiations.

All six of these services costs no more.

LEE SKARIN Maybe even less! INC. & ASSOCIATES Lee Skarin & Associates is Cali- fornia’s leading Dental Practice Broker. Their in-house attor- Lee Skarin & Associates ney, Kurt Skarin, PhD., J.D., has scores of Buyers in their specializes in these matters. He does all of the above, and more. database. The Buyers’ profiles He is the catalytic agent that personal desires and financial makes the sale happen - quick- ability have been categorized to ly and smoothly. expertly select the right Buyer for your practice. Expert Buyer selection solidifies a deal. Lee Skarin & Associates services Dental Practice Brokers 2IÀFHV all of Southern California. CA DRE #00863149 805.777.7707

Your calls are invited. Put our thirty years of experience to work for you! 818.991.6552 Visit our website for current listings: www.LeeSkarinandAssociates.com 800.752.7461 Ethics CDA JOURNAL, VOL 46, Nº8

Write, Maintain Up-To-Date Patient Records Joanne Lagos, DDS, MSPH

r. Anonymous was opening Patient records are legal Many of us never received formal his mail when he saw a letter training on the art of writing thorough from his dental society’s peer documents and must be legible, records, or perhaps we don’t take the review committee. His heart signed and dated by the doctor time to write the records or we dictate sank as he read that a patient in order to stand up in court the job to an assistant or hygienist. Dhad fi led a complaint and the committee Whatever the reason, the responsibility was asking for a copy of his records. The should it ever be necessary. lies with the dentist to write or review doctor immediately reviewed his records the records. If a staff member is writing and noticed that relevant information had the notes, the doctor is responsible for been omitted from this patient’s record. reviewing the record, making changes He proceeded to make written additions legal or other reasons. Good records also and additions as necessary and signing. to the record, which included notes serve as a follow-up to a thorough exam, Patient records are legal documents regarding additional treatment, qualifying treatment and communication that helps and must be legible, signed and dated reasons for treatment, comments establish a relationship with the patient. by the doctor in order to stand up in about instructions and discussions There are certain standard court should it ever be necessary. with the patient, and comments about evaluations and discussions that should If records are requested, never send the quality of treatment rendered. take place with both new and existing original records, only copies. Due to This copy of the treatment record, patients to attain information to be HIPAA, an authorized and signed however, differed from the record that had able to treat the patient appropriately. release of records is required. If a request previously been given to the patient when This also helps to develop trusting for records is made by the peer review they requested it from a staff member. relationships with patients as they see the committee or the CDA Judicial Council, There were more than 40 additions doctor’s thoroughness and consistency. you must respond by the deadline date on multiple pages. Due to a suspected The patient record starts off with a good or else you may be faced with a violation violation of Section 2A (false statements) health history signed, reviewed and dated by of Section 3 of the CDA Code of Ethics of the CDA Code of Ethics, the Council the patient and the doctor. Appropriate and (failure to comply with duly constituted on Peer Review referred the dentist to the well-taken radiographs that are current are committees). For more comprehensive CDA Judicial Council. When the judicial imperative for treatment. If a patient refuses information on record keeping and council investigated the allegations, the radiographs, this must be documented, lengths of time to retain records, refer dentist admitted to adding a few notes signed and dated by the patient. to the CDA and TDIC websites. ■ to ensure completeness and clarity. Progress notes for all appointments The dentist was charged with a should include the treatment notes for Joanne Lagos, DDS, MSPH, is a violation of Section 2A (false statements) procedures, anesthesia, materials used, general dentist practicing in Oakland, Ca. of the CDA Code of Ethics and the problems encountered, changes in She currently serves as ethics chairman dentist’s membership was placed on treatment, signifi cant interactions with for the Alameda County Dental Society probation for three years. As is required the patient, doctor and staff, prescriptions, and is a former member of the CDA by law, CDA reported this adverse referrals and postoperative instructions. Judicial Council. For more information action on the dentist’s membership to It is best to update the records the same on patient records, please contact the the National Practitioner Data Bank day. If something is forgotten or an Judicial Council at 916.554.4965. and the Dental Board of California. amended entry needs to be made, draw The Dental Board of California a single line over the incorrect portion initiated a separate investigation. (if is a written record), add the date Writing and maintaining good records the correction or new entry is entered for new, existing, former and deceased as “addendum to,” add the corrected patients is imperative for many reasons. As information and sign. In order to reduce can be seen from the above true case, one your liability should the records ever be never knows if records will be needed for requested, never delete or erase entries.

