Functional dyspepsia (FD) is a gastrointestinal disorder of unknown etiology. Although micro-inflammation appears to be important in the pathogenesis, studies evaluating immune activation in FD have been inconsistent. A systematic review of literature and meta-analysis was performed to compare immunologic cell counts and cytokine levels in the mucosa and peripheral blood of individuals with FD and healthy controls. PubMed, Embase, and the Cochrane library were searched. Data on immunologic cell counts and cytokines levels among individuals with FD and control groups were extracted and compared by calculating standard mean differences (SMD). Thirty-seven studies met the inclusion criteria. Mast cell (SMD = 0.94, 95%CI 0.26-1.62, P = .007) and eosinophil counts (SMD = 0.36, 95%CI 0.06-0.68, P = .03) in the stomach were increased, among individuals with FD compared to controls. Similarly, mast cell (SMD = 0.66, 95%CI 0.20-1.13, P = 0.005) and eosinophil (SMD = 0.95, 95%CI 0.66-1.24; P < .001) counts in the duodenum were also increased in those with FD compared to controls. In a subgroup analysis, elevated eosinophil counts in the duodenum were observed in both post-prandial distress syndrome (SMD = 0.97, 95%CI 0.46-1.47, P = .0002) and epigastric pain syndrome subtypes (SMD = 1.16, 95%CI 0.48-1.83, P = .0008). No differences in mucosal intraepithelial lymphocyte, enterochromaffin cell, and neutrophil counts, as well as, peripheral interlukin-6 (IL-6) and IL-10 levels were observed among individuals with FD and controls. Micro-inflammation in the form of local immune cell infiltration, particularly eosinophils and mast cells, characterizes the pathogenesis of FD.

Surface temperature measured by an infrared temperature-scanning thermometer was used to evaluate disease severity and predict imminent death in a murine model of pneumococcal pneumonia. We showed that a decrease in temperature was associated with increasing severity of disease and concomitant histological changes and also that a temperature of 30°C or less was a predictor of death. Furthermore, viable bacterial counts in the lungs of mice euthanized at a temperature of < 30°C were not significantly different from those seen in the lungs of mice allowed to die without intervention. These data support temperature change as a more subtle indicator of outcome than death and demonstrate that this could be used as a reliable end point for euthanasia. To test the utility of our model in a drug trial, we examined the efficacies of moxifloxacin and levofloxacin by using temperature as a measure of disease severity prior to and during treatment. Regardless of the antibiotic used, mice assessed as moderately ill (temperature > 32°C) at the start of treatment had better clinical and bacteriological outcomes than mice assessed as severely ill (temperature < 32°C). However, moxifloxacin offered better protection and greater bacterial clearance than did levofloxacin in all infected mice independent of disease severity. This model not only allows a more subtle evaluation of drug efficacy but also ensures a better degree of standardization and a more humane approach to drug efficacy studies involving animals.

Shp2 negatively regulates thrombus stability under pathological shear rate. Shp2 suppresses TXA2 receptor‐mediated platelet dense granule secretion. Through αIIbβ3 outside‐in signaling, Shp2 targets calmodulin‐dependent activation of Akt. Shp2 may serve to prevent the formation of unwanted occlusive thrombi. Summary BackgroundPerpetuation is the final phase of thrombus formation; however, its mechanisms and regulation are poorly understood. ObjectiveTo investigate the mechanism of Shp2 in platelet function and thrombosis. Methods and resultsWe demonstrate that the platelet‐expressed Src homology region 2 domain‐containing protein tyrosine phosphatase Shp2 is a negative regulator of thrombus stability under high shear stress. In a ferric chloride‐induced mesenteric arteriole thrombosis model, megakaryocyte/platelet‐specific Shp2‐deficient mice showed less thrombi shedding than wild‐type mice, although their occlusion times were comparable. In accordance with this in vivo phenotype, a microfluidic whole‐blood perfusion assay revealed that the thrombi formed on collagen surfaces by Shp2‐deficient platelets were more stable under high shear rates than those produced by wild‐type platelets. Whereas Shp2 deficiency did not alter platelet responsiveness towards thrombin, ADP and collagen stimulation, Shp2‐deficient platelets showed increased dense granule secretion when stimulated by the thromboxane A2 analog U46619. Shp2 appears to act downstream of integrin αIIbβ3 outside‐in signaling, inhibiting the phosphorylation of Akt (Ser473 and Thr308) and dense granule secretion. Calmodulin was also shown to bind both Shp2 and Akt, linking Shp2 to Akt activation. ConclusionsPlatelet Shp2 negatively regulates thrombus perpetuation under high shear stress. This signaling pathway may constitute an important mechanism for the prevention of unwanted occlusive thrombus formation, without dramatically interfering with hemostasis.