Sensorineural Hearing Loss in Sjögren's Syndrome.

Sjögren's syndrome is a chronic autoimmune disease characterized by systemic dysfunction of exocrine glands, mainly the salivary and lachrymal glands. Sjögren's syndrome consists of two forms: primary Sjögren's syndrome, which is characterized by dry eyes and dry mouth without autoimmune diseases; and secondary Sjögren's syndrome, which is characterized by symptoms associated with other autoimmune diseases, such as systemic lupus erythematosus. Disease severities vary considerably from mild glandular dryness to severe glandular involvement with numerous extraglandular and systemic features. Sensorineural hearing loss is sometimes observed in both primary and secondary Sjögren's syndrome. This review article consists of (1) Pathology of Sjögren's syndrome, (2) Clinical manifestation of Sjögren's syndrome, (3) Autoimmune inner ear disease, (4) Histoanatomical features of the inner ear, (5) Immunological characteristics of the inner ear, (6) Pathophysiology of autoimmune inner ear disease, (7) Treatment for sensorineural hearing loss in Sjögren's syndrome, and (8) Future direction. Finally, we introduce a recently developed disease model of salivary gland inflammation and discuss future expectations for the treatment of sensorineural hearing loss in Sjögren's syndrome.

PAR-2-activated secretion by airway gland serous cells: role for CFTR and inhibition by Pseudomonas aeruginosa.

Airway submucosal gland serous cells are important sites of fluid secretion in conducting airways. Serous cells also express the cystic fibrosis (CF) transmembrane conductance regulator (CFTR). Protease-activated receptor 2 (PAR-2) is a G protein-coupled receptor that activates secretion from intact airway glands. We tested if and how human nasal serous cells secrete fluid in response to PAR-2 stimulation using Ca2+ imaging and simultaneous differential interference contrast imaging to track isosmotic cell shrinking and swelling reflecting activation of solute efflux and influx pathways, respectively. During stimulation of PAR-2, serous cells exhibited dose-dependent increases in intracellular Ca2+. At stimulation levels >EC50 for Ca2+, serous cells simultaneously shrank ∼20% over ∼90 s due to KCl efflux reflecting Ca2+-activated Cl- channel (CaCC, likely TMEM16A)-dependent secretion. At lower levels of PAR-2 stimulation (

Evaluation of lymphocytic infiltration in the bronchial glands of Sjögren's syndrome in transbronchial lung cryobiopsy.

BACKGROUND: Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by deteriorated exocrine gland function with associated lymphocytic infiltration. However, there are few pathological studies on bronchial glands in SS. In this study, we aimed to clarify pathological features of bronchial glands in SS. METHODS: We retrospectively evaluated infiltration of lymphocytes in the bronchial glands incidentally collected by transbronchial lung cryobiopsy (TBLC), which were performed for the diagnosis of diffuse lung diseases. The degrees of lymphocyte infiltration in the bronchial glands were classified into four grades (grade 0-3). We compared the degrees of infiltration of SS with those of other diffuse lung diseases. RESULTS: TBLC for diagnosis of diffuse lung diseases were performed on 432 cases during the study period. The samples of 50 cases included bronchial glands. Of those, 20 cases were excluded due to insufficient size or influence of therapy. The remaining 30 cases included 17 of idiopathic interstitial pneumonias, 5 of chronic hypersensitivity pneumonia, 6 of connective tissue disease (SS; n = 4, systemic sclerosis; n = 1, dermatomyositis; n = 1) and 2 of other diseases. In SS, infiltration of lymphocytes was observed in all cases; grade 1 in one, grade 2 in one, and grade 3 in two cases. In contrast, 11 of 26 in other diseases showed no lymphocytes infiltration, with the remaining 15 of grade 1 infiltration. Grade 2 or more infiltration were found only in SS but not in other diseases. CONCLUSION: Our results suggested that high-grade lymphocytic infiltration of bronchial glands is a distinct characteristics in SS.

Role of submucosal glands in the development and progression of carcinoma in Barrett's oesophagus.

