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Purpose: Bisphosphonate-associated osteonecrosis (BON) is a recently recognized oral complication of bisphosphonate (BP) therapy. Currently, research into the pathogenesis of BON has been hampered by being deficient in studies capable of measuring the level of BP in saliva or at the bone-soft tissue interface. The objective of this current study was to develop a novel bioassay model representative of the oral levels of BPs in patients presenting with or at risk for BON.Methods: Zoledronic acid (ZA) injectable was used to develop standardized MTS cell proliferation assay curves at concentrations of 0-10 microM, which were used either in a dilution in normal media, mimicking BP freed from bone or used to "spike" saliva individuals not taking BPs and mimicking BP levels being excreted. This bioassay was then used to estimate BP levels from samples of saliva and bone ex vivo from patients with and without BON.Results: Saliva and bone from patients with existing BON showed levels of BP ranging from 0.4 to 4.6 microM, while patients receiving IV infusion of BP and naïve to BON showed levels in saliva ranging from 0.4 to 5 microM. All control specimens and patients naïve to BP showed levels at 0 microM.Conclusions: Given the fact that BPs are poor candidates for detection using standard methods (HPLC), this bioassay provides us with the ability to estimate clinically relevant concentrations of BP capable of producing apoptosis and the inhibition cell proliferation of oral mucosal cells based on previous studies. Subsequently, apoptosis and the inhibition of proliferation could lead to BON, secondary to the exposure of the bone in the unique microenvironment of the oral cavity. [ABSTRACT FROM AUTHOR]

AIM: The anti-viral efficacy of oral antimicrobial rinses has not been adequately studied in terms of potential clinical significance. As a follow-up to an in vitro study on the effect of oral antiseptics on Herpes simplex virus, Type 1, this study was undertaken to evaluate the in vivo effect of an essential oil containing oral antiseptic on the reduction of viral titer in saliva during active viral infection. METHOD: Patients were recruited and evaluated in a single visit protocol at the onset of a perioral outbreak, consistent historically and clinically with recurrent Herpes labialis. Direct immunofluorescence of cytological smears of the lesions/oral fluids was used to confirm Herpes simplex virus types I or II. Patients were randomly assigned to one of two treatment groups: (1) active ingredient and (2) sterile water control. The viral lesion was evaluated as to clinical stage according to standard protocol. Salivary fluid samples were taken: (1) at baseline; (2) immediately following a 30 s rinse; (3) 30 min. after the 30 s rinse; and (4) on the repeat trial, also at 60 min. after the 30 s rinse. All samples were evaluated for viral titer and results compared. RESULTS: In Trial 1, the sample population consisted of 19 males and 21 females with an average age of 29.2 and in Trial 2, 21 males, 19 females with an average age of 28. In both Trials 1 and 2, recoverable infectious virions were reduced to zero after a 30 s experimental rinse; whereas, the control rinse resulted in a non-significant (p>0.05) reduction. The experimental group also demonstrated a continued significant (p<0.05) reduction 30 min. post rinse when compared with baseline while the control group returned to baseline levels. In Trial 2, the 60 min. post rinse follow-up demonstrated a 1-2 log residual reduction from baseline in the experimental group; however, this was not significant. CONCLUSIONS: There is clinical efficacy in utilizing an oral rinse with the antimicrobial agent Listerine Antiseptic in reducing the presence of viral contamination in oral fluids for at least 30 min. after oral rinse. The risk of viral cross contamination generated from these oral fluids in person to person contact or during dental treatment may be reduced. [ABSTRACT FROM AUTHOR]

The oral cavity remains an underappreciated site for SARS-CoV-2 infection despite the myriad of oral conditions in COVID-19 patients. Recently, SARS-CoV-2 was shown to replicate in the salivary gland cells causing tissue inflammation. Given the established association between inflammation and microbiome disruption, we comparatively profiled oral microbial differences at a metagenomic level in a cohort of hospitalized COVID-19 patients and matched healthy controls. Specifically, we aimed to evaluate colonization by the opportunistic fungal pathogen Candida albicans , the etiologic agent of oral candidiasis. Comprehensive shotgun metagenomic analysis indicated that, overall, COVID-19 patients exhibited significantly reduced bacterial and viral diversity/richness; we identified 12 differentially abundant bacterial species to be negatively associated with COVID-19, and the functional pathways of certain bacteria to be highly associated with COVID-19 status. Strikingly, C. albicans was recovered from approximately half of the COVID-19 subjects but not from any of the healthy controls. The prevalence of Candida is likely linked to immune hypo-dysregulation caused by COVID-19 favoring Candida proliferation, warranting investigations into the interplay between Candida and SARS-CoV2 and potential therapeutic approaches directed toward oral candidiasis. Collectively, our findings prompt a reassessment of oral opportunistic infection risks during COVID-19 disease and their potential long-term impacts on oral health.

Saliva contains antimicrobial peptides considered integral components of host innate immunity, and crucial for protection against colonizing microbial species. Most notable is histatin-5 which is exclusively produced in salivary glands with uniquely potent antifungal activity against the opportunistic pathogen Candida albicans . Recently, SARS-CoV-2 was shown to replicate in salivary gland acinar cells eliciting local immune cell activation. In this study, we performed mechanistic and clinical studies to investigate the implications of SARS-CoV-2 infection on salivary histatin-5 production and Candida colonization. Bulk RNA-sequencing of parotid salivary glands from COVID-19 autopsies demonstrated statistically significant decreased expression of histatin genes. In situ hybridization, coupled with immunofluorescence for co-localization of SARS-CoV-2 spike and histatin in salivary gland cells, showed that histatin was absent or minimally present in acinar cells with replicating viruses. To investigate the clinical implications of these findings, salivary histatin-5 levels and oral Candida burden in saliva samples from three independent cohorts of mild and severe COVID-19 patients and matched healthy controls were evaluated. Results revealed significantly reduced histatin-5 in SARS-CoV-2 infected subjects, concomitant with enhanced prevalence of C. albicans . Analysis of prospectively recovered samples indicated that the decrease in histatin-5 is likely reversible in mild-moderate disease as concentrations tended to increase during the post-acute phase. Importantly, salivary cytokine profiling demonstrated correlations between activation of the Th17 inflammatory pathway, changes in histatin-5 concentrations, and subsequent clearance of C. albicans in a heavily colonized subject. The importance of salivary histatin-5 in controlling the proliferation of C. albicans was demonstrated using an ex vivo assay where C. albicans was able to proliferate in COVID-19 saliva with low histatin-5, but not with high histatin-5. Taken together, the findings from this study provide direct evidence implicating SARS-CoV-2 infection of salivary glands with compromised oral innate immunity, and potential predisposition to oral candidiasis.