AUGUST 2018 527

Largest BAY AREA BAY AREA CONTINUED NORTHERN CALIFORNIA CONTINUED NORTHERN CALIFORNIA CONTINUED

AC-649 SAN FRANCISCO Facility: Richmond Dis- DG-844 SAN JOSE: Beloved pracce delivers quality EG-788 ROSEVILLE: HN-773 SUTTER CREEK: Seller Movated! Broker in trict, 3 ops+1 add’l. $120k care and warm relaonships which paents have . Reduce Price $275k/ Real Estate Available ! $175k AC-782 SAN FRANCISCO: Well maintained, Profes- come to expect. 1500sf 3 ops + 1 add’l. $195k EG-849 AUBURN: HN-816 CHESTER/ALMANOR AREA: sional Medical Complex. 1450 sf w/ 5 ops $195k DG-854 SUNNYVALE: Do your best denstry here to Northern AG-852 SAN FRANCISCO: PRIME LOCATION! 600 sf an educated, diverse, family-oriented, business- $350k Pracce $140k/ Real Estate TBD w/ 2 fully equipped, computerized ops $375k friendly populaon! 782sf w/ 3 ops $875k EN-800 SACRAMENTO: AN-752 SAN FRANCISCO Facility: 2 months Free Rent! DG-865 SANTA MARIA: Live and pracƟce in this Seller Movated! $150k CENTRAL VALLEY California Opportunies like this one are few and far between! desirable collegiate coastal community! 930sf w/ 3 EN-797 WOODLAND:

1007sf w/ 4ops. $79k ops $395k Pracce $575k/ Real Estate TBD IC-468 SAN JOAQUIN VALLEY AN-864 SAN CARLOS Lease: “Turn-Key” Dental DN-771 SOQUEL Facility: The perfect place to sink EN-831 SACRAMENTO $425k Office for Rent w/ Equipment! Ideal for a special- down roots, raise a family & build an empire! “a cut above” $775k IG-832 OAKHURST: Over $34.5M ist! 2 op + 1 add’l. $6,500 mon. 1100sf w/2 ops + 1 add’l. $50k EN-836 CITRUS HEIGHTS: BC-710 WALNUT CREEK: Stand-alone, single-story DN-774 FREMONT: This opportunity has it all and $188k $235k/ Real Estate 375k bldg. 1313sf w/ 3 ops $150k awaits your talent and skill! 1,150sf w/3 ops + 1 EN-824 SIERRA FOOTHILLS: IN-764 STOCKTON: in 2017 sales BC-741 DANVILLE (FACILITY): Move in Ready facility add’l $150k $625 $267.5k to build the practice of your dreams! ~ 1600sf w/ DG-785 SANTA CRUZ: Great price and cash flow for EN-858 ORANGEVALE: JC-811 FRESNO COUNTY:

3 fully equipped ops $150k only 3 days a week!! 1000sf w/ 4 ops. Reduced Priced to Sell Only $70k! $350k BC-789 OAKLAND (Facility): Perfect layout for Pedo Price: $190k FC-650 FORT BRAGG: JC-823 LOS BANOS: Extensive Buyer or Ortho. 2800 sf w/ 6 fully equipped ops. Plumb- DG-842 FREMONT: Imagine being able to live, $350k for the Pracce & $400k for the Real Estate $80k er for 2 add’l $135k pracce and play here! 3200 sf w/ 10 ops $395k FG-841 ARCATA: JG-778 FRESNO: Database & BG-734 ANTIOCH: The perfect place to work, live DG-857 SAN JOSE: Do the math - this associate- $275k/Real Estate TBD $275k and play! Located in desirable professional neigh- driven pracce with profitability consistently! FN-754 SO. HUMBOLDT: JG-807 FRESNO: Unsurpassed borhood. 1,323 sf w/ 4 ops. $315k 1709 sf w/5 ops $595k $158k BG 838 HAYWARD: If Alameda County is where you DN-806 WATSONVILLE: This quality, family-oriented Now $150k! Exposure allows want to be, then THIS is the pracce for you! 800sf pracce thrives $ focuses on delivering quality care. FN-855 NO. HUMBOLDT: SOUTHERN CALIFORNIA w/ 2 ops. $125k 1,182 SF W/ 4 OPS. $495K/ Real Estate TBD $275k us to offer you BG-839 PINOLE: Sink your roots into this community DN-845 FREMONT Facility: Build your dream Prac- GN-746 YUBA CITY: Includes the latest technol- KG-779 SAN CLEMENTE Ortho: which retains many “turn-of-the-century” buildings! ce! Primed for success in this proven locaon! ogy in CBCT Imaging. $325k/ Real Estate

