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This study was conducted to determine whether a secretome from mesenchymal stem cells (MSC) modulated by hypoxic conditions to contain therapeutic factors contributes to salivary gland (SG) tissue remodeling and has the potential to improve irradiation (IR)-induced salivary hypofunction in a mouse model. Human adipose mesenchymal stem cells (hAdMSC) were isolated, expanded, and exposed to hypoxic conditions (O2 < 5%). The hypoxia-conditioned medium was then filtered to a high molecular weight fraction and prepared as a hAdMSC secretome. The hAdMSC secretome was subsequently infused into the tail vein of C3H mice immediately after local IR once a day for seven consecutive days. The control group received equal volume (500 μL) of vehicle (PBS) only. SG function and structural tissue remodeling by the hAdMSC secretome were investigated. Human parotid epithelial cells (HPEC) were obtained, expanded in vitro, and then irradiated and treated with either the hypoxia-conditioned medium or a normoxic control medium. Cell proliferation and IR-induced cell death were examined to determine the mechanism by which the hAdMSC secretome exerted its effects. The conditioned hAdMSC secretome contained high levels of GM-CSF, VEGF, IL-6, and IGF-1. Repeated systemic infusion with the hAdMSC secretome resulted in improved salivation capacity and increased levels of salivary proteins, including amylase and EGF, relative to the PBS group. The microscopic structural integrity of SG was maintained and salivary epithelial (AQP-5), endothelial (CD31), myoepithelial (α-SMA) and SG progenitor cells (c-Kit) were successfully protected from radiation damage and remodeled. The hAdMSC secretome strongly induced proliferation of HPEC and led to a significant decrease in cell death in vivo and in vitro. Moreover, the anti-apoptotic effects of the hAdMSC secretome were found to be promoted after hypoxia-preconditioning relative to normoxia-cultured hAdMSC secretome. These results show that the hAdMSC secretome from hypoxic-conditioned medium may provide radioprotection and tissue remodeling via release of paracrine mediators.

Salivary gland sialoceles are relatively common and may be a complication of trauma with a penetrating salivary gland injury or may be a complication of salivary gland surgery. The development of new diagnostic tools such as magnetic resonance sialography and endoscopic techniques has led to further improvements in the clinical and diagnostic assessment of this condition, and botulinum toxin therapy has recently been described in the management of parotid sialoceles. We here report the case of a 41-year-old patient with an unusually complicated parotid sialocele following an unsuccessful attempt to remove a stone located in the distal third of Stensen's duct. Magnetic resonance sialography and sialoendoscopy were used in order to obtain an adequate diagnostic assessment. The patient underwent extracorporeal lithotripsy that led to partial symptom regression. After the development of a parotid abscess, he received antibiotics and a botulinum toxin type A injection that induced spontaneous drainage and disappearance of the symptoms. Magnetic resonance sialography and sialoendoscopy are promising new diagnostic techniques for better noninvasive management of iatrogenic sialoceles.

ObjectivesThe aims of this study were (1) to assess the effect of rituximab (RTX; anti-CD20) treatment in patients with primary Sjögren's syndrome (pSS) based on sequential parotid biopsies obtained in a placebo-controlled, randomised clinical trial, and (2) to assess the prognostic value of the histological characteristics of parotid gland tissue with regard to responsiveness to RTX treatment.MethodsIn a double-blinded, placebo-controlled trial, sequential parotid gland biopsies were taken from 20 RTX-treated and 10 placebo-treated patients with pSS, at baseline and 12 weeks after treatment. The relative amount of lymphocytic infiltrate (stained for CD45), absolute number of T cells and B cells per mm2 parenchyma (stained for CD3 and CD20, respectively), focus score, number of germinal centres and of lymphoepithelial lesions per mm2 in parotid gland parenchyma were assessed. Histopathological data were compared between clinical responders (decrease in European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) score of ≥3 at 12 weeks compared with baseline) and non-responders (change in ESSDAI<3) to RTX treatment.ResultsIn RTX-treated patients, a significant reduction in the number of CD20+ B cells/mm2 parenchyma was observed, while no such reduction was observed in placebo-treated patients. The number of CD3+ T cells/mm2 in parenchyma did not change in either group. Furthermore, the number and the severity of lymphoepithelial lesions/mm2 and number of germinal centres/mm2 was significantly reduced in RTX-treated patients, but did not change in placebo-treated patients. When comparing the pretreatment characteristics of clinical responders with non-responders, the median number of CD20+ B cells/mm2 parenchyma at baseline was significantly higher in responders (1871 vs 353 cells/mm2, p<0.05). Other histopathological baseline characteristics were not predictive for response to RTX treatment.ConclusionsRTX treatment in pSS leads to a major reduction of lymphocytic infiltration and to fewer B cells, germinal centres and lymphoepithelial lesions in parotid gland parenchyma. A high pretreatment number of CD20+ B cells/mm2 parotid gland parenchyma predicts better responsiveness of patients with pSS to RTX treatment. Pretreatment parotid gland histopathological characteristics could therefore contribute to a more personalised treatment approach to pSS.

