The Aldol-Tishchenko Reaction of Butanone, Cyclobutanone and a 3-Pentanone Derived Sulfinylimine and DFT Calculations of the Stereo-determining Step.

Herein, we present a highly diastereoselective method to furnish acyclic 3-amino-1,5-diol derivatives using a tandem double-aldol-Tishchenko protocol (dr up to >99 : 1) using a butanone derived sulfinylimine. In most cases only 1 diastereomer predominates, from a possible 16. The reaction is also regioselective. In addition, the highly challenging cyclobutanone and 3-pentanone derivatives are also amenable to a double-aldol-Tishchenko reaction, although the dr values are modest. Despite that, clean single diastereomers can be isolated, which should prove very useful in medicinal chemistry and other areas. Detailed DFT calculations support the observed stereoselectivities in all cases, providing a rationale for the excellent dr values in the butanone series and the moderate values for the 3-pentanone class.

Mechanism and Origins of Stereoselectivity of the Aldol-Tishchenko Reaction of Sulfinimines.

Density functional theory computations have elucidated the mechanism and origins of stereoselectivity in McGlacken's aldol-Tishchenko reaction for the diastereoselective synthesis of 1,3-amino alcohols using Ellman's t-butylsulfinimines as chiral auxiliaries. Variations of stereochemical outcome are dependent on the nature of the ketone starting materials used, and the aspects leading to these differences have been rationalized. The intramolecular hydride transfer step is the rate- and stereochemistry-determining step, and all prior steps are reversible.

Synthesis and characterisation of cross-linked chitosan composites functionalised with silver and gold nanoparticles for antimicrobial applications.

We present a study of a range of cross-linked chitosan composites with potential antimicrobial applications. They were formed by cross-linking chitosan and siloxane networks and by introducing silver and gold nanoparticles (NPs). The aim was to investigate whether adding the metal NPs to the chitosan-siloxane composite would lead to a material with enhanced antimicrobial ability as compared to chitosan itself. The composites were synthesised in hydrogel form with the metal NPs embedded in the cross-linked chitosan network. Spectroscopic and microscopic techniques were employed to investigate the structural properties of the composite and the tensile strength of the structures was measured. It was found that the addition of metal NPs did not influence the mechanical strength of the composite. A crystal violet attachment assay results displayed a significant reduction in the attachment of E. coli to the cross-linked chitosan surfaces. Release profile tests suggest that the metal NPs do not contribute to the overall antimicrobial activity under neutral conditions. The contribution to the mechanical and antimicrobial properties from cross-linking with siloxane is significant, giving rise to a versatile, durable, antimicrobial material suitable for thin film formation, wound dressings or the coating of various surfaces where robustness and antimicrobial control are required.

Systemic inflammation and oxidative stress contribute to acute kidney injury after transcatheter aortic valve implantation.

BACKGROUND: Acute kidney injury (AKI) is a frequent complication of transcatheter aortic valve implantation (TAVI) and has been linked to preexisting comorbidities, peri-procedural hypotension, and systemic inflammation. The extent of systemic inflammation after TAVI is not fully understood. Our aim was to characterize the inflammatory response after TAVI and evaluate its contribution to the mechanism of post-procedural AKI. METHODS: One hundred and five consecutive patients undergoing TAVI at our institution were included. We analyzed the peri-procedural inflammatory and oxidative stress responses by measuring a range of biomarkers (including C-reactive protein [hsCRP], cytokine levels, and myeloperoxidase [MPO]), before TAVI and 6, 24, and 48 hours post-procedure. We correlated this with changes in renal function and patient and procedural characteristics. RESULTS: We observed a significant increase in plasma levels of pro-inflammatory cytokines (hsCRP, interleukin 6, tumor necrosis factor alpha receptors) and markers of oxidative stress (MPO) after TAVI. The inflammatory response was significantly greater after transapical (TA) TAVI compared to transfemoral (TF). This was associated with a higher incidence of AKI in the TA cohort compared to TF (44% vs. 8%, respectively, p < 0.0001). The incidence of AKI was significantly lower when N-acetylcysteine (NAC) was given peri-procedurally (12% vs. 38%, p < 0.005). In multivariate analysis, only the TA approach and no use of NAC before the procedure were independent predictors of AKI. CONCLUSIONS: TAVI creates a significant post-procedural inflammatory response, more so with the TA approach. Mechanisms of AKI after TAVI are complex. Inflammatory response, hypoperfusion, and oxidative stress may all play a part and are potential therapeutic targets to reduce/prevent AKI.

