Serum Human ß-Defensin 2 Is Increased in Angioedema Accompanying Chronic Spontaneous Urticaria.

INTRODUCTION: Chronic spontaneous urticaria (CSU) is a common cutaneous disease caused by mast-cell degranulation. Human ß-defensin 2 (HBD2) is a well-known antimicrobial peptide that is also a pruritogen inducing vascular permeability via non-IgE-mediated mast-cell degranulation. OBJECTIVE: We investigated the associations between serum HBD2 levels and the clinical characteristics of CSU patients. METHODS: Serum samples from 124 CSU patients and 56 healthy controls were screened for the levels of HBD2 and translationally controlled tumor protein (TCTP)_ by using ELISA. The urticaria activity score over 7 days (UAS7) was used to measure disease activity in CSU patients. Accompanying angioedema was self-reported. RESULTS: Serum HBD2 levels were higher in the CSU group than in healthy subjects (median [interquartile range], 84.1 [43.5, 142.5] vs. 59.5 [26.7, 121.5], p = 0.034). In CSU patients, serum HBD2 level was negatively correlated with the peripheral basophil percentages (Spearman's rho = -0.229, p = 0.01) and vitamin D levels (-0.262, p = 0.02), but positively correlated with TCTP levels (0.252, p = 0.006). In CSU patients, HBD2 level was higher in those with than without angioedema (101.7 [50.9, 184.2] vs. 66.7 [37.9, 132.0], p = 0.019). It did not differ by aspirin hypersensitivity or atopy status, or autologous serum skin test positivity. CONCLUSION: A known mast-cell degranulator, HBD2 was elevated in the sera from CSU patients compared to healthy controls and may be involved in the pathogenesis of accompanying angioedema.

Role of microglia and toll-like receptor 4 in the pathophysiology of delirium.

Delirium is a serious medical condition that commonly afflicts elderly inpatients. This is especially common in the post-operative setting where it increases mortality, length of hospital stay and health care costs. The exact mechanisms involved in its pathogenesis remain uncertain and there is currently no effective pharmacological therapy for treatment or prevention of delirium. We hypothesize that microglia-mediated neuroinflammation via toll-like receptor 4 signalling is a significant contributor to post-operative delirium. Based on our proposed mechanism, three novel pharmacological therapies have been suggested to be effective to prevent or treat delirium. Curcumin, ibudilast and minocycline have been shown to interfere with various steps in the proinflammatory microglial activation intracellular signalling pathway, disrupting the subsequent neuroinflammatory cascade. We hypothesize that these drugs could be a novel pharmacotherapy that could significantly improve the outcome of post-operative delirious patients.

Normalization of negative T-wave on electrocardiography and right ventricular dysfunction in patients with an acute pulmonary embolism.

BACKGROUND/AIMS: Right ventricular dysfunction (RVD) is associated with poor prognosis in patients with acute pulmonary embolism (APE). Echocardiography and computed tomography (CT)-angiography may be difficult to perform in a serial follow up, unlike electrocardiography (ECG). Many ECG findings specific for APE have been reported, and many studies have found that negative T-waves (NTW) in precordial leads are most frequently observed in patients with APE. We analyzed serial changes in precordial NTW to detect RVD and predict the recovery of RVD in patients with APE. METHODS: We examined 81 consecutive patients diagnosed with APE using CT-angiography or echocardiography. ECG, transthoracic echocardiography, and laboratory tests were performed within 24 hours of admission, and daily ECG follow-up was performed. Precordial NTWs were defined by the new development of pointed and symmetrical inverted T-waves in at least three leads. Recovery of NTW was defined as flattening or upright inverted T-waves in more than two leads. RESULTS: Of the 81 patients with APE, 52 (64%) had RVD according to echocardiography. Among the patients with RVD, 33 (63%) showed precordial NTW. The multivariate logistic regression analysis revealed that NTW was the strongest independent predictor for RVD (odds ratio, 22.8; 95% confidence interval, 2.4 to 221.4; p = 0.007). Time to normalization of NTW was associated with improvement of RVD on echocardiography (r = 0.84, p < 0.01). CONCLUSIONS: Precordial NTW was a reliable finding to identify RVD in patients with APE. Improvements in RVD can be predicted by normalizing precordial NTW.

Essential roles of Atg5 and FADD in autophagic cell death: dissection of autophagic cell death into vacuole formation and cell death.

Autophagic cell death is characterized by the accumulation of vacuoles in physiological and pathological conditions. However, its molecular event is unknown. Here, we show that Atg5, which is known to function in autophagy, contributes to autophagic cell death by interacting with Fas-associated protein with death domain (FADD). Down-regulation of Atg5 expression in HeLa cells suppresses cell death and vacuole formation induced by IFN-gamma. Inversely, ectopic expression of Atg5 using adenoviral delivery induces autophagic cell death. Deletion mapping analysis indicates that procell death activity resides in the middle and C-terminal region of Atg5. Cells harboring the accumulated vacuoles triggered by IFN-gamma or Atg5 expression become dead, and vacuole formation precedes cell death. 3-Methyladenine or expression of Atg5(K130R) mutant blocks both cell death and vacuole formation triggered by IFN-gamma, whereas benzyloxycarbonyl-VAD-fluoromethyl ketone (Z-VAD-fmk) inhibits only cell death but not vacuole formation. Atg5 interacts with FADD via death domain in vitro and in vivo, and the Atg5-mediated cell death, but not vacuole formation, is blocked in FADD-deficient cells. These results suggest that Atg5 plays a crucial role in IFN-gamma-induced autophagic cell death by interacting with FADD.