Oral DiseasesVolume 24, Issue 1-2 p. 277-279 PROF SCULLY MEMORIAL ISSUE The importance of studying oral and craniofacial manifestations of Mendelian phenotypes JC Atkinson, Corresponding Author JC Atkinson jatkinso@mail.nih.gov orcid.org/0000-0001-9895-0298 Division of Extramural Research, National Institutes of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD USA Correspondence Jane C. Atkinson, Division of Extramural Research, National Institutes of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA. Email: jatkinso@mail.nih.govSearch for more papers by this author JC Atkinson, Corresponding Author JC Atkinson jatkinso@mail.nih.gov orcid.org/0000-0001-9895-0298 Division of Extramural Research, National Institutes of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD USA Correspondence Jane C. Atkinson, Division of Extramural Research, National Institutes of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA. Email: jatkinso@mail.nih.govSearch for more papers by this author First published: 26 February 2018 https://doi.org/10.1111/odi.12750Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume24, Issue1-2March 2018Pages 277-279 RelatedInformation

Although xerostomia is a commonly reported complaint in patients with chronic graft-versus-host disease (cGVHD), criteria for evaluating the prevalence and characteristics of salivary gland involvement have not been well defined in this patient population. Previous studies also have made no distinction between salivary and mucosal oral cGVHD. We systematically evaluated signs and symptoms of sicca in a large cohort of patients with cGVHD (n = 101) using instruments widely used to study Sjogren's syndrome. Xerostomia was reported by 77% of the patients and was associated with xerophthalmia in all but I case. The salivary flow rate was <= 0.2 mL/min in 27%, and <= 0.1 mL/min in 16%. Histopathological changes, consisting of mononuclear infiltration and/or fibrosis/atrophy, were present in all patients with salivary dysfunction. Importantly, there was no correlation of salivary and oral mucosal involvement in cGVHD. Patients with cGVHD-associated salivary gland involvement had diminished oral cavity-specific quality of life and lower body mass index. Salivary gland involvement is a common and clinically distinct manifestation of cGVHD. Formal evaluation of salivary function using standardized criteria is needed, and this could be incorporated as an outcome measure in clinical trials of cGVHD. Biol Blood Marrow Transplant 16: 1362-1369 (2010) Published by Elsevier Inc. on behalf of American Society for Blood and Marrow Transplantation

In the above mentioned article, the authors have noted an error in the abstract and Results sections. The original text of the abstract reads "Xerostomia was reported by 77% of the patients and was associated with xerophthalmia in all but 1 case." The correct text should read "Xerostomia was reported in 60 (77%) patients reporting ocular and 52 (67%) patients reporting oral complaints."

The objective of this short review is to help researchers improve the designs of their clinical studies. Also included is a discussion of the level of evidence provided by the various clinical research study designs.

BACKGROUND:The Hispanic and Latino population is projected to increase from 16.7 percent to 30.0 percent by 2050. Previous U.S. national surveys had minimal representation of Hispanic and Latino participants other than Mexicans, despite evidence suggesting that Hispanic or Latino country of origin and degree of acculturation influence health outcomes in this population. In this article, the authors describe the prevalence and mean number of cavitated, decayed and filled surfaces, missing teeth and edentulism among Hispanics and Latinos of different national origins.METHODS:Investigators in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL)-a multicenter epidemiologic study funded by the National Heart, Lung, and Blood Institute with funds transferred from six other institutes, including the National Institute of Dental and Craniofacial Research-conducted in-person examinations and interviews with more than 16,000 participants aged 18 to 74 years in four U.S. cities between March 2008 and June 2011. The investigators identified missing, filled and decayed teeth according to a modified version of methods used in the National Health and Nutrition Examination Survey. The authors computed prevalence estimates (weighted percentages), weighted means and standard errors for measures.RESULTS:The prevalence of decayed surfaces ranged from 20.2 percent to 35.5 percent, depending on Hispanic or Latino background, whereas the prevalence of decayed and filled surfaces ranged from 82.7 percent to 87.0 percent, indicating substantial amounts of dental treatment. The prevalence of missing teeth ranged from 49.8 percent to 63.8 percent and differed according to Hispanic or Latino background. Significant differences in the mean number of decayed surfaces, decayed or filled surfaces and missing teeth according to Hispanic and Latino background existed within each of the age groups and between women and men.CONCLUSIONS:Oral health status differs according to Hispanic or Latino background, even with adjustment for age, sex and other characteristics.PRACTICAL IMPLICATIONS:These data indicate that Hispanics and Latinos in the United States receive restorative dental treatment and that practitioners should consider the association between Hispanic or Latino origin and oral health status. This could mean that dental practices in areas dominated by patients from a single Hispanic or Latino background can anticipate a practice based on a specific pattern of treatment needs.