1212sf w/ 3 ops + 1 add’l. $350k 1800sf w/3 ops + 2 add’l. $100k Pracce $480k/ Real Estate TBD. Available! Call for Details!

CC-798 PETALUMA: Partially equipped dental office GG-769 REDDING AREA: for lease. Only $2500/mo for 1400 sf! Call for De- NORTHERN CALIFORNIA Pracce $390k/ Real Estate $540k SPECIALTY PRACTICES tails! GN-799 PARADISE: Better CC-802 SANTA ROSA: Retail shopping center w/ 1200 EC-729 GREATER SACRAMENTO AREA: Seller rer- Pracce $375k, Real Estate $325k AC-748 SAN FRANCISCO Perio: sf and 4 fully equipped ops $220k or $260k w/CT ing! FFS Pracce and Real Estate Available! GN-808 CHICO: $750k Scanner EN-664 SACRAMENTO Facility: Great corner loca- $395k/ Real Estate TBD BC-784 CENTRAL CONTRA COSTA CO Perio: Candidate C C -8 46 S AN R AFAEL: Prof/Retail Building Complex. 3 on, excellent visibility & easy access! 2300sf w/ 4 GN-853 REDDING: $395k ops 640 sf Collections $433k in 2017 $295k ops. Now Only: $30k $595k BG-843 WALNUT CREEK Perio: CG-616 NAPA: State-of-the-Art practice. Seller mov- EN-747 CITRUS HEIGHTS Facility: Be the only dental HG-732 GRASS VALLEY: $645k ing out of state! $425k office in this aracve, popular Retail Shopping $205k EN-821 DAVIS Perio: CG-859 SONOMA: On track to collect over $700k in Center! 2200sf w/5 ops + 6 add’l. $75k HG-815 SIERRA CO: $385k Better 2018! 2000sf w/ 4 ops highly esteemed FFS Practice EN-749 LINCOLN: Come sink your roots down and Reduced Price: $165k/ Real Estate $437k EN-822 SACRAMENTO Perio: $395k enjoy a fantasc lifestyle which can’t be beat! HG-827 SO. LAKE TAHOE: $790k CN-829 MILL VALLEY: This once-in-a-lifeme oppor- 1877sf w/4 ops + 1 add’l. $320k $310k IC-543 CENTRAL VALLEY Ortho: tunity awaits your drive, talent & skill! 1200sf w/ 3 EN-755 FOLSOM: A perfect locaon, envied by all! HG-851 SO LAKE TAHOE: $125k Fit ops + 1 add’l $310k Enjoy an amazing quality lifestyle in this thriving $425k JG-757 VISALIA Perio: DC-812 REDWOOD CITY Facility: Reasonable rent. city. 1200sf w/ 4 ops. $175k HN-618 SIERRA FOOTHILLS: 740 sf w/ 3 fully equipped ops $65k EN-791 SO. SACRAMENTO CO: Highly esteemed $65k Reduced Price: $350k DG-833 GILROY: Newly renovated, excellent visibility pracce to an adoring & appreciave paent HN-740 SHASTA CO: and easy accessibility lends to growth!! 1200 sf w/ 4 base! 1950sfw/ 5 ops. $450k $475k/ Better ops $235k Real Estate $350k