Introduction: Due to the radiation-sparing effects on salivary gland acini, changes in the composition of the oral microbiome may be a driver for improved outcomes in patients receiving proton radiation, with potentially worse outcomes in patients exposed to photon radiation therapy. To date, a head-to-head comparison of oral microbiome changes at a metagenomic level with longitudinal sampling has yet to be performed in these patient cohorts., Methods and Materials: To comparatively analyze oral microbiome shifts during head and neck radiation therapy, a prospective pilot cohort study was performed at the Maryland Proton Treatment Center and the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center. A longitudinal metagenomic comparative analysis of oral microbiome shifts was performed at three time points (pre-radiation, during radiation, and immediately post-radiation). Head and neck cancer patients receiving proton radiation ( n = 4) were compared to photon radiation ( n = 4). Additional control groups included healthy age- and sex-matched controls ( n = 5), head and neck cancer patients who never received radiation therapy ( n = 8), and patients with oral inflammatory disease ( n = 3)., Results: Photon therapy patients presented with lower microbial alpha diversity at all timepoints, and there was a trend towards reduced species richness as compared with proton therapy. Healthy controls and proton patients exhibited overall higher and similar diversity. A more dysbiotic state was observed in patients receiving photon therapy as compared to proton therapy, in which oral microbial homeostasis was maintained. Mucositis was observed in 3/4 photon patients and was not observed in any proton patients during radiation therapy. The bacterial de novo pyrimidine biosynthesis pathway and the nitrate reduction V pathway were comparatively higher following photon exposure. These functional changes in bacterial metabolism may suggest that photon exposure produces a more permissive environment for the proliferation of pathogenic bacteria., Conclusion: Oral microbiome dysbiosis in patients receiving photon radiation may be associated with increased mucositis occurrence. Proton radiation therapy for head and neck cancer demonstrates a safer side effect profile in terms of oral complications, oral microbiome dysbiosis, and functional metabolic status., Competing Interests: The author(s) declare(s) that there is no conflict of interest., (Copyright: © 2024 Meiller T, et al.)

Background: The social context of burning mouth syndrome (BMS) has received little attention in the scientific literature. However, social psychological theory and insights from those with lived experiences suggest that people living with BMS experience compounding effects of stigma related to their pain, diagnosis (or lack thereof), and intersectional identities., Objective: Our aim is to provide initial evidence and to motivate new directions for research on BMS. Here, we present the results of an exploratory pilot study (n = 16) of women living with BMS in the United States., Methods: Participants completed self-report measures of stigma, discrimination, and pain, as well as laboratory assessments of pain through quantitative sensory testing., Results: Results indicate a high prevalence of internalized BMS stigma, experience of BMS-related discrimination from clinicians, and gender stigma consciousness in this population. Moreover, results provide initial evidence that these experiences are related to pain outcomes. The most robust pattern of findings is that internalized BMS stigma was related to greater clinical pain severity, interference, intensity, and unpleasantness., Conclusion: Given the prevalence and pain-relevance of intersectional stigma and discrimination identified in this pilot study, lived experience and social context should be incorporated into future research on BMS., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The oral cavity remains an underappreciated site for SARS-CoV-2 infection despite the myriad oral conditions observed in COVID-19 patients. Recently, replicating SARS-CoV-2 was found inside salivary epithelial cells resulting in inflammation and atrophy of salivary glands. Saliva possesses healing properties crucial for maintaining the health of the oral mucosa. Specifically, salivary antimicrobial peptides, most notable, histatin-5 exclusively produced in salivary glands, plays a vital role in innate immunity against colonizing microbial species. The demonstration of SARS-CoV-2 destruction of gland tissue where histatin-5 is produced strongly indicate that histatin-5 production is compromised due to COVID-19. Here we present a case of a patient presenting with unexplained chronic oral dysesthesia and dysgeusia post-recovery from COVID-19. To explore potential physiological mechanisms behind the symptoms, we comparatively analyzed saliva samples from the patient and matched healthy subject for histatin-5 and key cytokines. Findings demonstrated significantly reduced histatin-5 levels in patient's saliva and activation of the Th17 inflammatory pathway. As histatin-5 exhibits potent activity against the opportunistic oral pathogen Candida albicans , we evaluated saliva potency against C. albicans ex vivo . Compared to control, patient saliva exhibited significantly reduced anti-candidal efficacy. Although speculative, based on history and salivary analysis we hypothesize that salivary histatin-5 production may be compromised due to SARS-CoV-2 mediated salivary gland destruction. With the current lack of emphasis on implications of COVID-19 on oral health, this report may provide lacking mechanistic insights that may lead to reassessment of risks for oral opportunistic infections and mucosal inflammatory processes in acutely-ill and recovered COVID-19 patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Alfaifi, Sultan, Montelongo-Jauregui, Meiller and Jabra-Rizk.)

