Gemigliptin suppresses salivary dysfunction in streptozotocin-induced diabetic rats.

Patients with diabetes commonly experience hyposalivation, which induces discomfort in eating, swallowing, dryness, smell, and speaking, as well as increases the incidence of periodontal disease. Dipeptidyl peptidase-4 (DPP4) inhibitors are frequently used as antidiabetic drugs that lower glucose levels by utilizing similar mechanisms; however, additional protective functions of each gliptin have been discovered. In this study, the protective roles of gemigliptin, a DPP4 inhibitor, against salivary dysfunction under diabetic conditions were investigated. Streptozotocin-induced diabetic rats received gemigliptin 10 mg/kg or 100 mg/kg via oral gavage for 3 weeks. The weights of salivary gland tissues, saliva secretion, and antioxidant capacity in salivary glands were reduced after diabetes induction, but were significantly preserved following gemigliptin treatment. In salivary gland analysis, expression of apoptotic proteins, as well as amylase and aquaporin-5 (AQP5) protein expression, were increased following gemigliptin treatment. Furthermore, the number of TUNEL-positive cells decreased after gemigliptin treatment. Therefore, gemigliptin has protective roles against salivary dysfunction observed in diabetes, mediated via antioxidant, anti-apoptotic, and salivary secretion mechanisms. These results may help in selecting a suitable drug for patients with diabetes experiencing salivary dysfunction.

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.

Salivary dysfunction caused by medication usage.

A considerable number of patients arriving in dental offices are being treated with ongoing medication for a variety of chronic diseases. As a result, dentists must be familiar with the potential side effects these therapeutic agents may have on the tissues of the oral cavity, and in particular on the salivary gland. Salivary gland function may be altered by a wide range of medications, leading to effects such as xerostomia, hyposalivation, hypersalivation or even swelling of the glands. These disorders can cause a variety of other health complications. This review will focus on the most common groups of drugs responsible for salivary gland dysfunction, including psychoactive drugs, antidepressants, antipsychotics, antihypertensives, and antihistamines.

Diaphragmatic CMAP amplitude from phrenic nerve stimulation predicts functional decline in ALS.

OBJECTIVE: To evaluate phrenic nerve motor amplitude (PhrenicAmp) as an independent predictor of functional decline in amyotrophic lateral sclerosis (ALS). We also assessed both PhrenicAmp and forced vital capacity (FVC) as predictors of functional loss in patients with bulbar dysfunction. METHODS: We included consecutive ALS patients with PhrenicAmp and FVC at baseline. Participants were evaluated with the revised ALS Functional Rating Scale (ALSFRS-R) at inclusion and at, at least, one subsequent follow-up visit. The outcome measure of functional decline was the percentage reduction in ALSFRS-R from baseline. Bulbar dysfunction was defined by the presence of any relevant symptom on the ALSFRS-R bulbar sub-score. Correlations and mixed-effects regressions were used to study the relationship between functional decline and both PhrenicAmp and FVC baseline evaluations. RESULTS: A total of 249 ALS patients were included; 64.2% of these had bulbar dysfunction. At inclusion, significant correlations were found between PhrenicAmp and FVC (p < 0.001), as well as between each respiratory measure and ALSFRS-R (all p < 0.001). The functional decline at first (median 3 months) and second (median 6 months) follow-up visits was significantly correlated with baseline values of both respiratory evaluations (all p < 0.01) in the entire ALS population, but only with baseline PhrenicAmp (all p < 0.05) in bulbar dysfunction cases. Regression analysis revealed that PhrenicAmp (all p < 0.05), but not FVC, was a significant independent predictor of functional decline in ALS patients and in those with bulbar dysfunction. CONCLUSION: Baseline PhrenicAmp is an independent predictor of functional decline in ALS, whether or not bulbar dysfunction is present.

Dynamics of Salivary Gland AQP5 under Normal and Pathologic Conditions.