Oesophageal submucosal glands secrete mucins and other chemicals that are believed to serve as protectants of the mucosal surface from luminal noxious agents, either ingested or refluxed. Changes in the type, distribution or number of submucosal glands may contribute to, or be associated with, the development of Barrett's oesophagus and progression to cancer. The aim of this study was to investigate the anatomical, morphological and immunohistochemical characteristics of submucosal glands in Barrett's oesophagus-associated neoplasia in 64 oesophageal resections for Barrett's oesophagus-associated adenocarcinoma and 32 squamous cell carcinomas (as a control group). Gland density was not significantly different between the oesophageal adenocarcinoma (0.91/cm) and squamous cell carcinoma (0.81/cm) groups (p=0.7). In the oesophageal adenocarcinoma group, glands underlying Barrett's oesophagus-associated neoplastic epithelium showed a significant decrease in the percentage of mucinous acini and a significant increase in the percentage of atrophic acini compared to glands underlying epithelium without dysplasia or carcinoma (74% vs 83%, p=0.03; and 24% vs 14%, p=0.01). There was also an increase in the percentage of glands with moderate to severe inflammation underlying neoplastic epithelium compared to glands underlying epithelium without dysplasia or carcinoma (53% vs 33%, p=0.001). None of these differences was seen in the squamous cell carcinoma group. The immunohistochemical characteristics of the different histological subtypes were also distinct. Atrophic and oncocytic acini were diffusely and strongly positive for CK7, SOX2, SOX9 and CK5/6 (a progenitor cell phenotype) while mucinous acini showed weak or moderate staining for those markers. Our results suggest that submucosal glands play a role in the progression of neoplasia, possibly by offering less protection to the mucosal surface of the oesophageal epithelium from chemical injury.

Let-7 microRNA is a critical regulator in controlling the growth and function of silk gland in the silkworm.

The silk gland is characterized by high protein synthesis. However, the molecular mechanisms controlling silk gland growth and silk protein synthesis remain undetermined. Here we demonstrated that CRISPR/Cas9-based knockdown of let-7 or the whole cluster promoted endoreduplication and enlargement of the silk gland, accompanied by changing silk yield, whereas transgenic overexpression of let-7 led to atrophy and degeneration of the silk gland. Mechanistically, let-7 controls cell growth in the silk gland through coordinating nutrient metabolism processes and energy signalling pathways. Transgenic overexpression of pyruvate carboxylase, a novel target of let-7, resulted in enlargement of the silk glands, which is consistent with the abnormal phenotype of the let-7 knockdown. Overall, our data reveal a previously unknown miRNA-mediated regulation of silk gland growth and physiology and shed light on involvement of let-7 as a critical stabilizer and booster in carbohydrate metabolism, which may have important implications for understanding of the molecular mechanism and physiological function of specialized organs in other species.

Preputial gland adenoma in a wild nutria (Myocastor coypus): a case report.

Tumor incidence in wild mammals is reportedly very low. Wild nutria, a large rodent, is known to carry many infectious diseases, but rarely exhibits neoplastic diseases. We necropsied a male wild nutria and found a large nodular mass in the left inguinal region, adjacent to the penis. Histopathologically, the mass was diagnosed as preputial gland adenoma. Spontaneous preputial gland adenomas are extremely rare in all animals. Moreover, reports of tumors in nutrias have been limited to adenocarcinomas of the lungs and uterus, as well as subcutaneous fibromas. Here, we describe preputial gland adenoma in a wild nutria.

Morphological alterations caused by manual venom extraction on the main venom gland of Bothrops asper and Crotalus simus snakes (Serpentes: Viperidae): Long-term implications for antivenom production.

The only scientifically validated treatment for snakebite envenomation is the administration of antivenoms. For their production, small quantities of snake venom are injected in animals to elicit a specific antibody response. Snakes are kept in captivity, and their venom is regularly extracted to assure antivenom access. It has already been reported that the pressure exerted upon the venom gland during this extraction can cause tissue damage and fibrosis, leading to a decrease in the venom yield. We described the histopathology of venom glands for B. asper and C. simus snakes used for antivenom production. Based on these reported tissue abnormalities, we quantify the tissue injury by a generated damage-SCORE and fibrosis. A variety of histopathological damages were found such as fibrosis, edema, necrosis, hemorrhage, and formation of anomalous structures, especially in C. simus, which is more prone to suffer severe damage. The level and severity of the damage depend on the frequency and the number of venom extractions. Furthermore, we design an experimental intensive venom extraction scheme with which we could confirm the causality of these effects. In addition to the histopathological damages, the LD50 and biochemical venom composition were also affected giving experimental evidence that the venom extraction not only causes tissue damage but also affects the composition stability and toxicity of the venom. In order to produce quality and effective antivenoms, an improvement of the management of snake collections could be established, such as rotation groups to assure the quality of the venom yielded.

