Psychiatric symptoms and expression of glucocorticoid receptor gene in cocaine users: A longitudinal study

Background Chronic cocaine users (CU) display reduced peripheral expression of the glucocorticoid receptor gene (NR3C1), which is potentially involved in stress-related psychiatric symptoms frequently occurring in CU. However, it is unknown whether psychiatric symptoms and lower NR3C1 expression are related to each other and whether reduction of drug consumption reverse them. Method At baseline, NR3C1 mRNA expression was measured in 68 recreational CU, 30 dependent CU, and 68 stimulant-naïve controls. Additionally, the Revised Symptom Checklist (SCL-90R) and the Barratt Impulsiveness Scale (BIS) were assessed. At a one-year follow-up, the association between change in NR3C1 expression and psychiatric symptoms was examined in 48 stimulant-naïve controls, 19 CU who increased and 19 CU who decreased their consumption. At both test sessions, cocaine concentrations in hair samples were determined. Mixed-effects models were used to investigate how changes in drug use intensity affect severity of psychiatric symptoms and NR3C1 expression over time. Results At baseline, recreational and dependent CU displayed elevated impulsivity and considerable symptom burden across most of the SCL-90R subscales. Time-group interaction effects were found for several impulsivity scores, SCL-90R Global Severity Index, Paranoid Thoughts, and Depression subscales as well as for NR3C1 expression. Pairwise comparisons showed that decreasing CU specifically improved in these SCL-90R subscales, while their NR3C1 expression was adapted. Finally, changes in NR3C1 expression were negatively correlated with changes in impulsivity but not SCL-90R scores. Conclusion Our findings suggest that NR3C1 expression changes and some psychiatric symptoms are reversible upon reduction of cocaine intake, thus favouring abstinence-oriented treatment approaches

Nanoelectropulse-driven membrane perturbation and small molecule permeabilization

BACKGROUND: Nanosecond, megavolt-per-meter pulsed electric fields scramble membrane phospholipids, release intracellular calcium, and induce apoptosis. Flow cytometric and fluorescence microscopy evidence has associated phospholipid rearrangement directly with nanoelectropulse exposure and supports the hypothesis that the potential that develops across the lipid bilayer during an electric pulse drives phosphatidylserine (PS) externalization. RESULTS: In this work we extend observations of cells exposed to electric pulses with 30 ns and 7 ns durations to still narrower pulse widths, and we find that even 3 ns pulses are sufficient to produce responses similar to those reported previously. We show here that in contrast to unipolar pulses, which perturb membrane phospholipid order, tracked with FM1-43 fluorescence, only at the anode side of the cell, bipolar pulses redistribute phospholipids at both the anode and cathode poles, consistent with migration of the anionic PS head group in the transmembrane field. In addition, we demonstrate that, as predicted by the membrane charging hypothesis, a train of shorter pulses requires higher fields to produce phospholipid scrambling comparable to that produced by a time-equivalent train of longer pulses (for a given applied field, 30, 4 ns pulses produce a weaker response than 4, 30 ns pulses). Finally, we show that influx of YO-PRO-1, a fluorescent dye used to detect early apoptosis and activation of the purinergic P2X(7 )receptor channels, is observed after exposure of Jurkat T lymphoblasts to sufficiently large numbers of pulses, suggesting that membrane poration occurs even with nanosecond pulses when the electric field is high enough. Propidium iodide entry, a traditional indicator of electroporation, occurs with even higher pulse counts. CONCLUSION: Megavolt-per-meter electric pulses as short as 3 ns alter the structure of the plasma membrane and permeabilize the cell to small molecules. The dose responses of cells to unipolar and bipolar pulses ranging from 3 ns to 30 ns duration support the hypothesis that a field-driven charging of the membrane dielectric causes the formation of pores on a nanosecond time scale, and that the anionic phospholipid PS migrates electrophoretically along the wall of these pores to the external face of the membrane

Elevated social stress levels and depressive symptoms in primary hyperhidrosis

<div><p>Primary hyperhidrosis is defined as excessive sweating of certain body areas without physiological reasons. Hyperhidrotic individuals report a high psychological strain and an impairment of their quality of life. Thus, the aim of the study is to investigate the relation between hyperhidrosis and different psychological as well as physiological aspects of chronic stress as a co-factor for the etiology of depression. In this study, forty hyperhidrotic subjects were compared to forty age- and sex-matched healthy control subjects. The Trier Inventory of Chronic Stress (‘<i>Trierer Inventar zum chronischen Stress’</i>: TICS), the Beck Depression Inventory (BDI-II) and the Screening for Somatoform Disorders (SOMS-2) were used to examine the correlation between primary hyperhidrosis and stress as well as accompanying depressive and somatic symptoms. The cortisol awakening response of each subject was analyzed as a physiological stress correlate. In hyperhidrotics, we found a significant lack of social recognition as well as significantly more depressive symptoms compared to the control subjects. A subgroup of patients with axillary hyperhidrosis had the highest impact on these increased issues of chronic stress, pointing to a higher embarrassment in these subjects. Especially in social situations, hyperhidrotics showed higher stress levels, whereby a vicious circle of stress and sweating is triggered. However, the cortisol awakening response did not significantly differ between hyperhidrotics and controls. Moreover, affected persons suffer from more depressive symptoms, which may be caused by feelings of shame and a lack of self-confidence. This initial study provides an impetus for further investigation to reveal a causative relationship between hyperhidrosis and its psychological concomitants.</p></div