This study aimed to evaluate the possible biochemical effects of the administration of benznidazole on the parotid and submandibular salivary glands and saliva of rats, as well as on salivary components for the first time. Male Wistar rats ( Rattus norvegicus ), 66-days-old, weighing approximately 250 g were randomized into two groups: control, administered distilled water by gavage and benznidazole, administered benznidazole at a dose of 19.6 mg/kg daily by gavage over 15 days. On the 16th day, the animals were anaesthetized and the parotid and submandibular salivary glands and saliva were collected for oxidative biochemistry and morphometric analyses, and the biochemical composition of the saliva was also assessed. On the 16th day, the animals were anesthetized and their pilocarpine-induced saliva was collected. They were then euthanized to collect the parotid and submandibular salivary glands for oxidative biochemical and morphometric analyses, and the biochemical composition of the saliva was also assessed. Shapiro–Wilk normality analysis and Student’s t-test was used for parametric data and non-parametric data, respectively, with a significance of p < 0.05. The oxidative biochemical results revealed a reduction in the antioxidant capacity of the parotid and submandibular glands in benznidazole group. Morphometric analyses revealed an increase in the average area of the acini in both glands and a reduction in the stromal area of the parotid gland in the benznidazole group. Salivary analyses demonstrated a decrease in antioxidant levels and an increase in pro-oxidant levels in the group exposed to benznidazole. Total proteins, amylase, and mucin levels reduced in the exposed group. Thus, administration of benznidazole conclusively caused biochemical alterations in the antioxidant and morphological capacities of the salivary glands, followed by biochemical and protein alterations in the saliva, highlighting the possible damage caused by the drug in patients during the treatment of Chagas disease.

Background Circular RNAs (circRNAs) are a novel kind of non-coding RNAs proved to play crucial roles in the development of multiple diabetic complications. However, their expression and function in diabetes mellitus (DM)-impaired salivary glands are unknown. Results By using microarray technology, 663 upregulated and 999 downregulated circRNAs companied with 813 upregulated and 525 downregulated mRNAs were identified in the parotid glands (PGs) of type2 DM mice under a 2-fold change and P  < 0.05 cutoff criteria. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analysis of upregulated mRNAs showed enrichments in immune system process and peroxisome proliferator-activated receptor (PPAR) signaling pathway. Infiltration of inflammatory cells and increased inflammatory cytokines were observed in diabetic PGs. Seven differently expressed circRNAs validated by qRT-PCR were selected for coding-non-coding gene co-expression (CNC) and competing endogenous RNA (ceRNA) networks analysis. PPAR signaling pathway was primarily enriched through analysis of circRNA-mRNA networks. Moreover, the circRNA-miRNA-mRNA networks highlighted an enrichment in the regulation of actin cytoskeleton. Conclusion The inflammatory response is elevated in diabetic PGs. The selected seven distinct circRNAs may attribute to the injury of diabetic PG by modulating inflammatory response through PPAR signaling pathway and actin cytoskeleton in diabetic PGs.

This study aims to determine the most efficacious dose of Botulinum neurotoxin type A (BoNT-A) in reducing sialorrhea in Asian adults with neurological diseases. A prospective, double-blind randomized controlled trial was conducted over 24 weeks. Thirty patients with significant sialorrhea were randomly assigned to receive a BoNT-A (Dysport®) injection into the submandibular and the parotid glands bilaterally via an ultrasound guidance. The total dose given per patient was either BoNT-A injection of (i) 50 U; (ii) 100 U; or (iii) 200 U. The primary outcome was the amount of saliva reduction, measured by the differential weight (wet versus dry) of intraoral dental gauze at baseline and at 2, 6, 12, and 24 weeks after injection. The secondary outcome was the subjective report of drooling using the Drooling Frequency and Severity Scale (DFS). Saliva reduction was observed in response to all BoNT-A doses in 17 patients who completed the assessments. Although no statistically significant difference among the doses was found, the measured reduction was greater in groups that received higher doses (100 U and 200 U). The group receiving 200 U of Dysport® showed the greatest reduction of saliva until 24 weeks and reported the most significant improvement in the DFS score.

