The TFOS DEWS II Pathophysiology Subcommittee reviewed the mechanisms involved in the initiation and perpetuation of dry eye disease. Its central mechanism is evaporative water loss leading to hyperosmolar tissue damage. Research in human disease and in animal models has shown that this, either directly or by inducing inflammation, causes a loss of both epithelial and goblet cells. The consequent decrease in surface wettability leads to early tear film breakup and amplifies hyperosmolarity via a Vicious Circle. Pain in dry eye is caused by tear hyperosmolarity, loss of lubrication, inflammatory mediators and neurosensory factors, while visual symptoms arise from tear and ocular surface irregularity. Increased friction targets damage to the lids and ocular surface, resulting in characteristic punctate epithelial keratitis, superior limbic keratoconjunctivitis, filamentary keratitis, lid parallel conjunctival folds, and lid wiper epitheliopathy. Hybrid dry eye disease, with features of both aqueous deficiency and increased evaporation, is common and efforts should be made to determine the relative contribution of each form to the total picture. To this end, practical methods are needed to measure tear evaporation in the clinic, and similarly, methods are needed to measure osmolarity at the tissue level across the ocular surface, to better determine the severity of dry eye. Areas for future research include the role of genetic mechanisms in non-Sjogren syndrome dry eye, the targeting of the terminal duct in meibomian gland disease and the influence of gaze dynamics and the closed eye state on tear stability and ocular surface inflammation.

TFOS DEWS II pathophysiology report

Structure–function relationship of estrogen receptor α and β: Impact on human health

Primary Sjogren's syndrome (pSS) is a prototypic autoimmune disorder, management of which has long suffered from a lack of knowledge of the underlying pathophysiological mechanisms; however, over the past decade major advances have been made in understanding the pathogenesis of pSS. The innate immune system has been demonstrated to have an important role at the early stage of the disease, notably through activation of the type I interferon (IFN) system. In addition, mechanisms of B-cell activation in pSS have become clearer, particularly owing to recognition of the involvement of the TNF family cytokine B-cell-activating factor, production of which is highly dependent on expression of type I and type II IFNs. Moreover, key inroads have been made in understanding lymphomagenesis, the most severe complication of pSS. IL-12 production and subsequent T-cell activation, mainly IFN-γ-secreting type 1 T-helper cells, have also been implicated in disease pathogenesis. Furthermore, evidence implicates neuroendocrine system dysfunction in pSS pathogenesis. These pathophysiological advances open new avenues of investigation. Indeed, the increased understanding of pSS pathogenesis has already led to the development of promising novel therapeutic strategies. This article summarizes recent findings regarding the pathogenic mechanisms involved in pSS and their implications.

Advances in understanding the pathogenesis of primary Sjögren's syndrome

MicroRNAs (miRNAs) are members of a non-coding RNA family. They act as negative regulators of protein translation by affecting messenger RNA (mRNA) stability; they modulate numerous signaling pathways and cellular processes, and are involved in cell-to-cell communication. Thus, studies on miRNAs offer an opportunity to improve our understanding of complex biological mechanisms. In the cardiovascular system, miRNAs control functions of various cells, such as cardiomyocytes, endothelial cells, smooth muscle cells and fibroblasts. The pivotal role of miRNAs in the cardiovascular system provides a new perspective on the pathophysiology of disorders like myocardial infarction, hypertrophy, fibrosis, heart failure, arrhythmia, inflammation and atherosclerosis. MiRNAs are differentially expressed in diseased tissue and can be released into circulation. Manipulation of miRNA activity may influence the course of a disease. Therefore, miRNAs have become an active field of research for developing new diagnostic and therapeutic tools. This review discusses emerging functions of miRNAs in cardiogenesis, heart regeneration and the pathophysiology of cardiovascular diseases.

/pdf/microrna-in-cardiovascular-biology-and-disease-40qcmkl1ks.pdf

MicroRNA in cardiovascular biology and disease.

Autoimmune regulator (AIRE) gene mutation is responsible for the development of organ-specific autoimmune disease with monogenic autosomal recessive inheritance. Although Aire has been considered to regulate the elimination of autoreactive T cells through transcriptional control of tissue-specific Ags in thymic epithelial cells, other mechanisms of AIRE-dependent tolerance remain to be investigated. We have established Aire-deficient mice and examined the mechanisms underlying the breakdown of self-tolerance. The production and/or function of immunoregulatory T cells were retained in the Aire-deficient mice. The mice developed Sjogren's syndrome-like pathologic changes in the exocrine organs, and this was associated with autoimmunity against a ubiquitous protein, alpha-fodrin. Remarkably, transcriptional expression of alpha-fodrin was retained in the Aire-deficient thymus. These results suggest that Aire regulates the survival of autoreactive T cells beyond transcriptional control of self-protein expression in the thymus, at least against this ubiquitous protein. Rather, Aire may regulate the processing and/or presentation of self-proteins so that the maturing T cells can recognize the self-Ags in a form capable of efficiently triggering autoreactive T cells. With the use of inbred Aire-deficient mouse strains, we also demonstrate the presence of some additional factor(s) that determine the target-organ specificity of the autoimmune disease caused by Aire deficiency.

