Test-retest reliability during fear acquisition and fear extinction in humans

Aims: Classical fear conditioning and extinction has been used to understand the neurobiology of fear learning and its inhibition. The recall of an extinction memory involves the ventromedial prefrontal cortex and the amygdala, and patients with posttraumatic stress disorder (PTSD) have been shown to exhibit deficits in this process. Furthermore, extinction forms the basis of exposure therapies commonly used to treat PTSD patients. It is possible that effective pharmacological and/or psychological treatment regimens could influence the activity of these regions, and thereby increase the ability to retain an extinction memory. However, to test this, a fear conditioning and extinction paradigm must demonstrate within‐subject reproducibility over time. We, therefore, sought to test the within‐subject reliability of a previously used 2‐day, classical fear conditioning and extinction paradigm. Methods: Eighteen healthy participants participated in a 2‐day paradigm on three occasions, each separated by at least 12 weeks. Conditioning and extinction took place on Day 1, and extinction recall and fear renewal were evaluated on Day 2 on each of the three occasions. The conditioned stimulus was a visual cue and the unconditioned stimulus was a mild electric shock to the fingers. Skin conductance was recorded throughout the experiment to measure conditioned responses. Results: We found that conditioning and extinction recall were not significantly different across time and were correlated within subjects. Conclusion: These data illustrate the reliability of this paradigm and its potential usefulness in evaluating the influence of a given treatment on the fear extinction network in longitudinal within‐subject designs.     

A selective AT2 receptor ligand with a gamma-turn-like mimetic replacing the amino acid residues 4-5 of angiotensin II

Three angiotensin II (Ang II) analogues encompassing a benzodiazepine-based gamma-turn-like scaffold have been synthesized. Evaluation of the compounds in a radioligand binding assay showed that they had no affinity to the rat liver AT(1) receptor. However, one of the compounds displayed considerable affinity to the pig uterus AT(2) receptor (K(i) = 3.0 nM) while the other two lacked affinity to this receptor. It was hypothesized that the reason for the inactivity of one of these analogues to the AT(2) receptor was that the guanidino group of the Arg(2) residue and/or the N-terminal end of the pseudopeptide could not interact optimally with the receptor. To investigate this hypothesis, a conformational analysis was performed and a comparison was carried out with the monocyclic methylenedithioether analogue cyclo(S-CH(2)-S)[Cys(3,5)]Ang II which is known to bind with high affinity to the AT(2) receptor (K(i) = 0.62 nM). This comparison showed that, in the compounds with high AT(2) receptor affinity, the guanidino group of the Arg(2) residue and the N-terminal end could access common regions of space that were not accessible to the inactive compound. To examine the importance of the guanidino group for binding, the Arg side chain was removed by substituting Arg(2) for Ala(2) in the analogue having the high affinity. This analogue lacked affinity to AT(2) receptors, which supports the role of the guanidino group in receptor binding.     

Relationship between peak serum estradiol levels and treatment outcome in in vitro fertilization cycles after embryo transfer on day 3 or day 5

OBJECTIVE: To examine the relationships between peak serum estradiol (E(2)) levels and treatment outcome in in vitro fertilization (IVF) cycles after embryo transfer (ET) on day 3 or day 5. DESIGN: Retrospective analysis of 697 IVF-ET cycles between January 1999 and December 2001. SETTING: A university-affiliated assisted reproduction program. PATIENT(S): Infertile patients undergoing IVF-ET cycles. INTERVENTION(S): Peak E(2) concentration in serum was determined on the day of human chorionic gonadotropin (hCG) administration. The IVF-generated embryos were cultured for 2 days until transfer on day 3. If more than four 8-cell embryos were present on day 3, embryo culture was continued until day 5 for blastocyst transfer. MAIN OUTCOME MEASURE(S): Clinical pregnancy rates. RESULT(S): High peak E(2) levels did not adversely affect treatment outcome. After the cycles were divided according to the day of ET, high peak E(2) levels were associated with improved pregnancy rates after ET on day 5 but not on day 3. CONCLUSION(S): Increasing peak E(2) levels in IVF cycles are associated with improved pregnancy rates after ET on day 5.     

