Oxetanes: Recent Advances in Synthesis, Reactivity and Medicinal Chemistry

The 4-membered oxetane ring has been increasingly exploited for its behaviors, i.e. influence on physicochemical properties as a stable motif in medicinal chemistry, and propensity to undergo ring opening reactions as a synthetic intermediate. These applications have driven numerous studies into the synthesis of new oxetane derivatives. This review takes an overview of the literature for the synthesis of oxetane derivatives, concentrating on advances in the last 5 years up to the end of 2015. These methods are clustered by strategy for preparation of the ring (Sections 3 and 4), and further derivatisation of preformed oxetane-containing building blocks (Sections 5-7). Examples of the use of oxetanes in medicinal chemistry are reported, including a collation of oxetane derivatives appearing in recent patents for medicinal chemistry applications. Finally examples of oxetane derivatives in ring opening and ring expansion reactions are described

An exploration of social and economic outcome and associated health-related quality of life after critical illness in general intensive care unit survivors: a 12-month follow-up study.

INTRODUCTION: The socio-economic impact of critical illnesses on patients and their families in Europe has yet to be determined. The aim of this exploratory study was to estimate changes in family circumstances, social and economic stability, care requirements and access to health services for patients during their first 12 months after ICU discharge. METHODS: Multi-center questionnaire-based study of survivors of critical illness at 6 and 12 months after ICU discharge. RESULTS: Data for 293 consenting patients who spent greater than 48 hours in one of 22 UK ICUs were obtained at 6 and 12 months post-ICU discharge. There was little evidence of a change in accommodation or relationship status between pre-admission and 12 months following discharge from an ICU. A negative impact on family income was reported by 33% of all patients at 6 months and 28% at 12 months. There was nearly a 50% reduction in the number of patients who reported employment as their sole source of income at 12 months (19% to 11%) compared with pre-admission. One quarter of patients reported themselves in need of care assistance at 6 months and 22% at 12 months. The majority of care was provided by family members (80% and 78%, respectively), for half of whom there was a negative impact on employment. Amongst all patients receiving care, 26% reported requiring greater than 50 hours a week. Following discharge, 79% of patients reported attending their primary care physician and 44% had seen a community nurse. Mobility problems nearly doubled between pre-admission and 6 months (32% to 64%). Furthermore, 73% reported moderate or severe pain at 12 months and 44% remained significantly anxious or depressed. CONCLUSIONS: Survivors of critical illness in the UK face a negative impact on employment and commonly have a care requirement after discharge from hospital. This has a corresponding negative impact on family income. The majority of the care required is provided by family members. This effect was apparent by 6 months and had not materially improved by 12 months. This exploratory study has identified the potential for a significant socio-economic burden following critical illness

Impact of wild-type and genetically modified Pseudomonas fluorescens on soil enzyme activities and microbial population structure in the rhizosphere of pea

The definitive version is available at www.blackwell-synergy.com. Copyright Blackwell Publishing DOI : 10.1046/j.1365-294x.1998.00367.xThe aim of this work was to determine the impact of wild type along with functionally and non-functionally modified Pseudomonas fluorescens strains in the rhizosphere. The wild type F113 strain carried a gene encoding the production of the antibiotic 2,4 diacetylphloroglucinol (DAPG) useful in plant disease control, and was marked with a lacZY gene cassette. The first modified strain was a functional modification of strain F113 with repressed production of DAPG, creating the DAPG negative strain F113 G22. The second paired comparison was a non-functional modification of wild type (unmarked) strain SBW25, constructed to carry marker genes only, creating strain SBW25 EeZY-6KX. Significant perturbations were found in the indigenous bacterial population structure, with the F113, (DAPG+) strain causing a shift towards slower growing colonies (K strategists) compared with the non-antibiotic producing derivative (F113 G22) and the SBW25 strains. The DAPG+ strain also significantly reduced, in comparison with the other inocula, the total Pseudomonas populations but did not affect the total microbial populations. The survival of F113 and F113 G22 were an order of magnitude lower than the SBW 25 strains. The DAPG+ strain caused a significant decrease in the shoot to root ratio in comparison to the control and other inoculants, indicating plant stress. F113 increased soil alkaline phosphatase, phosphodiesterase and aryl sulphatase activities compared to the other inocula, which themselves reduced the same enzyme activities compared to the control. In contrast to this, the -glucosidase, -galactosidase and N-acetyl glucosaminidase activities decreased with the inoculation of the DAPG+ strain. These results indicate that soil enzymes are sensitive to the impact of GMM inoculation.Peer reviewe

