Implications of two-component systems EnvZ/OmpR and BaeS/BaeR in in vitro temocillin resistance in Escherichia coli.

BACKGROUND: BaeS/BaeR is a two-component system of Escherichia coli that controls the expression of porins and efflux pumps. Its role in beta-lactam resistance is limited. OBJECTIVES: To study the role of baeS/baeR two-component system in temocillin resistance in E. coli. METHODS: E. coli strain BW25113 and single-gene deletion mutants related to two-component systems were collected from the KEIO collection. Double-gen deletion mutants were generated. Temocillin-resistant mutant frequencies were determined at 32 mg/L. E. coli BW25113 mutants were selected by selective pressure from serial passages. Biological costs were analysed by growth curves. Genomes of the generated mutants were sequenced. The expression level of the mdtA, mdtB, mdtC, acrD and tolC in the ΔbaeS mutant was determined by RT-PCR (with/without temocillin exposure). RESULTS: The frequency of temocillin mutants ranged from 2.12 × 10-8 to 4.51 × 10-8 in single-porin mutants. No mutants were recovered from E. coli BW25113 (>10-9). Selection of temocillin-resistant variants by serial passage yielded mutants up to 128 mg/L. Mutations were found in the baeS gene. Temocillin MICs ranged from 4 to 32 mg/L (highest MICs for ΔbaeS and ΔompR). The efflux pumps mdtA, mdtB, mdtC and acrD pumps were overexpressed 3-10-fold in the presence of temocillin in ΔbaeS compared to control. CONCLUSIONS: Mutations in the sensor histidine kinase, baeS, may be involved in temocillin resistance through the expression of the efflux pumps mdtABC and acrD. In addition, the low mutation rate may be a good predictor of temocillin activity.

Evaluation of temocillin efficacy against KPC-2-producing Klebsiella pneumoniae isolates in a hollow-fibre infection model.

BACKGROUND: Temocillin is an old antimicrobial that is resistant to hydrolysis by ESBLs but has variable activity against carbapenemase-producing Enterobacteriaceae. The current EUCAST susceptibility breakpoints for Enterobacterales are set at ≤16 mg/L (susceptible with increased exposure) based on a dose of 2 g q8h, but there is limited information on the efficacy of this dose against temocillin-susceptible carbapenemase-producing Klebsiella pneumoniae isolates. OBJECTIVES: To evaluate the efficacy of this dose using a hollow-fibre infection model (HFIM) against six KPC-2-producing clinical isolates of K. pneumoniae. METHODS: The isolates were characterized by WGS and temocillin susceptibility was determined using standard and high inoculum temocillin. Mutant frequencies were estimated and temocillin activity was tested in time-kill assays and in the HFIM. At standard conditions, three of the isolates were classified as susceptible (MIC ≤ 16 mg/L) and three as resistant (MIC > 16 mg/L). The HFIM was performed over 3 days to mimic human-like pharmacokinetics of 2 g q8h. Bacterial counts were performed by plating on Mueller-Hinton agar (MHA) and MHA containing 64 mg/L temocillin to detect resistant subpopulations. RESULTS: All isolates showed a reduction in bacterial population of at least 3 log cfu/mL within the first 8 h of simulated treatment in the hollow-fibre assay. Regrowth was observed for the three resistant isolates and one of the susceptible ones. The MIC value for these isolates was higher by at least two dilutions compared with their initial values. CONCLUSIONS: These data suggest that an optimized pharmacokinetic regimen may be of clinical interest for the treatment of KPC-2-producing K. pneumoniae susceptible to temocillin. These data showed activity of temocillin against KPC-2-producing K. pneumoniae susceptible to temocillin; however, a dose of 2g q8h administered over 30 min may be inadequate to prevent the emergence of resistant variants.

The impact of the COVID-19 lockdown on depression sufferers: a qualitative study from the province of Zaragoza, Spain.

