Decreased Activity and Genetic Polymorphisms of CYP2C19 in Behçet's Disease

Behçet's disease (BD) is a systemic autoimmune disorder. Cytochrome P450 enzymes (CYPs) are responsible for various drug metabolism reactions as well as those of endogenous substances which may be associated with autoimmune disease susceptibility. Recently, we reported that in patients with BD, CYP2C9 seems to be down‐regulated due to inflammation. In the same Turkish patients with BD, we investigated whether also CYP2C19 activity is decreased. Lansoprazole (30 mg) was given as a probe drug to evaluate CYP2C19 activity in 59 patients with BD and 27 healthy control volunteers. An HPLC method was used to determine plasma lansoprazole and its metabolite, 5‐hydroxy lansoprazole, concentrations. The genotyping for CYP2C19 *2, *3 and *17 polymorphisms was made using PCR‐RFLP. The median lansoprazole/5‐hydroxy lansoprazole metabolic ratio (MR) in patients with BD was 2.6‐fold higher as compared to the healthy control group (p = 0.001, 22.6 (1.3–26) and 8.8 (0.5–140) as median and range, respectively). The CYP2C19*17*17 genotype frequency was found to be significantly less in the BD group as compared to the healthy controls (1.7% versus 14.8% in controls, p = 0.01). Additionally, colchicine treatment did not affect the CYP2C19 enzyme activity in six patients (p = 0.43). In conclusion, the patients with BD had lower CYP2C19 enzyme activity and lower frequency of the CYP2C19*17 allele as compared to those of the healthy controls. Further studies are warranted on the mechanisms underlying this relation. This study should also be applied to other autoimmune diseases similarly characterized by local or systemic inflammation.     

Surgical Endoscopic Vacuum Therapy for Defects of the Upper Gastrointestinal Tract

Introduction

Intraluminal therapy used in the gastrointestinal (GI) tract was first shown for anastomotic leaks after rectal resection. Since a few years vacuum sponge therapy is increasingly being recognized as a new promising method for repairing upper GI defects of different etiology. The principles of vacuum-assisted closure (VAC) therapy remain the same no matter of localization: Continuous or intermittent suction and drainage decrease bacterial contamination, secretion, and local edema. At the same time, perfusion and granulation is promoted. However, data for endoscopic vacuum therapy (EVT) of the upper intestinal tract are still scarce and consist of only a few case reports and small series with low number of patients.

Objectives

Here, we present a single center experience of EVT for substantial wall defects in the upper GI tract.

Methods

Retrospective single-center analysis of EVT for various defects of the upper GI tract over a time period of 4 years (2011–2015) with a mean follow-up of 17 (2–45) months was used. If necessary, initial endoscopic sponge placement was performed in combination with open surgical revision.

Results

In total, 126 polyurethane sponges were placed in upper gastrointestinal defects of 21 patients with a median age of 72 years (range, 49–80). Most frequent indication for EVT was anastomotic leakage after esophageal or gastric resection (n?=?11) and iatrogenic esophageal perforation (n?=?8). The median number of sponge insertions was five (range, 1–14) with a mean changing interval of 3 days (range, 2–4). Median time of therapy was 15 days (range, 3–46). EVT in combination with surgery took place in nine of 21 patients (43 %). A successful vacuum therapy for upper intestinal defects with local control of the septic focus was achieved in 19 of 21 patients (90.5 %).

Conclusion

EVT is a promising approach for postoperative, iatrogenic, or spontaneous lesions of the upper GI tract. In this series, EVT was combined with operative revision in a relevant proportion of patients.

     

Arginase and α‐smooth muscle actin induction after hyperoxic exposure in a mouse model of bronchopulmonary dysplasia