Clinicopathological Characteristics of Atypical Glandular Cells Determined by Cervical Cytology in Japan: Survey of Gynecologic Oncology Data from the Obstetrical Gynecological Society of Kinki District, Japan.

BACKGROUND: The purpose of this study was to clarify the clinicopathological characteristics of, and the clinical approach used to identify, atypical glandular cells (AGCs) in Japan based on cervical cytology screening. OBJECTIVES: This study included 1,254 patients with AGCs who underwent cervical cytology. METHOD: Data from patients with AGCs were used to examine the practical management of AGCs and the histological results. RESULTS: The incidence of AGCs was 0.20% (1,254/614,791). The 1,254 AGC cases included 859 endocervical cells not otherwise specified (NOS), 3 glandular cells NOS, 91 endocervical cells favor neoplasia (FN), and 301 atypical endometrial cells (AEMCs). Among the 1,254 AGC patients, the histological diagnosis was benign in 666 (53.1%), cervical intraepithelial neoplasia (CIN) 1 in 60 (4.8%), CIN2 in 31 (2.5%), CIN3 in 52 (4.1%), squamous cell carcinoma in 19 (1.5%), adenocarcinoma in situ in 39 (3.1%), cervical adenocarcinoma in 106 (8.5%), endometrial carcinoma in 209 (16.7%), ovarian cancer in 26 (2.1%), other malignancy in 4 (0.3%), and other under follow-up in 42 (3.3%). When the 1,254 AGC patients were divided into three medical intervention degrees according to histology, AGC-NOS, AGC-FN, and AEMC required no medical intervention in 78.7, 13.2, and 25.9% (678, 12, and 78) of the patients, cervical cone resection in 13.0, 9.9, and 0.3% (112, 9, and 1) of the patients, and radical laparotomy for invasive cancer in 8.3, 76.9, and 73.8% (72, 70, and 222) of the patients, respectively. CONCLUSIONS: Our histological results supported the medical interventions applied for AGC diagnosis and treatment. AGC cases require careful histological evaluation.

Peribiliary gland damage due to liver transplantation involves peribiliary vascular plexus and vascular endothelial growth factor.

Extrahepatic bile ducts are characterized by the presence of peribiliary glands (PBGs), which represent stem cell niches implicated in biliary regeneration. Orthotopic liver transplantation may be complicated by non-anastomotic strictures (NAS) of the bile ducts, which have been associated with ischemic injury of PBGs and occur more frequently in livers obtained from donors after circulatory death than in those from brain-dead donors. The aims of the present study were to investigate the PBG phenotype in bile ducts after transplantation, the integrity of the peribiliary vascular plexus (PVP) around PBGs, and the expression of vascular endothelial growth factor-A (VEGF-A) by PBGs. Transplanted ducts obtained from patients who underwent liver transplantation were studied (N=62). Controls included explanted bile duct samples not used for transplantation (N=10) with normal histology. Samples were processed for histology, immunohistochemistry and immunofluorescence. Surface epithelium is severely injured in transplanted ducts; PBGs are diffusely damaged, particularly in ducts obtained from circulatory-dead compared to brain-dead donors. PVP is reduced in transplanted compared to controls. PBGs in transplanted ducts contain more numerous progenitor and proliferating cells compared to controls, show higher positivity for VEGF-A compared to controls, and express VEGF receptor-2. In conclusion, PBGs and associated PVP are damaged in transplanted extrahepatic bile ducts; however, an activation of the PBG niche takes place and is characterized by proliferation and VEGF-A expression. This response could have a relevant role in reconstituting biliary epithelium and vascular plexus and could be implicated in the genesis of non-anastomotic strictures.

Contribution of HIV Infection, AIDS, and Antiretroviral Therapy to Exocrine Pathogenesis in Salivary and Lacrimal Glands.

The structure and function of exocrine glands are negatively affected by human immunodeficiency virus (HIV) infection and its co-morbidities, including innate and adaptive immune responses. At the same time, exocrine function may also be influenced by pharmacotherapies directed at the infectious agents. Here, we briefly review the role of the salivary glands and lacrimal glands in normal physiology and exocrine pathogenesis within the context of HIV infection and acquired immune deficiency syndrome (AIDS), including the contribution of antiretroviral therapies on both. Subsequently, we discuss the impact of HIV infection and the types of antiretroviral therapy on disease management and therapy development efforts.

