Dysfunction of the Salivary and Lacrimal Glands After Radioiodine Therapy for Thyroid Cancer: Results of the START Study After 6-Months of Follow-Up.

Background: Understanding of changes in salivary and lacrimal gland functions after radioactive iodine therapy (131I-therapy) remains limited, and, to date, no studies have evaluated dose-response relationships between absorbed dose from 131I-therapy and dysfunctions of these glands. This study investigates salivary/lacrimal dysfunctions in differentiated thyroid cancer (DTC) patients six months after 131I-therapy, identifies 131I-therapy-related risk factors for salivary/lacrimal dysfunctions, and assesses the relationships between 131I-therapy radiation dose and these dysfunctions. Methods: A cohort study was conducted involving 136 DTC patients treated by 131I-therapy of whom 44 and 92 patients received 1.1 and 3.7 GBq, respectively. Absorbed dose to the salivary glands was estimated using a dosimetric reconstruction method based on thermoluminescent dosimeter measurements. Salivary and lacrimal functions were assessed at baseline (T0, i.e., immediately before 131I-therapy) and six months later (T6) using validated questionnaires and salivary samplings, with and without stimulation of the salivary glands. Statistical analyses included descriptive analyses and random-effects multivariate logistic and linear regressions. Results: There was no difference between T0 and T6 in the level of parotid gland pain, nor was there difference in the number of patients with hyposalivation, but there were significantly more patients with dry mouth sensation and dry eyes after therapy compared with baseline. Age, menopause, depression and anxiety symptoms, history of systemic disease, and not taking painkillers in the past three months were found to be significantly associated with salivary or lacrimal disorders. Significant associations were found between 131I-exposure and salivary disorders adjusted on the previous variables: for example, per 1-Gy increase in mean dose to the salivary glands, odds ratio = 1.43 [CI 1.02 to 2.04] for dry mouth sensation, ß = -0.08 [CI -0.12 to -0.02] mL/min for stimulated saliva flow, and ß = 1.07 [CI 0.42 to 1.71] mmol/L for salivary potassium concentration. Conclusions: This study brings new knowledge on the relationship between the absorbed dose to the salivary glands from 131I-therapy and salivary/lacrimal dysfunctions in DTC patients six months after 131I-therapy. Despite the findings of some dysfunctions, the results do not show any obvious clinical disorders after the 131I-therapy. Nevertheless, this study raises awareness of the risk factors for salivary disorders, and calls for longer follow-up. Clinical Trials Registration: Number NCT04876287 on the public website (ClinicalTrials.gov).

AMPK Activation Restores Salivary Function Following Radiation Treatment.

Head and neck cancers represent a significant portion of cancer diagnoses, with head and neck cancer incidence increasing in some parts of the world. Typical treatment of early-stage head and neck cancers includes either surgery or radiotherapy; however, advanced cases often require surgery followed by radiation and chemotherapy. Salivary gland damage following radiotherapy leads to severe and chronic hypofunction with decreased salivary output, xerostomia, impaired ability to chew and swallow, increased risk of developing oral mucositis, and malnutrition. There is currently no standard of care for radiation-induced salivary gland dysfunction, and treatment is often limited to palliative treatment that provides only temporary relief. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an enzyme that activates catabolic processes and has been shown to influence the cell cycle, proliferation, and autophagy. In the present study, we found that radiation (IR) treatment decreases tissue levels of phosphorylated AMPK following radiation and decreases intracellular NAD+ and AMP while increasing intracellular adenosine triphosphate. Furthermore, expression of sirtuin 1 (SIRT1) and nicotinamide phosphoribosyl transferase (NAMPT) was lower 5 d following IR. Treatment with AMPK activators, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and metformin, attenuated compensatory proliferation (days 6, 7, and 30) following IR and reversed chronic (day 30) salivary gland dysfunction post-IR. In addition, treatment with metformin or AICAR increased markers of apical/basolateral polarity (phosphorylated aPKCζT560-positive area) and differentiation (amylase-positive area) within irradiated parotid glands to levels similar to untreated controls. Taken together, these data suggest that AMPK may be a novel therapeutic target for treatment of radiation-induced salivary damage.

Salivary gland involvement and oral health in patients with coeliac disease.