Abstract Oral health clinical trials have mainly focused on the diseases of dental caries and periodontal disease, but a limited number have involved other oral diseases and conditions. These include chronic facial pain, particularly associated with the temporomandibular joint, acute pain after extraction of third molars (wisdom teeth), xerostomia (dry mouth), and various oral mucosal diseases. This article focuses on phase III oral health clinical trials in terms of design and analyses, regulatory and management issues, and challenges of conducting trials involving specific oral diseases.

A 16-year-old girl with juvenile dermatomyositis reported having had bleeding gums that had not responded to traditional dental treatment. Close examination of the mouth revealed markedly dilated capillaries in the attached gingiva, with bushy loop formations that spread over the lower teeth.

Irradiation damage to salivary glands is a common iatrogenic consequence of treatment for head and neck cancers. The subsequent lack of saliva production leads to many functional and quality-of-life problems for affected patients and there is no effective conventional therapy. To address this problem, we developed an in vivo gene therapy strategy involving viral vector-mediated transfer of the aquaporin-1 cDNA to irradiation-damaged glands and successfully tested it in two pre-clinical models (irradiated rats and miniature pigs), as well as demonstrated its safety in a large toxicology and biodistribution study. Thereafter, a clinical research protocol was developed that has received approval from all required authorities in the United States. Patients are currently being enrolled in this study.

OBJECTIVEGraft-versus-host disease (GVHD) is a leading cause of morbidity and mortality in patients receiving hematopoietic cell transplant. It is estimated that 40-70% of engrafted patients surviving the initial transplant eventually develop chronic GVHD (cGVHD), which can persist for months to years and require long-term management from multiple disciplines. This review describes the oral component of this transplant complication.DESIGNThe search related to GVHD patho-biology, salivary gland disease after hematopoietic cell transplant and treatments for oral GVHD encompassed literature from 1966 through 2008. Searches were limited to the MEDLINE/PubMed database and English language literature in peer-reviewed journals.RESULTSOur understanding of the patho-biology of oral cGVHD is based on studies of other affected tissues. It is difficult to determine the prevalence and incidence of salivary gland disease after transplant because there is no universally accepted case definition. In general, clinical trials for treatment of oral cGVHD have been too small to make strong recommendations for use in clinical practice.CONCLUSIONSLarger well-designed clinical studies are needed to understand the patho-biology of oral cGVHD and determine best treatments for this disease.

Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome that is characterized by lacey reticular hyperpigmentation of the skin, dystrophic nails, mucous membrane leukoplakia and pancytopenia. Diagnosis may be delayed until clinical signs are apparent. Severe pancytopenia frequently causes early mortality of DC patients, who have an increased risk of developing oropharyngeal squamous cell carcinoma. Several case reports have described oral changes in DC, which include oral leukoplakia, increased dental caries, hypodontia, thin enamel structure, aggressive periodontitis, intraoral brown pigmentation, tooth loss, taurodontism and blunted roots. We determined the prevalence of these previously reported findings in a cohort of 17 patients with DC and 23 family members. The most common oral changes in DC patients were oral leukoplakia (65% of the entire DC population), decreased root/crown ratio (75% with sufficient tooth development) and mild taurodontism (57% with sufficient tooth development). From the clinical perspective, a diagnosis of DC or other inherited bone marrow failure syndrome should be considered in young persons with oral leukoplakia, particularly those with no history of smoking. Multiple permanent teeth with decreased root/crown ratios further suggest DC.