Development of Autoimmunity against Transcriptionally Unrepressed Target Antigen in the Thymus of Aire-Deficient Mice

Polyetheretherketone (PEEK) is a semi-crystalline linear polycyclic thermoplastic that has been proposed as a substitute for metals in biomaterials. PEEK can also be applied to dental implant materials as a superstructure, implant abutment, or implant body. This article summarizes the current research on PEEK applications in dental implants, especially for the improvement of PEEK surface and body modifications. Although various benchmark reports on the reinforcement and surface modifications of PEEK are available, few clinical trials using PEEK for dental implant bodies have been published. Controlled clinical trials, especially for the use of PEEK in implant abutment and implant bodies, are necessary.

https://www.mdpi.com/2304-6767/5/4/35/pdf

PEEK with Reinforced Materials and Modifications for Dental Implant Applications.

Although a number of autoimmune diseases are known to develop in postmenopausal women, the mechanisms by which estrogen deficiency influences autoimmune lesions remain unclear. We speculate that antiestrogenic actions might be a potent factor in the formation of pathogenic autoantigens. Previously, we have identified 120-kd alpha-fodrin as an important autoantigen in Sjogren's syndrome (SS). When healthy C57BL/6 (B6) mice were treated with an ovariectomy (Ovx), we found a significant increase in TUNEL(+)-apoptotic epithelial cells in the salivary gland cells associated with alpha-fodrin cleavage during 2 and 3 weeks after Ovx. By contrast, no apoptotic cells were found in estrogen receptor-alpha knockout mice. In in vitro studies using primary cultured mouse salivary gland cells and human salivary gland cells, we found a cleavage product of 120-kd alpha-fodrin in cells that had undergone tamoxifen (Tam)-induced apoptosis through caspase activation, especially caspase-1. Adoptive transfer of alpha-fodrin-reactive T cells into Ovx-B6 and -SCID mice resulted in the development of autoimmune exocrinopathy quite similar to SS. These results suggest that estrogen deficiency exerts a crucial influence on autoantigen cleavage, and may cause, in part, autoimmune exocrinopathy in postmenopausal women.

Development of Autoimmune Exocrinopathy Resembling Sjögren's Syndrome in Estrogen-Deficient Mice of Healthy Background

https://repo.lib.tokushima-u.ac.jp/files/public/10/109479/20170929143537616147/LID201507171004.pdf

MiR-494-3p induced by compressive force inhibits cell proliferation in MC3T3-E1 cells.

Objective
The purpose of this systematic review was to survey evidence pertaining to the sensation differences between natural teeth and osseointegrated dental implants.

Material and methods
Using the MEDLINE (online PubMed) database, Cochrane Library, and Scientific Citation index, we performed a systematic search of articles. We used the following search terms: “perception or sensation and dental implant.” The systematic review of the extracted articles was performed to see the sensation differences between natural teeth and dental implants.

Results
A total of six studies on oral sensation, “tactile sensibility,” and “thickness discrimination” were included in the meta-analysis. As to the “tactile sensibility”, all studies indicated the threshold levels of the implants were about 4–20 times higher than that of natural teeth. The tactile sensibility of an implant was significantly higher than that of a natural tooth, with an standardized mean difference (SMD) of 8.3619 (95% CI, 6.3920–10.3317) and a P < 0.0001. As to the “thickness discrimination”, all studies indicated the threshold levels of implants were about 1.2–2.3 times higher than that of natural teeth. The thickness discrimination was significantly higher than that of natural teeth with an SMD of 1.2368 (95% CI, 0.8699–1.6038) and a P < 0.0001.

Conclusion
This meta-analysis suggested that both tactile sensibility and thickness discrimination thresholds of implants were significantly higher than those of natural teeth. This meta-analysis reconfirms that sensation differences between dental implants and natural teeth exist.

Do sensation differences exist between dental implants and natural teeth?: a meta‐analysis

The purpose of this study was to survey the changes that occur in bolus texture from intake to swallowing during the mastication process for four types of food materials and to identify how texture is related to the number of chews. We recruited 15 young Japanese participants for this study. The subjects were asked to spit the food bolus just before swallowing when eating four different foods: cracker, boiled rice, hard gelatine gel, and soft gelatine gel. Three physical properties (hardness, adhesiveness, and cohesiveness) were measured in the bolus after being chewed for 25, 50, 75, 100, and 125% of the normal number of chews. Occlusal force and pressure as well as stimulated whole saliva volume were also measured. Extensive variation in the number of chews existed between subjects, but minimal intra-subject variation was observed. Hardness was observed to decrease, whereas cohesiveness and adhesiveness increased in a chew-dependent manner for the cracker, soft gelatine gel, and hard gelatine gel, but not boiled rice. Bolus texture appears to be largely related to the number of chews. Hardness also tended to be influenced by occlusion. The adhesiveness and hardness of the boiled rice were also greatly influenced by saliva volume and occlusal force, respectively. Hardness is an important rheological factor in food bolus texture and likely plays a significant role in determining the appropriate number of chews. Adhesiveness and cohesiveness appear to be secondary factors in this process.

Practical applications
We propose a model of oral processing for application in determining the appropriate number of chews for an individual. Hardness appears to be an important rheological factor in food bolus texture, with adhesiveness and cohesiveness being secondary aspects. When food is hard or difficult to swallow, chewing behavior will likely be more influenced by the perception of bolus texture.

Megumi Watanabe

Papers

PEEK with Reinforced Materials and Modifications for Dental Implant Applications.

Development of Autoimmune Exocrinopathy Resembling Sjögren's Syndrome in Estrogen-Deficient Mice of Healthy Background

MiR-494-3p induced by compressive force inhibits cell proliferation in MC3T3-E1 cells.

Do sensation differences exist between dental implants and natural teeth?: a meta‐analysis

Changes in food bolus texture during mastication.