BACKGROUND AND PURPOSE: The impact of COVID-19 and its control measures have exacerbated existing mental health conditions. Although the deleterious effects of mental health problems are well known, fewer studies have examined the links between the Social Determinants of Health (SDHs) and depression. This study provides insights into the relationship between SDHs and depression during the first strict lockdown in Spain, which lasted for a period of 7 weeks. METHODS: Fifty-two structured interviews were conducted with people diagnosed with depression during June 2020 in the province of Zaragoza (Spain). Interviews were conducted by telephone due to lockdown constraints. Inductive thematic content analysis was used to explore, develop, and define emergent categories of analysis, which were mapped against the SDH framework. RESULTS: Listening to people's experiences of living with depression during lockdown provided insights into their concerns and coping strategies, which are greatly influenced by the conditions in which they live, their job and their age. Examples of these factors include access to and quality of physical spaces, including housing conditions and public spaces for socialising, social support, adverse working conditions which include caring responsibilities, and access to digital technologies and healthcare services. CONCLUSION: SDHs have played a fundamental role in shaping people's health and well-being during the COVID-19 pandemic, and this study has shown that they have a considerable effect on depression outcomes. Governments should consider implementing social welfare programs to tackle both psychosocial problems and material need during crisis situations.

Factors That Affect the Accumulation of Strecker Aldehydes in Standardized Wines: The Importance of pH in Oxidation.

Strecker aldehydes (SA) can be formed in wine from the degradation of Strecker and, to a lesser degree, via the oxidation of higher alcohols. The objective of this article is to assess the magnitude of the differences introduced by wine compositional factors other than amino acids and Fe, in the accumulation of SA during oxidation. Eight red, two rosé and two white wines were oxidized. The accumulation of SA was analyzed. Whites and rosés presented negative accumulations for isobutyraldehyde, and in general, these wines accumulated smaller concentrations of the other SA than red wines. Only methional and phenylacetaldehyde were accumulated in all of the wines during oxidation. 2-methylbutanal and 3-methylbutanal were accumulated in 9 out of the 12 wines, whereas isobutyraldehyde was accumulated only in 5 out of the 12. 2-methylbutanal was, on average, the least accumulated aldehyde. Methional was the aldehyde formed most homogenously. Most of the observed differences can be attributed to three factors: the pH, oxidation time and native levels of Strecker aldehydes. The influence of pH was particularly intense in the cases of phenylacetaldehyde and methional. An independent test using synthetic wines with Strecker amino acids and 4-methylcatechol with different pHs (4.2, 3.5 and 2.8) was carried out in order to verify the higher pH value, the greater accumulation in SA after oxidation process. The results strongly suggest the important role played by pH in the accumulation of SA in wine oxidation.

Can aldehyde accumulation rates of red wines undergoing oxidation be predicted in accelerated conditions? The controverted role of aldehyde-polyphenol reactivity.

BACKGROUND: The accumulation of acetaldehyde and Strecker aldehydes during wine oxidation is detrimental to quality and often determines wine shelf-life. Knowing in advance the specific tendency of a wine to accumulate these compounds would help decision making during winemaking. An accelerated test based on a forced oxidation procedure at 45 °C (5 days) to measure aldehyde accumulation rates (AARs) is proposed and assessed by comparing results with those obtained by oxidation at 25 °C (36 days). Reactivities of aldehydes in those same wines stored in anoxia at both temperatures were also measured. RESULTS: Wine oxygen consumption rates at 25 °C are poorly correlated with those observed at 45 °C. By contrast, AARs of methional and of 2- and 3-methylbutanals measured during wine oxidation at 25 °C are equivalent to those measured at 45 °C. AARs from isobutanal and acetaldehyde are also correlated, while AARs from phenylacetaldehyde are not. Partial least squares models explaining AARs show intriguing differences regarding the apparent limiting role played by wine anthocyanins and other polyphenols in the ability of wines to accumulate aldehydes. Measured differences in aldehyde pattern are similar to those of the other Strecker aldehydes. CONCLUSION: The proposed assay makes it possible to obtain a reasonable estimate of a wine's tendency to accumulate aldehydes, with the exception phenylacetaldehyde, in 5 days. Neither differences in aldehyde reactivity between wines nor the change in reactivities with temperature support a major role for reactivity in differentially limiting AARs during wine oxidation. © 2021 The Authors. Journal of The Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

NT-proBNP levels in preeclampsia, intrauterine growth restriction as well as in the prediction on an imminent delivery.

