Tolerability of inhaled N-chlorotaurine in the pig model

<p>Abstract</p> <p>Background</p> <p>N-chlorotaurine, a long-lived oxidant produced by human leukocytes, can be applied in human medicine as an endogenous antiseptic. Its antimicrobial activity can be enhanced by ammonium chloride. This study was designed to evaluate the tolerability of inhaled N-chlorotaurine (NCT) in the pig model.</p> <p>Methods</p> <p>Anesthetized pigs inhaled test solutions of 1% (55 mM) NCT (n = 7), 5% NCT (n = 6), or 1% NCT plus 1% ammonium chloride (NH₄Cl) (n = 6), and 0.9% saline solution as a control (n = 7), respectively. Applications with 5 ml each were performed hourly within four hours. Lung function, haemodynamics, and pharmacokinetics were monitored. Bronchial lavage samples for captive bubble surfactometry and lung samples for histology and electron microscopy were removed.</p> <p>Results</p> <p>Arterial pressure of oxygen (PaO₂) decreased significantly over the observation period of 4 hours in all animals. Compared to saline, 1% NCT + 1% NH₄Cl led to significantly lower PaO₂values at the endpoint after 4 hours (62 ± 9.6 mmHg vs. 76 ± 9.2 mmHg, p = 0.014) with a corresponding increase in alveolo-arterial difference of oxygen partial pressure (AaDO₂) (p = 0.004). Interestingly, AaDO₂was lowest with 1% NCT, even lower than with saline (p = 0.016). The increase of pulmonary artery pressure (PAP) over the observation period was smallest with 1% NCT without difference to controls (p = 0.91), and higher with 5% NCT (p = 0.02), and NCT + NH₄Cl (p = 0.05).</p> <p>Histological and ultrastructural investigations revealed no differences between the test and control groups. The surfactant function remained intact. There was no systemic resorption of NCT detectable, and its local inactivation took place within 30 min. The concentration of NCT tolerated by A549 lung epithelial cells <it>in vitro </it>was similar to that known from other body cells (0.25–0.5 mM).</p> <p>Conclusion</p> <p>The endogenous antiseptic NCT was well tolerated at a concentration of 1% upon inhalation in the pig model. Addition of ammonium chloride in high concentration provokes a statistically significant impact on blood oxygenation.</p

Metabolic constituents of grapevine and grape-derived products

The numerous uses of the grapevine fruit, especially for wine and beverages, have made it one of the most important plants worldwide. The phytochemistry of grapevine is rich in a wide range of compounds. Many of them are renowned for their numerous medicinal uses. The production of grapevine metabolites is highly conditioned by many factors like environment or pathogen attack. Some grapevine phytoalexins have gained a great deal of attention due to their antimicrobial activities, being also involved in the induction of resistance in grapevine against those pathogens. Meanwhile grapevine biotechnology is still evolving, thanks to the technological advance of modern science, and biotechnologists are making huge efforts to produce grapevine cultivars of desired characteristics. In this paper, important metabolites from grapevine and grape derived products like wine will be reviewed with their health promoting effects and their role against certain stress factors in grapevine physiology

Spatial and temporal dynamics of innervation during the development of fetal human pancreas.

The delineation of pancreatic nerve innervations during fetal life may contribute to our understanding of pancreatic pain modalities after birth. The aim of this study was to characterize the spatial and temporal distribution of nerve structures in the human pancreas throughout gestation. Computer-based image morphometry with piecewise polynomial interpolation analysis was performed to quantify nervous structures in the head, body and tail of the pancreas. Nerve structures were detected by automatic immunostaining techniques using a polyclonal antibody against two S-100 proteins that reacts strongly with human S100A and B that are detected in Schwann cells. Immunoreactivity was found in the parenchyma of head, body and tail of the pancreas with the relative density being head> body> tail. In addition to this extensive set of nerve fibers terminating in the pancreas there were large bundles of en passant nerve fibers in the dorsal region of the pancreas that were 3D reconstructed and were associated with the superior mesenteric plexus. If at first glance, the perimeter and the width of the nerve fibers seem to increase at a continuous rate up to term in all three regions of the pancreas, spatial and temporal co-analysis identified that the head of the pancreas shows a two-peak growth increase at 14 and 22 weeks of gestation with regard to the area, perimeter and width of the nerve structures, while the body and tail regions show a unique peak at 20 weeks. A developmental deceleration was found between the 22nd and the 36th week of gestation for the head region only. This is the first systematic study of nerve innervation of the human pancreas throughout gestation. The developmental dynamics of the pancreas nerve innervation corresponds approximately to the remodeling of the intrahepatic biliary system. Understanding the factors and disease states that may alter the distribution of nerve structures can be of significance for the development of therapies in pancreatic disorders of child- and adulthood

Transcription factor binding sites downstream of the human immunodeficiency virus type 1 transcription start site are important for virus infectivity.

