Search

Aging-related salivary dysfunction commonly induces the poor oral health, including decreased saliva flow and dental caries. Although the clinical significance of the salivary glands is well-known, the complex metabolic pathways contributing to the aging-dysfunction process are only beginning to be uncovered. Here, we provide a comprehensive overview of the metabolic changes in aging-mediated salivary gland dysfunction as a key aspect of oral physiology. Several metabolic neuropeptides or hormones are involved in causing or contributing to salivary gland dysfunction, including hyposalivation and age-related diseases. Thus, aging-related metabolism holds promise for early diagnosis, increased choice of therapy and the identification of new metabolic pathways that could potentially be targeted in salivary gland dysfunction.

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 β-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., Competing Interests: The authors declare no conflict of interest.

Hundreds of minor salivary glands (MiSGs) are scattered in the oral cavity located at the submucosa layer. Beside their role in the oral cavity lubrication and immunity defence system, MiSGs are beneficial tissue source for diagnosing oral and non-oral related diseases. The advantage of MiSGs as a diagnostic tool reside on their fairly simple excisional procedure on one hand and negligible impact of the normal secretion capability of the salivary gland system on the other hand. The review focuses on pathologies related to developmental, reactive, metabolic, inflammatory and immunologic conditions, Iatrogenic causes and other undefined causes., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Background: Radioiodine (RI) treatments can destroy the cellular components of salivary glands (SG) and disrupt their function. This study investigated whether fucoidan could attenuate radioiodine-induced SG dysfunction in a mouse model., Methods: Female C57BL/6 mice (n = 36) were classified into three groups; i) a normal (control) group, ii) an RI-treated group (0.2 mCi/20 g mouse, administered orally), and iii) a fucoidan and RI-treated group. Mice in each group were classified into three subgroups and sacrificed at 2, 4, and 12 weeks after RI treatment. The measurements of salivary flow rates and lag times and histomorphologic examinations were performed, and apoptotic assays were conducted. Changes in salivary 99m Technetium (Tc)-pertechnetate parameters using single-photon emission computed tomography were followed., Results: Salivary flow rates and lag times in the fucoidan group were improved compared to the RI-treated group. Histologic examinations of SGs in the fucoidan group showed mucin-rich parenchymal areas and reduced periductal fibrosis as compared to the RI-treated group. Moreover, compared with the RI-treated group, fucoidan-treated groups showed evidence of cytoprotection, with a greater number of salivary epithelial cells and myoepithelial cells being observed. Fewer apoptotic cells were observed in the fucoidan group as compared to the RI group. The extent of 99m Tc pertechnetate excretion in the fucoidan group was similar to that of the control group., Conclusion: Our results demonstrate that fucoidan administration before RI treatment could attenuate RI-induced SG damage and provides a possible candidate for preventing SG damage induced by RI.

Background: Following radioiodine (RI) therapy, oxidative stress is a putative damage mechanism resulting in salivary gland (SG) dysfunction. Since ginseng is a known anti-oxidative herb, we examined the SG radioprotective effects of Korea red ginseng (KRG) in a mouse model, when administered prior to RI., Methods: Four-week-old mice (n = 60) were divided into four groups: (1) normal control, (2) RI only treated (0.01 mCi/g, orally), (3) KRG administered (0.2 mg/g, intraperitoneal injection) 0.5 and 24 hours before RI, and (4) amifostine-treated group (0.2 mg/g, intraperitoneally) 0.5 hour before RI. The salivary lag times and flow rates were assessed, and sampled tissues were subjected to histologic examinations including hematoxylin and eosin and immunohistochemical staining. Apoptosis was examined by the terminal deoxynucleotidyl transferase biotin-dUDP nick end labeling (TUNEL) assay, and excretion changes in salivary 99m Tc pertechnetate were evaluated by single-photon emission computed tomography., Results: The body weight of the KRG group was similar to the control group. Salivary lag times and flow rates in the RI + KRG group were faster than in the RI only group. There was no significant intergroup difference in the SG weight. The RI + KRG group exhibited more mucin-containing parenchyma and less fibrotic tissues than the RI only group. Salivary epithelial (aquaporin 5) and myoepithelial (smooth muscle actin) cells of the RI + KRG group were protected from radiation damage. Low 8-OhdG (oxidative stress biomarker) and high superoxide dismutase 2 (reactive oxygen species scavenger) immunostaining reactivity was detected in the RI + KRG group when compared with the RI only group. Fewer apoptotic cells were observed in the RI + KRG or amifostine group compared to the RI only group in the TUNEL assay. The 99m Tc pertechnetate excretion level recovered in the KRG group., Conclusion: Pretreatment with KRG before RI therapy is potentially beneficial in protecting against RI-induced salivary dysfunction.

Background: Respiratory illnesses are a leading cause of morbidity and medical discharge in the military. This study aimed to investigate the effects of baseline aerobic fitness on haematological, salivary and mood variables, and simultaneously, in a novel approach, to identify factors precipitating illness and attrition rate in recruits during military training., Methods: Thirty-five healthy male recruits from an Army Training Regiment undertaking 12 weeks of training were prospectively investigated. Their 2.4 km run time (RT) was used as a surrogate of baseline aerobic fitness. Saliva and venous blood samples were analysed for secretory IgA, full blood counts and cell cytokine production (interleukin (IL) 6 and IL-8), respectively. Each recruit completed questionnaires on mood profile, and gastrointestinal and upper respiratory tract symptoms (URTS)., Results: Significant salivary and haematological perturbations were observed and coincided with increased duration of URTS/week and mood disturbance over this military training period. From Start to End: leucocyte count decreased by 28% (p<0.001); neutrophil percentage (%) decreased by 13% (p<0.01); lymphocyte % increased by 17% (p<0.05); the neutrophil:lymphocyte ratio decreased by 22% (p<0.01); eosinophil% increased by 71% (p<0.01). From Start to Mid to End: monocyte% increased by 68% at Mid (p<0.01) but only by 30% at End (p<0.01); IL-6 increased by 39% at Mid (p<0.01) and a further 61% by End. The 2.4 km RT was significantly associated with URTS duration (p<0.01). In addition, a 1-min increase in 2.4 km RT increased a recruit's risk 9.8-fold of developing URTS lasting, on average, 3.36 days/week. In recruits ranked with high-URTS duration their RT was 48 s slower (p<0.01) than those with low-URTS, and their attrition rate reached 45%., Conclusions: The least fit recruits may have found training more physically demanding as reflected in the higher URTS duration, which may have led to a high attrition rate from the Army. It is worth considering that baseline aerobic fitness might be an important factor in illness development and attrition rate in recruits during this type of military training., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

