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.

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.

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.

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.

[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.

[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.

[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.

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.

Conditional overexpression of TGF-beta1 disrupts mouse salivary gland development and function.

Transforming growth factor-beta (TGF-beta) signaling is known to affect salivary gland physiology by influencing branching morphogenesis, regulating ECM deposition, and controlling immune homeostasis. To study the role of TGF-beta1 in the salivary gland, we created a transgenic mouse (beta1(glo)) that conditionally overexpresses active TGF-beta1 upon genomic recombination by Cre recombinase. beta1(glo) mice were bred with an MMTV (mouse mammary tumor virus)-Cre (MC) transgenic line that expresses the Cre recombinase predominantly in the secretory cells of both the mammary and salivary glands. Although most of the double positive (beta1(glo)/MC) pups die either in utero or just after birth, clear defects in salivary gland morphogenesis such as reduced branching and increased mesenchyme could be seen. Those beta1(glo)/MC mice that survived into adulthood, however, had hyposalivation due to salivary gland fibrosis and acinar atrophy. Increased TGF-beta signaling was observed in the salivary gland with elevated phosphorylation of Smad2 and concomitant increase in ECM deposition. In particular, aberrant TGF-beta1 overexpression caused salivary gland hypofunction in this mouse model because of the replacement of normal glandular parenchyma with interstitial fibrous tissue. These results further implicate TGF-beta in pathological cases of salivary gland inflammation and fibrosis that occur with chronic infections in the glands or with the autoimmune disease, Sjögren's syndrome, or with radiation therapy given to head-and-neck cancer patients.

A single centre retrospective analysis of AECG classification criteria for primary Sjogren's syndrome based on 112 minor salivary gland biopsies in a Japanese population.

OBJECTIVE: To assess the usefulness and performance of the American European Consensus Group (AECG) criteria based on minor salivary gland biopsy (MSGB) in Japanese patients with primary SS. METHODS: Among 208 MSGB cases, we retrospectively selected 112 subjects who satisfied the complete set of AECG classification criteria. Of the 112 subjects studied, 63 primary SS patients and 49 non-SS group subjects were classified according to the AECG criteria. The contribution of subjective and objective components was statistically analysed. RESULTS: Sex, dry eye, Saxon test, Schirmer's test, anti-SSA/Ro antibody, MSGB grading and sialography statistically contributed to the diagnosis. Multiple logistic regression analysis showed that positive MSGB [odds ratio (OR) 105; 95% CI 13, 849), positive anti-SSA/Ro antibody (OR 96; 95% CI 10, 923), a positive Saxon test (OR 46; 95% CI, 6, 340) and the existence of dry eye (OR 8, 95% CI 2, 43) were associated with the diagnosis of primary SS. Among the components of the AECG criteria, MSGB and anti-SSA/Ro antibody were very strong contributors. Furthermore, the abnormal-finding positive rate in sialography significantly correlated with MSGB grading (P-value for trend = 0.0006), although other subjective and objective components were not associated with MSGB grading. CONCLUSION: The usefulness of the AECG criteria for Japanese primary SS patients was confirmed.

A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life.

PURPOSE: This systematic review aimed to assess the literature for prevalence, severity, and impact on quality of life of salivary gland hypofunction and xerostomia induced by cancer therapies. METHODS: The electronic databases of MEDLINE/PubMed and EMBASE were searched for articles published in English since the 1989 NIH Development Consensus Conference on the Oral Complications of Cancer Therapies until 2008 inclusive. Two independent reviewers extracted information regarding study design, study population, interventions, outcome measures, results and conclusions for each article. RESULTS: The inclusion criteria were met by 184 articles covering salivary gland hypofunction and xerostomia induced by conventional, 3D conformal radiotherapy or intensity-modulated radiotherapy in head and neck cancer patients, cancer chemotherapy, total body irradiation/hematopoietic stem cell transplantation, radioactive iodine treatment, and immunotherapy. CONCLUSIONS: Salivary gland hypofunction and xerostomia are induced by radiotherapy in the head and neck region depending on the cumulative radiation dose to the gland tissue. Treatment focus should be on optimized/new approaches to further reduce the dose to the parotids, and particularly submandibular and minor salivary glands, as these glands are major contributors to moistening of oral tissues. Other cancer treatments also induce salivary gland hypofunction, although to a lesser severity, and in the case of chemotherapy and immunotherapy, the adverse effect is temporary. Fields of sparse literature included pediatric cancer populations, cancer chemotherapy, radioactive iodine treatment, total body irradiation/hematopoietic stem cell transplantation, and immunotherapy.

Mucus extravasation and retention phenomena: a 24-year study.

