Histopathological changes in salivary glands after radioactive iodine treatment for thyroid diseases.

OBJECTIVES: We aimed to evaluate the histopathological alterations in human salivary glands after radioactive iodine (RAI) treatment for thyroid diseases. STUDY DESIGN: We retrospectively selected patients with a history of RAI treatment for thyroid diseases from a database of patients who underwent surgery for oral and maxillofacial diseases and had specimens of salivary glands at Peking University School of Stomatology between December 2012 and July 2023. The patients' clinical records and histopathological slides of the salivary glands were carefully reviewed. RESULTS: Sixteen patients were included. Three symptomatic patients showed duct cell cytoplasmic vacuolization and increased numbers of disordered duct cell layers (3/3), severe duct stenosis and dilation (2/3), and exfoliated epithelial cells in the duct lumen (1/3). The glandular parenchyma showed severe acinar atrophy (2/2), fat content enhancement (2/2), and severe periductal fibrosis (3/3). Thirteen asymptomatic patients showed duct cell cytoplasmic vacuolization (5/13), acinar atrophy and increased fat content in the parenchyma (5/13), and periductal fibrosis (5/13). CONCLUSION: Main histopathologic changes in the salivary glands after RAI treatment for thyroid diseases are cytoplasmic vacuolization of duct cells, acinar atrophy, fat content enhancement, and periductal fibrosis. These changes were evident in symptomatic cases, and were also seen in some asymptomatic patients.

Comparison of epidermal growth factor expression and secretion in human salivary glands.

OBJECTIVE: To investigate the expression and secretion of epidermal growth factor (EGF) in major and minor salivary gland tissues of human subjects and to examine the potential influence of sex and age on EGF expression and secretion. DESIGN: Saliva samples from the oral cavity at rest and after citric acid stimulation, as well as serum samples, were collected from 150 healthy subjects, and the concentrations of EGF were measured with enzyme-linked immunosorbent assay (ELISA) and compared. The expression of EGF mRNA and protein in normal salivary gland tissues was measured by real-time polymerase chain reaction (RT-PCR), Western blot (WB), and immunohistochemistry (IHC). RESULTS: The EGF concentration in acid-stimulated saliva was significantly higher than that in resting saliva (P < 0.001), and significantly higher than that in serum (P < 0.001). No sex difference was observed in EGF levels of whole saliva and serum, whereas the EGF levels in saliva and serum were decreased with age (P < 0.001 and P < 0.001, respectively). The EGF concentration and compound secretion rate (CSR) in resting submandibular glands saliva were significantly higher than those in resting parotid glands saliva (P = 0.002 and P < 0.001, respectively). The EGF was expressed in all major and minor salivary glands and ranked in order of submandibular, parotid, sublingual, and labial glands. CONCLUSION: All salivary glands have the function of secreting EGF, and the submandibular gland is the main source of salivary EGF. Aging is a factor influencing the expression and secretion of EGF.

Salivary Gland Transplantation as a Promising Approach for Tear Film Restoration in Severe Dry Eye Disease.

With increased awareness of dry eye disease (DED), a multitude of therapeutic options have become available. Nevertheless, the treatment of severe DED remains difficult. In a patient whose DED is related to the loss of lacrimal function without severe destruction of the salivary glands, autologous transplantation of the latter as functioning exocrine tissue to rebuild a stable tear film is an attractive idea. All three major and minor salivary glands have been used for such transplantation. Due to the complications associated with and unfavorable prognosis of parotid duct and sublingual gland transplantation, surgeons now prefer to use the submandibular gland (SMG) for such procedures. The transplantation of the SMG not only has a high survival rate, but also improves dry eye symptoms and signs for more than 20 years post-surgery. The regulation of the secretion of the transplanted SMG is critical because the denervated SMG changes its mechanism of secretion. Innovative procedures have been developed to stimulate secretion in order to prevent the obstruction of the Wharton's duct and to decrease secretion when postoperative "epiphora" occurs. Among the minor salivary glands, the transplantation of the labial salivary glands is the most successful in the long-term. The measurement of the flow rates of minor salivary glands and donor-site selection are critical steps before surgery.