OBJECTIVES: Studies of cardiovascular function in pregnancy have shown inconsistent and, in some cases, contradictory results, particularly regarding cardiac output. While some studies report preeclampsia associated with high cardiac output, other studies suggest that preeclampsia should be further subdivided into women with high or low cardiac output. This study was conducted to examine the NT-proBNP levels in preeclampsia, intrauterine growth restriction, and hypertensive pregnancies without preeclampsia. We also examined N-terminal pro-B natriuretic peptide (NT-proBNP) levels three to four months after delivery, in preeclamptic women as well as the prediction of delivery within 10 days. In a reduced number of preeclamptic women and controls we performed echocardiograms to study their diastolic function. METHODS: We investigated the NT-proBNP levels in 213 subjects with preeclampsia only, 73 with intrauterine growth restriction, 44 with preeclampsia and intrauterine growth restriction, 211 who were hypertensive and 662 unaffected pregnancies (controls). We also performed echocardiograms on 36 preeclampsia and 19 controls before delivery and three to five months after delivery. RESULTS: NT-proBNP levels are higher in early onset preeclampsia than in late onset preeclampsia. Intrauterine growth restriction pregnancies showed a NT-proBNP levels similar to hypertensive and unaffected pregnancies. Compared with healthy pregnancies, women with preterm preeclampsia (<37 gestational weeks) had altered left atrial segments. CONCLUSIONS: We observed that NT-proBNP levels are higher in early onset preeclampsia than in late onset. Moreover, diastolic dysfunction is higher in early onset than in late-onset term preeclampsia. An NT-proBNP value >136 pg/mL has a high positive predictive value for an imminent delivery within 10 days.

The Health Inequalities Assessment Toolkit: supporting integration of equity into applied health research.

BACKGROUND: Despite insistent calls for more and better evidence to inform action to reduce health inequities, applied health research sensitive to these inequalities is rare. Recognising this problem, the Collaboration for Leadership in Applied Research and Care in the North West Coast (England) developed the Health Inequalities Assessment Toolkit (HIAT) to support those involved in health research to integrate equity into their work. OBJECTIVE: This paper reports on an evaluation of the extent to which HIAT enhances the equity focus of the work of users. METHODS: The evaluation used semi-structured interviews, focus groups and workshops (n = 131 respondents including Public Advisers, university, NHS and local government partners). Routine data included HIAT feedback forms. FINDINGS: HIAT can help to strengthen the equity focus of applied health research by: increasing understanding of how socioeconomic inequities impact on health; building capacity for integrating equity into all aspects of research, implementation and capacity building; stimulating thinking on action to address local structural drivers of health inequalities; and increasing understanding of the positive contribution public involvement can make to research. CONCLUSION: If we are to advance health equity goals delivering research and training needs to be combined with political commitment to create more equal societies.

From fringe to centre-stage: experiences of mainstreaming health equity in a health research collaboration.

BACKGROUND: Action to address the structural determinants of health inequalities is prioritized in high-level initiatives such as the United Nations Sustainable Development Goals and many national health strategies. Yet, the focus of much local policy and practice is on behaviour change. Research shows that whilst lifestyle approaches can improve population health, at best they fail to reduce health inequalities because they fail to address upstream structural determinants of behaviour and health outcomes. In health research, most efforts have been directed at three streams of work: understanding causal pathways; evaluating the equity impact of national policy; and developing and evaluating lifestyle/behavioural approaches to health improvement. As a result, there is a dearth of research on effective interventions to reduce health inequalities that can be developed and implemented at a local level. OBJECTIVE: To describe an initiative that aimed to mainstream a focus on health equity in a large-scale research collaboration in the United Kingdom and to assess the impact on organizational culture, research processes and individual research practice. METHODS: The study used multiple qualitative methods including semi-structured interviews, focus groups and workshops (n = 131 respondents including Public Advisers, university, National Health Service (NHS), and local and document review. RESULTS: utilizing Extended Normalization Process Theory (ENPT) and gender mainstreaming theory, the evaluation illuminated (i) the processes developed by Collaboration for Leadership in Applied Health Research and Care North West Coast to integrate ways of thinking and acting to tackle the upstream social determinants of health inequities (i.e. to mainstream a health equity focus) and (ii) the factors that promoted or frustrated these efforts. CONCLUSIONS: Findings highlight the role of contextual factors and processes aimed at developing and implementing a robust strategy for mainstreaming health equity as building blocks for transformative change in applied health research.

