formula: see text The stereo- and regioselective synthesis of ultra-short-acting nondepolarizing neuromuscular blocker GW 0430 (5a) is described. Key steps involved the enantioselective transfer ...hydrogenation of imine 8 employing Noyori's catalyst, the stereoselective crystallization and methanolysis of trans-bataines 11 and 12, and the stereo- and regioselective trans elimination of hydrogen chloride from 14. The latter transformation allowed complete control of the position of the chloro substituent and stereochemistry at the double bond of the linker in 15.
Genome-wide association studies (GWAS) with intermediate phenotypes, like changes in metabolite and protein levels, provide functional evidence to map disease associations and translate them into ...clinical applications. However, although hundreds of genetic variants have been associated with complex disorders, the underlying molecular pathways often remain elusive. Associations with intermediate traits are key in establishing functional links between GWAS-identified risk-variants and disease end points. Here we describe a GWAS using a highly multiplexed aptamer-based affinity proteomics platform. We quantify 539 associations between protein levels and gene variants (pQTLs) in a German cohort and replicate over half of them in an Arab and Asian cohort. Fifty-five of the replicated pQTLs are located in trans. Our associations overlap with 57 genetic risk loci for 42 unique disease end points. We integrate this information into a genome-proteome network and provide an interactive web-tool for interrogations. Our results provide a basis for novel approaches to pharmaceutical and diagnostic applications.
The Endeavour segment of the Juan de Fuca Ridge is one of the most active and long‐lived hydrothermal areas of the mid‐ocean ridge system. However, the permeability structure that gives rise to ...long‐term venting at well‐established fields, such as the High Rise, Main Endeavour, and Mothra fields, is not fully understood. Here we jointly invert Pg and Sg traveltimes from a seismic refraction experiment conducted at the Endeavour segment using P‐to‐S coupling constraints. We then calculate porosity and crack density as a function of crack aspect ratio by applying the differential effective medium theory to the seismic velocities. At 1.4‐km depth, average Vp ~5 km off axis increases by ~0.4 km/s compared to the ridge axis. The average Vp/Vs has a minimum of ~1.75 on the ridge axis and increases to a maximum of ~1.84 off axis. The inferred porosity and crack density distributions show that the proportion of thick versus thin cracks decreases from the ridge axis to the flanks, since theoretical models indicate that Vp/Vs increases going from thick to thin cracks (aspect ratio decreasing from 0.1 to 0.01). The dominant presence of thick cracks on the axis may provide long‐term conduits for upflow in high‐temperature hydrothermal circulation potentially forming the vent fields. The increased proportion of thin cracks on the flanks, coupled with the increased seismic velocity, indicates a decrease in permeability caused by progressive clogging of thick cracks due to mineral precipitation likely in the downflow zone of hydrothermal circulation.
Key Points
A 3‐D tomographic model of Vp, Vs, and Vp/Vs informs crack aspect ratios in the upper crust at the Endeavour segment, Juan de Fuca Ridge
Seafloor spreading produces thick cracks with low Vp/Vs, which fill within a few kilometers of the ridge axis by hydrothermal circulation
Thick cracks on the axis may provide long‐lived conduits for hydrothermal upflow beneath the high‐temperature vent fields
Cerebral hyperperfusion syndrome van Mook, Walther NKA; Rennenberg, Roger JMW; Schurink, Geert Willem ...
Lancet neurology,
12/2005, Letnik:
4, Številka:
12
Journal Article
Recenzirano
Cerebral hyperperfusion syndrome (CHS) after carotid endarterectomy is characterised by ipsilateral headache, hypertension, seizures, and focal neurological deficits. If not treated properly it can ...result in severe brain oedema, intracerebral or subarachnoid haemorrhage, and death. Knowledge of CHS among physicians is limited. Most studies report incidences of CHS of 0–3% after carotid endarterectomy. CHS is most common in patients with increases of more than 100% in perfusion compared with baseline after carotid endarterectomy and is rare in patients with increases in perfusion less than 100% compared with baseline. The most important risk factors in CHS are diminished cerebrovascular reserve, postoperative hypertension, and hyperperfusion lasting more than several hours after carotid endarterectomy. Impaired autoregulation as a result of endothelial dysfunction mediated by generation of free oxygen radicals is implicated in the pathogenesis of CHS. Treatment strategies are directed towards regulation of blood pressure and limitation of rises in cerebral perfusion. Complete recovery happens in mild cases, but disability and death can occur in more severe cases. More information about CHS and early institution of adequate treatment are of paramount importance in order to prevent these potentially severe complications.