Price 800.641.4179 [email protected] “ASK THE BROKER” WWW.WESTERNPRACTICESALES.COM

Timothy Giroux, DDS Jon B. Noble, MBA Mona Chang, DDS John M. Cahill, MBA Edmond P. Cahill, JD Largest BAY AREA BAY AREA CONTINUED NORTHERN CALIFORNIA CONTINUED NORTHERN CALIFORNIA CONTINUED

AC-649 SAN FRANCISCO Facility: DG-844 SAN JOSE: EG-788 ROSEVILLE: Do not pass up on this remarkable opportunity! HN-773 SUTTER CREEK: Seller Movated! Locaon known for beauful scen- Broker in $120k 2700sf w/ 6 ops.. Reduce Price $275k/ Real Estate Available ery, excellent wine & rich history! 1536sf w/4 ops + 1 add’l!! $175k AC-782 SAN FRANCISCO: $195k EG-849 AUBURN: Imagine living in a peaceful, rural town that has an HN-816 CHESTER/ALMANOR AREA: The perfect place to work, live and $195k DG-854 SUNNYVALE ideal climate and “big city” amenies less than an hour away. 1400 sf w/ play! Do not hesitate, or this pracce will be gone! 1250 sf w/ 4ops. Northern AG-852 SAN FRANCISCO: 4 ops $350k Pracce $140k/ Real Estate TBD $375k $875k EN-800 SACRAMENTO: Awaing your talent and skill to take it to the next AN-752 SAN FRANCISCO Facility: 2 months Free Rent! level! 1200sf w/ 4 ops. Seller Movated! $150k CENTRAL VALLEY California EN-797 WOODLAND: Do not hesitate or this enviable opportunity will fulfill

$79k someone else’s dream! 2316sf w/ 6 ops. Pracce $575k/ Real Estate TBD IC-468 SAN JOAQUIN VALLEY: High-end restorave pracce! 6 ops in AN-864 SAN CARLOS Lease: DN-771 SOQUEL Facility: EN-831 SACRAMENTO: Locaon & pracce philosophy make this opportunity 2500+sf office. Call for Details! $425k Ideal for a special- “a cut above” others! ~1600sf w/4 ops. $775k IG-832 OAKHURST: Have you ever dreamed of living and praccing by beau- Over $34.5M ist! $6,500 mon $50k EN-836 CITRUS HEIGHTS: well-established, quality pracce comes loaded W/ ful mountain ranges, surrounded by nature? 2048sf w/3 ops + 1 add’l. BC-710 WALNUT CREEK: DN-774 FREMONT: 30+ years of goodwill. 1300sf w/3 ops + 2 add’l. $188k $235k/ Real Estate 375k $150k EN-824 SIERRA FOOTHILLS: well-known, well-loved, well-established prac- IN-764 STOCKTON: Well-established, fully computerized, paperless, digital- in 2017 sales BC-741 DANVILLE (FACILITY): $150k ce focused on quality dental care! 1000sf w. 4 ops. $625 ized pracce just waing for your talent & skill! 5,000sf w/10 ops $267.5k DG-785 SANTA CRUZ: EN-858 ORANGEVALE: Perfect for a second locaon or satellite situaon! JC-811 FRESNO COUNTY: Amazing Opportunity! Considerable Goodwill in