Development of a Third Trimester Contingent Prognostic Prediction Scheme for Suspected Early-Onset Pre-Eclampsia.

INTRODUCTION: Short-term prediction of pre-eclampsia (PE) using soluble FMS-like tyrosine kinase-1 (sFlt-1)/ placental growth factor (PlGF) ratio has high false-positive rate. Therefore, we developed a prognostic prediction tool that predicts early-onset PE leading to delivery within 1 week on pregnancies with an sFlt-1/PlGF ratio above 38 and compared it with an analogous model based on sFlt-1/PlGF ratio and with the 655 sFlt-1/PlGF ratio cutoff. METHODS: Cohort study of 363 singleton pregnancies with clinical suspicion of PE before 34 weeks of gestation, allowing repeated assessments (522). 213 samples with an sFlt-1/PlGF ratio above 38 were assessed to construct and identify the best-fit linear mixed model. N-terminal pro-B-type natriuretic peptide (NT-proBNP), sFlt-1 MoM, PlGF MoM, and sFlt-1/PlGF ratio combined with gestational age (GA) were assessed. RESULTS: None of the pregnancies with an sFlt-1/PlGF ratio of 38 or below developed early-onset PE (309 samples from 240 pregnancies). Conversely, 47 women of 213 assessments (22.1%) with an sFlt-1/PlGF ratio above 38 developed the assessed outcome. The selected model included sFlt-1 MoM, NT-proBNP, and GA. Differences in area under the curve were observed between the selected model and the GA + sFlt-1/PlGF model (p = 0.04). At an sFlt-1/PlGF ratio cutoff of 655, detection rate was 31.9% (15/47), while the selected model detection was 55.3% (26/47) (p = 0.008). DISCUSSION: Considering repeated assessments, the sFlt-1/PlGF ratio of 38 or below adequately ruled out early-onset PE, leading to delivery within 1 week. However, when sFlt-1/PlGF ratio is above 38, the prediction tool derived from linear mixed model based on GA, NT-proBNP, and sFlt-1 MoM, provided a better prognosis prediction than the sFlt-1/PlGF ratio.

Gestational Age-Specific Reference Ranges for the sFlt-1/PlGF Immunoassay Ratio in Twin Pregnancies.

OBJECTIVE: Establish reference ranges for the Elecsys® soluble fms-like tyrosine kinase-1 (sFlt-1)/placental growth factor (PlGF) immunoassay ratio in twin pregnancies. METHODS: Data analyzed were from 3 prospective studies: Prediction of Short-Term Outcome in Pregnant Women with Suspected Preeclampsia (PE) (PROGNOSIS), Study of Early-onset PE in Spain (STEPS), and a multicenter case-control study. Median, 5th, and 95th percentiles for sFlt-1, PlGF, and the sFlt-1/PlGF ratios were determined for normal twin pregnancies for 7 gestational windows and compared with the previous data for singleton pregnancies. RESULTS: The reference range analysis included 269 women with normal twin pregnancies. Before 29 weeks' gestation, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios did not differ between twin and singleton pregnancies. From 29 weeks' gestation to delivery, median, 5th, and 95th percentiles for sFlt-1/PlGF ratios were substantially higher in twin versus singleton pregnancies. sFlt-1 values were higher in women with twin pregnancies across all gestational windows. PlGF values were similar or higher in twin versus singleton pregnancies; PlGF concentrations increased from 10 weeks + 0 days to 28 weeks + 6 days' gestation. CONCLUSIONS: Reference ranges for the sFlt-1/PlGF ratio are similar in women with twin and singleton pregnancies until 29 weeks' gestation but appear higher in twin pregnancies thereafter.