Application of Botulinum Toxin at the Yonsei Point for the Treatment of Gummy Smile: A Randomized Controlled Trial.

BACKGROUND: Demand for less-invasive procedures for treating gummy smile, such as botulinum toxin A injections, has increased substantially over the years. Meanwhile, the optimal injection site for botulinum toxin A injection is debated. The authors aimed to investigate the efficacy of botulinum toxin A injection at the Yonsei point for treating gummy smile. METHODS: In this double-blind, single-site, randomized clinical trial, healthy participants with a gummy smile (anterior gingival exposure of ≥3.0 mm) were enrolled and randomized (1:1 ratio) into two groups. The experimental group was administered 6 U of botulinum toxin A at the Yonsei point (a single-site injection of 3 U to the right Yonsei point and 3 U to the left Yonsei point), and the control group received the same dose in the bilateral levator labii superioris alaeque nasi muscle sites. The patients were assessed at baseline and 4, 12, 24, and 48 weeks after the first injection using a digital vernier caliper. RESULTS: A total of 49 participants were enrolled. Anterior and bilateral posterior gingival exposure were reduced at 4, 12, and 24 weeks ( P ≤ 0.05) and returned to baseline at 48 weeks in both groups; there was no difference between the groups at these time points. The increase in satisfaction among patients was significant, and few adverse events were observed. CONCLUSION: Both the Yonsei point and the levator labii superioris alaeque nasi muscle site can be used as botulinum toxin A injection sites for treating gummy smile. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, I.

Characteristics and management of vascular compromise after an organ transplantation surgery of the head and neck region: Analysis of 220 submandibular glands with autologous transplantation.

BACKGROUND: Microvascular submandibular gland transplantation (SMGT) for severe dry eye disease (DED) has rarely been reported in the literature. The aim of this study was to report a case series of SMGT with the special focus on monitoring and management of postoperative vascular compromise. METHODS: Using a retrospective single-cohort study design, the investigators enrolled a sample of DED patients undergoing SMGT in a Chinese university hospital during 1999 and 2021. The main outcomes were baseline and surgical data, post-operative manifestations, and surgical results. Descriptive, uni- and bivariate statistics were computed with the significant P < 0.05. RESULTS: During the study period, 220 DED patients (55.9% female) with a mean age of 32.66±14.47 years underwent SMGT. Vascular compromises occurred in 27 grafted glands (12.3%; 22 venous compromises and 5 arterial compromises) at a median of 27 h(range, 3.3 to 288 h) after surgery. Harden texture and swelling of the covering skin flap of the donor indicated venous compromises, while some specific sign was absent for arterial compromise. The accompanying vein of the facial artery (FAV) as a donor's vein was associated with less vascular compromise compared to the anterior facial vein (AFV). Timely reexploration was performed in 25 glands (92.6%), with a salvaged rate of 48%, and more venous compromises were salvaged compared to artery compromises (54.6% vs. 0%, P = 0.047). Temporary hypersecretion on postoperative 2-5 days was noticed in the grafted glands with no or salvaged vascular compromise (Schirmer's test, 35 mm/5 min and 37 mm/5 min, respectively, P = 0.749), while they were absent for the 15 surgically failed grands (Schirmer's test 0 mm/5 min, P<0.001). CONCLUSIONS: Vascular compromise appears to be a common complication of SMGT. Postoperative hypersecretion of the grafted glands may indicate good circulation, and the use of FAV as the donor's vein could help to decrease the risk of vascular compromise.

Establishment of a Beagle Dog Model of Dry Eye Disease.