Spatial evaluation of the multiple benefits of sustainable drainage systems

Traditional approaches to understanding the multiple benefits of sustainable drainage systems often rely on value transfer. This converts each benefit into a monetary value, which can then be compared with the cost of the project. The approach, while well-developed, is limited because it does not systematically incorporate the spatial nature of the benefits. This paper discusses the development of an alternative way of evaluating and comparing benefits, allowing spatial distribution and local context and circumstances to be taken into consideration. The suggested approach is to create a score for each benefit category, which is normalised against a defined initial condition state on a scale of 0 to 10. This approach allows a direct comparison of the relative magnitude of benefits for a given location and provides a clear understanding of how and to whom multiple benefits accrue. The approach allows a singular significant benefit to be compared against many minor benefits. It can also easily be modified to reflect local preferences by weighting each benefit category appropriately. The method is demonstrated by three case studies in Newcastle, UK.This research was performed as part of an interdisciplinary project programme undertaken by the Blue-Green Cities (BGC) Research Consortium (www.bluegreencities.ac.uk) The BGC Consortium is funded by the UK Engineering and Physical Sciences Research Council under grant EP/K01366 1/1, with additional contributions from the Environment Agency and Rivers Agency (Northern Ireland) and National Science Foundatio

VAMPIRE® fundus image analysis algorithms:Validation and diagnostic relevance in hypertensive cats

OBJECTIVES: To validate a retinal imaging software named VAMPIRE® (Vascular Assay and Measurement Platform for Images of the Retina) in feline patients and test the clinical utility in hypertensive cats. ANIMALS STUDIED: One hundred and five healthy cats were enrolled. They represented the normal dataset used in the validation (group 1). Forty-three hypertensive cats with no noticeable retinal abnormalities were enrolled for the clinical validity of the software (group 2). PROCEDURES: Eleven points (4 veins, 4 arteries, and 3 arterial bifurcations) were measured for each digital image. Repeatability and reproducibility of measurements were assessed using two independent operators. Data were statistically analyzed by the Mann-Whiney and Tukey box plot. Significance was considered when P < 0.05. RESULTS: Two hundred and ten retinal images were analyzed for a total of 2310 measurements. Total mean was 9.1 and 6.1 pixels for veins and arteries, respectively. First, second, and third arteriolar bifurcations angles were 73.6°, 76.9°, and 85.4°, respectively. A comparison between groups 1 and 2 showed a statistically significant reduction in arteriolar diameter (mean 3.3 pixels) and branch angle (55°, 47.8° and 59.9°) associated with increasing vein diameter (mean 24.15 pixels). CONCLUSIONS: Current image analysis techniques used in human medicine were investigated in terms of extending their use to veterinary medicine. The VAMPIRE® algorithm proved useful for an objective diagnosis of retinal vasculature changes secondary to systemic hypertension in cats, and could be an additional diagnostic test for feline systemic hypertension

Contralateral fatigue during severe-intensity single-leg exercise: influence of acute acetaminophen ingestion.

This is the author accepted manuscript. The final version is available from American Physiological Society via the DOI in this recordExhaustive single-leg exercise has been suggested to reduce time to task failure (Tlim) during subsequent exercise in the contralateral leg by exacerbating central fatigue development. We investigated the influence of acetaminophen (ACT), an analgesic which may blunt central fatigue development, on Tlim- during single-leg exercise completed both with, and without, prior fatiguing exercise of the contralateral leg. Fourteen recreationally-active men performed single-leg, severe-intensity knee extensor exercise to Tlim on the left (Leg1) and right (Leg2) legs without prior contralateral fatigue, and on Leg2 immediately following Leg1 (Leg2-CONTRA). The tests were completed following ingestion of 1 g ACT or maltodextrin (placebo) capsules. Intramuscular phosphorous-containing metabolites and substrates, and muscle activation, were assessed using 31P-MRS and electromyography, respectively. Tlim was not different between the Leg1ACT and Leg1PL conditions (402 ± 101 vs. 390 ± 106 s; P=0.11). There was also no difference in Tlim between Leg2ACT-CONTRA and Leg2PL-CONTRA (324 ± 85 vs. 311 ± 92 s; P=0.10), but Tlim was shorter in these tests compared to Leg2CON (385 ± 104 s; both P0.05). These findings suggest that levels of metabolic perturbation and muscle activation are not different at task failure during single-leg severe-intensity knee extensor exercise completed with or without prior fatiguing exercise of the contralateral leg. Despite the existence of contralateral fatigue, ACT ingestion did not alter neuromuscular responses or exercise performance.NIH