A more accurate prediction to rule in and rule out pre-eclampsia using the sFlt-1/PlGF ratio and NT-proBNP as biomarkers.

Background The management of potential pre-eclamptic patients using the soluble FMS-like tyrosine kinase 1 (sFlt-1)/ placental growth factor (PlGF) ratio is characterised by frequent false-positive results. Methods A retrospective cohort study was conducted to identify and validate cut-off values, obtained using a machine learning model, for the sFlt-1/PlGF ratio and NT-proBNP that would be predictive of the absence or presence of early-onset pre-eclampsia (PE) in singleton pregnancies presenting at 24 to 33 + 6 weeks of gestation. Results For the development cohort, we defined two sFlt-1/PlGF ratio cut-off values of 23 and 45 to rule out and rule in early-onset PE at any time between 24 and 33 + 6 weeks of gestation. Using an sFlt-1/PlGF ratio cut-off value of 23, the negative predictive value (NPV) for the development of early-onset PE was 100% (95% confidence interval [CI]: 99.5-100). The positive predictive value (PPV) of an sFlt-1/PlGF ratio >45 for a diagnosis of early-onset PE was 49.5% (95% CI: 45.8-55.6). When an NT-proBNP value >174 was combined with an sFlt-1/PlGF ratio >45, the PPV was 86% (95% CI: 79.2-92.6). In the validation cohort, the negative and positive values were very similar to those found for the development cohort. Conclusions An sFlt-1/PlGF ratio <23 rules out early-onset PE between 24 and 33 + 6 weeks of gestation at any time, with an NPV of 100%. An sFlt-1/PlGF ratio >45 with an NT-proBNP value >174 significantly enhances the probability of developing early-onset PE.

Mainstreaming public involvement in a complex research collaboration: A theory-informed evaluation.

INTRODUCTION: There is an extensive literature on public involvement (PI) in research, but this has focused primarily on experiences for researchers and public contributors and factors enabling or restricting successful involvement in specific projects. There has been less consideration of a 'whole system' approach to embedding PI across an organization from governance structures through to research projects. OBJECTIVE: To investigate how a combination of two theoretical frameworks, one focused on mainstreaming and the other conceptualizing quality, can illuminate the embedding of positive and influential PI throughout a research organization. METHODS: The study used data from the evaluation of a large UK research collaboration. Primary data were collected from 131 respondents (including Public Advisers, university, NHS and local government staff) via individual and group interviews/workshops. Secondary sources included monitoring data and internal documents. FINDINGS: CLAHRC-NWC made real progress in mainstreaming PI. An organizational vision and infrastructure to embed PI at all levels were created, and the number and range of opportunities increased; PI roles became more clearly defined and increasingly public contributors felt able to influence decisions. However, the aspiration to mainstream PI throughout the collaboration was not fully achieved: a lack of staff 'buy-in' meant that in some areas, it was not experienced as positively or was absent. CONCLUSION: The two theoretical frameworks brought a novel perspective, facilitating the investigation of the quality of PI in structures and processes across the whole organization. We propose that combining these frameworks can assist the evaluation of PI research.

Use of the sFlt-1/PlGF ratio to rule out preeclampsia requiring delivery in women with suspected disease. Is the evidence reproducible?

BACKGROUND: Soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) ratio has been proven to predict preeclampsia occurrence. METHODS: Blood samples from 195 pregnant women with suspected preeclampsia were obtained at obstetric triage admission or from the high-risk pregnancy outpatient office. Serum PlGF and sFlt-1 were measured by an electrochemiluminescence immunoassay (ECLIA) on the immunoanalyser Cobas e601 (Roche Diagnostics) and the corresponding ratio was calculated. Final outcomes were reviewed by an independent obstetrician. Only the first determination was considered. RESULTS: A sFlt-1/PlGF ratio of 38 or lower ruled out the need for pregnancy termination due to preeclampsia in the subsequent week with a negative predictive value (NPV) of 99.1% (sensitivity 97.1% and specificity 67.5%). None of the 76 pregnancies with first determination of an sFlt-1/PlGF ratio of 38 or lower between 24 and 34 weeks of gestation delivered due to early-onset preeclampsia. Positive likelihood ratio (PLR) of an sFlt-1/PlGF ratio above 38 for prediction of pregnancy termination due to preeclampsia within 4 weeks is analogous to published evidence. CONCLUSIONS: Between 24 and 34 weeks of gestation, no subsequent determination was needed to completely rule out early-onset preeclampsia when the first sFlt-1/PlGF ratio determination was 38 or lower in singleton pregnancies with signs or symptoms of this syndrome. These findings, if confirmed, will reduce costs and facilitate the implementation of the sFlt-1/PlGF ratio in women with clinical suspicion of preeclampsia in the third trimester.