Comparison of general anaesthesia and non-general anaesthesia approach in transfemoral transcatheter aortic valve implantation.

OBJECTIVE: Performing transfemoral transcatheter aortic valve implantation (TAVI) without general anaesthesia (GA) has been increasingly adopted. We sought to study the impact of GA and non-GA approaches on procedural outcome and 30-day and 1-year mortality in transfemoral TAVI. METHODS: The UK TAVI registry holds information for every TAVI procedure in the UK. We analysed the data for patients implanted during 2013-2014 using either an Edwards Sapien or a Medtronic CoreValve prosthesis. Propensity score-matching analysis was performed to adjust for confounding factors. RESULTS: 2243 patients were studied (aged 81.4±7.5 years, 1195 males). 1816 (81%) underwent TAVI with GA and 427 (19%) without GA. Transoesophageal echocardiography (TOE) was used in 92.3% of GA and 12.4% of non-GA cases (p<0.001). There was no significant difference in the rate of successful valve deployment (GA 97.2% vs non-GA 95.7%, p=0.104) and in the incidence of more than mild aortic regurgitation (AR) at the end of the procedure (GA 5.6% vs non-GA 7.0%, p=0.295). However, procedure time was longer (131±60 vs 121±60mins, p=0.002) and length of stay was greater (8.0±13.5 vs 5.7±5.5 days, p<0.001) for GA cases. 30-day and 1-year mortality rates did not differ between the GA and non-GA cases. After propensity matching, these results remained unchanged. A second propensity analysis (adjusted for mode of anaesthesia) did not show an association between use of TOE and rate of successful valve deployment or frequency of significant AR. Neither was TOE associated with a longer procedural time or greater length of stay. CONCLUSION: Procedure outcome, and 30-day and 1-year mortality are not influenced by mode of anaesthesia. However, GA is associated with longer procedure duration and greater length of stay.

Is transnasal TEE imaging a viable alternative to conventional TEE during structural cardiac interventions to avoid general anaesthesia? A pilot comparison study of image quality.

AIM: The role of transoesophageal echocardiography in cardiac interventional structural procedures is well established and appreciated. However, the need for general anaesthesia (GA) throughout the procedure remains a controversial issue. The aim of the present study is to assess the feasibility and imaging quality of using a transnasal microrobe that allows the usage of conscious sedation in patients who undergo cardiac structural interventional procedures without missing the benefits, guidance and navigation of conventional trans-procedural TEE. METHODS: We analysed the trans-procedural images of 24 consecutive patients who underwent TAVI, TMVI or ASD/PFO closure, using a transnasal 2D microprobe (PHILIPS) and then we compared them with images taken by using a conventional 3D TEE probe (PHILIPS). In particular, we compared the imaging quality of the two probes regarding: (1) The anatomy, visualisation of valvular calcification and transvalvular colour Doppler of the aortic and mitral valve; (2) the imaging quality of PFO, ASD and interatrial communication colour flow; (3) the imaging of left ventricle systolic function and pericardial space and (4) transgastric imaging. RESULTS: All images were graded with a scale from 5 to 1. The average grade of imaging quality in the mitral valve was: anatomy, 4.3; calcification, 3.8; colour Doppler, 4.2. The average grade of imaging quality in the aortic valve was: anatomy, 4.3; calcification, 3.7; colour Doppler, 4.3. The average grade of imaging quality in PFO/ASD was 4.3. The average grade of imaging quality in LV/pericardial space was 4.2. The average grade of imaging quality in transgastric imaging was 4.1. CONCLUSION: These results suggest that transnasal TEE can provide good anatomical image quality of relevant cardiac structures during cardiac structural interventions and this may facilitate these procedures being performed during conscious sedation without having to lose TEE guidance.