Purpose: To establish a Beagle dog model of dry eye disease (DED). Methods: DED models were induced by surgical removal of orbital lacrimal glands and entire resection of third eyelids in the left eyes of six Beagle dogs. Intact right eyes served as self-controls. Non-anaesthetized Schirmer test (STT), tear break-up time (TBUT), and fluorescein staining grading were performed monthly after operation. Interleukin (IL)-1ß, IL-8, IL-10, and tumor necrosis factor-α (TNF-α) levels were detected in tears and conjunctiva tissues. Six months after surgery, conjunctiva and cornea were collected and histopathologically analyzed. Results: Signs of DED appeared within one month after surgery and then remained stable. STT values were significantly reduced by 88% within 3 weeks after operation and remained stable over months with 1.6 ± 0.4 mm. Mean TBUT decreased significantly within two months after operation and maintained 5.2 ± 1.1 seconds. The mean fluorescein staining score was highest at the first month and then was reduced, eventually reaching a balance with 11.0 ± 1.3 points. Elevated levels of IL-1ß, IL-8, IL-10, and TNF-α were detected in tears and conjunctivas of operated eyes. Hematoxylin and eosin staining showed cornea neovascularization in the corneal stroma with thickened stroma layer and disorganized collagen bundles. Periodic acid-Schiff staining revealed a reduced function of conjunctival goblet cells. Conclusions: A combined type of DED model on the Beagle dog was established by removal of the orbital lacrimal gland and resection of the third eyelid. This DED model is easily accessible and is stable at six-month observation. Translational Relevance: The surgery-induced Beagle dog DED model is easily accessible and stable over a relatively long time.

Submandibular Gland Transplantation vs Minor Salivary Glands Transplantation for Treatment of Dry Eye: A Retrospective Cohort Study.

PURPOSE: To compare submandibular gland (SMG) transplantation with minor salivary gland (MSG) transplantation for the treatment of different dry eye diseases (DED). DESIGN: Retrospective clinical cohort study. METHODS: A total of 73 refractory DED eyes were divided into 3 groups. Group A comprised 35 end-stage DED eyes that underwent SMG transplantation. Group B comprised 20 end-stage DED eyes with MSG transplantation. Group C comprised 18 non-end-stage DED eyes with MSG transplantation. Schirmer test (ST), tear break-up time (TBUT), corneal fluorescein staining (FL), and best-corrected visual acuity (BCVA) were measured before and after surgery. RESULTS: Hospital length of stay, length of operation, and hospital fee were significantly higher in group A than in group B or C. Eyes in group A showed the most severe DED disease, with preoperative ST, TBUT, FL, and BCVA of 0.36 mm per 5 minutes, 0.03 seconds, 10.97, and 0.11, respectively, which improved significantly to 20.23 mm per 5minutes, 1.74 seconds, 7.58, and 0.2 at >2-year follow-up. Group B had similar baseline data, and significant but limited improvement only in the ST (0.55 mm per 5 minutes to 3.79 mm per 5 minutes) and FL (11.10 to 9.58) after the operation. Group C had better baseline ST, TBUT, FL, and BCVA of 0.89 mm per 5min, 3.49 seconds, 1.83, and 0.81, respectively, which improved significantly (except for BCVA) to 9.35 mm per 5min, 9.08 s, 0.53, and 0.89 after MSG transplantation. CONCLUSION: SMG transplantation could be recommended to treat end-stage refractory DED. MSG transplantation may provide satisfying results for refractory DED with relatively less severe impairment of the eye.

Use of saliva flow rate measurement in minor salivary glands autotransplantation for treatment of severe dry eye disease.

