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.     

Inertial control chart “industrial application and feedback”

Besides finding the target values of every component of an assembled product, it is also necessary to find the best compromise between the quality product cost and the quality assembled cost. To this end, Genichi Taguchi and Don Clausing suggested using Taguchi’s lost function to evaluate these quality costs. Based on this function, Pillet suggested a new approach, called “inertial tolerancing”. This approach is a new language between the designer and the process engineering department. It allows a link to be made between the quality product cost and the quality assembled cost and then to use statistical tolerancing in the assembled design. This paper presents the efficiency of the use of this approach during the design phase for assembling two components and also its efficiency during the production phase for the monitoring with an inertia control chart. In order to illustrate this, these new approaches are used in industrial cases and compared to the traditional approach (tolerancing and monitoring) to underline the economic benefit which can be obtained using the inertial approach.     

The role of endoglin in atherosclerosis

Endoglin (CD 105, TGF-β receptor III) is a homodimeric transmembrane glycoprotein that plays a regulatory role in TGF-β signaling. Its functional role in the context of atherosclerosis has yet to be defined and should be stated here. Therefore, we focused on the role of endoglin in atherosclerosis in both humans and experimental animals. Endoglin expression was demonstrated in atherosclerotic vessels predominantly in endothelial cells and smooth muscle cells in various types of blood vessels in mice and humans, suggesting its participation in atherogenesis. Endoglin expression was also related to the expression of eNOS in endothelium, repair of the vessel wall, plaque neoangiogenesis, production of collagen and stabilization of atherosclerotic lesions. In addition, increased levels of soluble endoglin were associated with hypercholesterolemia, atherosclerosis, acute myocardial infarction and were related to inhibition of TGF-β signaling in the vessel wall. Moreover, soluble endoglin levels were significantly lowered after a series of extracorporeal eliminations in patients with familial hypercholesterolemia. Additionally, statin treatment decreased levels of soluble endoglin and increased its expression in aorta, which was related to reduced atherosclerosis in mice. In conclusion, we propose that measurement of soluble endoglin might give information about progression of the atherosclerotic process or the efficacy of therapeutic interventions, which is the task that must be answered in clinical trials.     

Further constraints on the Chauvet cave artwork elaboration

Since its discovery, the Chauvet cave elaborate artwork called into question our understanding of Palaeolithic art evolution and challenged traditional chronological benchmarks [Valladas H et al. (2001) Nature 413:419–479]. Chronological approaches revealing human presences in the cavity during the Aurignacian and the Gravettian are indeed still debated on the basis of stylistic criteria [Pettitt P (2008) J Hum Evol 55:908–917]. The presented ³⁶Cl Cosmic Ray Exposure ages demonstrate that the cliff overhanging the Chauvet cave has collapsed several times since 29 ka until the sealing of the cavity entrance prohibited access to the cave at least 21 ka ago. Remarkably agreeing with the radiocarbon dates of the human and animal occupancy, this study confirms that the Chauvet cave paintings are the oldest and the most elaborate ever discovered, challenging our current knowledge of human cognitive evolution.     

Clinical features of patients with recurrent invasive Streptococcus pneumoniae disease

IntroductionInvasive Streptococcus pneumoniae (pneumococcal) disease (IPD) carries a high risk of death, approximately 15% to 20% in pneumonia, 40% in meningitis and 10% to 15% in septicemia. The occurrence of 2 or more IPD (recurrent) in the same individual is uncommon. The authors investigated the clinical features of patients with recurrent IPD to assess whether they possessed risk factors that increased their likelihood of recurrent IPD.MethodsBetween 1983 and 2010, the authors identified 27 patients with recurrent IPD during inpatient surveillance of 889 patients with IPD in Huntington, WV, by recovery of pneumococci from otherwise sterile sites. Serotype/serogroup (ST/SG) was determined by capsular swelling and the penicillin MIC by E-strip. Clinical data were abstracted from hospital charts.ResultsSixteen (59%) of 27 patients were 65 years and older at first IPD, males predominated (67%), two-thirds had pneumonia and 21 (78%) had the same clinical diagnosis at both IPD. Four (80%) of 5 patients with the same ST experienced their second IPD 1 to 6 months apart, unlike most patients with discordant ST/SGs (P = 0.047). Eighty-four percent of ST/SGs were included in the 23-valent pneumococcal vaccine and occurred as often during the first and second IPD. Twenty (77%) of 26 adults suffered from comorbid diseases placing them at high risk of IPD, including multiple myeloma, HIV/AIDS, neoplasia of hematological origin and sickle cell disease.conclusionRecurrent IPD occurred uncommonly. Comorbid conditions including multiple myeloma and immunosuppressive/immunodeficient conditions, chronic alcoholism and splenectomy represented unique risk factors for recurrent IPD but did not predict recurrences.     

Relationship of climate, geography, and geology to the incidence of Rift Valley fever in Kenya during the 2006-2007 outbreak

We estimated Rift Valley fever (RVF) incidence as a function of geological, geographical, and climatological factors during the 2006-2007 RVF epidemic in Kenya. Location information was obtained for 214 of 340 (63%) confirmed and probable RVF cases that occurred during an outbreak from November 1, 2006 to February 28, 2007. Locations with subtypes of solonetz, calcisols, solonchaks, and planosols soil types were highly associated with RVF occurrence during the outbreak period. Increased rainfall and higher greenness measures before the outbreak were associated with increased risk. RVF was more likely to occur on plains, in densely bushed areas, at lower elevations, and in the Somalia acacia ecological zone. Cases occurred in three spatial temporal clusters that differed by the date of associated rainfall, soil type, and land usage.