Progressive rise in red cell distribution width is associated with poor outcome after transcatheter aortic valve implantation.

OBJECTIVE: To investigate the prognostic value of baseline and temporal changes in red cell distribution width (RDW) in patients undergoing transcatheter aortic valve implantation (TAVI). DESIGN: Single-centre retrospective observational study. SETTING: Tertiary cardiac centre. PATIENTS: 175 patients undergoing TAVI were included in this study. MAIN OUTCOME MEASURE: Survival. RESULTS: We analysed data from 175 TAVI patients (mean (± SD) age 83 ± 7 years, 49% men, mean Logistic EuroSCORE 23 ± 1, 66% preserved left ventricular ejection fraction (LVEF)). Immediately pre-TAVI, mean RDW was 14.6 ± 1.6% with an RDW>15% in 29% of patients. Over median follow-up of 12 months, the median rate of change in RDW was 0.2% per month, and 51 (29%) patients died. On multivariate survival analyses, baseline RDW ≥ 15.5% predicted death (adjusted HR 2.70, 95% CI 1.40 to 5.22, p=0.003) independently of LVEF, transfemoral approach, baseline pulmonary artery systolic pressure, moderate/severe mitral regurgitation and body mass index. A greater rate of increase in RDW over time was associated with increased mortality (adjusted HR 1.11, 95% CI 1.04 to 1.18, p=0.001) independently of baseline RDW and other significant temporal variables including a change in creatinine, bilirubin, mean cell haemoglobin concentration or urea. An increase in RDW>0.1%/month was associated with a twofold increased risk of mortality. CONCLUSIONS: Baseline RDW ≥ 15.5% and a rising RDW over time strongly correlate to an increased risk of death post-TAVI, and could be used to refine risk stratification. Investigating and ameliorating the causes of RDW expansion may improve survival.

Successful transcatheter aortic valve implantation (TAVI) is associated with transient left ventricular dysfunction.

OBJECTIVE: To investigate early haemodynamic changes after transfemoral transcatheter aortic valve implantation (TAVI) and the relationship with myocardial injury and neurohormonal activation. DESIGN: Single-centre prospective observational study. SETTING: Tertiary cardiac centre. PATIENTS: 42 patients undergoing transfemoral TAVI were included in this study. MAIN OUTCOME MEASURES: Haemodynamic measurements and echocardiography-derived indices characterising myocardial function were recorded at baseline, 6 and 24 h postprocedure. Postprocedural myocardial injury was quantified using serum troponin I and CK-MB levels. In addition, biomarkers of myocardial dysfunction/heart failure and neurohormonal activation were measured. RESULTS: 6 h Post-TAVI there was a significant deterioration in both systolic and diastolic function as measured by dP/dt(max)/EDV, myocardial performance index and mean E/e' index. Recovery of myocardial function was observed at 24 h. These haemodynamic changes were associated with a significant increase in both troponin I (0.07±0.01 vs 1.59±0.21 µg/l, p<0.005) and CK-MB (1.99±0.19 vs 6.82±0.7 ng/ml, p<0.005). There was a positive correlation among myocardial injury and NT-BNP (r=0.34, p<0.0005), aldosterone (r=0.56, p<0.0001) and ST2 levels (r=0.21, p<0.05). CONCLUSIONS: This is the first study to demonstrate that procedurally successful TF-TAVI results in a transient depression of both systolic and diastolic left ventricular function within the first 24 postoperative hours, despite impressive relief of previously severe, chronic pressure overload. The rise in the markers of myocardial damage suggests that this may be due to periprocedural myocardial injury. Complete recovery of contractility is generally observed after 24 h.