AIMS: To use minor salivary glands' flow rate (MSGFR) measurement in minor salivary glands (MSGs) autotransplantation for the treatment of severe dry eye disease (DED). METHODS: MSGs autotransplantations were performed in 18 eyes (17 patients) with severe DED. MSGFR were measured before operation. The upper or lower lip with higher MSGFR was selected as the donor site. Buccal mucosa was the back-up in cases labial MSGs showing markedly decreased MSGFRs. Two pieces of salivary lobules with the covering mucosa were harvested and transplanted to the recipient beds prepared in both upper and lower lids. RESULTS: The donor sites included lower lip in 12 eyes, upper lip in 5 eyes and buccal mucosa in 1 eye. Postoperative follow-up confirmed viable grafts in all cases. The overall subjective relief rate of DED symptoms was 58.8%, with Schirmer test values increasing from 0 mm to 4 mm (p<0.05). The mean preoperative MSGFR was 1.7 (range: 0.9-3.3) µL/min/cm2. ROC analysis indicated an outstanding discrimination power for preoperative MSGFR to predicate postoperative relief of DED symptoms (area under the curve (AUC)=0.948, p<0.01). The maximum sensitivity (100%) and specificity (72.7%) were reached at a cut-off of 1.785 µL/min/cm2. Patients with preoperative MSGFR >1.785 µL/min/cm2 showed greater improvement of Schirmer test values after surgery than those with MSGFR ≤1.785 µL/min/cm2 (p<0.05). CONCLUSION: MSGs transplantation proved to be useful for treating severe DED. The amount of postoperative lubrication and the treatment effect were positively correlated with preoperative MSGFR. MSGFR measurement and donor-site selection should be critical steps before the operation.

Clinical and histopathologic characteristics of submandibular gland in Stevens-Johnson syndrome: A comparative study.

OBJECTIVE: The objective of this study was to investigate the clinical manifestations and pathologic appearances of the submandibular gland (SMG) in Stevens-Johnson syndrome (SJS). STUDY DESIGN: Patients with autologous transplantation of SMG for treatment of severe dry eye between March 1998 and May 2018 were divided into the SJS group (70 cases) and non-SJS group (50 cases) according to the history of SJS. The SMG weight and computed tomography volume and salivary flow rate were measured. The concentration index and secretion index were estimated using scintigraphy with technetium-99m-pertechnetate. Histopathology studies of SMG tissues were conducted, and the acini parameters were measured using a digital image analyzer. RESULTS: A decreased computed tomography volume and weight was observed in 48.57% the SJS group and 2% in the non-SJS group (P < .01). The rest whole, acid-stimulated whole, and SMG rest salivary flow rates decreased in the SJS group (P < .05). The normal SMG concentration index (37.5% vs 96.67%, P < .001) and secretion index (35% vs 96.67%, P < .001) rates were lower in the SJS group than in the non-SJS group. The glandular parenchyma was reduced, the acinar space was widened, and the fat content was increased in the SJS group. CONCLUSION: SMG atrophic and degenerative changes occurred in the SJS group, with a decrease in salivary secretion function in more than half of the patients.

Natural developing process of immunoglobulin G4-related sialadenitis after submandibular gland excision: a retrospective cohort study.

OBJECTIVE: This study aimed to evaluate the long-term outcome and quality of life of IgG4-related sialadenitis (IgG4-RS) patients after submandibular gland (SMG) excision without immunomediate therapy. MATERIALS AND METHODS: This retrospective review included patients with IgG4-RS who did not undergo further treatment following SMG excision. All patients diagnosed with IgG4-RS between January 1955 and December 2012 at the Department of Oral and Maxillofacial Surgery, Peking University School of Stomatology, were enrolled. The main outcome measures included postoperative IgG4-RS progression rate and differences between patients with and without recurrent disease. The degree of subjective oral dryness was evaluated using the summated xerostomia inventory (SXI); the objective secretory function was assessed by whole saliva flow rate measurements. Serological findings were analyzed during the follow-up. RESULTS: SMG excision was adopted in all of the 83 patients. The median follow-up period was 108 (range 7-396) months. Clinical progression was observed in 54.2% of cases. Patients with other organ involvement (OOI) indicated higher progression rate to a significant extent (P = 0.015, HR = 2.108). The annual progression rate was 20.7% in the group with OOI and was 14.1% in the group without OOI. All cases showed higher levels of serum IgG4; the level was in positive correlation with follow-up time when no therapy was added. 82.4% of cases experienced xerostomia after the surgery, and the degree of dry mouth in patients underwent bilateral resection was significantly more severe than those in unilateral resection. CONCLUSIONS: Surgical excision of involved SMG cannot control the disease progression, which is not recommended for treatment of IgG4-RS. Differential diagnosis is crucial in order to prevent irreversible organ loss and relevant salivary gland dysfunction. Key Points • Surgical excision of involved SMG cannot control progression of IgG4-RS.

