Extinction,generalization, and return of fear: A critical review of renewal research in humans

The main behavioral signature of fear extinction is its fragility. This is exemplified by the renewal effect, where a change in the background context produces recovery of fear to a conditioned-and-extinguished stimulus. Renewal is the backbone of a widely accepted theory of extinction in animal research, as well as an important experimental model to screen novel treatment techniques. This has led to an explosion of fear renewal research in humans. However, the mere observation of return of fear in a renewal procedure is not sufficient to validate this particular theory of extinction in the tested sample/procedure. Here, we systematically outline a set of experimental tests that aid in evaluating alternative extinction/renewal mechanisms. We examine published renewal studies in human fear conditioning and conclude that the prevailing theory of extinction is often taken for granted, but critical tests are lacking. Including these tests in future research will not only reveal the fear extinction mechanism in humans, but also inspire further developments in extinction treatment research.     

De novo mTOR inhibitor‐based immunosuppression in ABO‐incompatible kidney transplantation

ABO‐incompatible (ABOi) kidney transplantation (KTx) has become an accepted therapeutic option in renal replacement therapy for patients without a blood group‐compatible living donor. Using different desensitization strategies, most centers apply B‐cell depletion with rituximab and maintenance immunosuppression (IS) with tacrolimus and mycophenolic acid. This high load of total IS leads to an increased rate of surgical complications and virus infections in ABOi patients. Our aim was to establish ABOi KTx using an immunosuppressive regimen, which is effective in preventing acute rejection without increasing the risk for viral infections. Therefore, we selected a de novo immunosuppressive protocol with low‐dose calcineurin inhibitor and the mTOR inhibitor everolimus for our ABOi program. Here, we report the first 25 patients with a complete three‐yr follow‐up treated with this regimen. Three‐yr patient survival and graft survival were 96% and 83%. The rate of acute T‐cell‐mediated rejections was low (12%). Cytomegalovirus (CMV) infection was evident in one patient only (4%). Surgical complications were common (40%), but mild in 80% of cases. We demonstrate that ABOi KTx with a de novo mTOR inhibitor‐based regimen is feasible without severe surgical or immunological complications and a low rate of viral infections.     

呼吸前反馈调节、情景想象和过度通气

通过大量的科学证据 ,我们论述了代谢的负反馈调节不是呼吸调节的唯一机制。醒觉时呼吸的前反馈调节起了主导作用 ,前反馈调节可以在血气异常引起的负反馈调节之前 ,对将要发生的异常进行纠正 ,预见性地改变通气 ,而代谢的变化随后发生 ,避免了负反馈调节所具有的波动和滞后的缺点 ,使呼吸调节系统具有更大的灵活性和适应能力。在前反馈调节的形成过程中 ,经典的巴甫洛夫条件反射学说可能起了重要作用 .尤其重要的是表象作为条件刺激形成的条件反射 ,研究表象作为条件刺激如何形成呼吸的前反馈调节对揭示高通气综合征的发病机制具有重要意义…     

Characterization and in vitro phase I microsomal metabolism of designer benzodiazepines: An update comprising flunitrazolam,norflurazepam, and 4'‐chlorodiazepam (Ro5–4864)

The number of newly appearing benzodiazepine derivatives on the new psychoactive substances (NPS) drug market has increased over the last couple of years totaling 23 ‘designer benzodiazepines’ monitored at the end of 2017 by the European Monitoring Centre for Drugs and Drug Addiction. In the present study, three benzodiazepines [flunitrazolam, norflurazepam, and 4′‐chlorodiazepam (Ro5–4864)] offered as ‘research chemicals' on the Internet were characterized and their main in vitro phase I metabolites tentatively identified after incubation with pooled human liver microsomes. For all compounds, the structural formula declared by the vendor was confirmed by gas chromatography?mass spectrometry (GC–MS), liquid chromatography?tandem mass spectrometry (LC MS/MS), liquid chromatography?quadrupole time of flight?mass spectrometry (LC?QTOF?MS) analysis and nuclear magnetic resonance (NMR) spectroscopy. The metabolic steps of flunitrazolam were monohydroxylation, dihydroxylation, and reduction of the nitro function. The detected in vitro phase I metabolites of norflurazepam were hydroxynorflurazepam and dihydroxynorflurazepam. 4’‐Chlorodiazepam biotransformation consisted of N‐dealkylation and hydroxylation. It has to be noted that 4′‐chlorodiazepam and its metabolites show almost identical LC–MS/MS fragmentation patterns to diclazepam and its metabolites (delorazepam, lormetazepam, and lorazepam), making a sufficient chromatographic separation inevitable. Sale of norflurazepam, the metabolite of the prescribed benzodiazepines flurazepam and fludiazepam, presents the risk of incorrect interpretation of analytical findings.