Structure-activity relationships in rhesus monkeys for a novel mixed-onium class of ultra-short-acting nondepolarizing tetrahydroisoquinolinium neuromuscular blockers (NMBs) are described. Bis-onium ...chlorofumarate 20a with (1R,2S)-benzyltetrahydroisoquinolinium groups was a potent lead compound (ED(95) = 0.079 mg/kg) with an ultra-short duration of NMB effect (7.1 min) and a selectivity index (SI: defined as a ratio of the cardiovascular threshold dose to the ED(95)) similar to that of mivacurium (3). The mean threshold dose for cardiovascular effects with 20a was ca. 20 times its ED(95) value (SI = 20). A novel mixed-onium analogue of 20a was prepared by replacing the benzyltetrahydroisoquinolinium group distal to the fumarate chlorine atom with a (1S,2R)-phenyltetrahydroisoquinolinium moiety. The resulting mixed-onium chlorofumarate 24a displayed good NMB potency (ED(95) = 0.063 mg/kg), ultra-short duration of action (5.6 min) and an improved selectivity index (SI = 57). Several other mixed-onium derivatives containing octanedioate (25a; ED(95) = 0.103 mg/kg), difluorosuccinate (27c; ED(95) = 0.056 mg/kg), and fluorofumarate (28a; ED(95) = 0.137 mg/kg) linkers were also potent, ultra-short-acting NMBs with good to excellent selectivity index values (SI = 37-96). Octanedioate 25a was longer acting at higher doses compared to difluorosuccinate 27c and chlorofumarate 24a. Durations of NMB effect following a 0.4 mg/kg bolus dose (100% block) of 25a, 27c, and 24a were 16.9, 13.0, and 10.0 min, respectively. Recovery time for mixed-onium chlorofumarate 24a following a 1 h continuous infusion at 10-20 microg/kg/min (95-100% block) was ca. 5 min which is similar to that observed following a 0.2 mg/kg bolus dose of this compound and indicates a lack of cummulative effects. Preliminary studies with chlorofumarate 24a in whole human blood revealed that mixed-onium thiazolidine 29 was the major metabolite and that plasma cholinesterases do not play the primary role in duration of NMB effect. The NMB properties of 24a in rhesus monkeys led to its clinical evaluation as a possible alternative to succinylcholine.
Patterning droplets with durotaxis Style, Robert W.; Che, Yonglu; Park, Su Ji ...
Proceedings of the National Academy of Sciences - PNAS,
07/2013, Letnik:
110, Številka:
31
Journal Article
Recenzirano
Odprti dostop
Numerous cell types have shown a remarkable ability to detect and move along gradients in stiffness of an underlying substrate—a process known as durotaxis. The mechanisms underlying durotaxis are ...still unresolved, but generally believed to involve active sensing and locomotion. Here, we show that simple liquid droplets also undergo durotaxis. By modulating substrate stiffness, we obtain fine control of droplet position on soft, flat substrates. Unlike other control mechanisms, droplet durotaxis works without imposing chemical, thermal, electrical, or topographical gradients. We show that droplet durotaxis can be used to create large-scale droplet patterns and is potentially useful for many applications, such as microfluidics, thermal control, and microfabrication.
