Effects of Short-Term Varenicline Administration on Emotional and Cognitive Processing in Healthy,Non-Smoking Adults: A Randomized,Double-Blind,Study

Varenicline is an effective and increasingly prescribed drug for smoking cessation, but has been associated with depressive symptoms and suicidal behavior. However, it remains unclear whether those changes in mood and behavior are directly related to varenicline use, or caused by smoking cessation itself or reflects depression and suicidality rates in smokers, independent of treatment. To investigate the influence of varenicline on mood and behavior independent of smoking and smoking cessation, we assessed the effects of varenicline on emotional processing (a biomarker of depressogenic effects), emotion-potentiated startle reactivity, impulsivity (linked with suicidal behavior), and cognitive performance in non-smoking subjects. We used a randomized, double-blind design, in which we administered varenicline or placebo to healthy subjects over 7 days (0.5 mg/day first 3 days, then 1 mg/day). Cognitive and emotional processing was assessed by a battery of computerized tasks and recording of emotion-potentiated startle response. A total of 41 subjects were randomized, with 38 subjects included in the analysis. The varenicline group did not differ from placebo in terms of negative biases in emotional processing or mood. However, compared with placebo, the varenicline group scored higher on working and declarative memory. In conclusion, short-term varenicline use did not influence negative biases in emotional processing or impulsivity in non-smoking subjects, thereby not supporting direct depressogenic or suicidal risk behavior-inducing effects. In contrast, varenicline may have cognitive-enhancing effects.     

Use and Evaluation of an Individually Tailored Website for Counselees Prior to Breast Cancer Genetic Counseling

This article explores the use and evaluation of a pre-visit website which aims to prepare counselees who are the first in their family to request breast cancer genetic counseling. This website E-info gene^ca provides computer-tailored information and a blank question prompt sheet (QPS) on which counselees can formulate their questions for the consultation. The objectives of this study are: first, to assess which factors influence the use of E-info gene^ca, including the duration of site and page views, the influence of topic sequence in the menu bar on the sequence of page views, and the relation between website use and the use of the QPS; second, to explore counselees’ evaluations of E-info gene^ca and relations with counselee characteristics. User statistics were analyzed to describe duration of site and page views. Multivariate analyses were used to predict duration of web and page views, sequence of page views, QPS use, and site evaluations. Independent variables were sociodemographic background, disease status, psychological functioning, and information needs. All 101 counselees who were provided with a login accessed the website and spent, on average, 21 min viewing the website. Counselees affected with breast cancer spent more time on the website than unaffected counselees. Half of all page views were within the sequence of topics in the menu and older counselees, and those who made less use of the internet more often navigated according to the menu sequence than others. Having viewed information about why it is important to ask questions increased QPS use. Counselees who had higher information needs considered the information more helpful. This hospital-provided website for breast cancer genetic counselees was accessible and was evaluated positively, even concerning older counselees and those who had not searched the internet for information about hereditary cancer. Counselees might navigate hospital-provided websites more in line with the sequence of topics in the menu bar, than generally accessible health websites.     

Expression of BNIP3 in invasive breast cancer: correlations with the hypoxic response and clinicopathological features

Background  

Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) is a pro-apoptotic member of the Bcl-2 family induced under hypoxia. Low or absent expression has recently been described in human tumors, including gastrointestinal tumors, resulting in poor prognosis. Little is known about BNIP3 expression in invasive breast cancer. The aim of the present study was to investigate the expression of BNIP3 in invasive breast cancer at the mRNA and protein level in correlation with the hypoxic response and clinicopathological features.     

Effects of social modeling on young women's nutrient-dense food intake

We examined whether a same-sex peer's vegetable consumption would predict the number of vegetable pieces eaten by the participant. A total of 116 Dutch women (M age = 20.28; M BMI = 21.68) participated. Their nutrient-dense food intake was measured during a 15-min break between two tasks, consisting of rating television advertisements. Participants consumed more vegetables when exposed to a peer eating a large number of vegetables than when exposed to a peer eating a small number or nothing. These findings suggest that social modeling processes may be relevant to interventions aimed at encouraging young women's nutrient-dense food intake.     

The effect of pulsating arteries on reflectance pulse oximetry: Measurements in adults and neonates

Objective. The objective of our study was to describe the results from human experiments during normoxia that demonstrate the effect of pulsating arteries on the measured arterial oxygen saturation (Spo₂) using a reflectance pulse oximeter sensor.Methods. In 6 healthy adults and 7 healthy neonates, a Nellcor reflection sensor (FS-10 oxisensor, Nellcor, Inc., Pleasanton, CA) was placed in three different positions: (1) on the forehead, (2) on the temporal area, with the photodiode placed over the superficial temporal artery, and (3) on the temporal area, with the light-emitting diodes (LEDs) placed over the superficial temporal artery.Results. Placement of the sensor in position 2 resulted in a significantly lower Spo₂ reading, compared to sensor position 1: 5.8% (p<0.01) lower for adults and 7.5% (p<0.01) lower for neonates. Placement of the sensor in position 3 resulted in significantly larger plethysmographic signals, compared to sensor position 1; but, the Spo₂ readings were alike.Conclusions. Pulsating arteries can affect the reliability of reflection pulse oximetry. Depending on the position of the sensor, a falsely low Spo₂ value can be observed.     