Coeliac disease (CD) is a chronic immune-mediated enteropathy triggered by ingestion of gluten. The aim of this study was to investigate if the salivary glands as a component of the mucosal immune system are involved in CD, leading to sialadenitis and salivary gland dysfunction and associated oral manifestations. Twenty patients with CD aged 49.2 (SD 15.5 years) and 20 age- and gender-matched healthy controls underwent an interview regarding general and oral health, serological analysis, a clinical oral examination including bitewing radiographs, Candida smear, assessment of salivary mutans streptococci and lactobacilli levels, unstimulated and chewing-stimulated whole and parotid saliva flow rates, analysis of secretory IgA, and a labial salivary gland biopsy. Xerostomia, mucosal lesions, dry/cracked lips and focal lymphocytic sialadenitis were more prevalent and extensive in patients with CD than in healthy controls. Moreover, the patients had less gingival inflammation and higher whole saliva flow rates than the healthy controls, but did not differ regarding dental health and levels of cariogenic bacteria and Candida. The major salivary gland function appears unaffected, contributing to maintenance of a balanced microbiota and oral health in CD patients. Xerostomia and labial dryness may be related to minor salivary gland inflammation and subsequent impaired mucosal lubrication.

Oral Health Messiers: Diabetes Mellitus Relevance.

This article aims to narrate the various oral complications in individuals suffering from diabetes mellitus. Google search for "diabetes mellitus and oral complications" was done. The search was also carried out for "diabetes mellitus" and its oral complications individually. Diabetes mellitus is a chronic metabolic disorder that is a global epidemic and a common cause of morbidity and mortality in the world today. Currently, there are about 422 million cases of diabetes mellitus worldwide. Diabetic patients can develop different complications in the body such as retinopathy, neuropathy, nephropathy, cardiovascular disease. Complications in the oral cavity have been observed in individuals suffering from diabetes mellitus. A study noted that more than 90% of diabetic patients suffered from oral complications. Another research has shown a greater prevalence of oral mucosal disorders in patients with diabetes mellitus than non-diabetic population: 45-88% in patients with type 2 diabetes compared to 38.3-45% in non-diabetic subjects and 44.7% in type 1 diabetic individuals compared to 25% in the non-diabetic population. Oral complications in people with diabetes are periodontal disease, dental caries, oral infections, salivary dysfunction, taste dysfunction, delayed wound healing, tongue abnormalities, halitosis, and lichen planus. The high glucose level in saliva, poor neutrophil function, neuropathy, and small vessel damage contribute to oral complications in individuals with uncontrolled diabetes. Good oral health is imperative for healthy living. Oral complications cause deterioration to the quality of life in diabetic patients. Complications like periodontal disease having a bidirectional relationship with diabetes mellitus even contribute to increased blood glucose levels in people with diabetes. This article intends to promote awareness regarding the oral health of diabetics and to stress the importance of maintaining proper oral hygiene, taking preventive measures, early detection, and appropriate management of oral complications of these patients through a multidisciplinary approach.

IL-17 drives salivary gland dysfunction via inhibiting TRPC1-mediated calcium movement in Sjögren's syndrome.

OBJECTIVES: This study aims to determine a role of interleukin-17A (IL-17) in salivary gland (SG) dysfunction and therapeutic effects of targeting IL-17 in SG for treating autoimmune sialadenitis in primary Sjögren's syndrome (pSS). METHODS: Salivary IL-17 levels and IL-17-secreting cells in labial glands of pSS patients were examined. Kinetic changes of IL-17-producing cells in SG from mice with experimental Sjögren's syndrome (ESS) were analysed. To determine a role of IL-17 in salivary secretion, IL-17-deficient mice and constructed chimeric mice with IL-17 receptor C (IL-17RC) deficiency in non-hematopoietic and hematopoietic cells were examined for saliva flow rates during ESS development. Both human and murine primary SG epithelial cells were treated with IL-17 for measuring cholinergic activation-induced calcium movement. Moreover, SG functions were assessed in ESS mice with salivary retrograde cannulation of IL-17 neutralisation antibodies. RESULTS: Increased salivary IL-17 levels were negatively correlated with saliva flow rates in pSS patients. Both IL-17-deficient mice and chimeric mice with non-hematopoietic cell-restricted IL-17RC deficiency exhibited no obvious salivary reduction while chimeric mice with hematopoietic cell-restricted IL-17RC deficiency showed significantly decreased saliva secretion during ESS development. In SG epithelial cells, IL-17 inhibited acetylcholine-induced calcium movement and downregulated the expression of transient receptor potential canonical 1 via promoting Nfkbiz mRNA stabilisation. Moreover, local IL-17 neutralisation in SG markedly attenuated hyposalivation and ameliorated tissue inflammation in ESS mice. CONCLUSION: These findings identify a novel function of IL-17 in driving salivary dysfunction during pSS development and may provide a new therapeutic strategy for targeting SG dysfunction in pSS patients.

