Impairment of chemical clearance is relevant to the pathogenesis of refractory reflux oesophagitis

BackgroundThe pathophysiological mechanisms underlying proton pump inhibitor-refractory reflux oesophagitis has been scarcely studied.AimsTo assess impedance-pH parameters relevant to the pathogenesis of refractory reflux oesophagitis.MethodsCases referred for heartburn/regurgitation refractory to high-dosage proton pump inhibitors between January 2008 and December 2012 were reviewed and subdivided into refractory oesophagitis (29 patients, 72% males, median age 50 years), healed oesophagitis (18 patients, 67% males, median age 54 years), and non-erosive reflux disease (49 patients, 53% males, median age 42 years). On-therapy impedance-pH tracings were blindly re-analysed by one observer to assess gastric and oesophageal acid exposure time and chemical clearance as expressed by the post-reflux swallow-induced peristaltic wave index.ResultsThe median gastric and oesophageal acid exposure time did not differ among the three groups (35%, 34%, 41% and 1.2%, 0.7%, 0.8%, respectively; P > 0.05 for all comparisons). A normal oesophageal acid exposure time was found in two thirds of patients with refractory oesophagitis. The post-reflux swallow-induced peristaltic wave index was significantly lower in refractory oesophagitis (16%) than in healed oesophagitis (30%) and non-erosive reflux disease (29%) (P = 0.003).ConclusionsRefractory reflux oesophagitis is characterized by impairment of chemical clearance. Adequate acid suppression is found in the majority of patients who would likely not benefit from further proton pump inhibitor dose escalation.     

Monocytes from Sjögren's syndrome patients display increased vasoactive intestinal peptide receptor 2 expression and impaired apoptotic cell phagocytosis

Sjögren's syndrome (SS) is a chronic autoimmune disease characterized by salivary and lacrimal gland dysfunction. Clinical observations and results from animal models of SS support the role of aberrant epithelial cell apoptosis and immune homeostasis loss in the glands as triggering factors for the autoimmune response. Vasoactive intestinal peptide (VIP) promotes potent anti‐inflammatory effects in several inflammatory and autoimmune disease models, including the non‐obese diabetic (NOD) mouse model of SS. With the knowledge that VIP modulates monocyte function through vasoactive intestinal peptide receptors (VPAC) and that immune homeostasis maintenance depends strongly upon a rapid and immunosuppressant apoptotic cell clearance by monocytes/macrophages, in this study we explored VPAC expression on monocytes from primary SS (pSS) patients and the ability of VIP to modulate apoptotic cell phagocytic function and cytokine profile. Monocytes isolated from individual pSS patients showed an increased expression of VPAC2 subtype of VIP receptors, absent in monocytes from control subjects, with no changes in VPAC1 expression. VPAC2 receptor expression could be induced further with lipopolysaccharide (LPS) in pSS monocytes and VIP inhibited the effect. Moreover, monocytes from pSS patients showed an impaired phagocytosis of apoptotic epithelial cells, as evidenced by reduced engulfment ability and the failure to promote an immunosuppressant cytokine profile. However, VIP neither modulated monocyte/macrophage phagocytic function nor did it reverse their inflammatory profile. We conclude that monocytes from pSS patients express high levels of VPAC2 and display a deficient clearance of apoptotic cells that is not modulated by VIP.     

HBsAg clearance by Peg-interferon addition to a long-term nucleos(t)ide analogue therapy

The ideal endpoint of hepatitis B virus (HBV) antiviral therapy is HBsAg loss, a difficult goal to obtain, especially in HBeAg negative patients. Herein, we report the results obtained by the addition of peg-interferon α-2a to a long-lasting nucleos(t)ide analogue therapy in a HBeAg negative, genotype D patient with steadily HBV-DNA negative/HBsAg positive values. In 2002, our Caucasian 44-year-old male patient received lamivudine and, 4 years later, added adefovir because of a virological breakthrough. In 2011, considering his young age, liver stiffness (4.3 kPa) and HBsAg levels (3533 IU/mL), we added Peg-interferon α-2a for six months (3 in combination with nucleos(t)ide analogues followed by 3 mo of Peg-interferon α-2a monotherapy). A decrease of HBsAg levels was observed after 1 mo (1.21 log) of Peg-interferon and 3 mo (1.88 log) after the discontinuation of all drugs. Later, a complete clearance of HBsAg was obtained with steadily undetectable HBV-DNA serum levels (< 9 IU/mL). HBsAg clearance by the addition of a short course of Peg-interferon α-2a represents an important result with clinical and pharmaco-economic implications, considering that nucleos(t)ide analogues therapy in HBeAg negative chronic hepatitis B patients is considered a long-lasting/life-long treatment.     