Anticipatory control of center of mass and joint stability during voluntary arm movement from a standing posture: interplay between active and passive control

Anticipatory control of upright posture is the focus of this study that combines experimental and modeling work. Individuals were asked to raise or lower their arms from two initial postures such that the final posture of the arm was at 90 degrees with respect to the body. Holding different weights in the hand varied the magnitude of perturbation to postural stability generated by the arm movement. Whole body kinematics and ground reaction forces were measured. Inverse dynamic analysis was used to determine the internal joint moments at the shoulder, hip, knee and ankle, and reaction forces at the shoulder. Center of mass (COM) of the arm, posture (rest of the body without the arms) and whole body (net COM) were also determined. Changes in joint moment at the hip, knee and ankle revealed a significant effect of the direction of movement. The polarities of the joint moment response were appropriate for joint stabilization. Net COM change showed a systematic effect of the direction of movement even though the arm COM was displaced by the same amount and in the same direction for both arm raising and lowering conditions. In order to determine the effects of the passive forces and moments on the posture COM, the body was modeled as an inverted pendulum. The model was customized for each participant; the relevant model parameters were estimated from data obtained from each trial. The ankle joint stiffness and viscosity were adjusted to ensure postural equilibrium prior to arm movement. Joint reactive forces and moments generated by the arm movements were applied at the shoulder level of this inverted pendulum; these were the only inputs and no active control was included. The posture COM profile from the model simulation was calculated. Results show that simulated posture COM profile and measured posture COM profile are identical for about 200 ms following the onset of arm movement and then they deviate. Therefore, the initial control of COM is passive in nature and the observed joint moment response is for joint stabilization and not for the control of COM.     

Comprehensive gynecologic endoscopic hospital privileging program. Implementation and assessment

OBJECTIVE: To describe a comprehensive gynecologic endoscopic privileging program at an urban teaching hospital and evaluate its effect on complication rates. STUDY DESIGN: In 1996, a gynecologic endoscopy privileging program was instituted. Initially, experienced surgeons were invited to apply for advanced privileges based on submission of a case list. Afterwards, new applications were approved by proctorship. Since 1995, charts have been reviewed using the following indicators; operating time, estimated blood loss, length of stay, readmission, diagnosis of cancer, reexploration and admission for hysteroscopic fluid overload. Cases were also independently identified when a major vascular or visceral injury occurred. RESULTS: Among the 3,880 gynecologic endoscopic procedures performed during the review period, 2,702 medical records were randomly screened. Following institution of the program, there was no change noted in rates of hysteroscopic fluid overload, readmission, reexploration or unrecognized diagnosis of cancer. However, a decrease was noted in excess blood loss (odds ratio [OR] 0.6, 90% confidence interval [CI] 0.4, 0.9) and operating time greater than four hours (OR 0.6, CI 0.4, 0.9). Length of hospital stay was also reduced in the year following implementation of the privileging process (OR 0.2, CI 0.1, 0.3). Fifty-four cases of visceral or major vascular injury occurred during the three-year period. The risk of visceral injury revealed a trend from 1.9% to 1.0% after institution of the privileging process (OR 0.5, CI 0.3, 1.0). CONCLUSION: Establishment of a comprehensive gynecologic endoscopic hospital privileging program was associated with a reduction in rates of excess blood loss and operating times and a decreasing trend in visceral injuries.     

Catalytic filtration: efficient C-C cross-coupling using Pd(II)-salen complex-embedded cellulose filter paper as a portable catalyst

