NOD1 mediates interleukin-18 processing in epithelial cells responding to Helicobacter pylori infection in mice.

The interleukin-1 family members, IL-1ß and IL-18, are processed into their biologically active forms by multi-protein complexes, known as inflammasomes. Although the inflammasome pathways that mediate IL-1ß processing in myeloid cells have been defined, those involved in IL-18 processing, particularly in non-myeloid cells, are still not well understood. Here we report that the host defence molecule NOD1 regulates IL-18 processing in mouse epithelial cells in response to the mucosal pathogen, Helicobacter pylori. Specifically, NOD1 in epithelial cells mediates IL-18 processing and maturation via interactions with caspase-1, instead of the canonical inflammasome pathway involving RIPK2, NF-κB, NLRP3 and ASC. NOD1 activation and IL-18 then help maintain epithelial homoeostasis to mediate protection against pre-neoplastic changes induced by gastric H. pylori infection in vivo. Our findings thus demonstrate a function for NOD1 in epithelial cell production of bioactive IL-18 and protection against H. pylori-induced pathology.

Tissue-nonspecific alkaline phosphatase is an anti-inflammatory nucleotidase.

Tissue-nonspecific alkaline phosphatase (TNAP) is necessary for skeletal mineralization by its ability to hydrolyze the mineralization inhibitor inorganic pyrophosphate (PPi), which is mainly generated from extracellular ATP by ectonucleotide pyrophosphatase phosphodiesterase 1 (NPP1). Since children with TNAP deficiency develop bone metaphyseal auto-inflammations in addition to rickets, we hypothesized that TNAP also exerts anti-inflammatory effects relying on the hydrolysis of pro-inflammatory adenosine nucleotides into the anti-inflammatory adenosine. We explored this hypothesis in bone metaphyses of 7-day-old Alpl+/- mice (encoding TNAP), in mineralizing hypertrophic chondrocytes and osteoblasts, and non-mineralizing mesenchymal stem cells (MSCs) and neutrophils, which express TNAP and are present, or can be recruited in the metaphysis. Bone metaphyses of 7-day-old Alpl+/- mice had significantly increased levels of Il-1ß and Il-6 and decreased levels of the anti-inflammatory Il-10 cytokine as compared with Alpl+/+ mice. In bone metaphyses, murine hypertrophic chondrocytes and osteoblasts, Alpl mRNA levels were much higher than those of the adenosine nucleotidases Npp1, Cd39 and Cd73. In hypertrophic chondrocytes, inhibition of TNAP with 25 µM of MLS-0038949 decreased the hydrolysis of AMP and ATP. However, TNAP inhibition did not significantly modulate ATP- and adenosine-associated effects in these cells. We observed that part of TNAP proteins in hypertrophic chondrocytes was sent from the cell membrane to matrix vesicles, which may explain why TNAP participated in the hydrolysis of ATP but did not significantly modulate its autocrine pro-inflammatory effects. In MSCs, TNAP did not participate in ATP hydrolysis nor in secretion of inflammatory mediators. In contrast, in neutrophils, TNAP inhibition with MLS-0038949 significantly exacerbated ATP-associated activation and secretion of IL-1ß, and extended cell survival. Collectively, these results demonstrate that TNAP is a nucleotidase in both hypertrophic chondrocytes and neutrophils, and that this nucleotidase function is associated with autocrine effects on inflammation only in neutrophils.

Planned ventral hernia following damage control laparotomy in trauma: an added year of recovery but equal long-term outcome.

PURPOSE: Significantly injured trauma patients commonly require damage control laparotomy (DCL). These patients undergo either primary fascial closure during the index hospitalization or are discharged with a planned ventral hernia. Hospital and long-term outcomes of these patients have not been extensively studied. METHODS: Patients who underwent DCL for trauma from 2003 to 2012 at a regional Level I trauma center were identified and a comparison was made between those who had primary fascial closure and planned ventral hernia. RESULTS: DCL was performed in 154 patients, 47% of whom sustained penetrating injuries. The mean age and injury severity score (ISS) were 40 and 25, respectively. Hospital mortality was 19%. Primary fascial closure was performed in 115 (75%) of those undergoing DCL during the index hospitalization. Of these, 11 (9%) had reopening of the fascia. Of the surviving patients, 22 (19%) never had primary fascial closure and were discharged with a planned ventral hernia. Patients with primary fascial closure and those with planned ventral hernia were similar in age, gender, ISS, and mechanism. Those with planned ventral hernias underwent more subsequent laparotomies (3.0 vs. 1.3, p < 0.001), and had more enteric fistulas (18.2 vs. 4.3%, p = 0.041) and intra-abdominal infections (46 vs. 15%, p = 0.007), and had a greater number of hospital days (38 vs. 25, p = 0.007) during the index hospitalization. Sixteen (73%) patients with a planned ventral hernia had definitive reconstruction (mean days = 266). Once definitive abdominal wall closure was achieved, the two groups achieved similar rates of return to work and usual activity (71 vs. 70%, p = NS). CONCLUSIONS: Following DCL for trauma, patients with a planned ventral hernia have definitive reconstruction nearly 9 months after the initial injury. Once definitive abdominal wall closure has been achieved; patients with primary fascial closure and those with planned ventral hernia have similar rates of return to usual activity.

Management of pituitary incidentalomas. A survey of British and American endocrinologists.

The results of a survey of endocrinologists concerning their approaches to the evaluation of a patient with an incidentally discovered pituitary mass are presented in this article. The practices of British and American endocrinologists are compared. The wide variation in diagnostic approaches to the practice of ordering tests in the United Kingdom and the United States highlights the need for research and debate regarding the most appropriate management of patients with such findings.

Sclerotherapy for malignant pleural effusions: alternatives to tetracycline.

Malignant pleural effusion (MPE) causes significant morbidity in cancer patients. Management is often challenging because of the recurrent nature of MPE and the inconsistent response rates of various treatments. In patients whose underlying malignancy is unresponsive to systemic chemotherapy or radiation, MPE is usually managed by tube thoracostomy with subsequent sclerotherapy. Selection of a sclerosing agent should be based on several factors, including efficacy, toxicity, cost, and convenience. Of the numerous agents available for managing MPE, doxycycline, bleomycin, and talc have emerged as the most promising. Even these agents have disadvantages, such as the high cost of bleomycin and the possible need for multiple dosing of doxycycline. Talc is clearly the most controversial of the three. Although its efficacy is well documented, its role remains unclear because of its unattractive side effect profile and inconvenient preparation and administration. Results of controlled comparative trials are needed to identify the optimal sclerosing agent.