The title triarylamine N,N‐bis(9,9‐dimethyl‐9H‐fluoren‐2‐yl)‐3′,3′,4′,7′‐tetramethyl‐2′,3′‐dihydrospirofluorene‐9,1′‐indene‐2‐amine is a new hole transport material for organic solar cells. After ...investigating different discovery approaches (Schemes 1 + 2), a multi gram‐scale synthetic sequence was developed (Scheme 4). The key intermediate 2‐bromo‐9‐(2,5‐dimethylphenyl)‐9H‐fluorene was accessible from 2‐bromo‐9‐fluorenone by either the sequence Grignard reaction, Et3SiH/BF3 reduction or by direct arylation of the corresponding 2‐bromo‐9‐fluorenol. Alkylation at C(9) of 2‐bromo‐9‐(2,5‐dimethylphenyl)‐9H‐fluorene with methallyl chloride and cyclization by an intramolecular Friedel‐Crafts alkylation led to the key building block 2‐bromo‐3′,3′,4′,7′‐tetramethyl‐2′,3′‐dihydrospirofluorene‐9,1′‐indene (Scheme 4). A Buchwald‐Hartwig coupling was employed (Scheme 3 + 4) for the assembly of the final triarylamines. The developed gram‐scale synthesis of the title compound is scalable and chromatography‐free with an overall yield >25 % over 5 steps.
Triarylamine 17 represents a new class of hole transport material for organic solar cells (OSC) and organic light emitting diodes (OLED). The scalable and chromatography‐free synthesis comprises five steps starting from commercially available 2‐bromo‐9‐fluorenone (5). An intramolecular Friedel‐Crafts alkylation is the key reaction for the formation of the bromo‐spirofluorene scaffold 16; subsequent Buchwald‐Hartwig cross‐coupling leads to the title triarylamine as crystalline solid.
Synthesis of azetidine-derived natural products by the opportunistic pathogen Pseudomonas aeruginosa is controlled by quorum sensing, a process involving the production and sensing of diffusible ...signal molecules that is decisive for virulence regulation. In this study, we engineered P. aeruginosa for the titratable expression of the biosynthetic aze gene cluster, which allowed the purification and identification of two new products, azetidomonamide C and diazetidomonapyridone. Diazetidomonapyridone was shown to have a highly unusual structure with two azetidine rings and an open-chain diimide moiety. Expression of aze genes strongly increased biofilm formation and production of phenazine and alkyl quinolone virulence factors. Further physiological studies revealed that all effects were mainly mediated by azetidomonamide A and diazetidomonapyridone, whereas azetidomonamides B and C had little or no phenotypic impact. The P450 monooxygenase AzeF which catalyzes a challenging, stereoselective hydroxylation of the azetidine ring converting azetidomonamide C into azetidomonamide A is therefore crucial for biological activity. Based on our findings, we propose this group of metabolites to constitute a new class of diffusible regulatory molecules with community-related effects in P. aeruginosa.
Treatment of 1,2-bis(trimethylsilylethynyl)benzene with di-tert-butylaluminum and di-tert-butylgallium hydrides afforded the simple addition products 1,2-(Me3Si)(R2E)CC(H)2C6H4 (R = CMe3; E = Al ...(1), Ga (2)), which could not be isolated in a pure crystalline form but have been characterized unambiguously by spectroscopic methods. Addition of the Lewis base ethyldimethylamine initiated condensation reactions which gave cage compounds (3 and 4) by the release of the corresponding tri-tert-butyl element derivatives. These cages contain two aluminum or gallium atoms which are bridged by three 1,2-bis(trimethylsilylethenyl)benzene spacers to form molecular capsules. The metal atoms are further coordinated by terminal amino groups. The amino ligands could not be removed from the dialuminum compound 4 without decomposition, but the ligand-free gallium compound 5 was obtained upon heating of 3 (E = Ga) to 80 °C under vacuum. Thermolysis of the aluminum compound 1 in boiling n-hexane gave a unique reaction by the release of tri-tert-butylaluminum and the formal elimination of trimethylsilylethyne (decarbalumination). The product 6 is dimeric in the solid state via Al−C−Al bridges and has a pentacyclic molecular structure.