Periodontology 2000Volume 45, Issue 1 p. 95-112 Mendelian forms of periodontitis Thomas C. Hart, Thomas C. HartSearch for more papers by this authorJane C. Atkinson, Jane C. AtkinsonSearch for more papers by this author Thomas C. Hart, Thomas C. HartSearch for more papers by this authorJane C. Atkinson, Jane C. AtkinsonSearch for more papers by this author First published: 10 September 2007 https://doi.org/10.1111/j.1600-0757.2007.00233.xCitations: 51Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume45, Issue1October 2007Pages 95-112 RelatedInformation

Objective. Allogeneic hematopoietic stem cell transplantation (allo-HCT) is frequently complicated by severe infections and graft-vs-host disease (GVHD). Saliva contains many components of adaptive and innate immune response crucial for local host defenses. Changes in salivary constituents could reflect systemic processes such as immune reconstitution and development of GVHD that occur posttransplant. This study was an initial evaluation of salivary protein changes that occur after allo-HCT.Patients and Methods. Serially collected saliva samples from 41 patients undergoing allo-HCT were evaluated. Changes in salivary proteome were initially examined by SELDI-TOF mass spectrometry. Individual protein changes were identified by 2-dimensional differential in-gel electrophoresis (2D-DIGE) with subsequent MS/MS sequencing and ELISA.Results. Significant increases and decreases in multiple salivary proteins that lasted at least 2 months posttransplant were detected by SELDI-TOF mass spectrometry. Lactoferrin and secretory leukocyte protease inhibitor demonstrated elevations 1 month post-HCT that persisted at least 6 months. Secretory IgA (sIgA) levels were decreased 1 month posttransplant, with recovery at approximately 6 months. Levels of salivary beta(2)-microglobulin were elevated at 6 months and correlated with sIgA levels.Conclusion. Allo-HCT is associated with long-term changes in several salivary proteins important for innate immune responses. These results support further studies on the association of salivary proteins with posttransplant complications including infections and GVHD. (c) 2007 International Society for Experimental Hematology. Published by Elsevier Inc.

HIV/AIDS is currently the leading cause of death in Africa and the fourth leading cause of death worldwide. This systematic review of the literature was conducted to evaluate the evidence for treatment of the most common oral lesions associated with HIV: oral candidiasis with or without oropharyngeal involvement (OPC), oral hairy leukoplakia (OHL), recurrent aphthous-like ulcerations (RAU), oral Kaposi's sarcoma (OKS), orolabial herpes simplex infection (HSV), oral herpes zoster infection (VZV), intraoral or perioral warts (HPV), and HIV-associated periodontal diseases. Treatment of HIV-associated salivary gland disease is addressed in a different section of this World Workshop. We found the largest body of evidence for treatment of OPC in HIV patients. Future trials will be needed to test drugs currently in development for treatment of Candida strains that are resistant to existing therapies. There were no double blind, placebo-controlled randomized clinical trials (RCT) for topical treatment of OHL, and only one RCT for systemic treatment of the lesion with desciclovir. Systemic thalidomide was the only drug tested in RCT for treatment or prevention of RAU. Only 1 double-blind RCT comparing vinblastine and sodium tetradecyl sulfate was identified for localized treatment of OKS. Three drugs (famciclovir, acyclovir, and valaciclovir) were shown to be effective in randomized, double-blind trials for treatment or suppression of mucocutaneous HSV lesions in HIV patients. In all 3 trials, the effects of these medications on orolabial HSV lesions were not reported separately. There were no double-blind, placebo-controlled RCT testing topical treatments for orolabial HSV lesions in HIV patients. No trials testing treatments of oral VZV were identified. There were no double-blind, placebo-controlled RCT for treatment of HIV-associated intraoral or perioral warts or periodontal diseases. In conclusion, there is a need for well-designed RCTs to assess the safety and efficacy of topical and systemic treatments of most oral mucosal and perioral lesions in HIV patients. There is also a need to develop newer drugs for treatment of resistant fungal and viral microorganisms. Finally, standardized outcome measures should be developed for future clinical trials to allow comparisons of studies using different populations.