Objectives To assess the persistence of immunoglobulin-producing cell populations in the parotid salivary glands of patients with primary Sjögren's syndrome (pSS) after B cell depletion therapy with rituximab. Methods Thirteen patients with pSS and four control patients were included in this study. Patients with pSS were treated with rituximab or placebo. Sequence analysis was carried out on IgA- and IgG-encoding transcripts extracted from parotid salivary gland biopsy specimens taken before treatment and at 12–16 and 36–52 weeks after treatment. Results At baseline, many clonally related sequences were seen in patients with pSS. The number of clonal expansions was significantly higher in patients with pSS than in control patients. Clonal expansions were composed of IgA- and/or IgG-expressing cells. Rituximab did not significantly alter the degree of clonal expansions. Groups of clonally related cells had members which were shared between biopsy specimens taken before and after treatment. Mutation frequencies of immunoglobulin sequences from clonally related cells in patients with pSS were higher after treatment. Conclusions Rituximab treatment does not alter the characteristic features of increased clonal expansions seen in the parotid salivary glands of patients with pSS. The presence of clonally related immunoglobulin-producing cells before and after rituximab treatment strongly suggests that immunoglobulin-producing cells persist in salivary glands of patients with pSS despite B cell depletion. The presence of mixed isotype expression within groups of clonally related cells indicates local class switching in salivary glands of patients with pSS. Persistent immunoglobulin-producing cells may underlie disease relapse after treatment.

We present the first case of simultaneous development of Graves’ disease and type 1 diabetes during anti‐programmed cell death 1 therapy. A 48‐year‐old man with parotid gland adenocarcinoma and lung metastasis had received five courses of nivolumab. Fourteen days after administration of the sixth course, his casual plasma glucose and hemoglobin A1c levels were 379 mg/dL and 7.2%, respectively. Furthermore, thyrotoxicosis was detected with a blood test. Serum total ketone body and thyroid‐stimulating hormone receptor antibody levels increased, and serum C‐peptide level decreased to 0.01 ng/mL thereafter. Thus, we concluded that he simultaneously developed anti‐programmed cell death 1 therapy‐associated type 1 diabetes and Graves’ disease. Among Japanese patients with autoimmune polyglandular syndrome type III, the frequency of human leukocyte antigen‐DRB1*04:05 is higher in those with both type 1 diabetes and Graves’ disease. Our case had human leukocyte antigen‐DRB1*04:05, which might be associated with the simultaneous development of the two diseases. We present the first case of simultaneous development of Graves’ disease and type 1 diabetes during anti‐programmed cell death 1 therapy. Among Japanese participants with autoimmune polyglandular syndrome type III, the frequency of human leukocyte antigen‐DRB1*04:05 is higher in those with both type 1 diabetes and Graves’ disease. The present participant carried the human leukocyte antigen‐DRB1*04:05; which might be associated with the simultaneous development of the two diseases.

Diffusion weighted imaging (DWI) has proven to be sensitive for detecting early injury to the parotid gland in pSS (primary Sjögren’s syndrome). Here, we explored the application of ADC histogram and texture analyses for evaluating the disease activity of pSS. A total of 55 patients with pSS who met the classification criteria of the 2002 AECG criteria prospectively underwent 3.0-T magnetic resonance imaging (MRI) including DWI ( b  = 0 and 1000 s/mm 2 ). According to the ESSDAI score, 35 patients were categorized into the low-activity group (ESSDAI < 5) and 20 into the moderate-high-activity group (ESSDAI ≥ 5). Via analysis of the whole-volume ADC histogram, the ADC mean , skewness, kurtosis, and entropy values of the bilateral parotid glands were determined. Multivariate analysis was used to identify independent risk factors for predicting disease activity. The diagnostic performance of the indexes was evaluated via receiver operating characteristic (ROC) analysis. ROC analysis showed that the anti-SSB, lip biopsy, MRI morphology, ADC, ADC mean , and entropy values were able to categorize the disease into two groups, particularly the entropy values. The multivariate model, which included anti-SSB, MRI morphology and entropy, had an area under the ROC curve of 0.923 (P < 0.001). The parotid entropy value distinguished disease activity in patients with pSS, especially combined with anti-SSB and MRI morphology.