Treatment of the Al/P-based frustrated Lewis pair (FLP) Mes
P–C(Al
Bu
)=C(H)-Ph (
) with benzophenone afforded the simple 1:1 adduct (
) with a O=CPh
molecule coordinated to the aluminum atom by an ...Al←O donor-acceptor bond. Steric repulsion may prevent an interaction between the electrophilic carbonyl carbon atom and the Lewis-basic phosphorus atom.
is unstable in solution at room temperature, the coordination to aluminium increases the polarisation of the carbonyl group and favours its reduction. As suggested by quantum chemical calculations, a C–H bond of a
Bu group approaches the electrophilic center and facilitates β-hydride elimination with the release of isobutene and the formation of an Al–OCHPh
ligation. An intact O=CPh
molecule completes the coordination sphere of the metal atom (
). The second
Bu group at aluminium reacts similarly by the selective formation of an Al(OCHPh
moiety (
). The thermodynamics of adduct formation and the mechanism of the hydride shift have been evaluated by quantum chemical DFT calculations.
IMPORTANCE: Surgical site infections frequently occur after open abdominal surgery. Intraoperative wound irrigation as a preventive measure is a common practice worldwide, although evidence ...supporting this practice is lacking. OBJECTIVE: To evaluate the preventive effect of intraoperative wound irrigation with polyhexanide solution. DESIGN, SETTING, AND PARTICIPANTS: The Intraoperative Wound Irrigation to Prevent Surgical Site Infection After Laparotomy (IOWISI) trial was a multicenter, 3-armed, randomized clinical trial. Patients and outcome assessors were blinded to the intervention. The clinical trial was conducted in 12 university and general hospitals in Germany from September 2017 to December 2021 with 30-day follow-up. Adult patients undergoing laparotomy were eligible for inclusion. The main exclusion criteria were clean laparoscopic procedures and the inability to provide consent. Of 11 700 screened, 689 were included and 557 completed the trial; 689 were included in the intention-to-treat and safety analysis. INTERVENTIONS: Randomization was performed online (3:3:1 allocation) to polyhexanide 0.04%, saline, or no irrigation (control) of the operative wound before closure. MAIN OUTCOME AND MEASURES: The primary end point was surgical site infection within 30 postoperative days according to the US Centers for Disease Control and Prevention definition. RESULTS: Among the 689 patients included, 402 were male and 287 were female. The median (range) age was 65.9 (18.5-94.9) years. Participants were randomized to either wound irrigation with polyhexanide (n = 292), saline (n = 295), or no irrigation (n = 102). The procedures were classified as clean contaminated in 92 cases (8%). The surgical site infection incidence was 11.8% overall (81 of 689), 10.6% in the polyhexanide arm (31 of 292), 12.5% in the saline arm (37 of 295), and 12.8% in the no irrigation arm (13 of 102). Irrigation with polyhexanide was not statistically superior to no irrigation or saline irrigation (hazard ratio HR, 1.23; 95% CI, 0.64-2.36 vs HR, 1.19; 95% CI, 0.74-1.94; P = .47). The incidence of serious adverse events did not differ among the 3 groups. CONCLUSIONS AND RELEVANCE: In this study, intraoperative wound irrigation with polyhexanide solution did not reduce surgical site infection incidence in clean-contaminated open abdominal surgical procedures compared to saline or no irrigation. More clinical trials are warranted to evaluate the potential benefit in contaminated and septic procedures, including the emergency setting. TRIAL REGISTRATION: drks.de Identifier: DRKS00012251
17q21 Variants Disturb Mucosal Host Defense in Childhood Asthma Jakwerth, Constanze A; Weckmann, Markus; Illi, Sabina ...
American journal of respiratory and critical care medicine,
2024-Apr-15, 2024-04-15, 20240415, Letnik:
209, Številka:
8
Journal Article
Recenzirano
Odprti dostop
The strongest genetic risk factor for childhood-onset asthma, the 17q21 locus, is associated with increased viral susceptibility and disease-promoting processes.
To identify biological targets ...underlying the escalated viral susceptibility associated with the clinical phenotype mediated by the 17q21 locus.