The metabolic profile of major salivary glands was evaluated by 13 C nuclear magnetic resonance isotopomer analysis ( 13 C NMR-IA) following the infusion of [U- 13 C]glucose in order to define the true metabolic character of submandibular (SM) and parotid (PA) glands at rest and during salivary stimulation, and to determine the metabolic remodeling driven by diabetes. In healthy conditions, the SM gland is characterized at rest by a glycolytic metabolic profile and extensive pyruvate cycling. On the contrary, the PA gland, although also dominated by glycolysis, also possesses significant Krebs' cycle activity and does not sustain extensive pyruvate cycling. Under stimulation, both glands increase their glycolytic and Krebs' cycle fluxes, but the metabolic coupling between the two pathways is further compromised to account for the much increased biosynthetic anaplerotic fluxes. In diabetes, the responsiveness of the PA gland to a salivary stimulus is seriously hindered, mostly as a result of the incapacity to burst glycolytic activity and also an inability to improve the Krebs' cycle flux to compensate. The Krebs' cycle activity in the SM gland is also consistently compromised, but the glycolytic flux in this gland is more resilient. This diabetes-induced metabolic remodeling in SM and PA salivary glands illustrates the metabolic need to sustain adequate saliva production, and identifies glycolytic and oxidative pathways as key players in the metabolic dynamism of salivary glands., (Copyright © 2016 John Wiley & Sons, Ltd.)

Radiation-induced salivary gland dysfunction is the most frequent side-effect of I-131 thyroid therapy. Here, a novel saliva sampling method with ordinary chewing gums administered to the patients at appropriate time intervals post-treatment (TIPT) was used to relate this effect to chewing gum saliva activity (CGSA) content. Saliva samples were acquired after the oral administration of prescribed I-131 activity (radioactivity administered [RA]) to 19 differentiated thyroid cancer (DTC) and 16 hyperthyroidism patients of the radioisotope unit (RIU) during 2014 and 2015. The error of this saliva collecting process was found to be 1.2%-2.05%, and so, the method was considered satisfactory. For each patient, the CGSA was plotted against the TIPT producing a curve, R(t). On this, two functions were fitted: a linear on the first few rising data points and a gamma variate over the peak of the R(t). From these, several parameters related to the radioactivity oral transit were calculated and the total radioactivity administered (TRA) during all past treatments of each patient was obtained from RIU records. The patients were asked to report any swelling, dry mouth, taste-smell change, or pain and were graded as a morbidity score (MS) describing the quality of life of each. The peak radioactivity in the saliva samples, R max , was found to be proportional to RA and was plotted against the CGSA extrapolated at 24 and 36 hours. The linear fits produced were used to estimate the salivary glands' activity average effective half-life (16.3 hours). The MS of DTC patients was found to depend linearly both on R max and TRA (MS = 0.0032 × R max - 0.7107 and MS = 0.1862 × TRA +0.66, respectively). Both lines were used to extrapolate symptom thresholds. The measurement of R max in DTC patients proved very useful for individualized radiation protection, and the dependence of MS on TRA should be used when additional treatments are considered for repeat DTC patients.

Aluminum absorption leads to deposits in several tissues. In this study, we have investigated, to our knowledge for the first time, aluminum deposition in the salivary glands in addition to the resultant cellular changes in the parotid and submandibular salivary glands in a model of chronic intoxication with aluminum citrate in rats. Aluminum deposits were observed in the parotid and submandibular glands. Immunohistochemical evaluation of cytokeratin-18 revealed a decreased expression in the parotid gland with no changes in the submandibular gland. A decreased expression of α-smooth muscle actin was observed in the myoepithelial cells of both glands. The expression of metallothionein I and II (MT-I/II), a group of metal-binding proteins, which are useful indicators for detecting physiological responses to metal exposure, was higher in both glands. In conclusion, we have shown that at a certain time and quantity of dosage, aluminum citrate promotes aluminum deposition in the parotid and submandibular glands, leads to an increased expression of MT-I/II in both the glands, damages the cytoskeleton of the myoepithelial cells in both glands, and damages the cytoskeleton of the acinar/ductal cells of the parotid glands, with the submandibular glands showing resistance to the toxicity of the latter.

Sclerosing polycystic adenosis (SPA) is a rare condition of salivary glands. The most common site is the parotid gland (80 % of cases). SPA shows no gender predilection and occurs over a wide age spectrum (9-84 years). SPA is mostly unifocal, but may rarely be multifocal. Histologically, SPA are sharply circumscribed mostly unencapsulated lesions composed of acinar and ductal components with variable cytomorphological characteristics, including foamy, vacuolated, apocrine, mucous, clear/ballooned, squamous, columnar and oncocyte-like cells. Characteristic for SPA is the presence of large acinar cells with abundant eosinophilic cytoplasmic granules. The stroma is densely collagenized, frequently harbouring a variably intense chronic inflammatory infiltrate and may contain fat. Rarely the stroma is myxoid. Some degree of intraductal epithelial proliferations have been reported in at least 50 % of cases. The proportion of cases with epithelial proliferations that fulfill criteria for high-grade ductal carcinoma in-situ is <10 %. Immunohistochemically, both ductal and acinar cells are positive for broad spectrum cytokeratins. There is variable immunoreactivity for epithelial membrane antigen and S-100 protein. CEA, p53 and HER2 is reportedly negative. Gross cystic disease fluid protein-15 is strongly expressed in the acinar component. There is consistent but variable expression of estrogen and progesterone receptors. The proliferative index (Ki-67) is low (1-2 %) in the benign (acinar and ductal) components. Using HUMARA methodology (non-random inactivation of X-chromosomes), six cases with atypical epithelial proliferations have been shown to be clonal processes. Recurrences have been reported in up to 19 % of cases.

Previously, we pointed out on a possible role of aquaporin 5 (AQP5) in the development of sialadenosis. The goal of the present study was to further assess the association of AQP5 in the development of this salivary gland disease. The acinar diameter and mean surface area appeared elevated in sialadenosis tissues, which is a typical observation in this disease. AQP5 expression was evaluated by immunohistochemistry using tissue samples derived from salivary glands of patients with confirmed sialadenosis either as a primary diagnosis or as a secondary diagnosis within the framework of other salivary gland diseases. Normal salivary gland tissue served as a control. In sialadenosis tissues, the AQP5 signal at the apical plasma membrane of acinar cells frequently appeared stronger compared with that in normal salivary glands. In addition, the distribution of AQP5 at the apical region seemed to differ between normal and sialadenosis tissues, where AQP5 frequently was diffusely distributed near or at the apical plasma membrane of the acinar cells in contrast to normal controls where the AQP5 signal was strictly confined to the apical plasma membrane. These observations suggest that sialadenosis is associated with a different AQP5 expression and distribution pattern in salivary acinar cells.