Erhöhte Stresslevel und depressive Symptome bei primärer Hyperhidrose

Unter Hyperhidrose versteht man übermäßiges Schwit-zen in einem Ausmaß, das die Regulation der Körpertemperatur übersteigt. Die Störung gilt bezüglich ihrer Ätiologie, Pathogenese und Genetik als kaum hinrei-chend beforscht. Allerdings übt die Erkrankung Schät-zungen zufolge auf eine Million Menschen in Deutschland mitunter einen erheblichen Leidensdruck aus. Im Mittelpunkt der Studie steht die primäre fokale Hyperhidrose, die meist an Händen, Füßen oder Achseln lokalisiert werden kann und der im Gegensatz zur sekundären Hyperhidrose keine körperliche Erkrankung zugrunde liegt. In der durchgeführten Studie gelang es, Daten von je-weils 40 gesunden und hyperhidrotischen Probanden zu erheben. Alle Versuchspersonen beantworteten Frage-bogen zu ihrer Erkrankung, zum chronischen Stress sowie zu depressiven und somatischen Symptomen. Zudem wurden allen Probanden Speichelproben zur Analyse des Stresshormons Cortisol entnommen. Aus einer Varianzanalyse und anschließender Teststär-kenanalyse resultierten folgende Ergebnisse: Die Hyperhidrotiker der Stichprobe zeigten höhere chronische Stresslevel sowie mehr depressive als auch mehr soma-tische Symptome als die Kontrollgruppe. Bemerkenswert ist, dass die Probanden, die vor allem unter den Achseln vermehrt schwitzen, die höchsten Stress- und Depressionslevel aufwiesen. Die sogenannte Cortisol Awakening Response (CAR) gibt Informationen über die Aktivität der Hypophysen-Hypothalamus-Nebennierenrinden-Achse (HHNA) und hat sich als zuverlässiges physiologisches Stresskorrelat erwiesen. Trotz der erhöhten Stresslevel und der erhöhten depres-siven Symptomatik bei Hyperhidrotikern konnte keine Veränderung in der CAR gefunden werden. Dazu muss erklärend hinzugefügt werden, dass die Mehrzahl der Hyperhidrotiker der vorliegenden Stichprobe keinen Stress von pathologischem Wert aufweist. In bisherigen Studien anderer Autoren konnte eine veränderte CAR lediglich bei sehr hoch belasteten Versuchspersonen nachgewiesen werden

Polymorphisms of genes related to the hypothalamic-pituitary-adrenal axis influence the cortisol awakening response as well as self-perceived stress

The hypothalamus-pituitary-adrenal (HPA) axis is a crucial endocrine system for coping with stress. A reliable and stable marker for the basal state of that system is the cortisol awakening response (CAR). We examined the influence of variants of four relevant candidate genes; the mineralocorticoid receptor gene (MR), the glucocorticoid receptor gene (GR), the serotonin transporter gene (5-HTT) and the gene encoding the brain-derived neurotrophic factor (BDNF) on CAR and self-perceived stress in 217 healthy subjects. We found that polymorphisms of GR influenced both, the basal state of the HPA axis as well as self-perceived stress. MR only associated with self-perceived stress and 5-HTT only with CAR. BDNF did not affected any of the investigated indices. In summary, we suggest that GR variants together with the CAR and supplemented with self reports on perceived stress might be useful indicators for the basal HPA axis activity

VIP-targeted cytotoxic nanomedicine for breast cancer

Cancer chemotherapy is hampered by serious toxicity to healthy tissues. Conceivably, encapsulation of cytotoxic drugs in actively-targeted, biocompatible nanocarriers could overcome this problem. Accordingly, we used sterically stabilized mixed micelles (SSMM) composed of biocompatible and biodegradable phospholipids to solubilize paclitaxel (P), a hydrophobic model cytotoxic drug, and deliver it to breast cancer in rats. To achieve active targeting, the surface of SSMM was grafted with a ligand, human vasoactive intestinal peptide (VIP) that selectively interacts with its cognate receptors overexpressed on breast cancer cells. We found that even in vitro cytotoxicity of P-SSMM-VIP was 2-fold higher that that of free paclitaxel (p<0.05). Given the unique attributes of P-SSMM and P-SSMM-VIP, most notable small hydrodynamic diameter (~15nm) and stealth properties, biodistribution of paclitaxel was significantly altered. Accumulation of paclitaxel in breast tumor was highest for P-SSMM-VIP, followed by P-SSMM and Cremophor based paclitaxel (PTX). Importantly, bone marrow accumulation of paclitaxel encapsulated in both SSMM-VIP and SSMM was significantly less than that of PTX. Administration of clinically-relevant dose of paclitaxel (5mg/kg) as P-SSMM-VIP and P-SSMM eradicated carcinogen-induced orthotopic breast cancer in rats, whereas PTX decreased tumor size by only 45%. In addition, a 5-fold lower dose (1mg/kg) of paclitaxel in actively targeted P-SSMM-VIP was associated with ~80% reduction in tumor size while the response to PTX and P-SSMM was significantly less. Hypotension was not observed when VIP was grafted onto SSMM. Based on our findings, we propose further development of effective and safe VIP-grafted phospholipid micelle nanomedicines of anti-cancer drugs for targeted treatment of solid tumors in humans