Experimental Animal Model Systems for Understanding Salivary Secretory Disorders.

Salivary secretory disorders are life-disrupting pathologic conditions with a high prevalence, especially in the geriatric population. Both patients and clinicians frequently feel helpless and get frustrated by the currently available therapeutic strategies, which consist mainly of palliative managements. Accordingly, to unravel the underlying mechanisms and to develop effective and curative strategies, several animal models have been developed and introduced. Experimental findings from these models have contributed to answer biological and biomedical questions. This review aims to provide various methodological considerations used for the examination of pathological fundamentals in salivary disorders using animal models and to summarize the obtained findings. The information provided in this review could provide plausible solutions for overcoming salivary disorders and also suggest purpose-specific experimental animal systems.

How Evidence-Based Dentistry Has Shaped the Practice of Oral Medicine.

Oral medicine is "the discipline of dentistry concerned with the oral health care of medically complex patients, including the diagnosis and primarily nonsurgical treatment and/or management of medically related conditions affecting the oral and maxillofacial region." In each of these areas, evidence-based medicine has shaped theoretic understanding and clinical practice. The available evidence allows for improved patient management. Further evidence, as it becomes available, should be reviewed on a regular basis to guide our clinical practice.

Salivary secretion in health and disease.

Saliva is a complex fluid produced by 3 pairs of major salivary glands and by hundreds of minor salivary glands. It comprises a large variety of constituents and physicochemical properties, which are important for the maintenance of oral health. Saliva not only protects the teeth and the oropharyngeal mucosa, it also facilitates articulation of speech, and is imperative for mastication and swallowing. Furthermore, saliva plays an important role in maintaining a balanced microbiota. Thus, the multiple functions provided by saliva are essential for proper protection and functioning of the body as a whole and for the general health. A large number of diseases and medications can affect salivary secretion through different mechanisms, leading to salivary gland dysfunction and associated oral problems, including xerostomia, dental caries and fungal infections. The first part of this review article provides an updated insight into our understanding of salivary gland structure, the neural regulation of salivary gland secretion, the mechanisms underlying the formation of saliva, the various functions of saliva and factors that influence salivary secretion under normal physiological conditions. The second part focuses on how various diseases and medical treatment including commonly prescribed medications and cancer therapies can affect salivary gland structure and function. We also provide a brief insight into how to diagnose salivary gland dysfunction.

Oxidative Modification in the Salivary Glands of High Fat-Diet Induced Insulin Resistant Rats.

Still little is known about the role of oxidative stress (OS) in the pathogenesis of the salivary gland dysfunction in the course of insulin resistance (IR). To induce IR rats was fed with a high fat diet (HFD) during 8 weeks. Stimulated and non-stimulated salivary flow rate, total protein, as well as oxidative damage markers: 4-HNE protein adduct, 8-isoprostanes (8-isoP), 8-hydroxy-D-guanosine (8-OHdG), advanced oxidation protein product (AOPP), and protein carbonyls (PC) were determined in the plasma and submandibular and parotid glands of IR and control rats. We have shown a significant decrease (45%) of the stimulated salivary flow rate, and in the total protein concentration in the parotid (35%) and submandibular (10%) glands of HFD IR as compared to the control rats. The level of 4-HNE protein adduct (15%) and 8-isoP (20%) in the submandibular glands of IR rats as well as total level of 4-HNE protein adduct (39%), 8-isoP (27%), AOPP (25%), PC (32%), and 8-OHdG (18%) in the parotid glands of IR rats were significantly higher as compared to the control group. We showed no correlation between the assessed OS parameters in the plasma and salivary glands. However, the redox balance in both glands shifted toward the oxidative status, parotid glands of IR rats are exposed to greater intensity OS. Stimulated secretory ability and mechanisms involved in the synthesis/secretion of proteins in the salivary glands are depressed in the course of IR. Oxidative damage in the salivary glands arises independently from the general OS in the course of insulin resistance induced by a high fat diet.

Association of salivary gland hypofunction with diabetes mellitus and drugs among the elderly in Karachi, Pakistan.