$150k Reduced 850 sf w/ 3 ops. Priced to Sell Only $70k! Community! 3,000 sf w/ 6 ops $350k BC-789 OAKLAND (Facility): Price: $190k FC-650 FORT BRAGG: Family-oriented pracce. 5 ops in 2000sf, 6 npts/ JC-823 LOS BANOS: Unique opportunity. Heavy emphasis on hygiene. Growth Extensive Buyer DG-842 FREMONT: mo $350k for the Pracce & $400k for the Real Estate potenal by increasing DDS days. 1000 sf w/ 3 ops $80k $135k $395k FG-841 ARCATA: Live and own a little slice of heaven, when you practice JG-778 FRESNO: What a steal. Consistent collecons over $600k with cash Database & BG-734 ANTIOCH: DG-857 SAN JOSE: here! 1114sf w/3 ops $275k/Real Estate TBD flow over $300k!! 1452 sf w/ 4 ops $275k FN-754 SO. HUMBOLDT: If you love the lure of sea air, a relaxed lifestyle JG-807 FRESNO: Reasonable Overhead, Stellar Reputaon, Excellent Loca- Unsurpassed $315k $595k & charm of coastal living, then look no further! 1500sf w/ 3 ops + 1 add’l. on! 1000 sf w/3 ops $158k BG 838 HAYWARD: DN-806 WATSONVILLE: Now $150k! Exposure allows FN-855 NO. HUMBOLDT: This long-established, quality 100% fee-for-service SOUTHERN CALIFORNIA $125k $495K/ Real Estate TBD pracce could be yours! 1600sf w/ 3ops + 1 add’l. $275k us to offer you BG-839 PINOLE: DN-845 FREMONT Facility: GN-746 YUBA CITY: State-of-the-Art Equipped! Includes the latest technol- KG-779 SAN CLEMENTE Ortho: Huge growth potential by expanding ogy in CBCT Imaging. Real Estate also available! 1600sf w/ 3 ops +1 add’l. relaxed work week! 2896 sf w/ 6 open bay chairs $325k/ Real Estate

$350k $100k Pracce $480k/ Real Estate TBD. Available! Call for Details!

CC-798 PETALUMA: GG-769 REDDING AREA: Offering a full spectrum of general denstry and NORTHERN CALIFORNIA total care! 2700sf w/ 6ops. Pracce $390k/ Real Estate $540k SPECIALTY PRACTICES GN-799 PARADISE: This remarkable opportunity is undeniably too good to Better CC-802 SANTA ROSA: EC-729 GREATER SACRAMENTO AREA: be true! 1800sf w/ 4 ops. Pracce $375k, Real Estate $325k AC-748 SAN FRANCISCO Perio: Reputable PERIO practice with million dollar $220k or $260k w/CT GN-808 CHICO: It just doesn’t get any beer than this! Hesitate & you Bay views! 980 sf w/ 3 ops $750k Scanner EN-664 SACRAMENTO Facility: might miss out! 2800sf w/ 5 ops. $395k/ Real Estate TBD BC-784 CENTRAL CONTRA COSTA CO Perio: Seasoned Staff. Office runs like Candidate CC-846 SAN RAFAEL: GN-853 REDDING: A great place to visit…and an even beer place to live, well-oiled machine! 3 ops $395k $295k Now Only: $30k work and play! 1450sf w/ 5 ops $595k BG-843 WALNUT CREEK Perio: Collecons over $1M! Desirable area w/20- CG-616 NAPA: EN-747 CITRUS HEIGHTS Facility: HG-732 GRASS VALLEY: Seller retiring. Well established practice. 1250sf w/ 3 30 new pts per month. Professional building on major thoroughfare $645k $425k ops. Real Estate also available. $205k EN-821 DAVIS Perio: Live, pracce & play here! It’ll be the BEST decision CG-859 SONOMA: $75k HG-815 SIERRA CO: Perfect location for outdoor enthusiast! 1000 sf w/ 3 ops you’ll ever make! 1700sf w/4 ops + 1 add’l. $385k Better EN-749 LINCOLN: Reduced Price: $165k/ Real Estate $437k EN-822 SACRAMENTO Perio: This pracce is known throughout Sacramento $395k HG-827 SO. LAKE TAHOE: Ski, live, play and pracce here where your for its stellar reputaon! 2200sf w/ 5 ops + 1add’l. $790k CN-829 MILL VALLEY: $320k lifestyle can’t be beat! 1200sf w/4 ops. $310k IC-543 CENTRAL VALLEY Ortho: 1650sf w/ 5 chairs in open bay & plumbed EN-755 FOLSOM: HG-851 SO LAKE TAHOE: Don’t wait another day to start living your dream of for 2 add’l. Strong referrals and PT base $125k Fit $310k a serene lifestyle! 2100 sf w/ 5 ops $425k JG-757 VISALIA Perio: Keep implants in house and imagine the growth DC-812 REDWOOD CITY Facility: $175k HN-618 SIERRA FOOTHILLS: Seller Retiring! Huge opportunity for growth by possibilities! 9 hygiene days per week! Rare Gem! 2,000 sf w/ 5 ops $65k EN-791 SO. SACRAMENTO CO: increasing office hours! 750sf w/ 2 ops $65k Reduced Price: $350k DG-833 GILROY: HN-740 SHASTA CO: Beauful mountain community, well-established $450k pracce, exceponal long-term staff. 2400+sf w/5 ops + 1 add’l. $475k/ Better $235k Real Estate $350k