A new approach has been developed for environmentally friendly C-C cross-coupling reactions using bi-functional Pd(ii)-salen complex-embedded cellulose filter paper (FP@Si-Pd^II-Salen-[IM]OH). A Pd(ii)-salen complex bearing imidazolium [OH]⁻moieties was covalently embedded into a plain filter paper, then used as an efficient portable catalyst for the Heck, Suzuki, and Sonogashira cross-coupling reactions under environmentally friendly conditions via the filtration method. The catalytic filter paper properties were studied by EDX, XPS, TGA, ATR, XRD, and FESEM analyses. The reactions were catalyzed during reactants'' filtration over the catalytic filter paper. The modified filter paper was set up over a funnel and the reactants were passed through the catalytic filter paper several times. The effect of reaction parameters including loading of Pd(ii)-salen complex, temperature, solvent, and contact time were carefully studied and also the optimal model of conditions was presented by the design expert software. High to excellent yields were obtained for all C–C coupling types with 5 to 8 filtration times. Under optimal conditions, all coupling reactions showed high selectivity and efficiency. Another advantage of the modified filter paper was its stability and reusability for several times with preservation of catalytic activity and swellability.

A new platform has been developed for environmentally friendly C–C cross-coupling reactions via filtration of reactants through a portable Pd^(II)-salen complex-embedded filter paper.     

Efficacy of Probiotics in Prevention and Treatment of Infectious Diseases

Deaths from infectious diseases and deep concerns about increases in microbial resistance make it necessary for scientists to develop innovative therapeutic solutions and complementary therapies. Growing evidence is available on the therapeutic effects of probiotics. There are also documents about the beneficial effects of probiotics, but it is difficult to draw a definitive conclusion regarding the results of these studies because of the small sample size, the limitations of the study methods, and the use of different strains of probiotic bacteria. This review study summarizes the articles available on the scientific and electronic databases Embase, Medline, and Scopus until the end of 2017, including case studies describing beneficial microbes as tools for improving the process of controlling infectious diseases. Until the development of novel vaccines or other approaches occurs, the use of probiotics seems to be a logical way to attempt to control certain infectious diseases.     

Dual oxidase 1 promotes antiviral innate immunity

Dual oxidase 1 (DUOX1) is an NADPH oxidase that is highly expre-ssed in respiratory epithelial cells and produces H₂O₂ in the airway lumen. While a line of prior in vitro observations suggested that DUOX1 works in partnership with an airway peroxidase, lactoperoxidase (LPO), to produce antimicrobial hypothiocyanite (OSCN⁻) in the airways, the in vivo role of DUOX1 in mammalian organisms has remained unproven to date. Here, we show that Duox1 promotes antiviral innate immunity in vivo. Upon influenza airway challenge, Duox1^−/− mice have enhanced mortality, morbidity, and impaired lung viral clearance. Duox1 increases the airway levels of several cytokines (IL-1β, IL-2, CCL1, CCL3, CCL11, CCL19, CCL20, CCL27, CXCL5, and CXCL11), contributes to innate immune cell recruitment, and affects epithelial apoptosis in the airways. In primary human tracheobronchial epithelial cells, OSCN⁻ is generated by LPO using DUOX1-derived H₂O₂ and inactivates several influenza strains in vitro. We also show that OSCN⁻ diminishes influenza replication and viral RNA synthesis in infected host cells that is inhibited by the H₂O₂ scavenger catalase. Binding of the influenza virus to host cells and viral entry are both reduced by OSCN⁻ in an H₂O₂-dependent manner in vitro. OSCN⁻ does not affect the neuraminidase activity or morphology of the influenza virus. Overall, this antiviral function of Duox1 identifies an in vivo role of this gene, defines the steps in the infection cycle targeted by OSCN⁻, and proposes that boosting this mechanism in vivo can have therapeutic potential in treating viral infections.