CTRP3 promotes TNF-α-induced apoptosis and barrier dysfunction in salivary epithelial cells.

BACKGROUND: C1q/tumour necrosis factor-related protein 3 (CTRP3) plays important roles in metabolism and inflammatory responses in various cells and tissues. However, the expression and function of CTRP3 in salivary glands have not been explored. METHODS: The expression and distribution of CTRP3 were detected by western blot, polymerase chain reaction, immunohistochemical and immunofluorescence staining. The effects of CTRP3 on tumour necrosis factor (TNF)-α-induced apoptosis and barrier dysfunction were detected by flow cytometry, western blot, co-immunoprecipitation, and measurement of transepithelial resistance and paracellular tracer flux. RESULTS: CTRP3 was distributed in both acinar and ductal cells of human submandibular gland (SMG) and was primarily located in the ducts of rat and mouse SMGs. TNF-α increased the apoptotic rate, elevated expression of cleaved caspase 3 and cytochrome C, and reduced B cell lymphoma-2 (Bcl-2) levels in cultured human SMG tissue and SMG-C6 cells, and CTRP3 further enhanced TNF-α-induced apoptosis response. Additionally, CTRP3 aggravated TNF-α-increased paracellular permeability. Mechanistically, CTRP3 promoted TNF-α-enhanced TNF type I receptor (TNFR1) expression, inhibited the expression of cellular Fas-associated death domain (FADD)-like interleukin-1ß converting enzyme inhibitory protein (c-FLIP), and increased the recruitment of FADD with receptor-interacting protein kinase 1 and caspase 8. Moreover, CTRP3 was significantly increased in the labial gland of Sjögren's syndrome patients and in the serum and SMG of nonobese diabetic mice. CONCLUSIONS: These findings suggest that the salivary glands are a novel source of CTRP3 synthesis and secretion. CTRP3 might promote TNF-α-induced cell apoptosis through the TNFR1-mediated complex II pathway.

C1q/tumor necrosis factor-related protein-6 attenuates TNF-α-induced apoptosis in salivary acinar cells via AMPK/SIRT1-modulated miR-34a-5p expression.

C1q/tumor necrosis factor-related protein-6 (CTRP6) is a newly identified adipokine involved in diverse biological processes. However, its role in salivary glands remains unknown. Here, we demonstrated that CTRP6 was mainly distributed in the nuclei, apicolateral membranes, and cytoplasm of human submandibular glands (SMGs), serous cells of parotid glands, and ducts and apicolateral membranes of serous cells in rats and mice. CTRP6 inhibited the apoptosis rate and reversed the increased levels of cleaved caspase 3, caspase 8, caspase 9, and cytochrome C and the decreased Bcl-2 expression induced by tumor necrosis factor (TNF)-α in both SMG-C6 cells and cultured human SMG tissues. Microarray analysis identified 43 differentially expressed microRNAs (miRNAs) in the SMGs of nonobese diabetic mice. miR-34a-5p was selected due to its upregulation by TNF-α, which was abolished by CTRP6. The miR-34a-5p inhibitor promoted whereas the miR-34a-5p mimic suppressed the effects of CTRP6 on TNF-α-induced apoptosis. CTRP6 increased AMP-activated protein kinase (AMPK) phosphorylation and reversed TNF-α-induced SIRT1 downregulation in salivary cells. AraA, an AMPK inhibitor, reversed the effects of CTRP6 on TNF-α-induced alterations in the levels of SIRT1, miR-34a-5p, Bcl-2, and cleaved caspase 3 in vitro and ex vivo, whereas activating AMPK by AICAR reversed the decrease in SIRT1 expression and increase in miR-34a-5p expression induced by TNF-α. Inhibition of SIRT1 by EX527 suppressed the effects of CTRP6 on TNF-α-induced changes in miR-34a-5p and apoptosis-related proteins. Our findings indicate that salivary glands are novel sites for CTRP6 synthesis and secretion. CTRP6 protects acinar cells against TNF-α-induced apoptosis via AMPK/SIRT1-modulated miR-34a-5p expression.