The transmission of herpesviruses depends on viral shedding at mucosal surfaces. The salivary gland represents a major site of persistent viral replication for many viruses, including cytomegalovirus. We established a mouse model of salivary gland dysfunction after acute viral infection and investigated the cellular requirements for the loss of secretion. Murine cytomegalovirus (MCMV) infection severely impaired saliva secretion independently of salivary gland virus levels. Lymphocytes or circulating monocytes/macrophages were not required for secretory dysfunction. Dysfunction occurred before glandular inflammation, suggesting that a soluble mediator initiated the disruption of acinar cell function. Despite genetic differences in innate resistance to MCMV, NK cells protected the host against acinar atrophy and the loss of secretions under conditions of an exceedingly low virus inoculum. NK cells also modulated the type of glandular inflammation after infection, as they prevented an influx of Siglec-F(+) polymorphonuclear leukocytes (PMNs). Therefore, beyond their recognized role in controlling MCMV replication, NK cells preserve organ integrity and function and regulate the innate inflammatory response within the gland.

Background & Aims: Excessive Ca2+ influx mediates many cytotoxic processes, including those associated with autoimmune inflammatory diseases such as acute pancreatitis and Sjögren syndrome. Transient receptor potential (canonical) channel (TRPC) 3 is a major Ca2+ influx channel in pancreatic and salivary gland cells. We investigated whether genetic or pharmacologic inhibition of TRPC3 protects pancreas and salivary glands from Ca2+-dependent damage., Methods: We developed a Ca2+-dependent model of cell damage for salivary gland acini. Acute pancreatitis was induced by injection of cerulein into wild-type and Trpc3-/- mice. Mice were also given the Trpc3-selective inhibitor pyrazole 3 (Pyr3)., Results: Salivary glands and pancreas of Trpc3-/- mice were protected from Ca2+-mediated cell toxicity. Analysis of Ca2+ signaling in wild-type and Trpc3-/- acini showed that Pyr3 is a highly specific inhibitor of Tprc3; it protected salivary glands and pancreas cells from Ca2+-mediated toxicity by inhibiting the Trpc3-mediated component of Ca2+ influx., Conclusions: TRPC3-mediated Ca2+ influx mediates damage to pancreas and salivary glands. Pharmacologic inhibition of TRPC3 with the highly selective TRPC3 inhibitor Pyr3 might be developed for treatment of patients with acute pancreatitis and Sjögren syndrome., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: Among the diverse forms of amyloidosis, secondary type is the most frequent one. Diagnosis of amyloid deposition is based on the identification of the fibrillary protein amyloid by means of Congo Red (CR) or crystal violet (CV) stains, but these techniques do not differentiate between the different types of amyloid fibrils. The aim of this study was to identify by immunofluorescence (IF) AA amyloid a pathological fibrillar low-molecular-weight protein formed by cleavage of serum amyloid A (SAA) protein in labial salivary gland (LSG) biopsies from patients with secondary amyloidosis., Study Design: 98 LSG were studied, 65 were from patients with secondary amyloidosis and 33 from subjects with chronic inflammatory diseases without evidence of this anomaly. All sections were stained with hematoxylin and eosin (H &E), CV, CR and IF using anti-AA antibodies. Positive and negative controls were used for all techniques., Results: CV and CR demonstrated that the amyloid substance was found mainly distributed periductally (93.8%), followed by periacinar and perivascular locations (p <0.001); however, the IF demonstrated that amyloid AA substance predominates in the periacinar area (73.8%), followed by periductal and perivascular locations (p <0.001). IF has a sensitivity of 83%, 100% of specificity, 100% of predictive positive value and 75% of predictive negative value., Conclusions: The results of this study confirm the efficacy of the LSG biopsy as a highly reliable method for diagnosis of secondary amyloidosis.

Branching morphogenesis is a crucial developmental process in which vertebrate organs generate extensive epithelial surface area while retaining a compact size. In the vertebrate submandibular salivary gland, branching morphogenesis is crucial for the generation of the large surface area necessary to produce sufficient saliva. However, in many salivary gland diseases, saliva-producing acinar cells are destroyed, resulting in dry mouth and secondary health conditions. Systems-based approaches can provide insights into understanding salivary gland development, function, and disease. The traditional approach to understanding these processes is the identification of molecular signals using reductionist approaches; we review current progress with such methods in understanding salivary gland development. Taking a more global approach, multiple groups are currently profiling the transcriptome, the proteome, and other 'omes' in both developing mouse tissues and in human patient samples. Computational methods have been successful in deciphering large data sets, and mathematical models are starting to make predictions regarding the contribution of molecules to the physical processes of morphogenesis and cellular function. A challenge for the future will be to establish comprehensive, publicly accessible salivary gland databases spanning the full range of genes and proteins; plans are underway to provide these resources to researchers in centralized repositories. The greatest challenge for the future will be to develop realistic models that integrate multiple types of data to both describe and predict embryonic development and disease pathogenesis., (© 2010 John Wiley & Sons, Inc.)

Usually no distinction is made between female and male salivary glands although cyclic changes of and ⁄ or differences in serum and salivary sex steroid concentrations characterize women and men. Moreover, sexual dimorphism is well recognized in salivary glands of rodents.Salivary glands contain estrogen and androgen receptors and are, according to modern high throughput technologies,subjected to gender differences not explainable by gene dose effects by the X chromosome alone. Because sex steroids are lipophilic, it is often thought that approximately 10% of them passively diffuse from plasma to saliva. Indeed, saliva can find use as sample material in sports medicine, pediatrics, veterinary medicine and behavioral sciences. Last but not least, humans and other primates are unique in that they have a reticular zone in their adrenal cortex, which produces dehydroepiandrosterone and androstendione pro-hormones. These are processed in peripheral tissues, not only in female breast and uterus and male prostate, but also in salivary glands by an intracrine enzymatic machinery to active 17b-estradiol,dihydrotestosterone and others, to satisfy and buffer against a constantly changing needs caused by circadian,menstrual, pregnancy and chronobiological hormonal changes in the systemic circulation. Female dominance of Sjögren's syndrome and certain forms of salivary gland cancer probably reflect these gender-based differences.

Sclerosing polycystic adenosis (SPA) is a pathology of the salivary gland which occurs infrequently and has a controversial etiology. In this study, we investigated the possible roles of HPV and EBV in the pathogenesis of SPA. Archived cases of salivary gland lesions were retrieved, and their diagnoses were re-evaluated; cases that fit the diagnosis of SPA were selected and subjected to Alcian Blue-Periodic Acid Schiff's histochemical staining and immunohistochemical staining for HPV-1, EBV, S-100, and Bcl-2 proteins in addition to the proliferative marker Ki-67. In addition, RNA extracted from formalin-fixed, paraffin-embedded tissues was subjected to RT-PCR to confirm any positive immunohistochemical results. Co-localization of EBV and Bcl-2 in lesional cells was the most striking finding; Ki-67 was expressed in basal cells, while no expression was seen in the adjacent salivary gland cells. Our EBV (+) ve immunostaining results were confirmed by RT-PCR using RNA extracted from paraffin sections. Our results suggest a significant pathogenic role of EBV in SPA. Moreover, they provide new evidence on the neoplastic nature of SPA.

