Synthetic ionophores for cations

A series of 14-crown-4 derivatives bearing amide substituents have been prepared in order to develop ionophores selective for lithium. Complexation with lithium ions was monitored using (^13)C and IR spectroscopy and liquid membrane electrodes prepared and evaluated using a fixed interference method. The highest selectivities with respect to sodium ions were obtained for di-n-butylamide-oNPOE and a di-n-benzylamide-oNPOE derivatives; log(^POT)(_ Li,Na) = -2.92 and -2.93 respectively. A series of amide and amide-ester N-functionalised coronands based upon [12]-N202 , [15]-N203 and [18]-N204 parent macrocycles has been prepared. Complexation of certain alkali and alkaline-earth cations was monitored by (^13)C NMR and IR specteoscopy, enthalpies of complexation measured in methanolic solution using micro-calorimetry and stability constants measured in aqueous media by potentiometric methods. Strong complexation of Ca2+ in aqueous media was observed with good selectivity over Na+ and K+. Lower free energies of binding for Ha cations were displayed by the tertiary amide derivative (of [12]N(_2)O(_2)), than by its secondary analogue, despite displaying higher enthalpies of complexation. Thus the lower free energies result from significantly lower entropies of complexation. Two sets of oxa-amide and oxa-ester tripodal ligands have been prepared and solvent membranes fabricated. The effects of the nature of the plasticiser, bis (butylpentyl)adipate (BBPA) verses o -nitrophenyl octyl ether (oNPOE), the ligand structure and the ionic strength of the analyte solution on the electrode response to la and Ila cations were studied. The performance of the oxa-amides was superior to that of the oxa-esters particularly at higher ionic strengths, however super-Nernstian responses were observed with the more charge-dense ions in the presence of chloride and/or with the less polar plasticiser BBPA. Measurements of intracellular sodium concentration could be effected with a sensor based upon bis (N,N',N"-tributyl)-4,4',4"-propylidintris(3-oxabutanamide) and oNPOE for which -log KPOT = 2.64 and -log KPOT =3.0, whilst bis (N,N',N"-tributyl)Na,K Na,Mg-2,2',2"-phenylmethylidintris(3-oxabutamide) and oNPOE functioned as a calcium sensor, displaying excellent selectivity over Mg. -log KPOT= 4.3.Ca,MgAdditionally a triamide based upon a cyclohexane triol skeleton was prepared, a membrane fabricated and its performance assessed as a sodium sensor

Emotional Complexity and the Neural Representation of Emotion in Motion

According to theories of emotional complexity, individuals low in emotional complexity encode and represent emotions in visceral or action-oriented terms, whereas individuals high in emotional complexity encode and represent emotions in a differentiated way, using multiple emotion concepts. During functional magnetic resonance imaging, participants viewed valenced animated scenarios of simple ball-like figures attending either to social or spatial aspects of the interactions. Participant’s emotional complexity was assessed using the Levels of Emotional Awareness Scale. We found a distributed set of brain regions previously implicated in processing emotion from facial, vocal and bodily cues, in processing social intentions, and in emotional response, were sensitive to emotion conveyed by motion alone. Attention to social meaning amplified the influence of emotion in a subset of these regions. Critically, increased emotional complexity correlated with enhanced processing in a left temporal polar region implicated in detailed semantic knowledge; with a diminished effect of social attention; and with increased differentiation of brain activity between films of differing valence. Decreased emotional complexity was associated with increased activity in regions of pre-motor cortex. Thus, neural coding of emotion in semantic vs action systems varies as a function of emotional complexity, helping reconcile puzzling inconsistencies in neuropsychological investigations of emotion recognition

Comprehensive computerised primary care records are an essential component of any national health information strategy: report from an international consensus conference

In many countries, primary care informatics has developed to the point that it is recognised as an important enabler of quality improvement; this has not occurred to date in the United States. With this conference, we aimed to build an international consensus as to whether primary care has unique characteristics that require an informatics subspecialty; and, if so, to establish the role of an international audience of 53 health informaticians, mostly working in primary care. There was consensus among the participants that primary care has many unique characteristics that justify the existence of an informatics subspecialty: primary care informatics (PCI). The conference identified principles and practical examples of: (1) the effective deployment of information technology to underpin the provision of records, communication and access to information; (2) the need to harness the extensive knowledge base about the practice of PCI; and (3) the contribution of the primary care informatics in improving patient care, and to enable its recognition in the national strategy. The conference was organised by the primary care informatics working groups of AMIA, EFMI, IMIA and Wonca and took place at Medinfo 2004 in San Francisco. It consisted of two plenary lectures, two small-group work sessions and a panel discussion to summarise the day. It was attended by experimental work and theory that underpins the science of PCI. These principles and examples of their practical application were largely derived from the extensive knowledge base which has been built up in countries that have developed PCI over the last one to two decades