Burning mouth syndrome (BMS) is a chronic orofacial pain condition that mainly affects postmenopausal women. BMS type I patients report little to no spontaneous pain in the morning and increases in pain through the day, peaking in the afternoon. Quantitative sensory testing (QST) findings from BMS type 1 patients are inconsistent as they fail to capture this temporal variation. We examined how QST in BMS type 1 ( n = 18) compared to healthy participants ( n = 33) was affected by time of day. QST of the face and forearm included warmth detection threshold (WDT), cold detection threshold (CDT), and heat pain thresholds (HPT), ratings of suprathreshold heat, and pressure pain thresholds (PPT), and was performed twice: once in the morning and once in the afternoon. Compared to healthy participants, BMS patients had higher pain sensitivity to phasic heat stimuli at most temperatures (35°C U = 126.5, p = 0.0006, 39°C U = 186.5, p = 0.0386, 41°C U = 187.5, p = 0.0412, 43°C U = 171, p = 0.0167, 45°C U = 168.5, p = 0.0146) on the forearm, but no differences in pain thresholds (HPT and PPT) regardless of time of day or body area tested. BMS patients had higher WDT (U = 123, p = 0.0172), and lower CDT (U = 98, p = 0.0021) of the forearm and lower WDT of the face (U = 55, p = 0.0494). The differences in forearm WDT (U = 71.5, p = 0.0113) and CDT (U = 70, p = 0.0096) were most pronounced in the morning. In summary, BMS type I patients had increased pain sensitivity on the forearm, but no differences in pain thresholds on the face or forearm. Patients also showed altered thermal sensitivity, which depended on body area tested (heightened in the orofacial region but blunted on the forearm), and was more pronounced in the morning plausibly due to hypervigilance., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Payano Sosa, Da Silva, Burrowes, Yoo, Keaser, Meiller and Seminowicz.)

Purpose: Define incidence and risk factors of osteonecrosis of the jaw (ONJ) and explore oral microbial signatures and host immune response as reflected by cytokine changes in saliva and serum in multiple myeloma (MM) patients on bisphosphate (BP) therapy., Patients and Methods: A single center observational prospective study of MM patients (n = 110) on >2 years of BP, none had ONJ at enrollment. Patients were followed every 3 months for 18 months with clinical/dental examination and serial measurements of inflammatory cytokines, bone turnover markers, and angiogenic growth factors. Oral microbiota was characterized by sequencing of 16S rRNA gene from saliva., Results: Over the study period 14 patients (13%) developed BRONJ, at a median of 5.7 years (95% CI: 1.9-12.0) from MM diagnosis. Chronic periodontal disease was the main clinically observed risk factor. Oral microbial profiling revealed lower bacterial richness/diversity in BRONJ. Streptococcus intermedius , S. mutans , and S. perioris were abundant in controls; S. sonstellatus and S anginosus were prevalent in BRONJ. In the saliva, at baseline patients who developed BRONJ had higher levels of MIP-1β; TNF-α and IL-6 compared to those without BRONJ, cytokine profile consistent with M-1 macrophage activation. In the serum, patients with BRONJ have significantly lower levels of TGF beta and VEGF over the study period., Conclusion: Periodontal disease associated with low microbial diversity and predominance of invasive species with a proinflammatory cytokine profile leading to tissue damage and alteration of immunity seems to be the main culprit in pathogenesis of BRONJ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Badros, Meddeb, Weikel, Philip, Milliron, Lapidus, Hester, Goloubeva, Meiller and Mongodin.)

Background: Patients with metastatic breast cancer may develop oral morbidities that result from therapeutic interventions. Mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis (mIAS) is a common adverse event (AE), secondary to mTOR inhibitor therapy, that can have a negative impact on treatment adherence, quality of life, and health care costs. A multidisciplinary team approach is important to minimize mIAS and to maximize treatment benefits to patients with breast cancer. In this review, we discuss the pathophysiology, diagnosis, and natural history of mIAS. Current and new management strategies for the prevention and treatment of mIAS are described in the context of fostering a coordinated team care approach to optimizing patient care., Types of Studies Reviewed: The authors conducted a PubMed search from 2007 through 2017 using the terms "stomatitis," "mIAS," "everolimus," "mTOR," "metastatic breast cancer," and "oral care." They selected articles published in peer-reviewed journals that reported controlled trials and evidence-based guidelines., Results: mIAS can be distinguished from mucositis caused by cytotoxic chemotherapy or radiotherapy on the basis of cause, clinical presentation, and treatment paradigms. Specific preventive and therapeutic management strategies can be implemented across the continuum of patient oral health care., Practical Implications: Oral health care providers are on the frontline of oral health care for patients with metastatic breast cancer and are uniquely positioned to provide patient education, advocate accurate reporting of mIAS, and support early identification, monitoring, and prompt intervention to mitigate the severity and duration of this manageable, potentially dose-limiting AE., (Copyright © 2018 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Background: Stomatitis is a class effect associated with the inhibition of mTOR and is associated with everolimus therapy for breast cancer. Topical steroids might reduce stomatitis incidence and severity, and the need for dose reductions and interruptions of everolimus. Anecdotal use of topical steroid oral prophylaxis has been reported in patients with breast cancer. We aimed to assess dexamethasone-based mouthwash for prevention of stomatitis in patients with breast cancer., Methods: This US-based, multicentre, single-arm, phase 2 prevention study enrolled women aged 18 years and older with postmenopausal status who had histologically or cytologically confirmed metastatic hormone receptor-positive, HER2-negative breast cancer. Beginning on day 1 of cycle 1, patients received everolimus 10 mg plus exemestane 25 mg daily, with 10 mL of alcohol-free dexamethasone 0·5 mg per 5 mL oral solution (swish for 2 min and spit, four times daily for 8 weeks). After 8 weeks, dexamethasone mouthwash could be continued for up to eight additional weeks at the discretion of the clinician and patient. The primary endpoint was incidence of grade 2 or worse stomatitis by 8 weeks assessed in the full analysis set (patients who received at least one dose of everolimus and exemestane and at least one confirmed dose of dexamethasone mouthwash) versus historical controls from the BOLERO-2 trial (everolimus and exemestane treatment in patients with hormone receptor-positive advanced breast cancer who were not given dexamethasone mouthwash for prevention of stomatitis). This trial is registered at ClinicalTrials.gov, number NCT02069093., Findings: Between May 28, 2014, and Oct 8, 2015, we enrolled 92 women; 85 were evaluable for efficacy. By 8 weeks, the incidence of grade 2 or worse stomatitis was two (2%) of 85 patients (95% CI 0·29-8·24), versus 159 (33%) of 482 patients (95% CI 28·8-37·4) for the duration of the BOLERO-2 study. Overall, 83 (90%) of 92 patients had at least one adverse event. The most frequently reported grade 3 and 4 adverse events in the safety set were hyperglycaemia (seven [8%] of 92 patients), rash (four [4%]), and dyspnoea (three [3%]). Serious adverse events were reported in 20 (22%) patients; six (7%) were deemed treatment related, with dyspnoea (three [3%]) and pneumonia (two [2%]) reported most frequently. 12 (13%) of 92 patients had adverse events suspected to be related to treatment that led to discontinuation of everolimus and exemestane (the most common were rash, hyperglycaemia, and stomatitis, which each affected two [2%] patients)., Interpretation: Prophylactic use of dexamethasone oral solution substantially reduced the incidence and severity of stomatitis in patients receiving everolimus and exemestane and could be a new standard of oral care for patients receiving everolimus and exemestane therapy., Funding: Novartis Pharmaceuticals Corporation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