AQP5 plays an important role in the salivary gland function. The mRNA and protein for aquaporin 5 (AQP5) are expressed in the acini from embryonic days E13-16 and E17-18, respectively and for entire postnatal days. Ligation-reopening of main excretory duct induces changes in the AQP5 level which would give an insight for mechanism of regeneration/self-duplication of acinar cells. The AQP5 level in the submandibular gland (SMG) decreases by chorda tympani denervation (CTD) via activation autophagosome, suggesting that its level in the SMG under normal condition is maintained by parasympathetic nerve. Isoproterenol (IPR), a ß-adrenergic agonist, raised the levels of membrane AQP5 protein and its mRNA in the parotid gland (PG), suggesting coupling of the AQP5 dynamic and amylase secretion-restoration cycle. In the PG, lipopolysaccharide (LPS) is shown to activate mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signalings and potentially downregulate AQP5 expression via cross coupling of activator protein-1 (AP-1) and NF-κB. In most species, Ser-156 and Thr-259 of AQP5 are experimentally phosphorylated, which is enhanced by cAMP analogues and forskolin. cAMP-dependent phosphorylation of AQP5 does not seem to be markedly involved in regulation of its intracellular trafficking but seems to play a role in its constitutive expression and lateral diffusion in the cell membrane. Additionally, Ser-156 phosphorylation may be important for cancer development.

Salivary gland performance in autoimmune diseases: review and meta-analysis.

Objectives: Autoimmune diseases include a spectrum of disorders in which immune response to the autoantigens leads to tissue damage or dysfunction. Xerostomia, salivary gland dysfunction and lack of saliva are some common symptoms associated with many autoimmune diseases.Methods: In this review study, the meta-analysis technique is used to objectively review the relationship between autoimmune diseases and salivary gland dysfunction. We have searched Medline and Embase and Google Scholar. By Revman 5.3, meta-analysis was performed to investigate the salivary flow rate in both stimulatory and non-stimulatory saliva. The sample size obtained from these studies was 130 people with autoimmune diseases and 100 healthy individuals.Results: The results showed a significant decrease in the level of non-stimulatory saliva in people with autoimmune diseases.Conclusions: A complete and comprehensive understanding of the clinical manifestation of systemic diseases is crucial in early diagnosis of diseases and identifying the mechanisms that develop the disease. Other than xerostomia, there is a significant reduction in salivary flow rate in patients with autoimmune diseases. As saliva plays a very important role in oral health and has significant functions, more attention is needed for monitoring and managing of hyposalivation in autoimmune patients.

Diagnostic value of acustic radiation force impulse imaging in the assessment of salivary gland involvement in primary Sjögren's sydrome.

AIMS: The aim of this study is to investigate the diagnostic value of Acoustic Radiation Force Impulse (ARFI) imaging in the assessment of salivary gland involvement in primary Sjögren's syndrome (pSS). MATERIAL AND METHODS: Twenty five patients with pSS and 25 healthy volunteers were included. First, echostructures and the thickness of the submandibular and parotid glands were evaluated by B-mode ultrasonography. Then, ARFI imaging with Virtual Touch Quantification® was performed. Ten independent shear wave velocity measurements were taken from each gland. Finally, the mean shear wavevelocity (SWV) values were calculated, and used for further analysis. RESULTS: The mean SWV values of parotid and submandibular glands were significantly higher in the pSS patients than in the healthy control group (p<0.001). The cut-off of SWV values were calculated to be 1.98 m/s for submandibular glands, and 1.93 m/s for parotid glands. In pSS patients, the mean SWV values of parotid glands were higher than those of the submandibular glands (p<0.001) and no statistically significant relationships between symptom duration or the degree of xerostomia and mean SWV values of parotid and submandibularglands were found (all p>0.005). CONCLUSIONS: Our findings indicate that ARFI imaging may provide a non-invasive, simple and fast means of assessment of glandular impairment as an alternative test when other salivary gland tests are inconclusive or cannot be performed. ARFI may be a valuable adjunct for the clinical diagnosis of pSS.

Radioactive iodine: An unappreciated threat to salivary gland function.

Thyroid cancer is an endocrine malignancy whose prevalence is increasing in the United States. Nearly 57,000 new cases of thyroid cancer are estimated to be diagnosed in 2017. The standard of care for differentiated thyroid cancer is thyroidectomy followed by ablation of thyroid remnants with high-dose radioactive iodine (131 I). Apart from thyroid glands, 131 I accumulates in cells of salivary glands and compromises its function. Xerostomia is, therefore, a frequent and often persistent complaint of patients. Despite adoption of standard preventive measures, parenchymal damage and chronic salivary dysfunction are observed in a substantial number of patients. Saliva is important for oral homeostasis, and its reduction increases the risk of oral morbidity. As differentiated thyroid cancer patients have an excellent survival rate, preservation of salivary gland function carries added significance. A focus on treatments that preserve or restore long-term salivary flow can significantly improve the quality of life of thyroid cancer survivors.

[A case of swelling of salivary gland due to drug treatment for threatened premature labor].