Identifying Prenatal and Postnatal Determinants of Infant Growth: A Structural Equation Modelling Based Cohort Analysis

The growth and maturation of infants reflect their overall health and nutritional status. The purpose of this study is to examine the associations of prenatal and early postnatal factors with infant growth (IG). A data-driven model was constructed by structural equation modelling to examine the relationships between pre- and early postnatal environmental factors and IG at age 12 months. The IG was a latent variable created from infant weight and waist circumference. Data were obtained on 274 mother-child pairs during pregnancy and the postnatal periods. Maternal pre-pregnancy BMI emerged as an important predictor of IG with both direct and indirect (mediated through infant birth weight) effects. Infants who gained more weight from birth to 6 months and consumed starchy foods daily at age 12 months, were more likely to be larger by age 12 months. Infant physical activity (PA) levels also emerged as a determinant. The constructed model provided a reasonable fit ( (11) = 21.5, < 0.05; RMSEA = 0.07; CFI = 0.94; SRMR = 0.05) to the data with significant pathways for all examined variables. Promoting healthy weight amongst women of child bearing age is important in preventing childhood obesity, and increasing daily infant PA is as important as a healthy infant diet

Classification of accelerometer wear and non-wear events in seconds for monitoring free-living physical activity

OBJECTIVE: To classify wear and non-wear time of accelerometer data for accurately quantifying physical activity in public health or population level research. DESIGN: A bi-moving-window-based approach was used to combine acceleration and skin temperature data to identify wear and non-wear time events in triaxial accelerometer data that monitor physical activity. SETTING: Local residents in Swansea, Wales, UK. PARTICIPANTS: 50 participants aged under 16 years (n=23) and over 17 years (n=27) were recruited in two phases: phase 1: design of the wear/non-wear algorithm (n=20) and phase 2: validation of the algorithm (n=30). METHODS: Participants wore a triaxial accelerometer (GeneActiv) against the skin surface on the wrist (adults) or ankle (children). Participants kept a diary to record the timings of wear and non-wear and were asked to ensure that events of wear/non-wear last for a minimum of 15 min. RESULTS: The overall sensitivity of the proposed method was 0.94 (95% CI 0.90 to 0.98) and specificity 0.91 (95% CI 0.88 to 0.94). It performed equally well for children compared with adults, and females compared with males. Using surface skin temperature data in combination with acceleration data significantly improved the classification of wear/non-wear time when compared with methods that used acceleration data only (p<0.01). CONCLUSIONS: Using either accelerometer seismic information or temperature information alone is prone to considerable error. Combining both sources of data can give accurate estimates of non-wear periods thus giving better classification of sedentary behaviour. This method can be used in population studies of physical activity in free-living environments

Maternal nutrition at conception modulates DNA methylation of human metastable epialleles.

In experimental animals, maternal diet during the periconceptional period influences the establishment of DNA methylation at metastable epialleles in the offspring, with permanent phenotypic consequences. Pronounced naturally occurring seasonal differences in the diet of rural Gambian women allowed us to test this in humans. We show that significant seasonal variations in methyl-donor nutrient intake of mothers around the time of conception influence 13 relevant plasma biomarkers. The level of several of these maternal biomarkers predicts increased/decreased methylation at metastable epialleles in DNA extracted from lymphocytes and hair follicles in infants postnatally. Our results demonstrate that maternal nutritional status during early pregnancy causes persistent and systemic epigenetic changes at human metastable epialleles