In recent years oral mucosal injury has been increasingly recognized as an important toxicity associated with mammalian target of rapamycin (mTOR) inhibitors, including in patients with breast cancer who are receiving everolimus. This review addresses the state-of-the-science regarding mTOR inhibitor-associated stomatitis (mIAS), and delineates its clinical characteristics and management. Given the clinically impactful pain associated with mIAS, this review also specifically highlights new research focusing on the study of the molecular basis of pain. The incidence of mIAS varies widely (2-78%). As reported across multiple mTOR inhibitor clinical trials, grade 3/4 toxicity occurs in up to 9% of patients. Managing mTOR-associated oral lesions with topical oral, intralesional, and/or systemic steroids can be beneficial, in contrast to the lack of evidence supporting steroid treatment of oral mucositis caused by high-dose chemotherapy or radiation. However, steroid management is not uniformly efficacious in all patients receiving mTOR inhibitors. Furthermore, technology does not presently exist to permit clinicians to predict a priori which of their patients will develop these lesions. There thus remains a strategic need to define the pathobiology of mIAS, the molecular basis of pain, and risk prediction relative to development of the clinical lesion. This knowledge could lead to novel future interventions designed to more effectively prevent mIAS and improve pain management if clinically significant mIAS lesions develop., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Oral candidiasis (OC), caused by the fungal pathogen Candida albicans, is the most common opportunistic infection in HIV(+) individuals and other immunocompromised populations. The dramatic increase in resistance to common antifungals has emphasized the importance of identifying unconventional therapeutic options. Antimicrobial peptides have emerged as promising candidates for therapeutic intervention due to their broad antimicrobial properties and lack of toxicity. Histatin-5 (Hst-5) specifically has exhibited potent anticandidal activity indicating its potential as an antifungal agent. To that end, the goal of this study was to design a biocompatible hydrogel delivery system for Hst-5 application. The bioadhesive hydroxypropyl methylcellulose (HPMC) hydrogel formulation was developed for topical oral application against OC. The new formulation was evaluated in vitro for gel viscosity, Hst-5 release rate from the gel, and killing potency and, more importantly, was tested in vivo in our mouse model of OC. The findings demonstrated a controlled sustained release of Hst-5 from the polymer and rapid killing ability. Based on viable C. albicans counts recovered from tongues of treated and untreated mice, three daily applications of the formulation beginning 1 day postinfection with C. albicans were effective in protection against development of OC. Interestingly, in some cases, Hst-5 was able to clear existing lesions as well as associated tissue inflammation. These findings were confirmed by histopathology analysis of tongue tissue. Coupled with the lack of toxicity as well as anti-inflammatory and wound-healing properties of Hst-5, the findings from this study support the progression and commercial feasibility of using this compound as a novel therapeutic agent., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Aim: This study compared lactoferrin (LF) levels in the gingival crevicular fluid (GCF) and saliva between HIV-infected and noninfected patients with chronic periodontitis., Methods: For each subject, LF levels were analyzed in one shallow site (SS; PD ≤3 mm), one deep site (DS; PD >5 mm) and in resting whole saliva. Two groups, 28 HIV-infected and 10 noninfected, were selected., Results: Although the salivary LF levels were higher in HIV-infected than in noninfected individuals, especially in AIDS patients, this was not statistically significant (P > 0.05). Subgingival LF levels for SS and DS were lower among HIV-infected individuals, although AIDS patients showed the lowest levels. Age, smoking, gender, T CD4 lymphocytes levels and viral load did not influence subgingival LF levels, neither for SS nor for DP. Positive fungal culture was observed in 24 HIV-infected patients, but only observed in one in the control group. Overall, LF concentration was significantly higher in DS than SS, both in HIV-infected and noninfected individuals (P < 0.05) and salivary LF levels were always higher than GCF levels., Conclusion: The data indicate that LF levels in the GCF and saliva are not different between HIV-infected and noninfected patients with chronic periodontitis., (© 2014 Wiley Publishing Asia Pty Ltd.)