Ritodrine hydrochloride (luteonin), a beta-agonist with predominant effects on beta adrenoreceptors such as those of the uterus, is effective in suppressing premature uterine contractions. This medicine was used in drug treatment in the case of threatened premature labor. A 26-year-old female who complained of acute swelling of the bilateral salivary glands was consulted to our otorhinolaryngological department. The soft swelling of the bilateral parotid and submandibular glands had developed after intravenous administration of ritodrine hydrochloride for treatment of her threatened premature labor. In addition, serum amylase levels were elevated. The swelling of the salivary glands and the elevation of the serum amylase subsided following discontinuation of the ritodrine hydrochloride. In salivary glands, too, the beta-adrenoreceptors exist. Following stimulation of those receptors in those glands increased secretion of amylase occurs. Our findings suggested that beta-stimulation by ritodrine hydrochloride led to the swelling of the salivary glands and the elevation of the serum amylase. To our knowledge, in Japan, our case is the first otorhinolaryngological report of swelling of the salivary glands due to ritodrine hydrochloride. Otolaryngologist should therefore have full knowledge regarding swelling of salivary glands due to ritodrine hydrochloride.

Obstructive sialadenitis of a transplanted submandibular gland: chronic inflammation secondary to ductal obstruction.

AIMS: To determine the pathological basis and clinical features of obstructive sialadenitis in transplanted submandibular glands (SMGs). METHODS: A total of 161 patients (174 eyes) with keratoconjunctivitis sicca underwent microvascular SMG transplantation. Patients were followed up at approximately 1 and 4 months and annually thereafter. Clinical data, including dry eye discomfort, symptoms of ductal obstruction, and Schirmer test, were recorded. Sialography was performed in six patients. In addition, SMG autotransplantation was performed in 22 rabbits. Salivary flow was recorded and the morphology of glands was examined at 6 months postoperatively by light microscopy. RESULTS: Among the patients, 16 out of 172 glands during the latent period (0-3 months) and 2 out of 154 glands with long-term follow-up (>1 year) showed obstructive sialadenitis. Typical manifestations were continuous small volumes of viscous secretions, recurrent gland swelling, decreased Schirmer test values, and irregular dilation of the main duct on sialography. The transplanted SMGs eventually showed no secretion in five cases. Of the 22 rabbit SMGs, 4 had obstructive sialadenitis. Morphological examination showed chronic inflammatory infiltration with salivary deposits. CONCLUSIONS: Obstructive sialadenitis of transplanted SMGs is a chronic inflammation secondary to ductal obstruction, which leads to insufficient ocular lubrication and potential treatment failure.

Chronic inflammation in the pancreas and salivary glands--lessons from similarities and differences in pathophysiology and treatment modalities.

The pancreas and salivary glands have similar anatomical structures and physiological functions producing bicarbonate-rich fluid containing digestive enzymes and other components to be delivered into the gut. Despite these similarities, the two organs are also different in numerous respects, especially regarding the inflammatory diseases affecting them. This article will summarize the pathophysiology and current and potential pharmacological treatments of chronic inflammatory diseases such as chronic pancreatitis, autoimmune pancreatitis, Sjögren's syndrome and irradiation-induced salivary gland atrophy. Despite the differences, in both organs the inflammatory process is accompanied by epithelial tissue destruction and fibrosis. Both in pancreatic and in salivary research, an important task is to stop or even reverse this process. The utilization of stem/progenitor cell populations previously identified in these organs and the application of mesenchymal stem cells are very promising for such regenerative purposes. In addition, gene therapy and tissue engineering research progressively advance and have already yielded clinically beneficial preliminary results for salivary gland diseases. For the hard-to-access, hard-to-regenerate pancreas these developments may also offer new solutions, especially since salivary and pancreatic progenitors are very similar in characteristics and may be mutually useful to regenerate the respective other organ as well. These novel developments could be of great significance and may bring new hope for patients since currently used therapeutic protocols in salivary and in pancreatic chronic inflammatory diseases offer primarily symptomatic treatments and limited beneficial outcome.

Salivary gland disease in Sjögren's syndrome: sialoadenitis to lymphoma.

Although the cause and molecular pathways of Sjögren's syndrome are still unknown, basic, clinical, and translational science have started to identify linkages to other known processes. With the advent of newer, more sensitive, and more accurate chemokine, cytokine, and genetic analysis, the molecular progression of the disease may be understood. The modern technology of sialoendoscopy to treat obstructive sialoadenitis from mucous plugging, and the addition of rituximab to current chemotherapy, have allowed patients with Sjögren's syndrome to have a better quality of life and, if they develop lymphomatous changes, a significant increase in their disease remission and survival rate.