Modulation of Apoptosis by Cytotoxic Mediators and Cell-Survival Molecules in Sjögren's Syndrome.

The pathogenesis of Sjögren's syndrome (SS) involves multiple factors including genetic background, cell death, and exocrine dysfunction. We here discuss apoptotic control in exocrine glands in SS by showing various pro- and anti-apoptotic pathways. Although the membrane-bound and soluble form of the Fas/Fas ligand system is a leading player with activation of the death domain and caspase 8/3 cleavage, the role of soluble Fas/FasL (including its polymorphism) in apoptosis is controversial. The tumor necrosis factor related apoptosis-inducing ligand (TRAIL)-mediated apoptosis of salivary gland epithelial cells (SGECs) involves a mitochondrial pathway that includes caspase 9 cleavage. The involvement of innate immunity cells such as toll-like receptors (TLRs) has been investigated; TLR2-4 and TLR7-9 are associated with the induction of inflammation in exocrine glands of SS patients. TLR3 has the potential to induce the apoptosis of SS patients' SGECs. Linkage of epidermal growth factor (EGF) was shown in exocrine glands in SS, and it inhibited the Fas/FasL system with the help of cell-survival factors. TLR3 has dual actions to cause inflammation as well as apoptosis, which are inhibited by EGF. In conclusion, apoptosis in exocrine glands of SS patients is tightly controlled by balance of pro-apoptotic signals and growth factor.

Sex-Pairing Pheromones in Three Sympatric Neotropical Termite Species (Termitidae: Syntermitinae).

Termite colonies are almost always founded by a pair of winged dispersers, in spite of the high costs and low success rates inherent in independent colony foundation. The dispersal flights of imagoes from natal colonies are followed by mate search, mediated by sex-pairing pheromones. Here, we studied the chemistry of sex-pairing pheromones and the related aspects of mate search in winged imagoes of two facultatively parthenogenetic species, Embiratermes neotenicus and Silvestritermes minutus, and an additional species from the same subfamily, Silvestritermes heyeri. All three species are widespread in the Neotropics, including the rainforests of French Guiana. After the dispersal flight and spontaneous loss of wings, females expose their hypertrophied tergal glands situated under abdominal tergites VIII - X. The females are attractive to males and, upon direct contact, the two sexes form characteristic tandems. Chemical analyses indicated that the females secrete species-specific combinations of unbranched, unsaturated C12 primary alcohols from the tergal glands, (3Z,6Z,8E)-dodeca-3,6,8-trien-1-ol (approx. 200 pg per female) and (3Z)-dodec-3-enol (185 pg) in E. neotenicus, (3Z,6Z)-dodeca-3,6-dien-1-ol (3500 pg) in S. heyeri, and (3Z,6Z)-dodeca-3,6-dien-1-ol (300 pg) and (3Z)-dodec-3-enol (50 pg) in S. minutus. (3Z,6Z,8E)-Dodeca-3,6,8-trien-1-ol and (3Z,6Z)-dodeca-3,6-dien-1-ol act as major pheromone components in the respective species and mimic the function of female tergal gland extracts in electrophysiological and behavioral experiments. Biologically relevant amounts of the third compound, (3Z)-dodec-3-enol, elicited non-significant reactions in males of E. neotenicus and S. minutus, and slight synergistic effects in males of S. minutus when tested in combination with the major component.

[Female prostate cancer?] / Weibliches Prostatakarzinom?

We present a case of a female patient who had a clinically suspected advanced urothelial carcinoma of the urethra. Histopathological examination surprisingly revealed a malignant tumor with morphological and immunohistochemical features of prostate cancer, leading to the diagnosis of the extremely rare entity of Skene's gland adenocarcinoma.

Atypical mucinous glandular proliferations in endometrial samplings: follow-up and other clinicopathological findings in 41 cases.