Objective: Signal transducer and activator of transcription 3 (Stat3) and survivin have been shown to exert oncogenic effects in various human neoplasms. The purpose of this study was to evaluate the expression of tyrosine phosphorylated (active) Stat3 and survivin in various benign and malignant salivary gland tumors (SGTs)., Study Design: Eighty-six SGTs (65 malignant and 21 benign tumors of various histopathologic subtypes) were immunohistochemically stained with antisurvivin or anti-phosphorylated tyrosine-705 (p-tyr) Stat3 antibodies. Immunohistochemical reactivity was graded in a semiquantitative manner; a combined score of immunohistochemical positivity (0-6) was calculated for each tumor by adding the individual scores for percentage of tumor cells (0-3) and intensity of staining (0-3)., Results: Survivin was immunohistochemically detected in all studied benign and malignant SGTs; p-tyr Stat3 was also detected in the majority (91%) of SGTs. The average combined scores for survivin and p-tyr Stat3 immunohistochemical expression in the studied malignant SGTs was 4.40 and 3.35, respectively; the corresponding combined scores for survivin and p-tyr Stat3 in the studied benign SGTs were 4.37 and 3.22, respectively. No statistically significant differences (P > .05) in p-tyr Stat3 or survivin expression were detected between the benign and malignant groups, or among the various examined histopathologic subtypes of SGTs. In contrast, normal salivary gland tissues revealed only weak and focal survivin or p-tyr Stat3 immunoreactivity, mainly localized to ductal and mucous cells., Conclusions: Our data indicate an almost universal expression of activated Stat3 and survivin in benign and malignant SGTs. Considering the well established proliferative and antiapoptotic properties of these molecules and their functional interrelationship, selective targeting techniques against Stat3 and/or survivin may represent promising therapeutic strategies against neoplasms of salivary gland origin.

Background and Objectives: Minimal-to-low grade fluorodeoxyglucose (FDG) uptake in the parotid glands is regarded as a normal variant in a whole-body survey with FDG-PET. Not frequently, however, a relatively intense or asymmetric FDG uptake is encountered in the parotid glands. The aim of this study was to determine the causes and characteristics of this 'FDG accumulation of uncertain significance' in the parotid glands in patients without any known or suspected pathologies at the time of whole-body FDG-PET. In addition, we also examined patients in whom there was no documented evidence of parotid pathology before FDG-PET scan and a suspicion of disease involvement was first raised in the reports in view of focal uptake in the FDG-PET images., Materials and Methods: A total of 25 patients with 49 PET examinations [46 PET and three PET/computed tomography (CT) scans] were identified from the retrospective examination of PET reports and were analyzed in this study. Only those cases with no earlier history of disease involvement of parotid gland or known parotid pathology before FDG-PET were selected for this analysis. These patients were selected from a population of patients with a known malignancy elsewhere who underwent conventional whole-body FDG-PET or PET/CT for staging, disease viability assessment, or treatment monitoring purposes and had demonstrated varying patterns of FDG uptake (unilateral, bilateral, symmetric, or asymmetric) in the parotid glands. FDG uptake in the parotid glands was reported to be of uncertain significance in the majority of these patients and further correlation was suggested in the PET reports. In five patients with asymmetric and focally enhanced FDG uptake, a suspicion of disease involvement was raised in the reports. The results of appropriate correlative investigations with MRI, low-dose nonenhanced attenuation CT images (based on PET/CT scans), and histopathology (in cases in which focal lesions were revealed by the anatomic imaging modalities and biopsy was performed) carried out subsequent to the FDG-PET scans were reviewed for a definitive conclusion with regard to the significance of the FDG uptake in the parotid glands in these patients. In the absence of any focal pathology, clinical and follow-up FDG-PET data were reviewed for a logical conclusion, which were available in a majority of these patients. Standardized uptake values (maximum) were calculated by generating a manual region of interest over FDG activity. The pattern and the intensity of the FDG uptake were correlated with the final diagnosis., Results: In six of the 25 patients with diffuse and symmetrical FDG uptake no clearcut pathology was demonstrated by clinical or radiological examinations. Five patients of this subgroup also demonstrated associated enhanced FDG activity in the submandibular salivary glands. Nineteen patients (76%) demonstrated asymmetric FDG uptake. Among these, focally enhanced uptake was observed in seven patients (28% of the total number of patients and 36.8% of the patients who demonstrated asymmetric FDG uptake in the parotids). Twelve patients (48% of total patients and 63.2% of the patients who demonstrated asymmetric FDG uptake) demonstrated asymmetric and diffuse FDG uptake pattern. No revelation of disease either by the MRI or follow-up clinical and FDG-PET examinations was observed in patients with asymmetric diffuse uptake. Five of the seven patients, who had asymmetric focal uptake in one of the parotids, were found to have focal lesions in either correlative MRI or low-dose nonenhanced CT. The final diagnosis based upon histopathology revealed primary parotid tumors (e.g., Warthin's tumor and pleomorphic adenoma, which presented as FDG-avid parotid incidentaloma) or metastatic disease involvement., Conclusion: Both the pattern and intensity of FDG uptake have important implications for differential diagnosis in the salivary glands in whole-body FDG-PET. A bilaterally symmetrical increased uptake is usually physiological. An asymmetrical uptake, especially when focal, would warrant further radiological and histopathological correlation to rule out disease involvement. At times, this can lead to the detection of an asymptomatic hitherto unknown etiology, which would have been otherwise interpreted as a metastatic disease in the background of an existing malignancy in these patients; this is noteworthy as it may have a bearing on the subsequent management of these patients.

Unlabelled: Gastro-esophageal reflux disease (GERD) is associated with a decreased salivary flow as well as gastric acid production. This study therefore aimed to investigate functional disorders of salivary glands in patients with GERD., Methods: Thirty-one consecutive patients with GERD underwent salivary gland scintigraphy., Results: If the results defined the optimal cutoff point for determining the decreased salivary secretion as 51 % in parotid glands and 36 % in submandibular glands, a decreased salivary secretion of right parotid gland, left parotid gland, right submandibular gland, and left submandibular gland was found in 39 %, 32 %, 36 %, and 58 %, respectively. Overall, salivary function disorder of at least one major salivary gland was found in 24 patients (78 %) with GERD. There was no difference in the incidence of impaired salivary function between GERD patients with and without erosive esophagitis. Salivary gland function was more frequently diminished than expected in GERD. We concluded that the presence of impaired salivary gland function was considered to be one of risk factors for developing GERD symptoms.