Many children with HIV have oral manifestations of the infection (Table 21.1), including some that are part of the 1994 CDC classification system [1]. Since the introduction of antiretroviral therapy and highly active antiretroviral therapy (ART and HAART), the prevalence of these oral manifestations has decreased. However, in many countries where therapy is less than ideal, such as Romania, Brazil, and Mexico, HIV-associated oral lesions are more common, with prevolenic ranging from 55%–61% [2–4]. Their presence can still be used as markers for progression of disease. Referral to a dentist before 1 year of age is recommended for all children, but this is especially important for the HIV-infected child. Careful examination of the soft tissues and teeth is essential.

This consensus document provides an update for pathologists and clinicians about the interpretation of biopsy results and use of this information in the management of hematopoietic cell transplantation patients. Optimal sampling and tissue preparation are discussed. Minimal criteria for the diagnosis of graft-versus-host disease (GVHD) are proposed, together with specific requirements for the diagnosis of chronic GVHD. Four final diagnostic categories (no GVHD, possible GVHD, consistent with GVHD, and definite GVHD) reflect the integration of histopathology with clinical, laboratory, and radiographic information. Finally, the Working Group developed a set of worksheets to facilitate communication of clinical information to the interpreting pathologist and to aid in clinicopathologic correlation studies. Forms are available at . The recommendations of the Working Group represent a consensus opinion supplemented by evaluation of available peer-reviewed literature. Consensus recommendations and suggested data-capture forms should be validated in prospective clinicopathologic studies.

The treatment of most patients with head and neck cancer includes ionizing radiation (IR). Salivary glands in the IR field suffer significant and irreversible damage, leading to considerable morbidity. Previously, we reported that adenoviral (Ad)-mediated transfer of the human aquaporin-1 (hAQP1) cDNA to rat [C. Delporte, B.C. O'Connell, X. He, H.E. Lancaster, A.C. O'Connell, P. Agre, B.J. Baum, Increased fluid secretion after adenoviral-mediated transfer of the aquaporin-1 cDNA to irradiated rat salivary glands. Proc. Natl. Acad. Sci. U S A. 94 (1997) 3268-3273] and miniature pig [Z. Shan, J. Li, C. Zheng, X. Liu, Z. Fan, C. Zhang, C.M. Goldsmith, R.B. Wellner, B.J Baum, S. Wang. Increased fluid secretion after adenoviral-mediated transfer of the human aquaporin-1 cDNA to irradiated miniature pig parotid glands. Mol. Ther. 11 (2005) 444-451] salivary glands ∼16 weeks following IR resulted in a dose-dependent increase in salivary flow to ≥80% control levels on day 3. A control Ad vector was without any significant effect on salivary flow. Additionally, after administration of Ad vectors to salivary glands, no significant lasting effects were observed in multiple measured clinical chemistry and hematology values. Taken together, the findings show that localized delivery of AdhAQP1 to IR-damaged salivary glands is useful in transiently increasing salivary secretion in both small and large animal models, without significant general adverse events. Based on these results, we are developing a clinical trial to test if the hAQP1 cDNA transfer strategy will be clinically effective in restoring salivary flow in patients with IR-induced parotid hypofunction.

