Influence of norepinephrine transporter inhibition on hemodynamic response to hypergravitation

Hintergrund: Die Aufrechterhaltung eines adäquaten Blutdruckes während erhöhter Schwerkraftbelastung erfolgt über einen sympathisch vermittelten Herzfrequenzanstieg und eine Vasokonstriktion, um einen schwerkraftbedingten Bewusstseinsverlust (G-LOC) zu verhindern. Die Hemmung des Noradrenalin- Transporters (NET) verlängert die Zeit bis zum Eintreten vasovagaler Reaktionen im Kipptischversuch. Deshalb scheint es möglich, dass eine Hemmung des NET auch die Toleranz gegenüber vermehrter Schwerkraftbelastung erhöht. Methoden: Wir führen eine doppelblinde, randomisierte, placebokontrollierte Crossover-Studie mit 12 gesunden Männern (26±1 Jahre, BMI 24±1 kg/m2) durch. Diese erhielten entweder 4 mg des Selektiven Noradrenalin- Wiederaufnahmehemmers (SNRI) Reboxetin oder Placebo 25, 13 und 1h vor Versuchsbeginn. Wir bestimmten die Herzfrequenz, den Blutdruck und die thorakale Bioimpedanz in drei verschiedenen Körperpositionen (liegend, sitzend, stehend) und während einer graduellen Zentrifugenuntersuchung (Erhöhung um 0,5 g alle 3 min, bis maximal 3 g). Ergebnisse: Noradrenalin- Wiederaufnahmehemmung erhöht den Blutdruck und die Herzfrequenz im Liegen. Unter Placebo erhöhte sich der Blutdruck im Sitzen und war im Stehen ausgeglichen. Unter Noradrenalin-Wiederaufnahmehemmung zeigte sich sowohl im Sitzen als auch im Stehen ein signifikanter Blutdruckabfall. Während erhöhter Schwerkraftbelastung zeigte sich unter Placebo ein kontinuierlicher Anstieg des Blutdruckes. Unter Noradrenalin-Wiederaufnahmehemmung war der Blutdruckanstieg mit zunehmender Schwerkraftbelastung im Vergleich zu Placebo signifikant abgeschwächt. Dagegen war der Anstieg der Herzfrequenz im Sitzen, Stehen und bei erhöhter Schwerkraftbelastung unter Noradrenalin- Wiederaufnahmehemmung im Vergleich zu Placebo deutlich erhöht. Schlussfolgerung: Eine kurzzeitige Noradrenalin-Wiederaufnahmehemmung führte entgegen unseren Erwartungen nicht zu einer erhöhten Toleranz gegenüber vermehrter Schwerkraftbelastung. Eine Umverteilung der Sympathikusaktivität zum Herzen, beziehungsweise Änderungen in der Baroreflex-Kontrolle könnten den beobachteten, deutlich erhöhten Herzfrequenzanstieg erklären.Background: Sympathetically-mediated tachycardia and vasoconstriction maintain blood pressure during hypergravitational stress, thereby preventing gravitation-induced loss of consciousness (g-LOC). Norepinephrine transporter (NET) inhibition prevents neurally-mediated (pre)syncope during gravitational stress imposed by head-up tilt testing. Thus, it seems reasonable that NET inhibition could increase tolerance to hypergravitational stress. Methods. We performed a double-blind, randomized, placebo-controlled crossover study in 11 healthy men (261 yrs, BMI 241 kg/m2) who ingested the selective NET inhibitor reboxetine (4 mg) or matching placebo 25, 13, and 1 h before testing on separate days. We monitored heart rate, blood pressure, and thoracic impedance in three different body positions (supine, seated, standing) and during a graded centrifuge run (incremental steps of 0.5 g for 3 min each, up to a maximal gz-load of 3 g). Results. NET inhibition increased supine blood pressure and heart rate. With placebo, blood pressure increased in the seated position and was well maintained during standing. However, with NET inhibition blood pressure decreased in the seated and standing position. During hypergravitation, blood pressure increased in a graded fashion with placebo. With NET inhibition, the increase in blood pressure during hypergravitation was profoundly diminished. Conversely, the tachycardic response to sitting, standing, and hypergravitation all were greatly increased with NET inhibition. Conclusions. In contrast to our expectation, short term NET inhibition did not improve tolerance to hypergravitation. Redistribution of sympathetic activity to the heart or changes in baroreflex responses could explain the excessive tachycardia we observed

Regulation of hepatic microRNAs in response to early stage Echinococcus multilocularis egg infection in C57BL/6 mice.