Burning mouth syndrome (BMS) is a debilitating, idiopathic chronic pain condition. For many BMS patients, burning oral pain begins in late morning and becomes more intense throughout the day, peaking by late afternoon or evening. We investigated brain gray matter volume (GMV) with voxel-based morphometry (VBM), white matter fractional anisotropy (FA) with diffusion tensor imaging (DTI), and functional connectivity in resting state functional MRI (rsfMRI) in a tightly screened, homogeneous sample of 9 female, postmenopausal/perimenopausal BMS patients and 9 matched healthy control subjects. Patients underwent 2 scanning sessions in the same day: in the morning, when ongoing pain/burning was low, and in the afternoon, when pain/burning was significantly higher. Patients had increased GMV and lower FA in the hippocampus (Hc), and decreased GMV in the medial prefrontal cortex (mPFC). rsfMRI revealed altered connectivity patterns in different states of pain/burning, with increased connectivity between mPFC (a node in the default mode network) and anterior cingulate cortex, occipital cortex, ventromedial PFC, and bilateral Hc/amygdala in the afternoon compared with the morning session. Furthermore, mPFC-Hc connectivity was higher in BMS patients than control subjects for the afternoon but not the morning session. mPFC-Hc connectivity was related to Beck depression inventory scores both between groups and between burning states within patients, suggesting that depression and anxiety partially explain pain-related brain dysfunction in BMS. Overall, we provide multiple lines of evidence supporting aberrant structure and function in the mPFC and Hc, and implicate a circuit involving the mPFC and Hc in regulating mood and depressive symptoms in BMS., (Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

HIV-infected individuals constitute a population highly susceptible to opportunistic infections, particularly oral candidiasis caused by the most pathogenic human fungal species Candida albicans . Host-produced salivary antimicrobial peptides are considered to be an important part of the host innate immune system involved in protection of the oral cavity against colonization and infection by microbial species. Histatin-5 (Hst-5) specifically has exhibited potent anti-candidal properties in vitro . However, its importance in protecting the oral mucosa against candidal colonization and importantly, its contribution to the observed enhanced susceptibility of HIV-infected individuals to candidiasis has not been previously investigated. To that end, a novel immunoassay was used to demonstrate significant decrease in salivary Hst-5 levels in HIV+ individuals concomitant with enhanced candidal prevalence. Further, saliva's anti-candidal potency was found to be proportional to Hst-5 concentration and significantly compromised in HIV+ subjects compared to controls. The key role for Hst-5 was further confirmed upon exposure to the Hst-5-specific antibody where saliva's initial killing activity was substantially compromised. Combined, these findings identify Hst-5 as a key anti-candidal salivary component and demonstrate its decreased levels in HIV infection providing new insights into oral Innate immune defense mechanisms and the enhanced susceptibility of HIV+ individuals to oral candidiasis.

The recognition, diagnosis, and management of common oral conditions requires knowledge of the lesion's clinical characteristics as well as the underlying pathology of the lesion. A thorough medical history, knowledge of normal anatomy, and a complete head and neck examination are necessary for the early recognition of oral lesions. Once any oral pathology is noted, clinical characteristics of size, location, texture, color, symptoms, and duration are necessary to arrive at a working plan and eventually a definitive diagnosis. In the end, the diagnosis often requires a biopsy or culture of the lesion. The clinical and histopathologic and/or mycologic correlation renders a final diagnosis leading to therapeutic options. A thorough knowledge of common oral lesions will allow the dentist/specialist to provide proper therapy or allow for referral to an oral medicine or oral surgery specialist. This review covers common infectious, reactive/traumatic, white, red, and bone lesions, as well as the vesiculobullous/desquamative gingival conditions, with a focus on periodontology and implantology. We cover the etiology, clinical features, histopathology, and treatment of each oral pathological condition., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Bisphosphonates (BPs) were designed for the prevention of skeletal-related events secondary to bone metastases. The purpose of this study was to show that zoledronic acid (ZA) directly eradicates highly tumorigenic and potentially metastatic cancer cells., Materials and Methods: Human prostate and breast highly tumorigenic (PC3, MCF 7) and low- or non-tumorigenic (LNCaP, MCF 10a) cell lines, respectively, were exposed to different concentrations of ZA (0-10 μM). Reverse transcriptase double quantitative polymerase chain reaction was used for quantitative gene expression analysis. Apoptosis and cell proliferation were determined using microscopic observation and MTS assays. Western blot was used to confirm the translational effects of apoptotic genes on protein expression., Results: Human prostate and breast highly tumorigenic (PC3, MCF 7) and low- or non-tumorigenic (LNCaP, MCF 10a) cell lines, respectively, showed multiple genes demonstrating differential expressions, including TRAF, TRADD, BCL2, CASPASES and IAP families. Increasing ZA concentrations showed a greater concentration-time response on cell proliferation and apoptosis in the highly tumorigenic cells. These results were confirmed by both reversing and enhancing the effect of ZA on cell proliferation with caspase 3, 7 or survivin siRNA, respectively. Pro-apoptotic proteins bax and caspase 2, 3, 7 and 9 were up-regulated, while the anti-apoptotic proteins bcl2, birc3 and survivin were down-regulated only in the highly tumorigenic cells., Conclusions: This explains the ability of ZA to inhibit bony metastasis in highly tumorigenic cells compared with the low- or non-tumorigenic cells through a significant decrease in cell proliferation and increase in apoptosis through gene-regulated and translational-mediated down-regulation of survivin coupled with the inhibition of caspase 3 or 7. This has significant implications toward understanding the pharmacophysiology of BPs in metastasis and supports the clinically observed effect of BPs when administered adjunctively with anticancer drugs such as cyclophosphamide/methotrexate/5-fluorouracil, epirubicin in combination with cyclophosphamide or docetaxel, and doxorubicin.

Osteonecrosis of the jaw secondary to bisphosphonate infusion (zoledronic acid-ZA) is assumed to be a bone disease. This study investigated the effects of ZA on soft tissues using oral mucosal cells as an in vitro model of soft tissue cell death in the pathogenesis of bone necrosis. Human gingival fibroblast and keratinocyte cell lines were exposed to different concentrations of ZA (0.25-3 micromol/l), using 1 micromol/l as the expected baseline concentration. A dose-response effect on apoptosis and cell proliferation [Terminal deoxynucleotidyl transferase-mediated dUTP-Biotin End Labelling and Annexin V or Coulter counter and 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium), respectively] was observed with increasing ZA concentrations; both reversed using siRNA against caspase 3 or 9. Gene expression analysis using RT(2) Profiler polymerase chain reaction Arrays demonstrated the differential expression of multiple genes involved in apoptosis including those that encode TNF, BCL-2, Caspase, IAP, TRAF and Death Domain families. Western blot analysis confirmed the presence of activated forms of caspase 3 and 9 and underexpression of survivin protein expression. This study demonstrated that low concentrations of ZA rapidly and directly affected the oral mucosal tissues though the induction of a gene-regulated apoptotic process. These findings support the potential for soft tissue injury as an initiating/potentiating event for osteonecrosis.