Exploratory randomised controlled trial of a mindfulness-based weight loss intervention for women

To explore the efficacy of a mindfulness-based weight loss intervention for women. Sixty-two women (ages 19-64; BMI 22.5-52.1) who were attempting to lose weight were randomised to an intervention or control condition. The former were invited to attend four 2-h workshops, the latter were asked to continue with their normal diets. Data were collected at baseline, 4 and 6 months. BMI, physical activity, mental health. At 6 months intervention participants showed significantly greater increases in physical activity compared to controls (p<.05) but no significant differences in weight loss or mental health. However, when intervention participants who reported 'never' applying the workshop principles at 6 months (n=7) were excluded, results showed both significantly greater increases in physical activity (3.1 sessions per week relative to controls, p<.05) and significantly greater reductions in BMI (0.96 relative to controls, equivalent to 2.32 kg, p<0.5). Reductions in BMI were mediated primarily by reductions in binge eating. Despite its brevity, the intervention was successful at bringing about change. Further refinements should increase its efficacy

A Manual for the Glasgow Outcome Scale-Extended Interview

The Glasgow Outcome Scale-Extended (GOSE) has become one of the most widely used outcome instruments to assess global disability and recovery after traumatic brain injury. Achieving consistency in the application of the assessment remains a challenge, particularly in multi-center studies involving many assessors. We present a manual for the GOSE interview that is designed to support both single- and multi-center studies and promote inter-rater agreement. Many patients fall clearly into a particular category; however, patients may have outcomes that are on the borderline between adjacent categories, and cases can present other challenges for assessment. The Manual includes the general principles of assessment, advice on administering each section of the GOSE interview, and guidance on “borderline” and “difficult” cases. Finally, we discuss the properties of the GOSE, including strengths and limitations, and outline recommendations for assessor training, accreditation, and monitoring

Genome sequencing of the extinct Eurasian wild aurochs, Bos primigenius, illuminates the phylogeography and evolution of cattle

Background Domestication of the now-extinct wild aurochs, Bos primigenius, gave rise to the two major domestic extant cattle taxa, B. taurus and B. indicus. While previous genetic studies have shed some light on the evolutionary relationships between European aurochs and modern cattle, important questions remain unanswered, including the phylogenetic status of aurochs, whether gene flow from aurochs into early domestic populations occurred, and which genomic regions were subject to selection processes during and after domestication. Here, we address these questions using whole-genome sequencing data generated from an approximately 6,750-year-old British aurochs bone and genome sequence data from 81 additional cattle plus genome-wide single nucleotide polymorphism data from a diverse panel of 1,225 modern animals. Results Phylogenomic analyses place the aurochs as a distinct outgroup to the domestic B. taurus lineage, supporting the predominant Near Eastern origin of European cattle. Conversely, traditional British and Irish breeds share more genetic variants with this aurochs specimen than other European populations, supporting localized gene flow from aurochs into the ancestors of modern British and Irish cattle, perhaps through purposeful restocking by early herders in Britain. Finally, the functions of genes showing evidence for positive selection in B. taurus are enriched for neurobiology, growth, metabolism and immunobiology, suggesting that these biological processes have been important in the domestication of cattle. Conclusions This work provides important new information regarding the origins and functional evolution of modern cattle, revealing that the interface between early European domestic populations and wild aurochs was significantly more complex than previously thought

Dysexecutive symptoms and carer strain following acquired brain injury: changes measured before and after holistic neuropsychological rehabilitation