Recently, we reported development of the C57BL/6.NOD-Aec1Aec2 mouse carrying two genetic intervals derived from the NOD mouse. These two genetic regions confer full Sjögren's syndrome (SjS)-like disease in SjS-non-susceptible C57BL/6 mice. The current study was undertaken to apply microarray technology to define the molecular basis underlying onset of SjS-disease in C57BL/6.NOD-Aec1Aec2 mice. Using oligonucleotide microarrays, gene expression profiles of submandibular glands derived from 8- to 12-week-old C57BL/6.NOD-Aec1Aec2 mice and 8-week-old C57BL/6 mice were performed for comparison. Significant differential expressions were determined using the Mann-Whitney U test. Hybridizations using submandibular cDNA probes revealed 75 differentially expressed genes at 8 weeks and 105 differentially expressed genes at 12 weeks of age in C57BL/6.NOD-Aec1Aec2 mice compared to 8-week-old C57BL/6 mice. These genes were related generally to basic cellular activities such as transcription, translation, DNA replication, and protein folding. During the predisease phase, genes upregulated encode proteins associated with the IFN-gamma signal-transduction-pathway (Jak/Stat1), TLR-3 (Irf3 and Traf6) and apoptosis (casp11 and casp3), indicative of chronic proinflammatory stimuli, especially IL-1. Between 8 and 12 weeks of age, sets of clustered genes were upregulated that are associated with adaptive immune responses, especially B cell activation, proliferation and differentiation (Baffr, Taci, Bcma, Blys, April, CD70, CD40L, Traf1, Traf3, Pax5, c-Jun, Elk1 and Nf-kB), and neural receptors (Taj/Troy). Altered gene expressions of TLR3 and TNF-superfamily-receptors and ligands during this early phase of SjS suggest a possible viral etiology in the altered glandular homeostasis with an upregulated, possibly overstimulated, B-lymphocyte activation in the early autoimmune response present in the submandibular glands. The importance of NF-kappaB as a critical signal transduction pathway is also suggested but its link is not yet clear.

This study evaluated the flow rate and composition of whole saliva in patients with chronic renal failure undergoing hemodialysis. In the group on dialysis (RG) (n = 15), saliva was collected just prior to hemodialysis CT1) and at completion (T2), while in the healthy subjects (HG)(n = 15) saliva was collected at the same time of day as the pre-dialysis. Saliva samples were analyzed by inductively coupled argon plasma with atomic emission spectrometry. Significant differences were found in the flow rate, potassium, magnesium and phosphorus concentrations at the RG-T1 and HG (p < 0.05). Sodium concentration at RG-T1 and RG-T2 were higher than HG (p < 0.05). Total protein concentration was higher at RG-T1 than at the other two analyses. Salivary peroxidase activity at RG-T1 and RG-T2 was lower than at HG. Our findings suggest that in patients with chronic renal failure, the saliva is altered. Hemodialysis, however, seems to help control saliva composition and flow rate.

Objectives: To investigate the topography of E-cadherin and its possible correlation with the histological phenotype of salivary gland tumours., Material and Methods: Archival formalin-fixed, paraffin-embedded sections of 54 benign and 56 malignant tumours and 24 samples of normal and inflamed salivary gland tissue were studied immunohistochemically using an Envision/horseraddish peroxidase (HRP) technique., Results: In normal and inflamed salivary gland samples, E-cadherin was expressed at the membrane of acinar, myoepithelial and ductal cells located at cell-cell contact points. Reduction and/or absence of E-cadherin was only observed in pleomorphic adenoma at the peripheral cells of the duct-like or island structures, or in the cells exhibiting plasmacytoid or stromal differentiation. Neoplastic epithelium in Warthin's tumours and in myoepithelial and oncocytic adenomas was strongly positive. Furthermore, a weak to moderate loss of expression which was related to tissue tumour subtype was seen in malignant tumours such as: adenoid cystic carcinomas; polymorphous low-grade adenocarcinomas; acinic cell carcinomas; and mucoepidermoid low-grade, epithelial-myoepithelial, lymphoepithelial and squamous low-grade carcinomas. Moderate to extreme loss or alternative cytoplasmic non-functional expression were observed in cases of salivary ductal carcinoma, carcinosarcoma, myoepithelial carcinoma, oncocytic adenocarcinoma, unspecified adenocarcinoma and squamous high-grade carcinomas., Conclusion: This study suggests a direct association of E-cadherin expression with neoplastic histologic phenotype, which is lost in the more undifferentiated and invasive epithelial salivary gland tumours.

The fortuitous observation of salivary microliths in ferret was pursued in the present investigation. Major salivary glands obtained post-mortem from mature ferrets of either sex were examined with the use of histology and light microscopical histochemistry for calcium, protein, amino acids, mucosubstances and hydrolytic enzymes. Microliths were detected in most parotids, but were absent from submandibular and sublingual glands. The microliths were usually seen in lumens, and occasionally in parenchyma and interstices. They were variably stained for calcium, tryptophan, and neutral and acidic mucosubstances, similarly to acinar or ductal secretory granules. Unlike secretory granules, microliths showed autofluorescence, high levels of tyrosine and a low concentration of -SS- groups. Acid phosphatase and beta-glucuronidase reaction surrounded non-luminal microliths. The present data establish ferret as a new model for the investigation of salivary microliths and do not support the notion of microliths being almost absent from the parotid. Probably there is secretory inactivity in ferret parotid and this fosters the formation and accumulation of microliths containing calcium and disintegrated secretory material.

Sclerosing polycystic adenosis is a recently described, extremely rare, reactive, sclerosing, inflammatory process somewhat similar to fibrocystic changes and adenosis tumor of the breast. To date, there have been 22 cases described in the literature. Because of the infrequency of this lesion, we describe our combined experience with 16 cases, 1 of which has been previously reported. Thirteen tumors arose in the parotid gland, two involved the submandibular gland, and one arose in the buccal mucosa. There were 9 men and 7 women. Patients ranged in age from 9 to 75 years. Fourteen patients presented with a primary mass. Two were incidental findings in patients with a mixed tumor and an oncocytoma. Tumors ranged in size from 0.3 to 6 cm in greatest dimension. They are typically well circumscribed and are composed of densely sclerotic lobules with prominent cystic change. Hyperplasia of ductal and acinar elements and areas of apocrine-like metaplasia are frequent. Foci with mild ductal epithelial atypia were frequent with >50% of cases demonstrating at least focal areas of duct epithelial hyperplasia with atypia. Follow-up ranged from 1.5 to 40 years. One tumor recurred twice; no patient has developed metastases or died of disease.

33 patients with complaints of hyposalivation (21 in a 33 with syaloadenopatya and 12 in a 33 with syalosis out of the acute stage of disease) were examined. Complex examination of the saliva glands, analysis of the haemokynes in the various mediums of organism and thyoles compounds in the blood plasma was carried out. Tendency to increase in contents of haemokynes in the mixed saliva and in the tissue samples (from low in the syaloadenopatya to expressed in the syalosis) was revealed. Reduction of thyosulfide index in the blood plasma of these patients was determined. Use of antioxidant remedy in complex treatment of syaloadenopatya and syalosis was substanciated in this paper.

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.

