Evidence That Interspecies Polymorphism in the Human and Rat Cholecystokinin Receptor-2 Affects Structure of the Binding Site for the Endogenous Agonist Cholecystokinin

The cholecystokinin (CCK) receptor-2 exerts very important central and peripheral functions by binding the neuropeptides cholecystokinin or gastrin. Because this receptor is a potential therapeutic target, great interest has been devoted to the identification of efficient antagonists. However, interspecies genetic polymorphism that does not alter cholecystokinin-induced signaling was shown to markedly affect activity of synthetic ligands. In this context, precise structural study of the agonist binding site on the human cholecystokinin receptor-2 is a prerequisite to elucidating the molecular basis for its activation and to optimizing properties of synthetic ligands. In this study, using site-directed mutagenesis and molecular modeling, we delineated the binding site for CCK on the human cholecystokinin receptor-2 by mutating amino acids corresponding to that of the rat homolog. By doing so, we demonstrated that, although resembling that of rat homolog, the human cholecystokinin receptor-2 binding site also displays important distinct structural features that were demonstrated by susceptibility to several point mutations (F120A, Y189A, H207A). Furthermore, docking of CCK in the human and rat cholecystokinin receptor-2, followed by dynamic simulations, allowed us to propose a plausible structural explanation of the experimentally observed difference between rat and human cholecystokinin-2 receptors.

Bone mineral density in relation to medical and lifestyle risk factors for osteoporosis in premenopausal, menopausal and postmenopausal women in general practice

Background: Interest in the prevention of osteoporosis is increasing and thus there is a need for an acceptable osteoporosis prevention programme in general practice. AIM. A study was undertaken to identify a cohort of middle-aged women attending a general practice who would be eligible for a longitudinal study looking at bone mineral density, osteoporosis and the effectiveness of hormone replacement therapy. This study aimed to describe the relationship between medical and lifestyle risk factors for osteoporosis and the initial bone density measurements in this group of women. METHOD. A health visitor administered a questionnaire to women aged between 48 and 52 years registered with a Belfast general practice. The main outcome measures were menopausal status, presence of medical and lifestyle risk factors and bone mineral density measurements. RESULTS. A total of 358 women our of 472 (76%) took part in the study which was conducted in 1991 and 1992. A highly significant difference was found between the mean bone mineral density of premenopausal, menopausal and postmenopausal women within the narrow study age range, postmenopausal women having the lowest bone mineral density. A significant relationship was found between body mass index and bone mineral density, a greater bone mineral density being found among women with a higher body mass index. Risk factors such as smoking and sedentary lifestyle were common (reported by approximately one third of respondents) but a poor relationship was found between these two and all the other risk factors and bone mineral density in this age group. CONCLUSION. Risk of osteoporosis cannot be identified by the presence of risk factors in women aged between 48 and 52 years. In terms of a current prevention strategy for general practice it would be better to take a population-based approach except for those women known to be at high risk of osteoporosis: women with early menopause or those who have had an oophorectomy.

Genome-wide association study identifies 12 new susceptibility loci for primary biliary cirrhosis

In addition to the HLA locus, six genetic risk factors for primary biliary cirrhosis (PBC) have been identified in recent genome-wide association studies (GWAS). To identify additional loci, we carried out a GWAS using 1,840 cases from the UK PBC Consortium and 5,163 UK population controls as part of the Wellcome Trust Case Control Consortium 3 (WTCCC3). We followed up 28 loci in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 new susceptibility loci (at a genome-wide significance level of P <5 × 10?8) and replicated all previously associated loci. We identified three further new loci in a meta-analysis of data from our study and previously published GWAS results. New candidate genes include STAT4, DENND1B, CD80, IL7R, CXCR5, TNFRSF1A, CLEC16A and NFKB1. This study has considerably expanded our knowledge of the genetic architecture of PBC.

LC- HRMS based metabolomics in food safety and doping control – DeTECH21

Issues surrounding the misuse of prohibited and licensed substances in animals destined for food production and performance sport competition continue to be an enormous challenge to regulatory authorities charged with enforcing their control. Efficient analytical strategies are implemented to screen and confirm the presence of a wide range of exogenous substances in various biological matrices. However, such methods rely on the direct measurement of drugs and/or their metabolites in a targeted mode, allowing the detection of restricted number of compounds. As a consequence, emerging practices, in particular the use of natural hormones, designer drugs and low-dose cocktails, remain difficult to handle from a control point of view. A new SME-led FP7 funded project, DeTECH21, aims to overcome current limitations by applying an untargeted metabolomics approach based on liquid chromatography coupled to high resolution mass spectrometry and bioinformatic data analysis to identify bovine and equine animals which have been exposed to exogenous substances and assist in the identification of administered compounds. Markerbased strategies, dealing with the comprehensive analysis of metabolites present in a biological sample (urine/plasma/tissue), offer a reliable solution in the areas of food safety and animal sport doping control by effective, high-throughput and sensitive detection of exogenously administered agents. Therefore, the development of the first commercially available forensic test service based on metabolomics profiling will meet 21st century demands in animal forensics.