Salivary and lacrimal gland dysfunction after remnant ablation with radioactive iodine in patients with differentiated thyroid carcinoma prepared with recombinant human thyrotropin.

BACKGROUND: One of the adverse effects of radioactive iodine (¹³¹I) treatment in patients with thyroid cancer is damage to the salivary and lacrimal glands. In almost all studies evaluating salivary and lacrimal gland dysfunction, the patients received ¹³¹I after levothyroxine (L-T4) withdrawal. Since the biokinetics of ¹³¹I after recombinant human thyrotropin (rhTSH) is not the same as in hypothyroidism, studies need to evaluate ¹³¹I-induced salivary and lacrimal toxicity after preparation with rhTSH. This prospective study investigated the occurrence of salivary and lacrimal damage after ablation with ¹³¹I using this preparation. METHODS: One hundred forty-eight patients who had a total thyroidectomy were included in the study. The subjects were evaluated after thyroidectomy during L-T4 use to exclude those who already showed symptoms or had a history of ocular or oral disease. Symptoms were investigated 12 and 18 months after ablation. In patients who had persistent symptoms, specific tests were performed to confirm glandular dysfunction and to rule out other causes. RESULTS: Twelve months after ablation, symptoms of salivary or lacrimal dysfunction were observed in 10 (6.7%) patients, including oral symptoms in 8 (5.4%) and ocular symptoms in 6 (4%). Eighteen months after ¹³¹I, symptoms persisted in eight (5.4%) patients, including oral symptoms in seven (4.7%) and ocular symptoms in five (3.4%). In all of the patients, glandular dysfunction was confirmed by specific tests and other causes were ruled out. No symptoms were seen in the patients who received a low ¹³¹I dose (30 mCi). In the patients who received high ¹³¹I doses (100 or 150 mCi), symptoms were noted 12 months after ¹³¹I in 10 patients (9.2%), and 18 months after ¹³¹I in 8 patients (7.4%). CONCLUSIONS: Apparently, the rates of salivary and lacrimal damage were lower than those reported in prospective studies that used similar ¹³¹I activities, but these studies were performed in patients who were hypothyroid at the time of ¹³¹I ablation. Further studies are needed to compare radiotoxicity between patients prepared for ¹³¹I ablation with rhTSH and those prepared for ¹³¹I ablation with L-T4 withdrawal.

Early responses to adenoviral-mediated transfer of the aquaporin-1 cDNA for radiation-induced salivary hypofunction.

No conventional therapy exists for salivary hypofunction in surviving head and neck cancer patients with Radiation Therapy Oncology Group late grade 2-3 toxicity. We conducted a phase I clinical trial to test the safety and biologic efficacy of serotype 5, adenoviral-mediated aquaporin-1 cDNA transfer to a single previously irradiated parotid gland in 11 subjects using an open label, single-dose, dose-escalation design (AdhAQP1 vector; four dose tiers from 4.8 × 10(7) to 5.8 × 10(9) vector particles per gland). Treated subjects were followed at scheduled intervals. Multiple safety parameters were measured and biologic efficacy was evaluated with measurements of parotid salivary flow rate. Symptoms were assessed with a visual analog scale. All subjects tolerated vector delivery and study procedures well over the 42-d study period reported. No deaths, serious adverse events, or dose-limiting toxicities occurred. Generally, few adverse events occurred, and all were considered mild or moderate. No consistent changes were found in any clinical chemistry and hematology parameters measured. Objective responses were seen in six subjects, all at doses <5.8 × 10(9) vector particles per gland. Five of these six subjects also experienced subjective improvement in xerostomia. AdhAQP1 vector delivery to a single parotid gland was safe and transfer of the hAQP1 cDNA increased parotid flow and relieved symptoms in a subset of subjects.

Xerostomia and salivary hypofunction in vulnerable elders: prevalence and etiology.

OBJECTIVE: The goal of this article is to review existing research on the prevalence and etiology of dry mouth in the vulnerable elders and identify knowledge gaps. STUDY DESIGN: Vulnerable elders (VE) are persons aged >65 years who have any or all of the following: limited mobility, limited resources, or complex health status. A systematic search was conducted of PubMed sources from 1989 to May 2010. Evidence was evaluated on the prevalence and etiology of xerostomia and salivary gland hypofunction (SGH) in VE. RESULTS: The search identified 1,422 publications. The inclusion/exclusion criteria yielded 348 articles, 80 of which are cited herein. CONCLUSIONS: Research has showed a high prevalence of xerostomia and SGH in VE. Common etiologies include medications, poor general health, female gender, and age. Gaps still exist in the evaluation of dry mouth in VE. Nonetheless, oral dryness will remain an important health issue as life expectancy increases.