We present a comprehensive analysis of the hepatic miRNA transcriptome at one month post-infection of experimental primary alveolar echinococcosis (AE), a parasitic infection caused upon ingestion of E. multilocularis eggs. Liver tissues were collected from infected and non-infected C57BL/6 mice, then small RNA libraries were prepared for next-generation sequencing (NGS). We conducted a Stem-loop RT-qPCR for validation of most dysregulated miRNAs. In infected mice, the expression levels of 28 miRNAs were significantly altered. Of these, 9 were up-regulated (fold change (FC) ≥ 1.5) and 19 were down-regulated (FC ≤ 0.66) as compared to the non-infected controls. In infected livers, mmu-miR-148a-3p and mmu-miR-101b-3p were 8- and 6-fold down-regulated, respectively, and the expression of mmu-miR-22-3p was reduced by 50%, compared to non-infected liver tissue. Conversely, significantly higher hepatic levels were noted for Mus musculus (mmu)-miR-21a-5p (FC = 2.3) and mmu-miR-122-5p (FC = 1.8). In addition, the relative mRNA expression levels of five genes (vegfa, mtor, hif1-α, fasn and acsl1) that were identified as targets of down-regulated miRNAs were significantly enhanced. All the five genes exhibited a higher expression level in livers of E. multilocularis infected mice compared to non-infected mice. Finally, we studied the issue related to functionally mature arm selection preference (5p and/or 3p) from the miRNA precursor and showed that 9 pre-miRNAs exhibited different arm selection preferences in normal versus infected liver tissues. In conclusion, this study provides first evidence that miRNAs are regulated early in primary murine AE. Our findings raise intriguing questions such as (i) how E. multilocularis affects hepatic miRNA expression;(ii) what are the alterations in miRNA expression patterns in more advanced AE-stages; and (iii) which hepatic cellular, metabolic and/or immunologic processes are modulated through altered miRNAs in AE. Thus, further research on the regulation of miRNAs during AE is needed, since miRNAs constitute an attractive potential option for development of novel therapeutic approaches against AE

How many persistent organic pollutants should we expect?

AbstractUnder the Stockholm Convention on Persistent Organic Pollutants (POPs), currently 22 chemicals or groups of chemicals are regulated as POPs. However, various screening exercises performed on large sets of chemicals indicate that the number of substances fulfilling the screening criteria defined in Annex D of the Stockholm Convention might be much higher. Most of these screening studies searched for highly persistent and bioaccumulative chemicals, but did not include the long-range transport potential, which is a key criterion under the Stockholm Convention. We apply the screening criteria for persistence, bioaccumulation and long-range transport potential of the Stockholm Convention to a set of 93 144 organic chemicals. Because no toxicity threshold is defined under the Stockholm Convention, we use the toxicity threshold of REACH, the chemicals regulation of the European Union. For the vast majority of the chemicals, the property data required for the assessment had to be estimated from the chemical structure. Assessment results for the acknowledged POPs and for POP candidates currently under review are discussed. Beyond these well-known substances, we find 510 chemicals that exceed all four critieria and can be considered potential POPs. Ninety eight percent of these chemicals are halogenated; frequent types of chemicals are halogenated aromatic compounds, including polychlorinated diphenylethers, tetrachloro benzyltoluenes, brominated and fluorinated naphthalenes and biphenyls; and highly or fully chlorinated and fluorinated alkanes (cyclic, linear, branched). Non-halogenated substances are highly branched alkanes and nitroaromatic compounds. Ten substances are high-production volume chemicals and 249 are pre-registered in the EU. We used uncertainty ranges of the chemical property data to estimate a lower and upper bound of the number of potential POPs; these bounds are at 190 and 1 200 chemicals. These results imply that several tens of potential POPs may have to be expected for future evaluation under the Stockholm Convention

Screening for PBT Chemicals among the “Existing” and “New” Chemicals of the EU

Under the European chemicals legislation, REACH, industrial chemicals that are imported or manufactured at more than 10 t/yr need to be evaluated with respect to their persistence (P), bioaccumulation potential (B), and toxicity (T). This assessment has to be conducted for several 10 000 of chemicals but, at the same time, empirical data on degradability, bioaccumulation potential and toxicity of industrial chemicals are still scarce. Therefore, the identification of PBT chemicals among all chemicals on the market remains a challenge. We present a PBT screening of approximately 95 000 chemicals based on a comparison of estimated P, B, and T properties of each chemical with the P, B, and T thresholds defined under REACH. We also apply this screening procedure to a set of 2576 high production volume chemicals and a set of 2781 chemicals from the EU’s former list of “new chemicals” (ELINCS). In the set of 95 000 chemicals, the fraction of potential PBT chemicals is around 3%, but in the ELINCS chemicals it reaches 5%. We identify the most common structural elements among the potential PBT chemicals. Analysis of the P, B, and T data for all chemicals considered here shows that the uncertainty in persistence data contributes most to the uncertainty in the number of potential PBT chemicals

Norepinephrine transporter function and tolerance to hypergravitational stress: A pilot study