The 2014 World Health Organization classification calls for endometrial mucinous proliferations that display "confluent or cribriform architecture with even minimal atypia" in sampling specimens to be classified as carcinoma, and others whose features are not diagnostic of carcinoma to be categorized as atypical mucinous glandular proliferations (AMGPs). Herein, we evaluate follow-up findings in 41 cases that were classified as AMGP from our files. The average patient age was 46years (range, 37-59 years). Postbiopsy follow-up duration ranged from 15 to 109weeks (mean, 40 weeks). There was no follow-up resection in 12 patients (9 with repeat biopsies, all 9 with no clinical evidence of disease, mean follow-up of 43weeks), and 29 patients underwent a hysterectomy an average of 2.4months after the index biopsy. The distribution of pathologic findings in the uteri was as follows: no residual AMGP or carcinoma (5/29; 17%), AMGP (11/29; 38%), and adenocarcinoma (13/29; 45%). All adenocarcinomas were grade I and stage I, and histotypes were endometrioid (n=8), mucinous (n=3), and endometrioid with mucinous differentiation (n=2). Only 3 (23%) carcinomas were myoinvasive, of which 1 case, a mucinous carcinoma with a 40% endometrioid component, showed greater than 50% myometrial invasion. None of a wide array of morphologic features was significantly associated with a hysterectomy diagnosis of carcinoma (versus AMGP) on univariate analyses. In conclusion, our cohort of AMGP represents a biologically variable spectrum of lesions that includes mucinous hyperplastic proliferations as well as endometrioid and mucinous adenocarcinomas that are occasionally myoinvasive. Morphologic features that optimally stratified AMGP cases into clinically relevant subgroups were not identified.

[Vaginal adenosis: A case report and literature review]. / Adénose vaginale : à propos d'une observation et revue de la littérature.

We report a case of vaginal adenosis in a woman of 42years. This is a rare congenital disorder since cessation of use of diethylstilbestrol (DES), usually of benign course, not to ignore in its tubo-endometrial histological form which may progress to atypical adenosis precursor of vaginal clear cell adenocarcinoma in patients exposed in utero to DES.

Mimotope mimicking epidermal growth factor receptor alleviates mononuclear cell infiltration in exocrine glands induced by muscarinic acetylcholine 3 receptor.

The muscarinic type 3 receptor (M3R) plays a pivotal role in the pathogenesis of Sjögren's syndrome (SS). Characterization of the crosstalk between M3R and EGFR has been investigated in some human malignancies. In the current study, we sought to investigate whether EGFR mimic immunization could alleviate the abnormal immune responses in an experimental SS-like model triggered by M3R peptides. After immunization with the combination of mimotope and M3R peptide, the active immunization targeting EGFR induced by the mimotope could reduce the marked infiltration of mononuclear cells, the high titer of antibodies against M3R and the accumulation of crucial pro-inflammatory cytokines in mice immunized with M3R peptide. Mechanistic analysis showed that mimotope immunization could alleviate the autoimmune response through inhibiting mitochondrion-mediated anti-apoptosis and up-regulating the FAS apoptosis pathway. These results may help to clarify the role of M3R in the pathogenesis of SS and suggested that transactivation of the EGFR signaling pathway may help M3R activate the autoimmune response in the pathogenesis of SS.

META-ANALYSIS OF HIGH RISK FACTORS OF RESIDUE OR RELAPSE OF CERVICAL INTRAEPITHELIAL NEOPLASIA AFTER CONIZATION.

This study assesses the high risk factors of residue or relapse after conization of cervical intraepithelial neoplasia. Literature on high risk factors of residue or relapse after conization of cervical intraepithelial neoplasia from January 2006 to June 2011 were selected from the Pubmed Database, Elsevier Database, Chinese Biomedicine Database and Chinese Journal Full-text Database of China National Knowledge Internet (CNKI). Software RevMan 4. 2 provided by Cochrane collaboration network was used in the statistical analysis of the data. According to the inclusion criteria, 10 essays were retrieved, including 348 cases in case groups and 1,608 cases in control groups. Information about residue or relapse after conization, incisal edge, HIV infection after six months of surgery, age, menopause status was obtained through the above method. Meta-analysis showed that positive surgical margin groups had a higher residual or recurrence rate than negative surgical margin groups after conization; groups where glands were involved had a higher residual or recurrence rate than non-involved glands groups after conization; positive HR-HPV infection after six months of conization groups had higher residual or recurrence rates than negative HR-HPV infection groups; 50 years or older groups had higher residual or recurrence rate than under 50 year-old groups after conization; postmenopausal groups had higher residual or recurrence rate than premenopausal groups. Menopause, 50 years old or older, gland involvement, positive surgical margin and HR-HPV infection after six months are high risk factors of residue or relapse after α - ß conization of CIN.