We carried out a retrospective study on non-neoplastic enlargement of the salivary glands at the Oral Histopathology Diagnostic Center of the Autonomous Metropolitan University at Xochimilco (UAM-Xochimilco) in Mexico during a period of 24 years (1979-2003). From 5,625 biopsies received and analyzed, a total of 461 (8.2%) were non-neoplastic enlargement of the salivary glands; for each case, we registered demographic data as well as clinic characteristics. These lesions were characterized as a heterogeneous group of pathologic entities among which we included local, obstructive, infectious, and immunopathologic lesions. The most frequent lesion was the extravasation cyst in 341 (74%) cases, followed by chronic sialoadenitis and Sjögren's syndrome with 54 (11.7%) and 41 (8.8%) cases, respectively, and at a lesser percentage mucous retention cyst, sialosis, benign lymphoepithelial lesions and those related with sialolytes. Females were affected more frequently; mean age was second to third life decades. These lesions were most frequently localized on inferior labial mucosa.

The insulin-like growth factors (IGF) are a family of growth factors, receptors and binding proteins that are involved in numerous growth and differentiation processes, as well as in various pathological conditions. The aim of this review is to summarize data that has been accumulating in recent years linking the IGF system to a number of physiological and pathological oral processes. The IGF system fulfills an important role in growth and development of teeth, mandible, maxillae, and tongue. It has been postulated that IGF-I may be of great value in the treatment of periodontal defects and in tissue healing. Furthermore, IGF-II has been shown to be overexpressed in salivary gland adenomas, suggesting that aberrant IGF signaling may be a key factor in the etiology of oral malignancies. Understanding the role and regulation of IGF system components in salivary glands and other oral structures will be of significant basic and clinical relevance.

Hirudotherapy was used in the treatment of 39 patients (10 male and 29 female) aged 28-58 years with chronic sialadenitis and sialadenosis. Control group consisted of 15 normal subjects without diseases of salivary glands. Lipid peroxidation (LPO) and antioxidant defense (AOD) parameters were under study. Hirudotherapy led to improvement of the clinical status in the majority of patients with sialadenosis; the content of superoxide dismutase (SOD) normalized and ceruloplasmin (CP) level increased. The status of patients with sialadenitis also improved; catalase and glutathione peroxidase levels normalized and SOD and CP levels increased. The best therapeutic effect was attained in patients with sialadenitis. No appreciable improvement was observed in patients with chronic parenchymatous parotitis in the presence of Sjogren's syndrome.

Objective: To investigate functional properties of the germinal center (GC)-like structures observed in salivary glands of patients with Sjögren's syndrome (SS) and to determine the frequency with which such structures develop., Methods: Hematoxylin and eosin-stained sections from 165 minor salivary gland biopsy samples were screened for GC-like structures. Expression of markers for GCs (CD3, CD20, Ki-67, CD35, CD31), adhesion molecules (intercellular adhesion molecule 1, lymphocyte function-associated antigen 1, vascular cell adhesion molecule 1, very late activation antigen 4), chemokines (CXCL13, CCL21, CXCL12), and production of autoantibodies (anti-Ro/SSA and anti-La/SSB) was investigated by immunohistochemistry. Apoptosis was investigated by TUNEL staining., Results: GC-like structures were observed in 28 of 165 patients (17%). When GCs were defined as T and B cell aggregates with proliferating cells with a network of follicular dendritic cells and activated endothelial cells, such microenvironments were found in all patients in whom structures with GC-like morphology were observed. The defined microenvironments were not found in patients without apparent GC-like structures. The GCs formed within the target tissue showed functional features with production of autoantibodies (anti-Ro/SSA and anti-La/SSB) and apoptotic events (by TUNEL staining), and the local production of anti-Ro/SSA and anti-La/SSB autoantibodies was significantly increased (P = 0.04) in patients with GC development., Conclusion: Lymphoid neogenesis and functional ectopic GC formation take place in salivary glands of a subset of patients with SS. Our data suggest that the ectopic secondary lymphoid follicles contain all elements needed for driving the autoimmune response. Our findings underscore a key role for the target organ in recruitment of inflammatory cells and propagation of the disease process.

Lymphoepithelial lesions (LELs, or epi-myoepithelial islands) in lymphoepithelial sialadenitis (LESA, or benign lymphoepithelial lesion) of the salivary gland are known to be mainly composed of duct epithelial cells. However, other constituent cells are poorly characterized. Formalin-fixed paraffin sections obtained from six surgical specimens of LESA were examined using immunohistochemistry for cytoskeletal proteins, inflammatory cells, vascular endothelial cells, and extracellular matrix (ECM) molecules as well as by in situ hybridization for ECM molecules. In addition to keratin-immunopositive (+) duct-like epithelial cells, there were CD31/CD34+ vascular endothelial cells-which were either scattered in a singular fashion, in formed sheets, or in tubular structures-, CD20+ B lymphocytes, CD45RO+ T lymphocytes, and CD68 macrophages in the LELs. ECM molecules, such as heparan sulfate proteoglycan and tenascin, were immunolocalized in hyaline materials in the LELs. Their mRNAs were demonstrated mainly in endothelial cells and, to a lesser extent, in lympho-monocytic cells around hyaline materials, but were not as evident in epithelial constituent cells of LELs. The results indicate that endothelial cells as well as inflammatory cells are important constituents of the LELs, and the hyaline ECM cores mainly result from the intra-LEL angiogenesis by endothelial cells with the assistance of inflammatory cells. This intra-LEL vasculature seems to support regeneration and proliferation of salivary epithelial remnant cells.

Objective: Quantitative analysis of (99m)Tc-pertechnetate salivary gland scintigraphy has been used in the evaluation of salivary gland function, but so far no one method can be considered optimal for this task. In this study, a semiquantitative method providing 2 functional parameters for objective assessment of salivary gland function by scintillation camera imaging was tested., Methods: Twenty-one patients referred for (99m)Tc-pertechnetate thyroid scanning were studied. Two patients with salivary complaints were also included. Dynamic imaging of the anterior head using a scintillation camera was started after a bolus intravenous injection of 185 MBq (5 mCi) (99m)Tc-pertechnetate at 1 frame per 30 s for 30 min. At 15 min after injection, diluted lemon juice was administered orally. Analysis of the dynamic study included time-activity curves of 4 salivary glands (right and left parotid and right and left submandibular). Two parameters of function were defined: uptake rate, taken as the value of the initial slope of the time-activity curve, and washout fraction, which was the relative mobilizable radioactivity from each salivary gland after ingestion of the sialogogue. A parametric image of the washout fraction was also generated., Results: The images showed gradual uptake in the parotid and submandibular glands. Washout was noted immediately after ingestion of the lemon juice. The pattern of the time-activity curve in all glands showed an early fast-rising part followed by a slow-rising component to nearly a plateau within 6-10 min after injection. The mean value of the uptake rate parameter was 0.10 +/- 0.09 cps/s. There was no significant difference between the parotid and submandibular glands or the right and left sides. Uptake in the parotid gland was 1.5-2 times that in the submandibular gland. The washout fraction was 1.40 +/- 1.60 for the parotid glands and 0.77 +/- 0.41 for the submandibular glands (P = 0.005)., Conclusion: The quantitative analysis method including the uptake rate and the washout fraction parameters would enable objective assessment of salivary function and provide a reproducible means for follow-up of functional impairment in certain diseases.