Oropharyngeal candidiasis is an opportunistic infection considered to be a harbinger of AIDS. The etiologic agent Candida albicans is a fungal species commonly colonizing human mucosal surfaces. However, under conditions of immune dysfunction, colonizing C. albicans can become an opportunistic pathogen causing superficial or even life-threatening infections. The reasons behind this transition, however, are not clear. In the oral cavity, salivary antimicrobial peptides are considered to be an important part of the host innate defense system in the prevention of microbial colonization. Histatin-5 specifically has exhibited potent activity against C. albicans. Our previous studies have shown histatin-5 levels to be significantly reduced in the saliva of HIV+ individuals, indicating an important role for histatin-5 in keeping C. albicans in its commensal stage. The versatility in the pathogenic potential of C. albicans is the result of its ability to adapt through the regulation of virulence determinants, most notably of which are proteolytic enzymes (Saps), involved in tissue degradation. In this study, we show that C. albicans cells efficiently and rapidly degrade histatin-5, resulting in loss of its anti-candidal potency. In addition, we demonstrate that this cellular activity is due to proteolysis by a member of the secreted aspartic proteases (Sap) family involved in C. albicans pathogenesis. Specifically, the proteolysis was attributed to Sap9, in turn identifying histatin-5 as the first host-specific substrate for that isoenzyme. These findings demonstrate for the first time the ability of a specific C. albicans enzyme to degrade and deactivate a host antimicrobial peptide involved in the protection of the oral mucosa against C. albicans, thereby providing new insights into the factors directing the transition of C. albicans from commensal to pathogen, with important clinical implications for alternative therapy. This report characterizes the first defined mechanism behind the enhanced susceptibility of HIV+ individuals to oral candidiasis since the emergence of HIV.

The oral cavity is a primary target for opportunistic infections, particularly oral candidiasis caused by the opportunistic pathogen Candida albicans. HIV+ individuals constitute a population highly susceptible to oral candidiasis possibly due to a change in the environment of the oral cavity as the result of salivary gland dysfunction. Histatins are a family of salivary antimicrobial peptides which under normal circumstances have a protective function on the oral mucosa. This study aimed to compare salivary histatin concentrations and oral fungal colonisation in an HIV+ and HIV- control populations. Oral samples for fungal cultures and parotid saliva were collected from all subjects. Fungal identification was determined using standard mycological procedures. In order to determine salivary histatin levels a semi-quantitative ELISA was designed using a specific polyclonal antibody and extensive statistical analysis was performed. Forty-seven percent of HIV+ and 17% of control subjects had positive fungal cultures. Mean histatin levels were 7.32 microg ml(-1) for the HIV+ group and 9.17 microg ml(-1) for control group (P = 0.003). The data from this study demonstrate that the level of fungal colonisation is significantly higher in HIV+ individuals whereas histatin-5 concentrations are significantly lower, likely contributing to the enhanced predisposition of this population to oral candidiasis.

Farnesol is a catabolite within the isoprenoid/cholesterol pathway that has exhibited significant antitumor activity. Farnesol was recently identified as a quorum-sensing molecule produced by the fungal pathogen Candida albicans. In this study, we hypothesize that synthetic and Candida-produced farnesol can induce apoptosis in vitro in oral squamous cell carcinoma (OSCC) lines. Cell proliferation, apoptosis, mitochondrial degradation, and survivin and caspase expressions were examined. In addition, global protein expression profiles were analyzed using proteomic analysis. Results demonstrated significant decrease in proliferation and increase in apoptosis in cells exposed to farnesol and C. albicans culture media. Concurrently, protein expression analysis demonstrated a significant decrease in survivin and an increase in cleaved-caspase expression, whereas fluorescent microscopy revealed the presence of active caspases with mitochondrial degradation in exposed cells. A total of 36 differentially expressed proteins were identified by proteomic analysis. Among the 26 up-regulated proteins were those involved in the inhibition of carcinogenesis, proliferation suppression, and aging. Most notable among the 10 down-regulated proteins were those involved in the inhibition of apoptosis and proteins overexpressed in epithelial carcinomas. This study demonstrates that farnesol significantly inhibits the proliferation of OSCCs and promotes apoptosis in vitro through both the intrinsic and extrinsic apoptotic signaling pathways. In addition, we report for the first time the ability of Candida-produced farnesol to induce a similar apoptotic response through the same pathways. The capability of farnesol to trigger apoptosis in cancer cells makes it a potential tool for studying tumor progression and an attractive candidate as a therapeutic agent.

Oral candidiasis caused by species other than Candida albicans has been observed. This study evaluated the prevalence of oral yeast species among 196 children during routine oral exam. Based on standard mycological testing, 130 (66%) subjects had fungal growth. Candida albicans isolates were recovered in 56% of children, but an extensive diversity in the non-albicans species was observed. Intrinsic differences in the pediatric population may favor the presence of yeast species other than C. albicans.

Mouthrinses that contain essential oils are effective for controlling plaque and periodontal disease. Recent studies have shown that such mouthrinses are effective at preventing the formation of biofilm in dental unit waterlines. However, there is no information in the literature regarding the effect of such mouthrinses on restorative materials used within the oral cavity. Specimens of three common restorative materials (a glass ionomer, a composite resin, and amalgam) were subjected to continuous exposure to Listerine and distilled water for 10 days; at that time, the strength, fluid sorption, and surface appearance of the specimens were compared. Specimens of the test materials also were placed in intraoral devices; volunteer patients wore these devices for 12 hours per day for a period of 10 days. During that time, the patients were instructed to rinse twice daily for 30 seconds with Listerine Cool Mint or a non-active mouthrinse. After 10 days, the specimens were salvaged from the devices and inspected by visible and SEM examination. This study indicates that routine use of mouthrinses containing essential oils (or even prolonged exposure to such mouthrinses) has no adverse effects on restorative materials that might be expected to react to such mixtures because of their chemical compositions. It was concluded that active mouthrinses do not appear to have any adverse effects on a variety of restorative biomaterials.