The use of hematopoetic stem cell transplantation (HSCT) has greatly expanded in the recent years for many neoplastic and hematological disorders. Chronic graft versus host disease (cGVHD) is a major complication of allogeneic HSCT and a major cause of morbidity and mortality. Oral mucosal involvement is frequent in cGVHD and contributes significantly to the overall burden of the condition. Oral medicine professionals should be familiar with various treatment options for oral cGVHD. This review discusses treatment modalities available for the management of oral mucosal manifestations of cGVHD. Available evidence for efficacy and safety of various systemic and topical agents, including corticosteroids, calcineurin antagonists, mycophenolate mofetil, and extracorporeal photopheresis, is reviewed.

OBJECTIVES To identify the most significant salivary biomarkers in Sjögren's syndrome (SS) using proteomic methods. METHODS Parotid saliva from 20 non-SS subjects and 41 primary SS patients was analysed. Protein expression profiles for each sample were generated by surface-enhanced laser desorption/ionization time-of-flight-mass spectrometry (SELDI-TOF-MS). Mean peak intensities of SS patients and non-SS subjects were compared by univariate analyses. Samples pooled by diagnosis (SS and non-SS) and labelled with different Cy dyes were compared by two-dimensional difference gel electrophoresis (2D-DIGE). Two protein levels that were most significantly different by SELDI-TOF-MS and 2D-DIGE were validated by enzyme-linked immunosorbent assay in individual samples. RESULTS SELDI-TOF-MS of 10-200 kDa peaks revealed eight peaks with >2-fold changes in the SS group that differed from non-SS at P < 0.005. Peaks of 11.8, 12.0, 14.3, 80.6 and 83.7 kDa were increased, while 17.3, 25.4, and 35.4 kDa peaks were decreased in SS samples. 2D-DIGE identified significant increases of beta-2-microglobulin, lactoferrin, immunoglobulin (Ig) kappa light chain, polymeric Ig receptor, lysozyme C and cystatin C in all stages of SS. Two presumed proline-rich proteins, amylase and carbonic anhydrase VI, were reduced in the patient group. Three of these ten biomarkers have not been associated previously with SS. CONCLUSIONS The salivary proteomic profile of SS is a mixture of increased inflammatory proteins and decreased acinar proteins when compared with non-SS. Future studies will test the ability of these biomarker levels, alone and in combination, to diagnose the salivary component of SS.

The treatment of most patients with head and neck cancer includes ionizing radiation (IR). Salivary glands in the IR field suffer significant and irreversible damage, leading to considerable morbidity. Previously, we reported that adenoviral (Ad)-mediated transfer of the human aquaporin-1 (hAQP1) cDNA to rat [C. Delporte, B.C. O'Connell, X. He, H.E. Lancaster, A.C. O'Connell, P. Agre, B.J. Baum, Increased fluid secretion after adenoviral-mediated transfer of the aquaporin-1 cDNA to irradiated rat salivary glands. Proc. Natl. Acad. Sci. U S A. 94 (1997) 3268-3273] and miniature pig [Z. Shan, J. Li, C. Zheng, X. Liu, Z. Fan, C. Zhang, C.M. Goldsmith, R.B. Wellner, B.J Baum, S. Wang. Increased fluid secretion after adenoviral-mediated transfer of the human aquaporin-1 cDNA to irradiated miniature pig parotid glands. Mol. Ther. 11 (2005) 444-451] salivary glands approximately 16 weeks following IR resulted in a dose-dependent increase in salivary flow to > or =80% control levels on day 3. A control Ad vector was without any significant effect on salivary flow. Additionally, after administration of Ad vectors to salivary glands, no significant lasting effects were observed in multiple measured clinical chemistry and hematology values. Taken together, the findings show that localized delivery of AdhAQP1 to IR-damaged salivary glands is useful in transiently increasing salivary secretion in both small and large animal models, without significant general adverse events. Based on these results, we are developing a clinical trial to test if the hAQP1 cDNA transfer strategy will be clinically effective in restoring salivary flow in patients with IR-induced parotid hypofunction.