Diagnostic utility of submandibular and labial salivary gland biopsy in IgG4-related sialadenitis.

OBJECTIVE: The diagnostic utility of labial salivary gland (LSG) biopsy for IgG4-related sialadenitis remains undetermined. The purpose of the present study was to determine whether submandibular gland biopsy could be replaced by LSG biopsy for diagnosing IgG4-RS. PATIENTS AND METHODS: Medical records of two groups of patients were reviewed. Group A contained 45 patients suspected to have IgG4-RS who underwent both SMG and LSG biopsies. Group B contained 25 patients who were clinically and pathologically diagnosed with Sjögren syndrome (SS). Biopsy samples were stained using hematoxylin and eosin (HE) and immunohistochemical techniques and observed under an optical microscope. Relevant data describing histopathological characteristics were collected and analyzed. RESULTS: SMG of IgG4-RS patients presented typical histopathological characteristics of fibrosis and IgG4-positive plasmacytic infiltration, while LSG showed varied characteristics. The sensitivity and accuracy of SMG for diagnosing IgG4-RS were greater than those of LSG (100% and 100% versus 55.3% and 75.7%, respectively, P < 0.05). CONCLUSIONS: Biopsy of SMG showed greater sensitivity and specificity, whereas LSG biopsy showed varied histopathological and immunohistochemical characteristics; thus, SMG biopsy cannot be replaced by LSG biopsy for diagnosis of IgG4-RS.

Quality of life and patient satisfaction after submandibular gland transplantation in patients with severe dry eye disease.

PURPOSE: Submandibular gland (SMG) transplantation improves the tear film and other ocular-surface features for patients with severe dry eye disease (DED). Using the dry eye-related quality of life (QOL) questionnaire, we aimed to evaluate whether DED patients' QOL would benefit from SMG transplantation and determine whether preoperative ophthalmologic and QOL measurements could predict which patients would be most satisfied with this surgery. METHODS: This prospective study included DED patients with successful SMG transplantation. Using the Chinese version of the Dry Eye Related Quality of Life (CDERQOL) instrument, QOL was measured before and 1-year after surgery. RESULTS: The QOL data of 51 consecutive patients were analyzed. Before surgery, all the patients had a poor QOL. One year after surgery, all five QOL domains (Dry Eye Symptom Bother, Impact on Daily Activities, Emotional Impact, Impact on Work, and Satisfaction with Treatment) showed significant improvement (P < 0.01). Unsuccessful treatment experience with cyclosporin eyedrops as well as pre-surgical low scores of visual acuity and all five QOL domains (except for "Satisfaction with Treatment") were found to significantly increase the post-surgical QOL scores (P < 0.01); however, pre-surgical Schirmer's test, break-up times of tear-film, and corneal fluorescein staining measurements showed no effects or contradictory correlations with post-surgical QOL scores. CONCLUSION: The life quality and satisfaction of DED patients showed significant improvement after SMG transplantation. Patients with severe and refractory DED could reap the benefits of surgery. A subjective QOL questionnaire is very valuable for predicting and evaluating the treatment effect.

Rate of Submandibular Gland Involvement in Oral Squamous Cell Carcinoma.