Although previously regarded as a toxic pollutant gas, nitric oxide (NO) is a short-lived molecule that plays a key role in many physiological and pathological processes. It is produced in vivo from the amino acid L-arginine by a complex family of enzymes termed nitric oxide synthase (NOS). Since its discovery as a biological messenger in 1987, NO has been implicated in many disease processes, ranging from septic shock to cancer. It is a highly reactive free radical and causes concentration-dependent conformational changes in proteins, enzymes and DNA, predominantly by its reaction with transition metals and thiol residues. Although high concentrations of NO are cytotoxic, the levels produced in many human cancers possibly facilitate tumour growth and dissemination. The interest in this molecule by scientists and clinicians involved with the oral cavity and head and neck regions is fairly recent, and only a tiny minority of 50,000 papers currently cited on NO relate to diseases in this anatomical area. This review gives an overview of NO, outlining its basic chemistry, formation by NOS and its possible roles in the oral diseases studied to date. The implications for possible therapeutic manipulation of NO are also discussed.

Background: The role of the salivary glands in the maintenance of nitrate and nitrite in saliva is poorly understood. The aim was to study alterations of nitrate and nitrite metabolisms in patients with Sjogren's syndrome (SS) or sialosis., Methods: Saliva, serum, and urine samples were collected from healthy volunteers (n = 29), patients with SS (n = 31), and patients with sialosis (n = 30). Concentrations of nitrate and nitrite were determined by high-performance liquid chromatography (HPLC)., Results: In the healthy group, the highest concentration of nitrate was found in parotid saliva (172 mg/l), followed by urine (160 mg/l), whole saliva (97 mg/l), and serum (33 mg/l). In the SS group, concentration of nitrate was decreased in parotid saliva and whole saliva, and increased significantly in urine. Concentration of nitrite in whole saliva was significantly decreased in the SS group and increased in the sialosis group., Conclusion: Hypofunction of the salivary glands is associated with significant changes of nitrate and nitrite levels in the saliva and urine.

The roles of apoptosis and mitosis of acinar and duct cells in the atrophy of the sublingual gland of rat induced by double duct ligation was investigated using immunohistochemistry for proliferating cell nuclear antigen (PCNA), terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-digoxigenin nick end labeling (TUNEL), and transmission electron microscopy (TEM). Many PCNA-positive duct cells were observed 3 days after duct ligation, and the numbers decreased thereafter. At 3 and 5 days, several TUNEL-positive acinar cells were observed and typical apoptotic acinar cells were identified by TEM. Necrotic acinar cells were also observed ultrastructurally. After 7 days, there were few acini but many ducts, as well as many structures representing transition from acinus to duct. These observations demonstrate that acinar cell loss by apoptosis and duct cell proliferation by mitosis occur in atrophic sublingual glands as well as in other atrophic salivary glands. In addition, it appears that the transition from acinar to duct cell and the necrosis of acinar cells play important roles in the atrophy of the sublingual gland.

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.

The oral cavity is exposed to a variety of environmental insults. Salivary secretions play a critical role in maintaining oral health via innate host defense mechanisms and secretion of secretory IgA. Human beta-defensins (hBD) are antimicrobial peptides that are a component of the innate immune response; they are expressed in epithelia and are proposed to have a role in mucosal defense. hBD-1 mRNA is constitutively expressed in numerous mucosal tissues, including human gingiva and submandibular and parotid glands. Our objective was to detect the expression and localization of hBD-1 peptide in human salivary glands and in saliva. Minor salivary gland tissue was obtained from biopsies of patients with mucoceles (n = 20). hBD-1 peptide was detected by immunohistochemistry; expression was localized to the ductal cells and not the acinar cells of these glands. The peptide was located apically, toward the lumen in the duct cells. Further evaluation showed stronger hBD-1 expression in ducts with periductal inflammation, as indicated by the immunostaining of serial sections with anti-CD45 specific for B- and T-lymphocytes. Statistical analysis showed a strong correlation of hBD-1 staining and inflammation. Results of immunolocalization suggest that hBD-1 functions to protect salivary glands from retrograde infection, that expression of the peptide is enhanced in inflamed sites, and that post-transcriptional regulatory mechanisms may be involved in hBD-1 peptide expression. Western immunoblot analysis also detected hBD-1 peptide in unstimulated, whole, acidified saliva from normal volunteers. However, hBD-1 peptide associated with salivary mucin resulted in loss of the detection in a dot-immunoblot assay. Association of hBD-1 with salivary mucin may facilitate peptide distribution and adherence to oral surfaces and aid its function within the oral cavity.

Trefoil factors are wound-healing peptides important in protection and healing of the human gastrointestinal tract. Their potential for therapy of gastrointestinal ulcers has been established. This study investigated the hypothesis that trefoil factors are also present in human salivary gland. Tissues from surgical biopsy specimens were collected fresh into ice and stored in liquid nitrogen. Breast, stomach, and colon constituted positive controls. Trefoil factor mRNAs were detected by reverse transcription polymerase chain reaction (RT-PCR) or by in situ hybridization (ISH) with formalin-fixed, paraffin-embedded sections. Amplified DNA fragments were ligated into pGEM-T Easy vector and used to transform competent Escherichia coli JM109, allowing sequencing to confirm identity of cloned fragments. Generation of amplifiable cDNA was confirmed using primers specific to the ubiquitously expressed abl gene. By RT-PCR, TFF1 (pS2) mRNA was detected in 14 of 15 glands, TFF3 (hITF) mRNA in 13, and TFF2 (hSP) in only 1 gland. ISH of 15 glands (7 of which had been studied by RT-PCR) showed the same pattern of expression and indicated that TFF1 mRNA was usually expressed at low levels by a few mucous cells, whereas TFF3 was produced abundantly by most mucous cells. There was no difference in patterns of expression comparing parotid, submandibular, and minor mucous glands. Nor was there an obvious relationship between trefoil factor expression and pathology, but those glands not expressing TFF1 or TFF3 had evidence of chronic inflammation or atrophy. Trefoil factors are likely to be important in healing, predisposition to, and therapy of, oral diseases.

The existence and distribution of melanocytes in the human minor salivary glands were investigated in a series of autopsy and biopsy materials. The cells with the following characteristics were regarded as melanocytes; spindle-shaped or dendritic cells with fine granular pigments: (i) stained brownish-black by hematoxylin-eosin stain, and black by Masson-Fontana's silver impregnation method; and (ii) disappeared after treatment with peroxide and potassium permanganate solution. In addition, the expression of antigen identified by anti-HMB-45 antibody in serial sections with melanocytes was examined. Melanocytes were found in eight (1.8%) of 445 cases, and there was no relationship between the existence of melanocytes and significant diseases of the subjects. Various numbers of melanocytes were distributed in fibrous tissue around the interlobular ducts, intralobular ducts and acini, but were not in direct contact with the epithelia. Neither melanocytes nor melanin granules were found in the salivary gland epithelia. HMB-45-positive cells without intracytoplasmic fine granules were found solitarily or in small groups in periductal and periacinar fibrous tissues with or without slight infiltration of small mononuclear cells.