Cowden syndrome is a rare condition defined by multiple hamartomatous growths and a guarded prognosis owing to the high risk of cancer development. The syndrome is inherited as an autosomal dominant trait with incomplete penetrance and variable expressivity. The PTEN/MMAC1/TEP1 tumor suppressor gene on chromosome 10q23.3, has proven to contain a germline mutation predisposing for uncontrolled cell growth and survival via the PI3K/AKT pathway. Presented here is a case of Cowden syndrome in a patient with multiple hamartomas of the nose, midfacial skin and oral mucosa, and fissured tongue; plus a history of bipolar disease, iron deficiency anemia, basal cell carcinoma, fibroids of the uterus, and arthritis. The family history was significant for a daughter diagnosed with lung cancer. A final diagnosis of Cowden syndrome was made on the basis of established criteria and confirmed using immunohistochemistry directed against PTEN and phosphorylated-AKT.

Staphylococcus aureus is among the leading pathogens causing bloodstream infections able to form biofilms on host tissue and indwelling medical devices and to persist and cause disease. Infections caused by S. aureus are becoming more difficult to treat because of increasing resistance to antibiotics. In a biofilm environment particularly, microbes exhibit enhanced resistance to antimicrobial agents. Recently, farnesol was described as a quorum-sensing molecule with possible antimicrobial properties. In this study, the effect of farnesol on methicillin-resistant and -susceptible strains of S. aureus was investigated. With viability assays, biofilm formation assessment, and ethidium bromide uptake testing, farnesol was shown to inhibit biofilm formation and compromise cell membrane integrity. The ability of farnesol to sensitize S. aureus to antimicrobials was assessed by agar disk diffusion and broth microdilution methods. For both strains of staphylococci, farnesol was only able to reverse resistance at a high concentration (150 microM). However, it was very successful at enhancing the antimicrobial efficacy of all of the antibiotics to which the strains were somewhat susceptible. Therefore, synergy testing of farnesol and gentamicin was performed with static biofilms exposed to various concentrations of both agents. Plate counts of harvested biofilm cells at 0, 4, and 24 h posttreatment indicated that the combined effect of gentamicin at 2.5 times the MIC and farnesol at 100 microM (22 microg/ml) was able to reduce bacterial populations by more than 2 log units, demonstrating synergy between the two antimicrobial agents. This observed sensitization of resistant strains to antimicrobials and the observed synergistic effect with gentamicin indicate a potential application for farnesol as an adjuvant therapeutic agent for the prevention of biofilm-related infections and promotion of drug resistance reversal.

Six cases of Candida dubliniensis fungemia were identified during an 8-month period in hospitalized patients with various conditions, including human immunodeficiency virus infection. Peptide nucleic acid fluorescent in situ hybridization analysis was used as a rapid and reliable test for differentiating C. dubliniensis from Candida albicans, making it feasible to determine the prevalence of C. dubliniensis fungemia.

The literature indicates that the addition of an antimicrobial mouthrinse to self-contained water systems in dental units will control biofilm and effluent contamination; however, reports have varied concerning the possible effects of such agents on adhesive dentistry bond strengths. This study evaluated shear bond strengths and the potential effects of a mouthrinse containing essential oils on cut tooth surfaces by grinding flat the buccal surface of extracted human teeth. Seven groups consisting of five teeth each were etched with 37% H3PO4 solution and rinsed with water or different dilutions of the mouthrinse. Each tooth was blotted dry before a film of adhesive resin was applied to the surface and photocured. A cylinder of composite was placed on the surface and photocured. Shear bond strength testing was performed using a universal test machine. The cut tooth surfaces were ground (using water or the test mouthrinse mixtures as coolant) and evaluated by scanning electron microscopy.

Superficial mucocele is considered a relatively common, uncomplicated, and truly benign oral lesion, although a systematic review of the literature revealed only 27 well-documented cases. The general dentist frequently is confronted with questions from patients regarding these often recurrent blisters. While trauma is suspected to be the cause, the etiology of these lesions is not understood clearly due to the insufficient number of reported cases; as a result, their optimal management remains in question. Insufficient knowledge of the clinical appearance and histopathologic features of this lesion may generate diagnostic confusion, leading to improper diagnosis and inadequate management. This article presents an atypical case of superficial mucocele and summarizes the findings of all previously reported cases to emphasize the variable clinical features and increase general dentists' knowledge of the clinical spectrum regarding this condition's signs and symptoms.

Candida species, including the novel opportunistic pathogen Candida dubliniensis, are now emerging as major agents of nosocomial infections. Many such manifestations of infections associated with the formation of Candida biofilms include those occurring on devices such as indwelling intravascular catheters. Fungal biofilm-associated infections are frequently refractory to conventional therapy because of resistance to antimicrobial agents. This resistance could be in part due to the surface-induced upregulation of drug efflux pumps. Biofilm-associated Candida show uniform resistance to a wide spectrum of the currently available conventional antifungal agents, which implies that antimicrobial drugs that specifically target biofilm-associated infections are needed. The novel classes of antifungal agents, the lipid formulation of amphotericins, and the echinocandins have demonstrated unique antifungal activity against the resistant Candida biofilms, providing a breakthrough in the treatment of life-threatening invasive systemic mycoses. The use of drugs effective in combating biofilm-associated infections could lead to major developments in the treatment of fungal implant infections.