Transition-Metal-Free Radical C(sp3)-C(sp2) and C(sp3)-C(sp3) Coupling Enabled by 2-Azaallyls as Super-Electron-Donors and Coupling-Partners.

The past decade has witnessed the rapid development of radical generation strategies and their applications in C-C bond-forming reactions. Most of these processes require initiators, transition metal catalysts, or organometallic reagents. Herein, we report the discovery of a simple organic system (2-azaallyl anions) that enables radical coupling reactions under transition-metal-free conditions. Deprotonation of N-benzyl ketimines generates semistabilized 2-azaallyl anions that behave as "super-electron-donors" (SEDs) and reduce aryl iodides and alkyl halides to aryl and alkyl radicals. The SET process converts the 2-azaallyl anions into persistent 2-azaallyl radicals, which capture the aryl and alkyl radicals to form C-C bonds. The radical coupling of aryl and alkyl radicals with 2-azaallyl radicals makes possible the synthesis of functionalized amine derivatives without the use of exogenous radical initiators or transition metal catalysts. Radical clock studies and 2-azaallyl anion coupling studies provide mechanistic insight for this unique reactivity.

Catalytic Asymmetric 1,3-Dipolar Cycloaddition/Hydroamination Sequence: Expeditious Access to Enantioenriched Pyrroloisoquinoline Derivatives.

A three-step reaction sequence has been developed to prepare a variety of enantioenriched pyrroloisoquinoline derivatives. The process involves a catalytic asymmetric azomethine ylide 1,3-dipolar cycloaddition followed by an intramolecular AuI-catalyzed alkyne hydroamination and enamine reduction.

Catalytic Asymmetric Synthesis of Bicycloprolines by a 1,3-Dipolar Cycloaddition/Intramolecular Alkylation Strategy.

The diastereoselective one-pot synthesis of hexahydrocyclopenta[b]pyrrole derivatives (bicycloprolines) has been achieved by base-mediated reactions of (E)-tert-butyl 6-bromo-2-hexenoate with α-imino esters. The catalytic asymmetric version of this process has been efficiently achieved using the Cu(I)/(R)-DTBM-Segphos complex as a catalyst following a two-step 1,3-dipolar cycloaddition/intramolecular alkylation sequence.

ECAMulticapa: Effectiveness of double-layered compression therapy for healing venous ulcers in primary care: a Study Protocol.

BACKGROUND: Chronic venous insufficiency, in its final stage can cause venous ulcers. Venous ulcers have a prevalence of 0.5 % to 0.8 % in the general population, and increases starting at 60 years of age. This condition often causes increased dependency in affected individuals, as well as a perceived reduced quality of life and family overload. Local Treating chronic venous ulcers has 2 components: topically healing the ulcer and controlling the venous insufficiency. There is evidence that compressive therapy favours the healing process of venous ulcers. The studies we have found suggest that the use of multilayer bandage systems is more effective than the use of bandages with a single component, these are mostly using in Spain. Multilayer compression bandages with 2 layers are equally effective in the healing process of chronic venous ulcers as 4-layer bandages and are better tolerated and preferenced by patients. More studies are needed to specifically compare the 2-layer bandages systems in the settings where these patients are usually treated. METHOD/DESIGN: Randomised, controlled, parallel, multicentre clinical trial, with 12 weeks of follow-up and blind evaluation of the response variable. The objective is to assess the efficacy of multilayer compression bandages (2 layers) compared with crepe bandages, based on the incidence of healed venous ulcers in individuals treated in primary care nursing consultations, at 12 weeks of follow-up. The study will include 216 individuals (108 per branch) with venous ulcers treated in primary care nursing consultations. The primary endpoint is complete healing at 12 weeks of follow-up. The secondary endpoints are the degree of healing (Resvech.2), quality of life (CCVUQ-e), adverse reactions related to the healing process. Prognosis and demographic variables are also recorder. Effectiveness analysis using Kaplan-Meier curves, a log-rank test and a Cox regression analysis. The analysis was performed by intention to treat. DISCUSSION: The study results can contribute to improving the care and quality of life of patients with venous ulcers, decreasing healing times and healthcare expenditure and contributing to the consistent treatment of these lesions. TRIAL REGISTRATION: This study has been recorded in the Clinical Trials.gov site with the code NCT02364921. 17 February 2015.