Protocolized versus non-protocolized weaning for reducing the duration of invasive mechanical ventilation in newborn infants: review

Background
Mechanical ventilation is a life-saving intervention for critically ill newborn infants with respiratory failure admitted to a neonatal intensive care unit (NICU). Ventilating newborn infants can be challenging due to small tidal volumes, high breathing frequencies, and the use of uncuffed endotracheal tubes. Mechanical ventilation has several short-term, as well as long-term complications. To prevent complications, weaning from the ventilator is started as soon as possible. Weaning aims to support the transfer from full mechanical ventilation support to spontaneous breathing activity.

Objectives
To assess the efficacy of protocolized versus non-protocolized ventilator weaning for newborn infants in reducing the duration of invasive mechanical ventilation, the duration of weaning, and shortening the NICU and hospital length of stay. To determine efficacy in predefined subgroups including: gestational age and birth weight; type of protocol; and type of protocol delivery. To establish whether protocolized weaning is safe and clinically effective in reducing the duration of mechanical ventilation without increasing the risk of adverse events.

Search methods
We searched the Cochrane Central Register of Controlled trials (CENTRAL; the Cochrane Library; 2015, Issue 7); MEDLINE In-Process and other Non-Indexed Citations and OVID MEDLINE (1950 to 31 July 2015); CINAHL (1982 to 31 July 2015); EMBASE (1988 to 31 July 2015); and Web of Science (1990 to 15 July 2015). We did not restrict language of publication. We contacted authors of studies with a subgroup of newborn infants in their study, and experts in the field regarding this subject. In addition, we searched abstracts from conference proceedings, theses, dissertations, and reference lists of all identified studies for further relevant studies.

Selection criteria
Randomized, quasi-randomized or cluster-randomized controlled trials that compared protocolized with non-protocolized ventilator weaning practices in newborn infants with a gestational age of 24 weeks or more, who were enrolled in the study before the postnatal age of 28 completed days after the expected date of birth.

Data collection and analysis
Four authors, in pairs, independently reviewed titles and abstracts identified by electronic searches. We retrieved full-text versions of potentially relevant studies.

Main results
Our search yielded 1752 records. We removed duplicates (1062) and irrelevant studies (843). We did not find any randomized, quasi-randomized or cluster-randomized controlled trials conducted on weaning from mechanical ventilation in newborn infants. Two randomized controlled trials met the inclusion criteria on type of study and type of intervention, but only included a proportion of newborns. The study authors could not provide data needed for subgroup analysis; we excluded both studies.

Authors' conclusions
Based on the results of this review, there is no evidence to support or refute the superiority or inferiority of weaning by protocol over non-protocol weaning on duration of invasive mechanical ventilation in newborn infants.

Investigating clinical predictors of arteriovenous fistula functional patency in a European cohort

Background: Arteriovenous fistula (AVF) failure to mature (FTM) rates contribute to excessive dependence on central venous catheters for haemodialysis. Choosing the most appropriate vascular access site for an individual patient is guided largely by their age, co-morbidities and clinical examination. We investigated the clinical predictors of AVF FTM in a European cohort of patients and applied an existing clinical risk prediction model for AVF FTM to this population.
Methods: A prospective cohort study was designed that included all patients undergoing AVF creation between January 2009 and December 2014 in a single centre (Belfast City Hospital) who had a functional AVF outcome observed by March 2015.
Results: A total of 525 patients had a functional AVF outcome recorded and were included in the FTM analysis. In this cohort, 309 (59%) patients achieved functional AVF patency and 216 (41%) patients had FTM. Female gender [P < 0.001, odds ratio (OR) 2.03 (CI 1.37–3.02)] and lower-arm AVF [P < 0.001, OR 4.07 (CI 2.77–5.92)] were associated with AVF FTM. The Lok model did not predict FTM outcomes based on the associated risk stratification in our population.
Conclusions: In this European study, female gender was associated with twice the risk of AVF FTM and a lower-arm AVF with four times the risk of FTM. The FTM risk prediction model was not found to be discriminative in this population. Clinical risk factors for AVF FTM vary between populations;we would recommend that units investigate their own clinical predictors of FTM to maximize AVF functional patency and ultimately survival in dialysis patients. Clinical predictors of AVF FTM may not be sufficient on their own to improve vascular access functional patency rates.

Green Space Attachment and Health: A Comparative Study in Two Urban Neighborhoods

The positive relationships between urban green space and health have been well documented. Little is known, however, about the role of residents’ emotional attachment to local green spaces in these relationships, and how attachment to green spaces and health may be promoted by the availability of accessible and usable green spaces. The present research aimed to examine the links between self-reported health, attachment to green space, and the availability of accessible and usable green spaces. Data were collected via paper-mailed surveys in two neighborhoods (n = 223) of a medium-sized Dutch city in the Netherlands. These neighborhoods differ in the perceived and objectively measured accessibility and usability of green spaces, but are matched in the physically available amount of urban green space, as well as in demographic and socio-economic status, and housing conditions. Four dimensions of green space attachment were identified through confirmatory factor analysis: place dependence, affective attachment, place identity and social bonding. The results show greater attachment to local green space and better self-reported mental health in the neighborhood with higher availability of accessible and usable green spaces. The two neighborhoods did not differ, however, in physical and general health. Structural Equation Modelling confirmed the neighborhood differences in green space attachment and mental health, and also revealed a positive path from green space attachment to mental health. These findings convey the message that we should make green places, instead of green spaces.