Genome-wide transcriptome analysis of nasal brush samples from 261 children (78 healthy, 79 with wheezing at preschool age, 104 asthmatic) within the ALLIANCE (All-Age-Asthma) cohort, with a median age of 10.0 (range, 1.0-20.0) years, was conducted to explore the impact of their 17q21 genotype (SNP
). Concurrently, nasal secretions from the same patients and visits were collected, and high-sensitivity mesoscale technology was employed to measure IFN protein levels.
This study revealed that the 17q21 risk allele induces a genotype- and asthma/wheeze phenotype-dependent enhancement of mucosal
expression as the only relevant 17q21-encoded gene in children with preschool wheeze. Increased
expression correlated with the activation of a type-1 proinflammatory, cell-lytic immune, and natural killer signature, encompassing key genes linked to an IFN type-2-signature (
,
,
,
,
,
). Conversely, there was a reduction in IFN type 1 and type 3 expression signatures at the mRNA and protein levels.
This study demonstrates a novel disease-driving mechanism induced by the 17q21 risk allele. Increased mucosal
expression is associated with a cell-lytic immune response coupled with compromised airway immunocompetence. These findings suggest that
-related airway cell death and perturbations in the mucosal IFN signature account for the increased vulnerability of 17q21 risk allele carriers to respiratory viral infections during early life, opening new options for future biological interventions.The All-Age-Asthma (ALLIANCE) cohort is registered at www.clinicaltrials.gov (pediatric arm, NCT02496468).
The prospective GULLIVE-R study aimed to evaluate adherence to guideline recommended secondary prevention, physicians' and patients' estimation of cardiac risk, and patients' knowledge about target ...values of risk factors after acute myocardial infarction (AMI).
We performed a prospective study enrolling patients 9-12 months after AMI. Guideline recommended secondary prevention therapies and physicians as well as patients' estimation about their risk, and patients' knowledge about target values were prospectively collected.
Between 07/2019 and 06/2021 a total of 2509 outpatients were enrolled in 150 German centers 10 months after AMI. The mean age was 66 years, 26.4% were women, 45.3% had STEMI, 54.7% had NSTEMI, 93.6% had revascularization (84.0% PCI, 7.4% CABG, 1.8% both). Guideline recommended secondary drug therapies were prescribed in over 80% of patients, while only about 50% received all five recommended drugs (aspirin, P2Y12 inhibitors, statins, beta-blockers, RAAS inhibitors) and regular exercise was performed by only one third. About 90% of patients felt well informed about secondary prevention, but the correct target value for blood pressure was known in only 37.9% and for LDL-C in only 8.2%. Both, physicians and patients underestimated the objective risk for future AMIs as determined by the TIMI risk score for secondary prevention.
There is still room for improvement in patient education and implementation of guideline recommended non-pharmacological and pharmacological secondary prevention therapies in patients in the chronic phase after AMI.
Postoperative nausea and vomiting (PONV) is one of the most common and distressing complications after general anesthesia and surgery, with young non-smoking females receiving postoperative opioids ...being high-risk patients. This register-based study aims to evaluate the effect of low-dose haloperidol (0.5 mg intravenously) directly after induction of general anesthesia to reduce the incidence of PONV in the postoperative anesthesiological care unit (PACU).
Multivariable regression models were used to investigate the association between low-dose haloperidol and the occurrence of PONV using a patient registry containing 2,617 surgical procedures carried out at an university hospital.
Haloperidol 0.5 mg is associated with a reduced risk of PONV in the total collective (adjusted odds ratio = 0.75, 95% confidence interval: 0.56, 0.99, p = 0.05). The results indicate that there is a reduced risk in male patients (adjusted odds ratio = 0.45, 95% confidence interval: 0.28, 0.73, p = 0.001) if a dose of 0.5 mg haloperidol was administered while there seems to be no effect in females (adjusted odds ratio = 1.02, 95% confidence interval: 0.71, 1.46, p = 0.93). Currently known risk factors for PONV such as female gender, duration of anesthesia and the use of opioids were confirmed in our analysis.
This study suggests that low-dose haloperidol has an antiemetic effect in male patients but has no effect in female patients. A confirmation of the gender-specific effects we have observed in this register-based cohort study might have major implications on clinical daily routine.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