[Frequency and causes of functional disorders of salivation in people of different ages].

Frequency and causes of infringement of salivation in people of young, average, elderly and senile age who addressed for rendering assistance in out-patient stomatologic treatment-and-prevention establishments in connection with infringement of function of salivary glands were studied. It is established that frequency of addresses in connection with violations of functions of salivary glands increases with age. The analysis of methods of diagnostics and treatment applied to normalization of function of salivary glands shows that they remain at rather low level.

Diagnosis and gland-preserving minimally invasive therapy for Wharton's duct stenoses.

OBJECTIVES/HYPOTHESIS: The management of stenoses of Wharton's duct has so far been little investigated or systematized. The development of minimally invasive treatment methods, including sialendoscopy, has made preservation of gland function possible. STUDY DESIGN: Retrospective study in a tertiary referral center. METHODS: A total of 153 stenoses of the submandibular duct were diagnosed and treated in 138 patients. Ultrasound and sialendoscopy were the first-choice diagnostic measures. A total of 62.7% of the stenoses were located in the distal, 11.1% in the middle segment, and 18.3% in the proximal to posthilar duct. Diffuse stenoses were observed in 7.8% of the cases. Sialendoscopy-assisted intraductal cortisone administration, interventional sialendoscopy, and transoral ductal surgery were the treatment options. The mean period between treatment and data collection was 52.5 months. RESULTS: Fibrotic stenoses were diagnosed in 88.3% and bilateral involvement in 8.6% of the cases. Distal stenoses were treated predominantly by ductal incision (79.2%). Stenoses of the midsubmandibular duct were treated conservatively in 29.4% or with sialendoscopy or ductal incision in 35.3% of cases each. Proximal up to posthilar stenoses could be dilated by interventional sialendoscopy in 82.2%. In 25% of all diffuse stenoses, glandular resection was carried out, representing 2.6% of all stenoses. Glandular function was preserved in 97.8% of cases. CONCLUSIONS: Stenoses of the submandibular duct can be treated using minimally invasive procedures and with preservation of glandular function with a high success rate. Ductal incision procedures are the most important measure, but sialendoscopy becomes more important the more centrally the stenosis is located.

Assessment of orofacial dysfunctions, salivary cortisol levels and oral health related quality of life (ORHQoL) in young adults.

OBJECTIVE: To investigate the relationship of orofacial dysfunction and salivary cortisol levels with oral health quality of life (ORHQoL) in young adults. DESIGN: Thirty individuals of both genders (22.93±2.42 years) participated. The orofacial dysfunction was evaluated using the Nordic Orofacial Test-Screening (NOT-S) and the ORHQoL using the Oral Health Impact Profile (OHIP-49). Saliva samples were collected during three days, at waking up and 30 min after, obtaining the awakening cortisol response - ACR. The data were analysed by Mann-Whitney test, Spearman's correlation and multiple linear regression (α=0.05). The NOT-S scores and ACR (µg/dl) were dichotomized by the median (2.0 and 0.15, respectively). RESULTS: NOT-S and ACR showed similar values between genders (P>0.05). The individuals with NOT-S scores above the median presented values of "physical pain" domain significantly higher than the individuals with scores bellow or equal to the median. Significant correlations were found between the OHIP-49 domains "physical pain" and "physical disability" and NOT-S scores. In multiple linear regression, significant values were observed between NOT-S and OHIP-49 and the domains physical pain, physical disability, psychological disability, social disability and handicap, with determination coefficients ranging from 0.09 to 0.15. There was not association with the ACR. CONCLUSIONS: Individuals with orofacial dysfunction presented impairment in ORHQoL, but not enough to change salivary cortisol levels. Furthermore, gender did not have influence on ORHQoL in the studied sample.

[Xerostomia, hyposialia, sicca syndrome--quantitative disturbances of the salivary flow rate]. / Xerostomie, hyposialie, sicca syndrom--kvantitativní poruchy salivace.

Diseases of salivary glands may be associated with salivary flow rate disturbances. Production of the saliva is evaluated by sialometric tests. The stress is putted on salivary flow rate disturbances in Sjögren's syndrome, drug-induced and postirradiative sialopathy, and diabetes mellitus. The possibility of the stimulation and substitution of the saliva is discussed.