BACKGROUND: Mucoceles are benign lesions related to the minor salivary glands and their respective ducts frequently affecting oral structures which are generally asymptomatic. Mucoceles are generally characterized by swollen nodular lesions preferentially located on the lower lip and differ from the so-called ranulas, which are lesions located on the floor of the mouth and related to the sublingual or submandibular glands. METHODS: The objective of the present study was to analyze data such as age, gender, race and site of the lesion of 173 mucocele cases diagnosed at the Discipline of Stomatology, São José dos Campos Dental School, UNESP, over a period of 24 years (April 1980 to February 2003). RESULTS: Of the 173 cases analyzed, 104 (60.12%) were females and 69 (39.88%) were males. Age ranged from 4 to 70 years (mean +/- SD: 17 +/- 9.53) and most patients were in the second decade of life (n = 86, 49.42%); white (n = 124, 71.68%). The lower lip was the site most frequently affected by the lesions (n = 135, 78.03%), whereas the lowest prevalence was observed for the soft palate, buccal mucosa, and lingual frenum. CONCLUSION: In this study, mucoceles predominated in white female subjects in the second decade of life, with the lower lip being the most frequently affected site.

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.

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.

[Dry mouth--oral care for patients with oligoliasia and xerostomia]. / Mundtrockenheit--Ursachen, Diagnose und Betreuung von Patienten mit Oligosialie oder Xerostomie.

Reduced flow (oligosialia) or the complete absence of saliva (xerostomia) decrease the quality of life. While patients suffering from xerostomia are painfully aware of their condition, oligosialia all too often remains unnoticed. The causes of reduced saliva flow are manyfold: somatic or psychosomatic disease, medication, medical therapy, dehydration, age, to name a few. The respective patients suffer from thirst, difficulties in speaking (dysphonia), chewing, tasting (dysgeusia), swallowing (dysphagia) and are at a very high risk for caries as well as for bacterial, viral or fungal infections of the oral mucosa. Early diagnosis and care of oligosialia is mandatory Oral prophylactic care for and dental therapy of xerostomic patients are challenging both for the patients and the dental professionals.

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.

Modern management of obstructive salivary diseases.

Over the last fifteen years, increasing public demand for minimally-invasive surgery and recent technological advances have led to the development of a number of conservative options for the therapeutic management of obstructive salivary disorders such as calculi and duct stenosis. These include extracorporeal shock-wave lithotripsy, sialoendoscopy, laser intra-corporeal lithotripsy, interventional radiology, the video-assisted conservative surgical removal of parotid and sub-mandibular calculi and botulinum toxin therapy. Each of these techniques may be used as a single therapeutic modality or in combination with one or more of the above-mentioned options, usually in day case or one-day case under local or general anaesthesia. The multi-modal approach is completely successful in about 80% of patients and reduces the need for gland removal in 3%, thus justifying the combination of, albeit, time-consuming and relatively expensive techniques as part of the modern and functional management of salivary calculi. With regard to the management of salivary duct anomalies, such as strictures and kinkings, interventional radiology with fluoroscopically controlled balloon ductoplasty seems to be the most suitable technique despite the use of radiation. Operative sialoendoscopy alone is the best therapeutic option for all mobile intra-luminal causes of obstruction, such as microliths, mucous plugs or foreign bodies, or for the local treatment of inflammatory conditions such as recurrent chronic parotitis or autoimmune salivary disorders. Finally, in the case of failure of one of the above techniques and regardless of the cause of obstruction, botulinum toxin injection into the parenchyma of the salivary glands using colour Doppler ultrasonographic monitoring should be considered before deciding on surgical gland removal.

Gene transfer to salivary glands.

This article provides a review of the application of gene transfer technology to studies of salivary glands. Salivary glands provide an uncommon target site for gene transfer but offer many experimental situations likely of interest to the cell biologist. The reader is provided with a concise overview of salivary biology, along with a general discussion of the strategies available for gene transfer to any tissue. In particular, adenoviral vectors have been useful for proof of concept studies with salivary glands. Several examples are given, using adenoviral-mediated gene transfer, for addressing both biological and clinical questions. Additionally, benefits and shortcomings affecting the utility of this technology are discussed.

Electromyography monitoring of patients with salivary gland diseases.

OBJECTIVE: To provide a description of surface electromyography (sEMG) of spontaneous saliva swallowing (SSS) and monitoring of swallow rate in patients with salivary gland diseases. STUDY DESIGN: Numbers of SSS obtained during 2 hours of sEMG monitoring were compared with sialometry data for healthy volunteers (n = 100), patients with Sjögren syndrome (n = 10), and patients after parotid gland (n = 15) and submandibular gland (n = 16) surgery. RESULTS: Normative: 1 SSS every 2 minutes and 15 seconds; Sjögren: 1 SSS every 13 minutes (P < 0.001); parotid gland surgery: 1 SSS every 3 minutes and 24 seconds (P = 0.26); submandibular gland surgery: 1 SSS every 5 minutes and 04 seconds (P < 0.05). Sjögren patients and patients after submandibular surgery had hyposalivation correlated with less SSS. CONCLUSION: The established normal rate of SSS makes this modality applicable for evaluating salivary flow for potentially identifying and ruling out abnormalities. Parotid gland surgery does not significantly affect salivary flow rate. Sialometry combined with sEMG monitoring give a clinician more reliable data to evaluate salivary gland disorders than sialometry alone.