The L‐arginine/NO pathway is an important regulator of pulmonary hypertension, the leading cause of mortality in patients with the chronic lung disease of prematurity, bronchopulmonary dysplasia. L‐arginine can be metabolized by NO synthase (NOS) to form L‐citrulline and NO, a potent vasodilator. Alternatively, L‐arginine can be metabolized by arginase to form urea and L‐ornithine, a precursor to collagen and proline formation important in vascular remodelling. In the current study, we hypothesized that C3H/HeN mice exposed to prolonged hyperoxia would have increased arginase expression and pulmonary vascular wall cell proliferation. C3H/HeN mice were exposed to 14 days of 85% O₂ or room air and lung homogenates analyzed by western blot for protein levels of arginase I, arginase II, endothelial NOS (eNOS), ornithine decarboxylase (ODC), ornithine aminotransferase (OAT), and α‐smooth muscle actin (α‐SMA). Hyperoxia did not change arginase I or eNOS protein levels. However, arginase II protein levels were 15‐fold greater after hyperoxia exposure than in lungs exposed to room air. Greater protein levels of ODC and OAT were found in lungs following hyperoxic exposure than in room air animals. α‐SMA protein levels were found to be 7‐fold greater in the hyperoxia exposed lungs than in room air lungs. In the hyperoxia exposed lungs there was evidence of greater pulmonary vascular wall cell proliferation by α‐SMA immunohistochemistry than in room air lungs. Taken together, these data are consistent with a more proliferative vascular phenotype, and may explain the propensity of patients with bronchopulmonary dysplasia to develop pulmonary hypertension.     

MRI compatible MS2 nanoparticles designed to cross the blood–brain-barrier: providing a path towards tinnitus treatment

Fundamental challenges of targeting specific brain regions for treatment using pharmacotherapeutic nanoparticle (NP) carriers include circumventing the blood–brain-barrier (BBB) and tracking delivery. Angiopep-2 (AP2) has been shown to facilitate the transport of large macromolecules and synthetic nanoparticles across the BBB. Thus, conjugation of AP2 to an MS2 bacteriophage based NP should also permit transport across the BBB. We have fabricated and tested a novel MS2 capsid-based NP conjugated to the ligand AP2. The reaction efficiency was determined to be over 70%, with up to two angiopep-2 conjugated per MS2 capsid protein. When linked with a porphyrin ring, manganese (Mn²⁺) remained stable within MS2 and was MRI detectable. Nanoparticles were introduced intracerebroventricularly or systemically. Systemic delivery yielded dose dependent, non-toxic accumulation of NPs in the midbrain. Design of a multifunctional MRI compatible NP platform provides a significant step forward for the diagnosis and treatment of intractable brain conditions, such as tinnitus.     

Feasibility and reliability of strain and strain rate measurement in neonates by optimizing the analysis parameters settings

The optimal combination of region-of-interest (ROI) size and strain length (SL) allowing two-segment strain and strain rate analyses in term neonates was investigated. The impact of different ROI sizes and SLs on the strain and strain rate beat-to-beat variation (BBV) was assessed in 80 good-quality tissue velocity images. Both BBVs decreased with increased ROI length and with increased SL (p < 0.05). There were no significant differences in the BBVs for ROI width 2, 3 and 4 mm (p > 0.05). Among the combinations eligible for two segment analysis, the lowest BBVs were found using SL 10 mm, ROI length 1 mm and ROI width 3 mm. Using this combination, the mean difference between the single-cycle value and two-cycle compound value for peak systolic strain rate was 6.2%, peak systolic strain was 2.9% and end systolic strain was 3.2% of the two-cycle compound mean values. Hence, strain and strain rate measurement in tissue velocity images in neonates is feasible and reliable.     

Relationship between tooth loss/probing depth and systemic disorders in periodontal patients

During the last decades, many published studies have focused on the associations between periodontal disease and different systemic disorders. The purpose of the present investigation was to study the relationship between occurrence of systemic disorders and the two variables mean number of teeth and periodontal probing pocket depth after stratification according to smoking habits. The study was conducted as a retrospective study based on consecutive selection of patients at a specialist clinic of Periodontology. The study population consisted of 1854 individuals. Of these, 797 were males, and 1057 were females. Multiple regression analyses were adopted in order to calculate the partial correlations between the number of remaining teeth/the relative frequency of periodontal probing depths > or = 5 mm and presence of systemic disease for different strata according to sex and smoking habits with age included as an independent variable. Non-smoking men with cardiovascular disease, diabetes and rheumatoid disease had significantly fewer teeth compared to non-smoking men without systemic disorder. In conclusion, cardio-vascular disease, diabetes and rheumatoid disease may be regarded as risk indicators of tooth loss in men. However, in order to investigate hypotheses concerning potential risk factors, emerging from cross-sectional studies, being true risk factors of tooth loss, longitudinal prospective studies including established risk factors along with new exposures of interest as covariates are required.