DUOX1 is one of the seven members of the NADPH oxidase enzyme family (1). DUOX1 was first described in the thyroid gland (2) but was later also detected in several other tissues and organs including the tracheobronchial epithelium (3). DUOX1 localizes to the apical plasma membrane of ciliated respiratory epithelial cells and produces extracellular H₂O₂ into the airway lumen in a Ca²⁺-dependent manner (3, 4). DUOX1 is the major NADPH oxidase expressed and the main source of H₂O₂ in the airway epithelium (3, 5, 6).The respiratory epithelium employs several immune mechanisms against airborne microbes including the generation of reactive oxygen species. Respiratory epithelial cells have a proposed, rapid oxidative and extracellular antimicrobial system consisting of LPO, thiocyanate (SCN⁻), and hydrogen peroxide (H₂O₂) (7–10). LPO is found in a variety of body fluids including milk, saliva, lachrymal, and airway secretions (7, 8, 10–13). Its main substrate, SCN⁻, is abundant in the airway surface liquid (7, 9, 14). LPO oxidizes SCN⁻ into antimicrobial hypothiocyanite (OSCN⁻) using H₂O₂ (15). Prior in vitro data suggested that Duox1 is the epithelial H₂O₂ source that functions in partnership with LPO to produce antimicrobial OSCN⁻(2, 3, 16). SCN⁻ supplementation increases bacterial clearance in mouse lung infection, supporting an antibacterial role of OSCN⁻ in vivo (17, 18). While OSCN⁻ kills several microorganisms in vitro, its mechanism of action and the identity of the in vivo H₂O₂ source required to generate OSCN⁻ remained unknown. The in vivo role of Duox1 in mammals remained unproven to date (13, 19).Influenza remains a major clinical challenge worldwide. Seasonal influenza viruses infect between three and five million people and cause 290,000 to 650,000 global deaths annually (20). In this study, we show that Duox1 promotes innate immunity in vivo against influenza infection in a mouse model. We also identify virus binding and entry into host cells as the basis for the antiviral mechanism of action of OSCN⁻ in vitro. Overall, results shown here demonstrate the in vivo role of Duox1 and determine the steps in the influenza virus life cycle targeted by Duox1- and LPO-derived OSCN⁻.     

Effects of avasimibe on cytochrome P450 2C9 expression in vitro and in vivo.

Avasimibe, an acyl-CoA:cholesterol acyltransferase inhibitor, has been previously shown to be a potent inducer of CYP3A4 and multiple drug resistance protein 1. We have further characterized the drug interaction potential of avasimibe by studying the inductive and inhibitory effect of this compound on major drug-metabolizing enzymes. Enzymes known to be involved in the metabolism of drugs likely to be coadministered with avasimibe, such as CYP1A1/2, CYP2C, and CYP2B6, were evaluated further by microarray analysis, Western immunoblotting, and activity assays, using rifampicin and beta-naphthoflavone as positive controls. No change was observed in CYP1A1/2 mRNA or activity levels after avasimibe treatment. Differential induction of CYP2C9- and CYP2B6-immunoreactive protein and activity was observed depending on drug concentration and donor. Microarray analysis showed a similar increase in CYP2C and CYP2B6 mRNA levels. The inhibition potential of avasimibe on the major drug-metabolizing enzymes was assessed using pooled human liver microsomes. Avasimibe inhibited CYP2C9 (IC50 2.9 microM), CYP1A2 (IC50 13.9 microM), and CYP2C19 (IC50 26.5 microM). A clinical drug interaction study was conducted to determine whether avasimibe might interact with the CYP2C9 substrate warfarin. Volunteers received 750 mg of avasimibe and showed a 54.2% reduction in trough concentrations of S-warfarin and decreased prothrombin times by 12, 15, 19, and 21% on days 6 through 9, respectively. These results demonstrate that avasimibe's inductive spectrum resembles that of rifampin.     

Toxicity of organic selenium (Selemax) and its effects on haematological and biochemical parameters and histopathological changes of common carp (Cyprinus carpio L., 1758)

The aim of this study was to assess the effect of organic selenium (Selemax) on Common carp (Cyprinus carpio). The effect was determined on basis of acute toxicity, haematological, biochemical profile and histopathology. A static toxicity test was performed for the determination of 96?h median lethal concentration. The 96hLC50 value of Selemax was 0.54?mg/L. For investigation of chronic toxicity, the experimental group exposed to Selemax in concentration 0.054?mg/L (10% 96hLC50) during 28 days showed significant changes in haematological and biochemical profile and caused histopathological changes in liver, and kidney. According to those data, it was possible to classify organic selenium as highly toxic for carp. The alterations of these parameters can be used as suitable biomarkers in monitoring of organic selenium in the aquatic environment.