Price 800.641.4179 [email protected] “ASK THE BROKER” can now be found at WWW.WESTERNPRACTICESALES.COM Tech Trends CDA JOURNAL, VOL 46, Nº8

A look into the latest dental and general technology on the market

Slack (Free or customized for up to $15 per user, per month) notifi cation system, coordinating offi ce managers between Good team communication improves outcomes in dental practices. multiple practices, discussing and viewing de-identifi ed patient From increased clinical productivity to greater patient satisfaction, cases between collaborating providers and consolidating the gains are appreciable, undeniable and coveted, especially practice performance metrics from many individuals. in this world of multilocation clinics, constant connectivity and With its free price point, customizability and cross-platform friendliness, interprofessional practice. The market is saturated with products that Slack is a powerful, low-cost tool to help larger dental practices facilitate teamwork, and into this crowded space steps Slack. increase coordination and communication between its team members. Slack is a cloud-based collaboration hub that aims to contain — Alexander Lee, DMD conversations and connect them to tools and services to aid productivity and contextualize communications. It claims to be the fastest-growing business application in history, boasting a client Drops (Free, PLANB LABS OU) list full of Fortune 500 companies and more than 8 million daily Drops is an app that combines visual learning with a small daily active users. Slack’s core functionalities are free for all, but certain habit to help people learn a new language through an entertaining customizations and functionalities need to be purchased per user, and engaging user interface. per month. This review will focus on Slack’s free-user access level, which is by far their most popular option. Drops asks the user to enter two simple things in order to begin: a language to learn and current skill level, which is either beginner or Of important note for health care providers, the company’s advanced. Notifi cations can be enabled to remind users to spend terms of service state that for their free-user access level, “Slack time with the app daily. Once the learning session begins, a fi ve- is not a ‘Business Associate’ as defi ned in the Health Insurance minute countdown timer appears on the upper right corner of the Portability and Accountability Act and related amendments and screen. Learning activities consist of beautiful illustrations and words regulations as updated or replaced (‘HIPAA’), and that the both in the new language and an adaptive Romanized phonetic services are not HIPAA compliant.” Prior to using the application version. Users interact with all activities by swiping drops, which are for communicating protected health information, providers should simply visible content containers. For example, on a specifi c activity, check their own policies and whether custom arrangements were users can swipe down on a vocabulary word drop to choose to learn made with Slack to ensure HIPAA compliance. it or swipe up to skip it. Other activity examples include matching Slack supports a wide range of platforms, including but not word drops to picture drops and dragging letter drops to form a limited to iOS, Windows, Android and macOS. After logging phonetic word for a picture. All activities contain spoken audio in, users are met with a chatroom-like screen. Users can group feedback and have visual tutorials during their fi rst-time use. Once themselves (or be grouped by an administrator) into separate the fi ve-minute countdown clock has expired, users get a summary of channels so that conversations remain pertinent to their tasks. their progress and cannot start another activity until a specifi c time Switching between channels is easy and instantaneous; new period has expired. Users can get more time by purchasing various messages are consolidated into one space and linked to their subscriptions available that unlock more content and languages. respective channels for easy reference even when viewing on Addictive and fun to use, Drops shows how easy it can be to learn a a mobile device. Slack integrates collaboration tools like to-do new language, which is undoubtedly useful both in the dental offi ce lists, forms and information feeds that can be customized by and while traveling abroad. Utilizing a visual interface that does not users and controlled to where the information is disseminated. require much eff ort to understand, everyone can indeed aff ord fi ve Administrators can search through this archive, monitor task minutes a day to learn something new. progress and dole out or recategorize information. Common current uses for Slack in dental practices include a patient arrival — Hubert Chan, DDS

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