Microdissection of biopsy material from labial minor salivary glands followed by RT-PCR demonstrates extensive production of cytokines IL-2, 1L-6, IL-10, TNF-alpha, TGF-beta, and IFN-gamma in both normal glands and in glands affected by Sjögren's syndrome. Continuation of these studies should expand our knowledge of normal salivary gland function and the pathogenesis of Sjögren's syndrome.

We here in present a very rare case of primary localized amyloidosis with amyloid A protein of the sublingual gland. It presented a tumorous appearance on the left oral floor. Pretreatment with potassium premanganate made biopsy specimens unstained by Congo red. Immunohistochemical staining for AA protein was positive. Systemic amyloidosis was ruled out based on clinical and laboratory examinations. The gastric and the labial salivary glands biopsy showed no amyloid deposits. As far as we know, this is the first case of primary localized amyloidosis with amyloid A protein of the oral cavity, and tumor-formed amyloidosis of the sublingual gland.

Multistep tumorigenesis proceeds through activation of oncogenes and inactivation of tumor suppressor genes. Initiating oncoproteins induce secondary changes that maintain transformation in the absence of original stimuli. Time-dependent reversal of SV40 T antigen (TAg)-induced hyperplasia was studied using temporally controlled gene expression. Targeting TAg expression to the submandibular salivary gland of transgenic mice produces focal hyperplasias at age two weeks, which extend through large areas of the gland by four months. At twelve months, fibrosis and tumor foci accompany hyperplasia. Hyperplasia reverses when TAg expression in discontinued at four months but not at seven months. Secondary changes that maintain transformation appear to be time dependent. The system can be used to identify genetic events resulting in phenotypic reversal at four months and to expose factors preventing its occurrence at seven months. Expression of other proteins can be targeted to the salivary gland, and temporally controlled gene deletions can also be made using this system.

An indolent lesion of the salivary glands that mimics Sjøgren syndrome has been repeatedly reported in HIV-infected (HIV+) patients. It is characterized by the occurrence, usually in the parotid gland, of variably sized lymphoepithelial cysts (LECs), whose origin is still unclear. We have compared the morphological and immunohistochemical features of six cases of LEC in HIV+ patients with those of five cases of LEC in HIV-negative (HIV-) patients. The results of the study show that LECs have similar histological and immunohistochemical features in both HIV+ and HIV- patients, and that they may simultaneously affect the salivary gland parenchyma and the intrasalivary lymph nodes. Furthermore, a diffuse lymphoid infiltrate is invariably observed in the glandular tissue around LECs and it is consistently associated with ectatic changes of the striated ducts. These data and the finding of an equivalent proliferation fraction of the epithelial compartment in both LEC and salivary retention cysts, used as controls for this study, are consistent with the hypothesis that cyst formation is secondary to the obstruction of salivary ducts by exuberant lymphoid infiltration.

Cytokines play a major role in tissue destruction caused by autoimmune dysregulation. In Sjögren's syndrome (SS) patients, salivary glands are the target organs for autoimmune tissue damage. In the present study, reverse transcriptase-polymerase chain reaction (RT-PCR) was used to look for cytokine mRNA expressed in SS salivary glands. Focus score was used to determine the severity of the lesions. Cytokine production in supernatants of the salivary gland cell culture was measured by enzyme-linked immunosorbent assay (ELISA). Immunohistochemical staining was used to identify the local presence of transforming growth factor beta (TGF-beta). Interleukin (IL)-2, IL-6, and IL-10 mRNA were expressed in moderate to severe SS salivary gland lesions. TGF-beta mRNA was constitutively expressed in normal and SS salivary glands. In SS salivary gland cell cultures, IL-6 and IL-10 proteins were produced. TGF-beta production was reduced in high focus score SS glands. Normal and minimally involved SS salivary gland ductal epithelium and acinar cells were found to produce TGF-beta by immunostaining. In conclusion, an excess production of IL-2, IL-6, and IL-10 and a reduced production of the immunosuppressive cytokine, TGF-beta, may be responsible for the progression of the salivary gland lesion in SS. Specific immunotherapy can now be designed based on mechanisms to correct this cytokine imbalance and benefit patients with autoimmune diseases, such as SS.

An immunohistochemical study of p53 protein was carried out on 45 salivary gland lesions using a monoclonal antibody, Bp53-12, raised to the intracellular domain of the p53 protein. p53 protein expression was found in 34.4% of 32 salivary gland carcinomas. Nuclear p53 expression was detected in tumor cells but not in non-neoplastic cells, except in one salivary duct carcinoma. The perinuclear cytoplasm of luminal duct cells was specifically positive for the antibody used here. Cytoplasmic p53 expression was observed mostly in non-neoplastic cells. There was a tendency for the cytoplasmic staining of p53 protein to be observed in the normal cells adjacent to p53-positive carcinomas, but none of the normal cells were positive in the tissues surrounding p53-negative carcinomas. Cytoplasmic expression of p53 protein in salivary gland tissues seems to be correlated with tumorigenesis.

Duct-ligated submandibular and sublingual glands of rats were evaluated immunohistochemically for changes in keratin (MoAb 1164), actin, S-100 protein and rat-EGF (rEGF). Normal salivary glands were reactive for keratin, S-100 protein and rEGF in the granular convoluted tubule (GCT) and duct cells, and for actin in the myoepithelium. Submandibular glands showed a marked reduction of S-100 protein and rEGF staining following duct ligation, and no increased staining of proliferating epithelial cells of the late stage in duct ligated glands. Sublingual glands revealed no marked changes for actin staining in myoepithelial cells, irrespective of atrophic changes occurring in acinar and duct cells after duct ligation. Immunohistochemical patterns differed for each type of gland; changes associated with the obstructive lesion were more prominent in the submandibular gland.

Human immunodeficiency virus (HIV) associated salivary gland disease is defined as the presence of enlargement of one or more major salivary glands and/or diminished salivary function in an HIV infected individual. It has a number of similarities to, as well as differences from, Sjögren's syndrome (SS). We studied the sialochemistry of stimulated parotid saliva of 11 patients with HIV associated salivary gland disease and bilateral parotid gland enlargement, and compared these findings with those of 15 HIV negative controls, 13 HIV positive individuals with no salivary gland involvement and 18 individuals with SS. The patients with HIV associated salivary gland disease had a significant decrease in the level of salivary protein, with increases in salivary IgA, lysozyme and albumin compared to the HIV negative controls. There were no changes in concentration of electrolytes. The sialochemistry among the patients with HIV associated salivary gland disease was unrelated to the degree of immune suppression and did not change over a 6 month period. The observed changes were similar to those of SS but less pronounced. The similar clinical, histologic and sialochemical features of HIV associated salivary gland disease and SS suggest that these conditions share common pathogenetic mechanisms, which may be modified in the former by the HIV infection.