TSG-6 Produced by hMSCs Delays the Onset of Autoimmune Diabetes by Suppressing Th1 Development and Enhancing Tolerogenicity

Genetic and immunological screening for type 1 diabetes has led to the possibility of preventing disease in susceptible individuals. Here, we show that human mesenchymal stem/stromal cells (hMSCs) and tumor necrosis factor-α–stimulated gene 6 (TSG-6), a protein produced by hMSCs in response to signals from injured tissues, delayed the onset of spontaneous autoimmune diabetes in NOD mice by inhibiting insulitis and augmenting regulatory T cells (Tregs) within the pancreas. Importantly, hMSCs with a knockdown of tsg-6 were ineffective at delaying insulitis and the onset of diabetes in mice. TSG-6 inhibited the activation of both T cells and antigen-presenting cells (APCs) in a CD44-dependent manner. Moreover, multiple treatments of TSG-6 rendered APCs more tolerogenic, capable of enhancing Treg generation and delaying diabetes in an adoptive transfer model. Therefore, these results could provide the basis for a novel therapy for the prevention of type 1 diabetes.Recent advances in the use of genetic and immunological screening for identification of prediabetic patients (1–3) have opened up the opportunity to prevent, delay, or halt disease progression before the diagnosis of diabetes. Based on the success in animal models (4–6), clinical trials of oral or nasal insulin (7,8) and nicotinamide (9,10) have been conducted in humans to prevent type 1 diabetes. However, despite all efforts, these clinical trials have failed to show any improvement in the prevention of type 1 diabetes.Recently, we found that intravenously administered human mesenchymal stem/stromal cells (hMSCs) were activated to express the anti-inflammatory protein tumor necrosis factor (TNF)-α–stimulated gene 6 (TSG-6), which reduced excessive inflammatory response in the myocardial-infarcted heart in mice (11), chemically and mechanically injured cornea in rodent models (12,13), and zymosan-induced peritonitis in mice (14). Specifically, our recent observation revealed that TSG-6 attenuated zymosan-induced mouse peritonitis by decreasing TLR2-mediated NF-κB signaling in resident macrophages (14). This suppressive effect of TSG-6 on NF-κB signaling could provide the rationale for TSG-6 as a potential therapy for the prevention of type 1 diabetes, since several studies have already shown that inflammation and the innate immune system contribute to induction, amplification, and maintenance of the immune cell infiltrate as well as β-cell destruction during this preclinical period (15–17). Particularly, antigen-presenting cells (APCs) from NOD mice, mainly dendritic cells (DCs) and macrophages, have been shown to secrete substantially elevated levels of interleukin-12 (IL-12) and TNF-α (18,19) due to NF-κB hyperactivity (18,20), which leads to T-helper 1 (Th1) development and overt diabetes (21).Here, we tested whether a new treatment for the prevention of type 1 diabetes could be developed using TSG-6, which hMSCs produce in response to signals from injured tissues. Our data showed that systemic administration of hMSCs to prediabetic mice delayed the onset of type 1 diabetes in NOD mice in part by secreting TSG-6.     

Intraosseous carcinoma of the jaws—A clinicopathologic review. Part I: Metastatic and salivary‐type carcinomas

This is the first part of a 3‐part comprehensive review of intraosseous carcinoma of the jaws. We have outlined 4 groups of intraosseous carcinoma of the jaws (metastatic, salivary‐type, odontogenic, and primary intraosseous carcinoma), emphasizing the need for accurate diagnosis and the problems associated with changing classification systems, standardization of diagnostic criteria and nomenclature, and the accuracy of existing literature. In this first part, the features of metastatic and the very rare salivary‐type carcinomas of the jaws are examined with particular emphasis on histologic and immunohistochemical characteristics, diagnostic difficulties, and uncertainties. © 2012 Wiley Periodicals, Inc. Head Neck, 2012     

What are the symptoms of internal rectal prolapse?

Aim Although high‐grade internal rectal prolapse is believed to cause functional symptoms such as obstructed defaecation, little has been published on the exact distribution and frequency of symptoms. The aim of this study was to identify the most common symptoms of patients with high‐grade internal rectal prolapse. Method Patients were diagnosed with high‐grade prolapse (grade 3 and 4) on proctography using the Oxford Rectal Prolapse Grade. Information from a prospectively collected database was supplemented by a retrospective case note review. Results Eighty eight patients (94% of them women) were included for analysis. Faecal incontinence (56%) was the most common symptom at presentation. Symptoms related to obstructed defaecation syndrome were the next most common, including incomplete evacuation (45%), straining (34%), digital assistance (34%) and repetitive toilet visits (33%). Conclusion A variety of symptoms may be caused by high‐grade internal rectal prolapse Although symptoms of obstructed defaecation were frequent, urge faecal incontinence was the most common.     

Histamine regulation of pancreatitis and pancreatic cancer: a review of recent findings

The pancreas is a dynamic organ that performs a multitude of functions within the body. Diseases that target the pancreas, like pancreatitis and pancreatic cancer, are devastating and often fatal to the suffering patient. Histamine and histamine receptors (H1-H4HRs) have been found to play a critical role in biliary diseases. Accordingly, the biliary tract and the pancreas share similarities with regards to morphological, phenotypical and functional features and disease progression, studies related the role of H1-H4HRs in pancreatic diseases are important. In this review, we have highlighted the role that histamine, histidine decarboxylase (HDC), histamine receptors and mast cells (the main source of histamine in the body) play during both pancreatitis and pancreatic cancer. The objective of the review is to demonstrate that histamine and histamine signaling may be a potential therapeutic avenue towards treatment strategies for pancreatic diseases.Key Words: Histamine, pancreas, pancreatitis, pancreatic cancer