PURPOSE: Whether the submandibular gland (SMG) can be preserved during neck dissection in the surgical treatment of oral squamous cell carcinoma (OSCC) is controversial. This study investigated the SMG involvement rate and provides a basis for preserving the SMG during neck dissection in appropriate cases of OSCC. MATERIALS AND METHODS: A comprehensive systematic review was conducted on the PubMed and MEDLINE, Embase, and Cochrane Library databases for studies on SMG involvement in OSCC published before December 2017 with a data analysis technique. Predictor variables were numbers of patients and resected SMGs, primary site, and tumor, node, and metastasis stage. Outcome variables were the number of involved SMGs and mode of involvement. Other variables, namely first author, publication year, mean age, and condition of neck lymph nodes at level Ib, also were extracted. A random-effects model was used to analyze the rate of SMG involvement in OSCC. RESULTS: Twelve studies involving 2,126 patients with OSCC who underwent neck dissection were included in the study. Fifty-two SMGs were involved, and the pooled involvement rate was 2% (I2 = 73%; 95% confidence interval [CI], 1-3). Forty-eight SMGs were involved through direct spread from the primary site or extracapsular spread of positive lymph nodes, and the pooled involvement rate was 1.9% (I2 = 72%; 95% CI, 0.9-3.1). Except for direct spread, 4 SMGs were involved through the intraglandular lymph node or carcinoma growing along Wharton ducts, and the pooled involvement rate was only 0.1% (I2 = 0%; 95% CI, 0-0.2). CONCLUSIONS: The rate of SMG involvement in OSCC is very low, and the most common mode of involvement is by direct spread. The SMG might be preserved during neck dissection in OSCC when it is unlikely to be involved through direct spread.

Expression patterns of tight junction proteins in porcine major salivary glands: a comparison study with human and murine glands.

Tight junction (TJ) proteins play a dynamic role in paracellular fluid transport in salivary gland epithelia. Most TJ studies are carried out in mice and rats. However, the morphology of rodent salivary glands differs from that of human glands. This study aimed to compare the histological features and the expression pattern of TJ proteins in porcine salivary glands with those of human and mouse. The results showed that porcine parotid glands were pure serous glands. Submandibular glands (SMGs) were serous acinar cell-predominated mixed glands, whereas sublingual glands were mucous acinar cell-predominated. Human SMGs were mixed glands containing fewer mucous cells than porcine SMGs, whereas the acinar cells of murine SMGs are seromucous. The histological features of the duct system in the porcine and human SMGs were similar and included intercalated, striated and excretory ducts, but the murine SMG contained a specific structure, the granular convoluted tubule. TJ proteins, including claudin-1 to claudin-12, occludin and zonula occludin-1 (ZO-1), were detected in the porcine major salivary glands and human SMGs by RT-PCR; however, claudin-6, claudin-9 and claudin-11 were not detected in the murine SMG. As shown by immunofluorescence, claudin-1, claudin-3, claudin-4, occludin and ZO-1 were distributed in both acinar and ductal cells in the porcine and human SMGs, whereas claudin-1 and claudin-3 were mainly present in acinar cells, and claudin-4 was mainly distributed in ductal cells in the murine SMG. In addition, 3D images showed that the TJ proteins arranged in a honeycomb-like structure on the luminal surface of the ducts, whereas their arrangements in acini were irregular in porcine SMGs. In summary, the expression pattern of TJ proteins in salivary glands is similar between human and miniature pig, which may be a candidate animal for studies on salivary gland TJ function.

Management of duct obstruction in transplanted submandibular glands.

BACKGROUND: Submandibular gland (SMG) transplantation is a successful treatment approach for patients with severe dry eye. However, duct obstruction can occur post-transplant. METHODS: We studied nineteen patients with duct obstruction of transplanted SMGs, including five interventional modalities: stone removal; secretory stimulation (to mimic "internal irrigation" with substantial secretory flow); irrigation; surgical opening of stenosis and orifice reconstruction; cephalic vein bypass and Wharton's duct reconstruction. RESULTS: A solitary stone was found and removed in one patient. Duct blockages like mucus plug were cleared by secretory stimulation in three patients, and by normal saline irrigation in two grafts. In the remaining 13 patients, irrigation failed and surgical opening was performed. Orifice reconstruction succeeded in six of the eight patients, whose stenosis was near the orifice. Wharton's duct reconstruction was successful in two of the five cases where stenosis was located in the middle segment of the duct. CONCLUSION: Transplanted SMGs obstruct for various reasons. Stone, which is easy to diagnose and treat, should be excluded first. Non-organic blockage and stenosis were semblable in clinic. Therefore, subsequent steps should be a diagnostic/therapeutic trial of secretory stimulation, followed by irrigation; failure of these interventions suggests the diagnosis of duct stenosis, necessitating surgical recanalization.