When transcriptionally active, the human immunodeficiency virus (HIV) promoter contains a nucleosome-free region encompassing both the promoter/enhancer region and a large region (255 nucleotides [nt]) downstream of the transcription start site. We have previously identified new binding sites for transcription factors downstream of the transcription start site (nt 465 to 720): three AP-1 sites (I, II, and III), an AP3-like motif (AP3-L), a downstream binding factor (DBF) site, and juxtaposed Sp1 sites. Here, we show that the DBF site is an interferon-responsive factor (IRF) binding site and that the AP3-L motif binds the T-cell-specific factor NF-AT. Mutations that abolish the binding of each factor to its cognate site are introduced in an infectious HIV-1 molecular clone to study their effect on HIV-1 transcription and replication. Individual mutation of the DBF or AP3-L site as well as the double mutation AP-1(III)/AP3-L did not affect HIV-1 replication compared to that of the wild-type virus. In contrast, proviruses carrying mutations in the Sp1 sites were totally defective in terms of replication. Virus production occurred with slightly delayed kinetics for viruses containing combined mutations in the AP-1(III), AP3-L, and DBF sites and in the AP3-L and DBF-sites, whereas viruses mutated in the AP-1(I,II,III) and AP3-L sites and in the AP-1(I,II,III), AP3-L, and DBF sites exhibited a severely defective replicative phenotype. No RNA-packaging defect could be measured for any of the mutant viruses as determined by quantification of their HIV genomic RNA. Measurement of the transcriptional activity of the HIV-1 promoter after transient transfection of the HIV-1 provirus DNA or of long terminal repeat-luciferase constructs showed a positive correlation between the transcriptional and the replication defects for most mutants

ESOPHAGEAL 24H PH-METRY AND MULTICHANNEL INTRALUMINAL IMPEDANCE IN OBESE PATIENTS WITHOUT GERD SYMPTOMS

INTRODUCTION: Twenty-four hours pH-metry and multichannel intraluminal impedance monitoring (24h pH-metry+MII) allows the simultaneous assessment of the chemical and physical properties of the gastroesophageal reflux. AIMS & METHODS: To investigate 24h pH-metry+MII in obese and severely obese patients without GERD symptoms and in controls. A total of 30 patients (13M/17F, age 22−69 y, BMI 26–51.6 kg/m2) were admitted consecutively to the study, under informed consent. Our patients were off PPI therapy. 24h pH-metry+MII monitoring was carried out by recording system (Sandhill Scientific, Inc. Co, USA). Electrodes at 3, 5, 7, 9, 15 and 17 cm above LES. Ten normal weight subjects with normal 24-h pH-metry+MII were used as control group. The values were recorded as median (25th, 25th) 95th percentile. Statistical analysis was performed with PASW 18.0 (SPSS, Chicago, IL, USA). RESULTS: The table shows the 24h pH-metry+MII data (MACT= Mean Acid Clearance Time; MBCT= Mean Bolus Clearance Time) and reflux episodes in obese patients and in controls. Ten obese patients showed grade A-C erosive esophagitis (LA classification). CONCLUSION: Obese patients showed an increased number of refluxes with acid content. Acid reflux episodes with proximal extent, as well as Upright and Recumbent weakly acidic episodes were significantly higher than controls. Despite abnormal 24h pH-metry+MII indices, GERD symptoms were not observed in our obese patients. As previously observed, these finding may be related to an altered visceral perception which may also explain the abnormalities in the gastric accommodation and in the sensation of fullness (1). REFERENCE(S): [1] K¨uper MA, Kramer KM, Kischniak A, et al. Dysfunction of lower esophageal sphincter and dismotility of the tubular esophagus in morbidly obese patients. Obes Surg. 2009; 19: 1143

24-h pH-metry and multichannel intraluminal impedance monitoring in obese patients with and without gastroesophageal reflux disease symptoms

BACKGROUND: The 24-h ambulatory pH-metry with multichannel intraluminal impedance monitoring (24-h pH-metry+MII) allows the simultaneous assessment of chemical and physical properties of esophageal refluxes and the detection of its proximal migration. METHODS: Gastroesophageal reflux (GER) was investigated in obese symptomatic (obese gastroesophageal reflux disease, GERD) and asymptomatic (obese non-GERD) patients. The data were compared with those obtained from non-obese GERD patients and a control group. Thirty-five (20 non-GERD, 15 GERD) obese patients and 15 non-obese GERD were investigated with 24-h pH-metry+MII. Ten normal weight subjects with normal 24-h pH-metry+MII were used as control group. RESULTS: The percent time acid exposure was significantly higher in obese non-GERD than controls (p = 0.007). Acid reflux episodes were increased vs. controls in obese non-GERD (p = 0.005) and obese GERD (p = 0.034). Upright position showed a significant increase of reflux episodes in non-obese GERD (p = 0.034) and in obese non-GERD (p = 0.027) vs. controls. Recumbent position showed reflux episodes significantly increased vs. controls in obese non-GERD (p = 0.002), obese GERD (p = 0.021), and non-obese GERD (p = 0.033). In obese non-GERD, waist circumference (WC) correlated negatively with upright position episodes (r = -0.53; p = 0.043) and with proximal migration episodes, i.e., total (r = -0.60; p = 0.018), acid (r = -0.55; p = 0.033), and weakly acidic refluxes (r = -0.56; p = 0.031). CONCLUSIONS: Obese patients showed an increased number of refluxes with acid content. Refluxes with proximal extent were significantly higher in obese non-GERD than in controls and non-obese GERD patients. No difference was observed between the two obese patient groups. In asymptomatic obese patients, the WC correlated with proximal extent episodes