Reprogramming of virus-specific T cells into leukemia-reactive T cells using T cell receptor gene transfer

T cells directed against minor histocompatibility antigens (mHags) might be responsible for eradication of hematological malignancies after allogeneic stem cell transplantation. We investigated whether transfer of T cell receptors (TCRs) directed against mHags, exclusively expressed on hematopoietic cells, could redirect virus-specific T cells toward antileukemic reactivity, without the loss of their original specificity. Generation of T cells with dual specificity may lead to survival of these TCR-transferred T cells for prolonged periods of time in vivo due to transactivation of the endogenous TCR of the tumor-reactive T cells by the latent presence of viral antigens. Furthermore, TCR transfer into restricted T cell populations, which are nonself reactive, will minimize the risk of autoimmunity. We demonstrate that cytomegalovirus (CMV)-specific T cells can be efficiently reprogrammed into leukemia-reactive T cells by transfer of TCRs directed against the mHag HA-2. HA-2-TCR-transferred CMV-specific T cells derived from human histocompatibility leukocyte antigen (HLA)-A2+ or HLA-A2- individuals exerted potent antileukemic as well as CMV reactivity, without signs of anti-HLA-A2 alloreactivity. The dual specificity of these mHag-specific, TCR-redirected virus-specific T cells opens new possibilities for the treatment of hematological malignancies of HLA-A2+ HA-2-expressing patients transplanted with HLA-A2-matched or -mismatched donors.     

Electrophysiological safety of sertindole in dogs with normal and remodeled hearts

Inhibition of the potassium current IKr and QT prolongation are associated with drug-induced torsades de pointes arrhythmias (TdP) and sudden cardiac death. We investigated the cardiac electrophysiological effects of sertindole, an antipsychotic drug reported to prolong the QT interval in schizophrenic patients. In cell cultures, sertindole seemed to be a selective blocker of IHERG over other ion currents. For IHERG, the IC50 value was 64 +/- 7 nM, whereas ISCN5A, ICa,L, ICa,T, IKCNQ1/KCNE1, and IKv4.3 were blocked in the micromolar range. In canine ventricular myocytes, the IC50 value for IKr inhibition by sertindole was 107 +/- 21 nM. Action potentials in these cells prolonged in a reverse rate- and concentration-dependent manner at 10 to 300 nM sertindole. In vivo, sertindole was administered to anesthetized dogs at clinically relevant (0.05-0.20 mg/kg) and high doses (1.0-2.0 mg/kg) i.v. At 0.05 to 0.20 mg/kg sertindole (plasma concentrations 30-157 nM), QTc was prolonged by 1 to 5% in normal dogs and by 9 to 20% in dogs with remodeled hearts due to chronic atrioventricular block (CAVB). TdP was not induced at these doses in normal dogs or in CAVB dogs with reproducible induction of TdP by dofetilide in previous experiments. At 1.0 to 2.0 mg/kg sertindole (plasma concentrations 0.5-3.1 microM), QTc prolonged by 6 to 11% in normal dogs and by 22% in dofetilide-sensitive CAVB dogs. TdP occurred in three of five animals in the latter group. Thus, at high i.v. doses sertindole can pose a serious proarrhythmic risk when electrical remodeling of the ventricles is present. At clinically relevant doses, however, sertindole does not cause TdP in anesthetized dogs with normal or remodeled hearts.     

Connective tissue growth factor induces renal fibrosis via epidermal growth factor receptor activation

Connective tissue growth factor (CCN2/CTGF) is a matricellular protein that is overexpressed in progressive human renal diseases, mainly in fibrotic areas. In vitro studies have demonstrated that CCN2 regulates the production of extracellular matrix (ECM) proteins and epithelial–mesenchymal transition (EMT), and could therefore contribute to renal fibrosis. CCN2 blockade ameliorates experimental renal damage, including diminution of ECM accumulation. We have reported that CCN2 and its C‐terminal degradation product CCN2(IV) bind to epidermal growth factor receptor (EGFR) to modulate renal inflammation. However, the receptor involved in CCN2 profibrotic actions has not been described so far. Using a murine model of systemic administration of CCN2(IV), we have unveiled a fibrotic response in the kidney that was diminished by EGFR blockade. Additionally, in conditional CCN2 knockout mice, renal fibrosis elicited by folic acid‐induced renal damage was prevented, and this was linked to inhibition of EGFR pathway activation. Our in vitro studies demonstrated a direct effect of CCN2 via the EGFR pathway on ECM production by fibroblasts and the induction of EMT in tubular epithelial cells. Our studies clearly show that the EGFR regulates CCN2 fibrotic signalling in the kidney, and suggest that EGFR pathway blockade could be a potential therapeutic option to block CCN2‐mediated profibrotic effects in renal diseases. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.