Autonomic reinnervation and functional regeneration in autologous transplanted submandibular glands in patients with severe keratoconjunctivitis sicca.

Autologous submandibular gland (SMG) transplantation has been proved to ameliorate the discomforts in patients with severe keratoconjunctivitis sicca. The transplanted glands underwent a hypofunctional period and then restored secretion spontaneously. This study aims to investigate whether autonomic nerves reinnervate the grafts and contribute to the functional recovery, and further determine the origin of these nerves. Parts of the transplanted SMGs were collected from the epiphora patients, and a rabbit SMG transplantation model was established to fulfill the serial observation on the transplanted glands with time. The results showed that autonomic nerves distributed in the transplanted SMGs and parasympathetic ganglionic cells were observed in the stroma of the glands. Low-dense and unevenly distributed cholinergic axons, severe acinar atrophy and fibrosis were visible in the patients' glands 4-6 months post-transplantation, whereas the cholinergic axon density and acinar area were increased with time. The acinar area or the secretory flow rate of the transplanted glands was statistically correlated with the cholinergic axon density in the rabbit model, respectively. Meanwhile, large cholinergic nerve trunks were found to locate in the temporal fascia lower to the gland, and sympathetic plexus concomitant with the arteries was observed both in the adjacent fascia and in the stroma of the glands. In summary, the transplanted SMGs are reinnervated by autonomic nerves and the cholinergic nerves play a role in the morphological and functional restoration of the glands. Moreover, these autonomic nerves might originate from the auriculotemporal nerve and the sympathetic plexus around the supplying arteries.

Treatment of immunoglobulin G4-related sialadenitis: outcomes of glucocorticoid therapy combined with steroid-sparing agents.

BACKGROUND: Immunoglobulin G4-related sialadenitis (IgG4-RS) is a newly recognized immune-mediated systemic disease. Despite its good response to steroid therapy, its treatment protocol is not standardized and the long-term outcome is controversial. The study was conducted to determine the short-term and long-term outcomes of IgG4-RS patients treated with glucocorticoids and steroid-sparing immunosuppressive agents, to analyze secretory function, serological and radiological changes in salivary glands and to assess the usefulness of serum IgG4 level as an indicator of disease activity. METHODS: IgG4-RS patients who were treated for more than 3 months were enrolled. Serological tests, salivary gland function assessment and computed tomography (CT) were performed before treatment and during follow up. The treatment outcomes in the short and the long term were evaluated, and the relationship between serum IgG4 level and salivary gland volume was analyzed. RESULTS: Glucocorticoids were used in all 43 patients and steroid-sparing immunosuppressive agents in 38 patients (88.4%). The follow-up period was 24.6 ± 14.9 months. Clinical remission was achieved in all patients after induction therapy. During short-term observation, salivary gland secretion significantly increased, and the serum IgG4 levels, the volumes and CT values of submandibular and parotid gland decreased significantly (P < 0.001). For long term, relapse occurred in 32.5% patients within 55 months in the regularly treated group, while all seven irregularly treated patients relapsed. However, the relapse-free survival curves were not significantly different between the steroid monotherapy and the combination therapy groups (P = 0.566). Submandibular glands, lacrimal glands, sublingual glands, nasal and paranasal cavity were commonly relapsing organs. In clinically stable patients, a serologically unstable condition occurred in 54.9% patients within 55 months and medication adjustment was performed accordingly. Volume changes in the submandibular and parotid glands were associated with serum IgG4 levels and time of follow up (R2adjusted = 0.905, P < 0.0001 and R2adjusted = 0.9334, P < 0.0001, respectively). CONCLUSIONS: The combination of glucocorticoid and steroid-sparing agents could be effective for treating IgG4-RS, and restoring salivary gland function. Serum IgG4 levels could predict disease activity.