AIM: Studies from Pakistan on salivary dysfunction are lacking, and the Pakistani elderly population is rapidly growing. Among the most common problems in the elderly that could have a deleterious impact on their quality of life are salivary gland hypofunction (SGH), diabetes mellitus (DM), and the intake of drugs with adverse effects on salivary function. In the present study, we aimed to find the association of SGH with DM and drugs among the elderly in Karachi, Pakistan. METHODS: The inclusion criterion was affirmative answers to a series of standardized questions related to the symptoms of dry mouth. A total of 110 individuals were selected from a convenience sample of 200 people aged between 60 and 70 years. Diabetes, drug use, and SGH in the participants were determined by detailed medical and drug history, clinical examination, and sialometry. RESULTS: Similar to their international counterparts, the majority of the study participants demonstrated objective evidence of SGH. More importantly SGH was found to be statistically significant with respect to DM and medication (P < 0.05). For participants on medication, the minimum and maximum salivary flow rates were found to be 0.09 mL/min and 0.3 ml/min, respectively, whereas the minimum and maximum salivary flow rates in diabetic participants were 0.01 mL/min and 0.09 mL/min, respectively. CONCLUSION: In the present study, the majority of elderly participants whose presenting complaint was oral dryness was found to have objective evidence of SGH, with a statistically-significant association with DM and drugs.

Innate Immunity and Saliva in Candida albicans-mediated Oral Diseases.

The oral cavity is a unique niche where Candida albicans infections occur in immunocompetent as well as immunosuppressed individuals. Here we critically review the significance of human innate immune response in preventing oral candidiasis. One important line of defense against oropharyngeal candidiasis is the oral microbiota that prevents infection by competing for space and nutrients as well as by secreting antagonistic molecules and triggering local inflammatory responses. C. albicans is able to induce mucosal defenses through activation of immune cells and production of cytokines. Also, saliva contains various proteins that affect C. albicans growth positively by promoting mucosal adherence and negatively through immune exclusion and direct fungicidal activity. We further discuss the role of saliva in unifying host innate immune defenses against C. albicans as a communicating medium and how C. albicans overgrowth in the oral cavity may be a result of aberrations ranging from microbial dysbiosis and salivary dysfunction to epithelial damage. Last we underscore select oral diseases in which C. albicans is a contributory microorganism in immune-competent individuals.

Salivary Function after Radioiodine Therapy: Poor Correlation between Symptoms and Salivary Scintigraphy.

OBJECTIVE: Symptoms of salivary gland dysfunction frequently develop after radioactive iodine (RAI) therapy, but have generally not been correlated with assessment of salivary gland functioning. The aim of this study was to determine whether there was a correlation between salivary symptoms and salivary functioning as assessed by salivary scan parameters. METHODS: This was a non-randomized observational study. Fifteen patients receiving RAI therapy for differentiated thyroid cancer completed a questionnaire assessing their salivary and nasal symptoms prior to their therapy and 3 and 12 months after their therapy. Salivary gland scanning using technetium-99m pertechnetate was performed at the same time points. In addition, protective measures used at the time of radioiodine administration, such as use of fluids and sour candy, were also documented. Measures of salivary gland accumulation and secretion were correlated with scores of salivary and nasal symptomatology and any effects of protective measures were assessed. RESULTS: The mean number of salivary, nasal, and total symptoms at 3 months increased significantly over the number of symptoms at baseline by 3.7, 2.7, and 6.3 symptoms, respectively (p values 0.001, 0.0046, and <0.001, respectively). The mean increases in the number of salivary, nasal, and total symptoms at 12 months were non-significant at 1.3, 1.3, and 2.5 symptoms, respectively. The mean right parotid gland accumulation and secretion of radioisotope declined significantly at 3 months, compared with baseline. The changes in left parotid and right and left submandibular function were non-significant. There was no association between the increase in salivary, nasal, or total symptoms and the change in scintigraphy measures. However, the increases in nasal and total symptoms were significantly greater in those with co-existent Hashimoto's disease, compared with those without this condition (p values 0.01 and 0.04, respectively). Nasal symptoms decreased (p value 0.04) and total symptoms trended to decrease (p value 0.08) in those who used sour candies, compared with those who did not. Increasing body mass index was significantly associated with increasing nasal symptoms (p value 0.05). Greater decline in salivary parameters at 3 months compared with baseline was generally associated with heavier body weight, decreased thyroid cancer stage, absence of Hashimoto's thyroiditis, and pre-menopausal status. CONCLUSION: Salivary and nasal symptoms increased and salivary scintigraphy parameters decreased after radioiodine therapy. However, the increased symptoms did not correlate with decrements in salivary gland accumulation or secretion. Moreover, the variables associated with symptoms and changes in salivary scan parameters differed. Therefore, a better understanding of the relationship between salivary gland symptoms and functioning is needed. Factors affecting susceptibility to salivary and nasal damage after radioiodine therapy need to be better elucidated, so that modifiable factors can be identified.