Alkenyl Arenes as Dipolarophiles in Catalytic Asymmetric 1,3-Dipolar Cycloaddition Reactions of Azomethine Ylides.

The use of alkenyl arenes as dipolarophiles in the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides is reported. Under appropriate reaction conditions with a CuI or AgI catalyst either the exo or the endo adduct was obtained with high stereoselectivity. This process provides efficient access to highly enantiomerically enriched 4-aryl proline derivatives. The observed results are compatible with the blockage of one prochiral face of the 1,3-dipole, as well as with the efficient transmission of electrophilicity towards the terminal carbon atom of the dipolarophile. This polarization results in a change from a concerted to a stepwise mechanism.

Highly selective copper-catalyzed asymmetric [3+2] cycloaddition of azomethine ylides with acyclic 1,3-dienes.

The first examples of the catalytic asymmetric 1,3-dipolar cycloaddition of azomethine ylides with acyclic activated 1,3-dienes (and 1,3-enynes) are described. Under copper catalysis, a selective cycloaddition at the terminal γ,δ-C=C bond is observed. In addition, depending on the ligand used, either the exo or the endo adduct can be obtained with high selectivity. Under appropriate reaction conditions, the acyclic 1,6-addition product is detected, suggesting a stepwise mechanism. The resulting C4-alkenyl-substituted pyrrolidines are suitable substrates for further access to polycyclic systems, as highlighted by the preparation of hexahydrochromeno[4,3-b]pyrrole and the tetracyclic core of the alkaloid gracilamine.

Role of vitamin D and sFlt-1/PlGF ratio in the development of early- and late-onset preeclampsia.

BACKGROUND: The imbalanced production of placental biomarkers and vitamin D deficiency have been proposed as risk factors for the development of preeclampsia (PE). However, little is known about the relationship between them and their role in early- versus late-onset PE. The objectives were to assess the role of 25-hydroxyvitamin D [25(OH)D] concentrations and the soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PlGF) ratio in the development of early- and late-onset PE; and to evaluate the relationship between 25(OH)D and the biomarkers. METHODS: A retrospective, full-blinded cohort study was conducted at the Obstetric Emergency Service of a tertiary care hospital. Pregnant women (n=257) attending obstetric triage with suspicion of PE were included. sFlt-1, PlGF and 25(OH)D concentrations were measured by electrochemoluminescence (ECLIA) immunoassay and pregnancy outcome (development of PE) was registered from patients records. RESULTS: PE women showed lower 25(OH)D concentrations at clinical presentation than non-PE women (median: 35.0 nmol/L and 39.6 nmol/L, respectively; p=0.027). Women with 25(OH)D levels <50 nmol/L experienced an increased risk of developing late-onset PE [odds ratio (OR) 4.6, 95% confidence interval (CI) 1.4-15], but no association was found for early-onset PE. However, a sFlt-1/PlGF ratio above the corresponding cutpoints increased the risk of developing both early- and late-onset PE [ORs 58 (95% CI 11-312) and 12 (95% CI 5.0-27), respectively]. No association was found between 25(OH)D levels and sFlt-1/PlGF ratio. CONCLUSIONS: Low vitamin D status in women with suspected late-onset PE increases the risk of imminent development of the disease.