早期乳酸水平监测对血流感染相关脓毒性休克患者预后评价的价值

目的探讨ICU内血流感染所致脓毒性休克患者早期乳酸水平及乳酸清除率对其预后的预测价值。方法重症外科ICU内血流感染相关脓毒性休克患者42例,依据预后分为存活组（31例）和死亡组（11例）。收集两组患者早期复苏阶段不同时间点的乳酸水平及乳酸清除率,计算组间差异,探讨乳酸指标与预后的相关性;通过描绘各乳酸指标受试者的工作特征曲线（ROC曲线）比较ROC曲线下面积,获得与预后相关性最好的乳酸指标。结果复苏开始以后0,6,12 h的乳酸值以及6,12 h乳酸清除率存活组与死亡组间比较差别均有统计学意义（P＜0.05）,12 h的乳酸值的ROC曲线下面积最大。结论乳酸及乳酸清除率可用于ICU内血流感染相关脓毒性休克患者预后的评估,相比较其他时间点的乳酸指标,复苏12 h后的乳酸值与预后相关性更大     

Target-mediated clearance and bio-distribution of a monoclonal antibody against the Kunitz–type protease inhibitor 2 domain of Tissue Factor Pathway Inhibitor

Introduction

A humanised monoclonal antibody, concizumab, that binds with high affinity to the Kunitz-type protease inhibitor (KPI) 2 domain of human tissue factor pathway inhibitor (TFPI) is in clinical development. It promotes coagulation by neutralising the inhibitory function of TFPI and may provide a subcutaneous prophylaxis option for patients with haemophilia. We aimed to study biodistribution and pharmacokinetics (PK) of concizumab.

Materials and Methods

Blockage of cellular TFPI by concizumab was measured by tissue factor/Factor VIIa-mediated Factor X activation on human EA.hy926 cells. Biodistribution of concizumab was analysed in rabbits by immunohistology, and the PK was measured in rabbits and rats.

Results and Conclusions

Concizumab bound to cell surface TFPI on EA.hy926 cells and neutralised TFPI inhibition of Factor X activation. The antibody cross-reacted with rabbit TFPI, but not with rat TFPI, allowing for comparative PK studies. PK data in rats described a log-linear profile typical for a non-binding antibody, whereas PK data in rabbits revealed a non-linear, dose-dependent profile, consistent with a target-mediated clearance mechanism. Immunohistology in rabbits during target-saturation showed localisation of the antibody on the endothelium of the microvasculature in several organs. We observed a marked co-localisation with endogenous rabbit TFPI, but a negligible sub-endothelial build-up. Concizumab binds and neutralises the inhibitory effect of cell surface-bound TFPI. The PK profile observed in rabbits is consistent with a TFPI-mediated drug disposition. Double immunofluorescence shows co-localisation of the antibody with TFPI on the endothelium of the microvasculature and points to this TFPI as a putative target involved in the clearance mechanism.     

Automated impedance‐manometry analysis detects esophageal motor dysfunction in patients who have non‐obstructive dysphagia with normal manometry

Background Automated integrated analysis of impedance and pressure signals has been reported to identify patients at risk of developing dysphagia post fundoplication. This study aimed to investigate this analysis in the evaluation of patients with non‐obstructive dysphagia (NOD) and normal manometry (NOD/NM). Methods Combined impedance‐manometry was performed in 42 patients (27F : 15M; 56.2 ± 5.1 years) and compared with that of 24 healthy subjects (8F : 16M; 48.2 ± 2.9 years). Both liquid and viscous boluses were tested. MATLAB‐based algorithms defined the median intrabolus pressure (IBP), IBP slope, peak pressure (PP), and timing of bolus flow relative to peak pressure (TNadImp‐PP). An index of pressure and flow (PFI) in the distal esophagus was derived from these variables. Key Results Diagnoses based on conventional manometric assessment: diffuse spasm (n = 5), non‐specific motor disorders (n = 19), and normal (n = 11). Patients with achalasia (n = 7) were excluded from automated impedance‐manometry (AIM) analysis. Only 2/11 (18%) patients with NOD/NM had evidence of flow abnormality on conventional impedance analysis. Several variables derived by integrated impedance‐pressure analysis were significantly different in patients as compared with healthy: higher PNadImp (P < 0.01), IBP (P < 0.01) and IBP slope (P < 0.05), and shorter TNadImp_PP (P = 0.01). The PFI of NOD/NM patients was significantly higher than that in healthy (liquid: 6.7 vs 1.2, P = 0.02; viscous: 27.1 vs 5.7, P < 0.001) and 9/11 NOD/NM patients had abnormal PFI. Overall, the addition of AIM analysis provided diagnoses and/or a plausible explanation in 95% (40/42) of patients who presented with NOD. Conclusions & Inferences Compared with conventional pressure‐impedance assessment, integrated analysis is more sensitive in detecting subtle abnormalities in esophageal function in patients with NOD and normal manometry.