Preoperative radial artery volume flow is predictive of arteriovenous fistula outcomes

Objective: Guidelines recommend the creation of a wrist radiocephalic arteriovenous fistula (RAVF) as initial hemodialysis vascular access. This study explored the potential of preoperative ultrasound vessel measurements to predict AVF failure to mature (FTM) in a cohort of patients with end-stage renal disease in Northern Ireland

.Methods: A retrospective analysis was performed of all patients who had preoperative ultrasound mapping of upper limb blood vessels carried out from August 2011 to December 2014 and whose AVF reached a functional outcome by March 2015.

Results: There were 152 patients (97% white) who had ultrasound mapping andan AVF functional outcome recorded; 80 (54%) had an upper arm AVF created, and 69 (46%) had a RAVF formed. Logistic regression revealed that female gender (odds ratio [OR], 2.5; 95% confidence interval [CI], 1.12-5.55; P = .025), minimum venous diameter (OR, 0.6; 95% CI, 0.39-0.95; P = .029), and RAVF (OR, 0.4; 95% CI, 0.18-0.89; P = .026) were associated with FTM. On subgroup analysis of the RAVF group, RAVFs with an arterial volume flow <50 mL/min were seven times as likely to fail as RAVFs with higher volume flows (OR, 7.0; 95% CI, 2.35-20.87; P < .001).

Conclusions: In this cohort, a radial artery flow rate <50 mL/min was associated with a sevenfold increased risk of FTM in RAVF, which to our knowledge has not been previously reported in the literature. Preoperative ultrasound mapping adds objective assessment in the clinical prediction of AVF FTM.

Seven key actions to eradicate rheumatic heart disease in Africa: the Addis Ababa communiqué

Acute rheumatic fever (ARF) and rheumatic heart disease (RHD) remain major causes of heart failure, stroke and death among African women and children, despite being preventable and imminently treatable. From 21 to 22 February 2015, the Social Cluster of the Africa Union Commission (AUC) hosted a consultation with RHD experts convened by the Pan-African Society of Cardiology (PASCAR) in Addis Ababa, Ethiopia, to develop a 'roadmap' of key actions that need to be taken by governments to eliminate ARF and eradicate RHD in Africa. Seven priority areas for action were adopted: (1) create prospective disease registers at sentinel sites in affected countries to measure disease burden and track progress towards the reduction of mortality by 25% by the year 2025, (2) ensure an adequate supply of high-quality benzathine penicillin for the primary and secondary prevention of ARF/RHD, (3) improve access to reproductive health services for women with RHD and other non-communicable diseases (NCD), (4) decentralise technical expertise and technology for diagnosing and managing ARF and RHD (including ultrasound of the heart), (5) establish national and regional centres of excellence for essential cardiac surgery for the treatment of affected patients and training of cardiovascular practitioners of the future, (6) initiate national multi-sectoral RHD programmes within NCD control programmes of affected countries, and (7) foster international partnerships with multinational organisations for resource mobilisation, monitoring and evaluation of the programme to end RHD in Africa. This Addis Ababa communiqué has since been endorsed by African Union heads of state, and plans are underway to implement the roadmap in order to end ARF and RHD in Africa in our lifetime.

Arterial stiffness and arteriovenous fistula failure of maturation

PURPOSE: Increased arterial stiffness is a common finding in patients with end-stage renal disease. Following creation of an arteriovenous fistula (AVF), appropriate dilation of the feeding artery must occur to facilitate AVF maturation. Arterial stiffness may impair the arterial dilation required to facilitate AVF development and contribute to subsequent failure to mature (FTM). The aim of this pilot study was to investigate the association between measurements of central and peripheral arterial stiffness, and AVF FTM.

METHODS: Patients undergoing AVF creation in a single centre (Belfast City Hospital, UK) between January and December 2015 were invited to have their carotid-femoral pulse wave velocity (PWV), brachial-radial PWV and augmentation index (AI) measured prior to AVF creation. Subsequent AVF outcomes were identified.

RESULTS: Fifty-nine patients who had an AVF procedure were included in the final analysis (mean age 62 years); 50.8% had diabetes mellitus. The mean pre-operative arterial diameter for all AVFs was 3.9 mm. Average values for carotid-femoral PWV were 9.5 m/s, brachial-radial PWV 7.7 m/s and AI 25.6%. Using logistic regression, these arterial stiffness parameters did not predict AVF FTM: carotid-femoral PWV (P = 0.20), brachial-radial PWV (P = 0.13), AI (P = 0.50).

CONCLUSIONS: This is the largest study to date exploring the association between arterial stiffness and AVF FTM. The measured central and peripheral arterial stiffness parameters were not associated with AVF FTM. Further research is needed to define if non-invasive arterial physiological measurements would be clinically useful in the prediction of AVF FTM.