Oral disease profiles in chronic graft versus host disease.

At least half of patients with chronic graft-versus-host-disease (cGVHD), the leading cause of morbidity and non-relapse mortality after allogeneic stem cell transplantation, have oral manifestations: mucosal lesions, salivary dysfunction, and limited mouth-opening. cGVHD may manifest in a single organ or affect multiple organ systems, including the mouth, eyes, and the skin. The interrelationship of the 3 oral manifestations of cGVHD with each other and with the specific manifestations of extraoral cGVHD has not been studied. In this analysis, we explored, in a large group of patients with cGVHD, the potential associations between: (1) oral mucosal disease and erythematous skin disease, (2) salivary gland dysfunction and lacrimal gland dysfunction, and (3) limited mouth-opening and sclerotic skin cGVHD. Study participants, enrolled in a cGVHD Natural History Protocol (NCT00331968, n = 212), underwent an oral examination evaluating: (1) mucosal cGVHD [NIH Oral Mucosal Score (OMS)], (2) salivary dysfunction (saliva flow and xerostomia), and (3) maximum mouth-opening measurement. Parameters for dysfunction (OMS > 2, saliva flow ≤ 1 mL/5 min, mouth-opening ≤ 35 mm) were analyzed for association with skin cGVHD involvement (erythema and sclerosis, skin symptoms), lacrimal dysfunction (Schirmer's tear test, xerophthalmia), Lee cGVHD Symptom Scores, and NIH organ scores. Oral mucosal disease (31% prevalence) was associated with skin erythema (P < 0.001); salivary dysfunction (11% prevalence) was associated with lacrimal dysfunction (P = 0.010) and xerostomia with xerophthalmia (r = 0.32, P = 0.001); and limited mouth-opening (17% prevalence) was associated with skin sclerosis (P = 0.008) and skin symptoms (P = 0.001). There was no association found among these 3 oral cGVHD manifestations. This analysis supports the understanding of oral cGVHD as 3 distinct diseases: mucosal lesions, salivary gland dysfunction, and mouth sclerosis. Clear classification of oral cGVHD as 3 separate manifestations will improve clinical diagnosis, observational research data collection, and the definitions of outcome measures in clinical trials.

The Role of Salivary Gland Scintigraphy in the Evaluation of Salivary Gland Dysfunction in Uncontrolled Type II Diabetic Patients.

The aim of the present study was to evaluate the salivary gland dysfunction in patients with uncontrolled type II diabetes using salivary gland scintigraphy and then to compare these ratios with quantitative whole salivary secretion rates. Using a gamma camera (siemens-diacam) equipped with a low energy all-purpose collimator, 32 uncontrolled type II diabetic patients and 30 normal healthy patients were studied by injecting a radio isotope (technetium 99m pertechnetate) about 5 mCi was injected intravenously in to anticubital vein and the activity was measured for the 1(st), 20(th) and 40(th) min. At 20 min after injection, vitamin C chewable tablet was given to stimulate the secretion and continued until the end of the study period (40 min). Before scintigraphy, salivary sampling was carried out in both diabetic and normal individuals in a quiet room, saliva was allowed to accumulate and was expectorated into the collecting vessel approximately once a minute for 15 min and the volume was recorded as Unstimulated salivary flow rate and after 5 min break vitamin C chewable tablet was given to stimulate the secretion and the patient was asked to expectorate the saliva in the collecting vessel for 5 min. The expectorated volume was recorded as stimulated salivary flow rate. The mean of the measurements of scintigraphic ratio and salivary secretion rates were compared using the paired Student's t-test. The scintigraphic mean uptake and excretory ratio (ER) and the salivary flow rates were correlated. The result shows that there was a significant correlation between salivary flow rate and scintigraphic uptake and ER. However, statistically significant result could not be derived as it may be due to smaller sample size and marginal difference in the scintigraphic values between the groups. Salivary gland scintigraphy plays a significant role in the evaluation of salivary gland dysfunction. However, its role as an independent investigative procedure in the evaluation of salivary gland dysfunction requires a study with a larger sample size, may yield a statistical significant result and it can also act as an adjunct along with salivary flow rate procedure.