BACKGROUND: Following acquired brain injury (ABI), deficits in executive functioning (EF) are common. As a result many brain-injured patients encounter problems in every-day functioning, and their families experience significant strain. Previous research has documented the benefits of cognitive rehabilitation for executive dysfunction, and rehabilitation programmes designed to ameliorate functional problems associated with ABI. OBJECTIVES: This study primarily aims to evaluate whether a neuropsychological rehabilitation programme reduces reported symptoms of everyday dysexecutive behaviour and carer strain. METHODS: In this study 66 ABI outpatients attended comprehensive holistic neuropsychological rehabilitation programme. A repeated-measures design was employed to determine the effect of rehabilitation on EF and carer strain, as part of a service evaluation. Outcome measures comprised the dysexecutive questionnaire (DEX/DEX-I) and carer strain index (CSI), applied pre- and post-rehabilitation. RESULTS: Results indicate rehabilitation benefited clients and carers in 5 of 6 DEX/DEX-I subscales, and 2 of 3 CSI subscales, (p<.05). An effect of aetiology on rehabilitation was found on the metacognitive scale of the DEX-I. CONCLUSIONS: Therefore, this study supports a comprehensive holistic neuropsychological rehabilitation programme as effective in reducing reported symptoms of dysexecutive behaviour and carer strain following ABI

Cigarette smoke extract profoundly suppresses TNFα-mediated proinflammatory gene expression through upregulation of ATF3 in human coronary artery endothelial cells

Endothelial dysfunction caused by the combined action of disturbed flow, inflammatory mediators and oxidants derived from cigarette smoke is known to promote coronary atherosclerosis and increase the likelihood of myocardial infarctions and strokes. Conversely, laminar flow protects against endothelial dysfunction, at least in the initial phases of atherogenesis. We studied the effects of TNFα and cigarette smoke extract on human coronary artery endothelial cells under oscillatory, normal laminar and elevated laminar shear stress for a period of 72 hours. We found, firstly, that laminar flow fails to overcome the inflammatory effects of TNFα under these conditions but that cigarette smoke induces an anti-oxidant response that appears to reduce endothelial inflammation. Elevated laminar flow, TNFα and cigarette smoke extract synergise to induce expression of the transcriptional regulator activating transcription factor 3 (ATF3), which we show by adenovirus driven overexpression, decreases inflammatory gene expression independently of activation of nuclear factor-κB. Our results illustrate the importance of studying endothelial dysfunction in vitro over prolonged periods. They also identify ATF3 as an important protective factor against endothelial dysfunction. Modulation of ATF3 expression may represent a novel approach to modulate proinflammatory gene expression and open new therapeutic avenues to treat proinflammatory diseases

Epigenetic regulation of F2RL3 associates with myocardial infarction and platelet function

DNA hypomethylation at the F2RL3 (F2R like thrombin or trypsin receptor 3) locus has been associated with both smoking and atherosclerotic cardiovascular disease; whether these smoking-related associations form a pathway to disease is unknown. F2RL3 encodes protease-activated receptor 4, a potent thrombin receptor expressed on platelets. Given the role of thrombin in platelet activation and the role of thrombus formation in myocardial infarction, alterations to this biological pathway could be important for ischemic cardiovascular disease. METHODS: We conducted multiple independent experiments to assess whether DNA hypomethylation at F2RL3 in response to smoking is associated with risk of myocardial infarction via changes to platelet reactivity. Using cohort data (N=3205), we explored the relationship between smoking, DNA hypomethylation at F2RL3, and myocardial infarction. We compared platelet reactivity in individuals with low versus high DNA methylation at F2RL3 (N=41). We used an in vitro model to explore the biological response of F2RL3 to cigarette smoke extract. Finally, a series of reporter constructs were used to investigate how differential methylation could impact F2RL3 gene expression. RESULTS: Observationally, DNA methylation at F2RL3 mediated an estimated 34% of the smoking effect on increased risk of myocardial infarction. An association between methylation group (low/high) and platelet reactivity was observed in response to PAR4 (protease-activated receptor 4) stimulation. In cells, cigarette smoke extract exposure was associated with a 4.9% to 9.3% reduction in DNA methylation at F2RL3 and a corresponding 1.7-(95% CI, 1.2–2.4, P=0.04) fold increase in F2RL3 mRNA. Results from reporter assays suggest the exon 2 region of F2RL3 may help control gene expression. CONCLUSIONS: Smoking-induced epigenetic DNA hypomethylation at F2RL3 appears to increase PAR4 expression with potential downstream consequences for platelet reactivity. Combined evidence here not only identifies F2RL3 DNA methylation as a possible contributory pathway from smoking to cardiovascular disease risk but from any feature potentially influencing F2RL3 regulation in a similar manner