The quaternizations of dibenzoquinolizines 9 and 14 with 3-halo-1-propanols are highly cis-selective (94-100% cis), results consistent with the N-methylation of O-methylcapaurine (7b), but in ...contrast to the proposed trans-stereochemistry of dibenzoa,hquinolizine methiodide 10 and the analogous quaternizations of 1-benzyl- and 1-phenylisoquinoline congeners 5b and 5c. In this report, we describe stereoselective preparation of the unique cis-dibenzoquinolizinium propanols 15 and 16and their transformation into bis- and mixed-onium chlorofumarates 19, 20ab, and 26. Dibenzoa,gquinolizinium propanol 15 was prepared enantioselectively in three steps from dihydroisoquinoline 11. Asymmetric transfer hydrogenation of 11 in the presence of triethylamine/formic acid and Noyori's chiral ruthenium catalyst 12 produced R-(-)-5',8-dimethoxynorlaudanosine (13) in 98% yield and 87% ee. Pictet-Spengler cyclization of 13 in formalin/formic acid afforded the dibenzoa,gquinolizine 14 in 65% yield. Quaternization of 14 with 3-chloro-1-propanol under Finkelstein conditions generated cis-dibenzoquinolizinium propanol 15 in 85% yield with >94% cis-selectivity. The cis-dibenzoa,hquinolizinium propanol 16 was obtained as a single stereoisomer by reaction of the known tetramethoxyquinolizine 9 with neat 3-iodo-1-propanol. Bis-onium chlorofumarates 18 and 19 and the mixed-onium derivative 20ab were prepared by a pool synthesis procedure from (1R)-trans-6a, 16, and chlorofumaryl chloride (17). Mixed-onium alpha-chlorofumarate 26 was synthesized from (1S)-trans-6d, 15 and (+/-)-trans-2,3-dichlorosuccinic anhydride (22), employing a recently disclosed chlorofumarate mixed-diester synthesis. The title compounds (19, 20ab, and 26) displayed curare-like effects of ultrashort duration in rhesus monkeys.
Three different glucagon-like peptide-1 (GLP-1) receptor agonists reduce cardiovascular outcomes in people with type 2 diabetes at high cardiovascular risk with high glycated haemoglobin A1c (HbA1c) ...concentrations. We assessed the effect of the GLP-1 receptor agonist dulaglutide on major adverse cardiovascular events when added to the existing antihyperglycaemic regimens of individuals with type 2 diabetes with and without previous cardiovascular disease and a wide range of glycaemic control.
This multicentre, randomised, double-blind, placebo-controlled trial was done at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo. Randomisation was done by a computer-generated random code with stratification by site. All investigators and participants were masked to treatment assignment. Participants were followed up at least every 6 months for incident cardiovascular and other serious clinical outcomes. The primary outcome was the first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes (including unknown causes), which was assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01394952.
Between Aug 18, 2011, and Aug 14, 2013, 9901 participants (mean age 66·2 years SD 6·5, median HbA1c 7·2% IQR 6·6–8·1, 4589 46·3% women) were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). During a median follow-up of 5·4 years (IQR 5·1–5·9), the primary composite outcome occurred in 594 (12·0%) participants at an incidence rate of 2·4 per 100 person-years in the dulaglutide group and in 663 (13·4%) participants at an incidence rate of 2·7 per 100 person-years in the placebo group (hazard ratio HR 0·88, 95% CI 0·79–0·99; p=0·026). All-cause mortality did not differ between groups (536 10·8% in the dulaglutide group vs 592 12·0% in the placebo group; HR 0·90, 95% CI 0·80–1·01; p=0·067). 2347 (47·4%) participants assigned to dulaglutide reported a gastrointestinal adverse event during follow-up compared with 1687 (34·1%) participants assigned to placebo (p<0·0001).
Dulaglutide could be considered for the management of glycaemic control in middle-aged and older people with type 2 diabetes with either previous cardiovascular disease or cardiovascular risk factors.
Eli Lilly and Company.
The Competency Based Training in Intensive Care Education (CoBaTrICE) programme developed common standards of ICM training by describing competencies of an intensivist. Entrustable Professional ...Activities (EPAs) of Intensive Care Medicine (ICM) (EPAsICM) are presented as a new workplace-based assessment tool in competency-based training of intensivists. EPAs are activities to be entrusted to a trainee once he (or she) has attained competence. EPAs emphasise the role of trust between trainees and supervisors. EPAs bridge the gap between competencies and competence.
An expert panel of ICM (vice)programme directors and intensivists in The Netherlands integrated the CoBaTrICE and CanMEDS competencies into EPAsICM. Comment and feedback was sought from other ICM programme directors and educational experts and processed in the final version of EPAsICM before implementation in the Dutch ICM training programme.
A list of 15 EPAsICM are considered to reflect the spectrum of clinical practice while incorporating the competencies of CoBaTrICE and CanMEDS. The grading system is designed as a 5-point entrustment scale based on the amount of supervision a trainee needs, aligning with daily judgement of trainees by intensivists.
EPAsICM is an assessment tool that formalises entrustment decisions and can be a valuable addition in international ICM training.
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