Pharmacological norepinephrine transporter (NET) inhibition improves orthostatic tolerance on a tilt table while increasing heart rate. We tested the cardiovascular response to NET inhibition during a graded human centrifuge run in seven healthy men. g-Load was increased in 0.5 g steps with 3 g maximal g-load. On two separate days, patients were tested after selective NET inhibition with reboxetine or with placebo in a double-blind, randomized, crossover fashion. Resting diastolic blood pressure increased moderately with NET inhibition. Resting heart rate was profoundly increased by NET inhibition. NET inhibition augmented the heart rate response while attenuating the increase in blood pressure during hypergravitation. NET inhibition could be tested for its potential to improve cardiovascular g-tolerance

HHV-6 encoded small non-coding RNAs define an intermediate and early stage in viral reactivation

Virology: a biomarker for HHV-6 reactivation The human herpesvirus 6 (HHV-6) expresses high levels of small non-coding RNA (sncRNA) molecules early in its reactivation from latency. Bhupesh Prusty 
from the University of Würzburg, Germany, and colleagues developed a laboratory system for studying HHV-6 infections in a human bone cancer cell line. They reawakened the virus with a drug stimulus and detected several sncRNAs but few other viral RNAs that might promote replication or protein production. They term this unique stage of the viral life cycle ‘transactivation’, and show that it alters both host and viral physiology. The authors also describe a teenage girl with high sncRNA levels in her blood who fell ill after an acne drug spurred the reactivation of a dormant HHV-6 infection. They thus argue that sncRNAs could serve as an early diagnostic indicator of HHV-6 reactivation

Norepinephrine transporter inhibition alters the hemodynamic response to hypergravitation

Background. Sympathetically-mediated tachycardia and vasoconstriction maintain blood pressure during hypergravitational stress, thereby preventing gravitation-induced loss of consciousness (g-LOC). Norepinephrine transporter (NET) inhibition prevents neurally-mediated (pre)syncope during gravitational stress imposed by head-up tilt testing. Thus, it seems reasonable that NET inhibition could increase tolerance to hypergravitational stress. Methods. We performed a double-blind, randomized, placebo-controlled crossover study in 11 healthy men (26+/-1 yrs, BMI 24+/-1 kg/m2) who ingested the selective NET inhibitor reboxetine (4 mg) or matching placebo 25, 13, and 1 h before testing on separate days. We monitored heart rate, blood pressure, and thoracic impedance in three different body positions (supine, seated, standing) and during a graded centrifuge run (incremental steps of 0.5 g for 3 min each, up to a maximal gz-load of 3 g). Results. NET inhibition increased supine blood pressure and heart rate. With placebo, blood pressure increased in the seated position and was well maintained during standing. However, with NET inhibition blood pressure decreased in the seated and standing position. During hypergravitation, blood pressure increased in a graded fashion with placebo. With NET inhibition, the increase in blood pressure during hypergravitation was profoundly diminished. Conversely, the tachycardic response to sitting, standing, and hypergravitation all were greatly increased with NET inhibition. Conclusions. In contrast to our expectation, short term NET inhibition did not improve tolerance to hypergravitation. Redistribution of sympathetic activity to the heart or changes in baroreflex responses could explain the excessive tachycardia we observed

Encrustations on ureteral stents from patients without urinary tract infection reveal distinct urotypes and a low bacterial load

Abstract Background Current knowledge of the urinary tract microbiome is limited to urine analysis and analysis of biofilms formed on Foley catheters. Bacterial biofilms on ureteral stents have rarely been investigated, and no cultivation-independent data are available on the microbiome of the encrustations on the stents. Results The typical encrustations of organic and inorganic urine-derived material, including microbial biofilms formed during 3–6 weeks on ureteral stents in patients treated for kidney and ureteral stones, and without reported urinary tract infection at the time of stent insertion, were analysed. Next-generation sequencing of the 16S rRNA gene V3–V4 region revealed presence of different urotypes, distinct bacterial communities. Analysis of bacterial load was performed by combining quantification of 16S rRNA gene copy numbers by qPCR with microscopy and cultivation-dependent analysis methods, which revealed that ureteral stent biofilms mostly contain low numbers of bacteria. Fluorescence microscopy indicates the presence of extracellular DNA. Bacteria identified in biofilms by microscopy had mostly morphogenic similarities to gram-positive bacteria, in few cases to Lactobacillus and Corynebacterium, while sequencing showed many additional bacterial genera. Weddellite crystals were absent in biofilms of patients with Enterobacterales and Corynebacterium-dominated microbiomes. Conclusions This study provides novel insights into the bacterial burden in ureteral stent encrustations and the urinary tract microbiome. Short-term (3–6 weeks) ureteral stenting is associated with a low load of viable and visible bacteria in ureteral stent encrustations, which may be different from long-term stenting. Patients could be classified according to different urotypes, some of which were dominated by potentially pathogenic species. Facultative pathogens however appear to be a common feature in patients without clinically manifested urinary tract infection. Trial registration ClinicalTrials.gov, NCT02845726. Registered on 30 June 2016—retrospectively registered