Previously, we have used both biochemical and immunological approaches to determine that the two-component, histidine kinase Chk1p regulates cell wall biosynthesis in Candida albicans. These data were obtained by comparing wild-type cells to a strain of C. albicans deleted in CHK1. The dysregulation of cell wall biosynthesis in the mutant reduces its adherence to human esophageal tissue and results in avirulence. In the current study, we used transmission immune electron microscopy (IEM) to visualize the cell surface of both wild-type (CAF2) and the chk1 mutant (CHK21). IEM was performed using two IgM monoclonal antibodies to either an acid-stable mannan epitope (Mab B6) or to an acid-labile mannan epitope (Mab B6.1). We observed that the cell surface of the CHK21 mutant was more reactive than wild-type cells with Mab B6, while the reactivity of Mab B6.1 was similar for both CAF2 and CHK21. These observations correlate with previous data on the Western blotting of mutant and wild-type cells using the same monoclonal antibodies, i.e., greater activity with Mab B6 than with Mab B6.1. In addition to CHK1, two other histidine kinases (SLN1 and NIK1) have been described in C. albicans. Mutants in both sln1Delta and nik1Delta were compared by Western blotting using Mab B6 and Mab B6.1. Reactivity of each mutant to Mab B6 was similar to that observed with the chk1 mutant; on the other hand, the mannoprotein profiles obtained with Mab B6.1 in all mutants were similar to wild-type cells. We also compared the expression of 29 genes involved in mannan synthesis by reverse transcription-polymerase chain reaction (RT-PCR) and found that expression of a subset of six genes (ALG2, ALG6, ALG8, MNT3, PMT6, KRT2) was upregulated in all histidine kinase mutants, while increased expression of ALG7 was only observed in the sln1 and nik1 mutants, MNN1 was upregulated in the chk1 and nik1 mutants, and MNN4 was upregulated in the nik1Delta. Our data indicate that each of the C. albicans HK proteins may regulate similar functions in cell wall biosynthesis. This activity could be achieved in either a common or parallel, redundant signal transduction pathway(s).

Objective: Even though some chemical agents can disinfect biofilms in dental unit waterlines, there remains concern that all remnants of the biofilm matrix are not eliminated. Even with periodic treatments, the bacterial populations in dental unit waterlines recur rapidly. In addition, with some previously tested products, patient safety, as well as toxic, caustic and corrosive residual chemicals are also a concern. This study evaluated ICX, A-dec's new water treatment solution, in a series of experiments for prevention, microbial spectrum of activity, minimum inhibitory time determination, and treatment of established biofilms., Methodology: New dental unit waterline tubing was treated continuously during simulated patient care over 28 days with municipal water. It was then treated with ICX. Effluents from lines with established biofilms (averaging > 10(4) CFU/ml at day 0) were treated to assess levels of CFU counts within 21 days of exposure to ICX., Results: Tubing treated with ICX did not develop a detectable biofilm using ruthenium red staining, and microbes in effluents remained undetectable., Conclusion: ICX is effective in maintaining the effluent within the American Dental Association's and the Centers for Disease Control's recommendation for < 500 CFU/ml. In addition, considering the preliminary finding that ICX reduces microbial contamination of effluents from established biofilm lines, it may be useful in long-term treatment alone or when coupled with a shock treatment to assist in biofilm destruction.

Objective: The control of biofilm and effluent contamination of dental unit water lines (DUWL) includes additions of antimicrobial solutions, as well as automatic dosing units. There are, however, varying reports on the effects of such agents on the bond strength of restorative dental materials and, particularly, between these agents and dental hard tissues., Methodology: The possible effects of an antimicrobial DUWL treatment solution on the adhesion of composite resin to dentin was evaluated by shear bond strength (SBS) testing. A total of 20 caries-free human molar and premolar teeth were used as the test substrates. The teeth were divided into two sets of 10 teeth which, after appropriate cleaning with water and pumice, were embedded horizontally in dental die stone. The buccal surface of each tooth was ground flat to a 17 microns finish using water-lubricated SiC paper. The teeth were then etched for 15 seconds with 37% H3PO4 and rinsed with either water (control) or a proprietary DUWL treatment (ICX) solution. Thereafter, the teeth were lightly blown dry with clean dry air, and the dentin conditioned with Prime & Bond NT for 20 seconds. The excess solvent was then removed by gentle air drying for 5 seconds, and the conditioner cured with visible light for 10 seconds. A cylinder of composite was placed on the conditioned surface and cured. A second group of 20 caries-free human molar and premolar teeth were used as test substrates to evaluate the effect of the ICX DUWL treatment solution on a different dentin priming system (OptiBond Solo Plus). The teeth in the second group were divided into two sets and after a 15 second etch with 37% H3PO4, were rinsed with water (control) or the proprietary ICX DUWL treatment solution. Thereafter, the teeth were lightly blown dry with clean, dry air and the dentin conditioned with OptiBond Solo for 20 seconds. The excess solvent was then removed by gentle air drying for 5 seconds, and the conditioner cured with visible light for 10 seconds. A cylinder of composite was placed on the conditioned surface and cured. Shear bond strength testing was performed with a universal test machine at the default cross-head speed of 0.1 mm/min. A set of teeth, sectioned, mounted and etched as above but rinsed with a 0.01% mineral oil/water mix prior to conditioning and bonding, was used as the negative control. A separate corrosion testing was performed by immersing brass coupons in water and ICX for 31 days and measuring the weight loss. The brass coupons were bright-dipped, electroless nickel-plated and bright nickel electroplated., Results: The bonding studies indicated that the DUWL treatment solution applied to a cut and etched dentin surface prior to conditioning and bonding with an adhesive system has no effect (p > 0.05) on bond strength for either group of specimens, compared to water. Negative control specimens were found to have minimal bond strengths. The corrosion study indicated no difference in the behavior of the test specimens in ICX compared to those in water, although differences were noted between the different surface finishes applied to the brass substrate., Conclusion: The findings of this study demonstrate that exposure of an etched dentin surface to a water-based DUWL treatment mixture has no adverse effects on subsequent adhesion strength. Minimal corrosive attack was noted in the ICX solution and water for brass coupons provided with three different surface finishes.