A novel role of the corticotrophin-releasing hormone regulating peptide, teneurin C-terminal associated peptide 1, on glucose uptake into the brain.

Teneurin C-terminal associated peptide (TCAP) is an ancient paracrine signalling agent that evolved via lateral gene transfer from prokaryotes into an early metazoan ancestor. Although it bears structural similarity to corticotrophin-releasing hormone (CRH), it inhibits the in vivo actions of CRH. The TCAPs are highly expressed in neurones, where they induce rapid cytoskeletal rearrangement and are neuroprotective. Because these processes are highly energy-dependent, this suggests that TCAP has the potential to regulate glucose uptake because glucose is the primary energy substrate in brain, and neurones require a steady supply to meet the high metabolic demands of neuronal communication. Therefore, the objective of the present study was to assess the effect of TCAP-mediated glucose uptake in the brain and in neuronal cell models. TCAP-mediated 18 F-deoxyglucose (FDG) uptake into brain tissue was assessed in male wild-type Wistar rats by functional positron emission tomography. TCAP-1 increased FDG uptake by over 40% into cortical regions of the brain, demonstrating that TCAP-1 can significantly enhance glucose supply. Importantly, a single nanomolar injection of TCAP-1 increased brain glucose after 3 days and decreased blood glucose after 1 week. This is corroborated by a decreased serum concentration of insulin and an increased serum concentration of glucagon. In immortalised hypothalamic neurones, TCAP-1 increased ATP production and enhanced glucose uptake by increasing glucose transporter recruitment to the plasma membrane likely via AKT and mitogen-activated protein kinase/ERK phosphorylation events. Taken together, these data demonstrate that TCAP-1 increases glucose metabolism in neurones, and may represent a peptide signalling agent that regulated glucose uptake before insulin and related peptides.

Newborn screening for congenital heart defects: a systematic review and cost-effectiveness analysis.

OBJECTIVES: To provide evidence to inform policy decisions about the most appropriate newborn screening strategy for congenital heart defects, identifying priorities for future research that might reduce important uncertainties in the evidence base for such decisions. DATA SOURCES: Electronic databases. Groups of parents and health professionals. REVIEW METHODS: A systematic review of the published medical literature concerning outcomes for children with congenital heart defects was carried out. A decision analytic model was developed to assess the cost-effectiveness of alternative screening strategies for congenital heart defects relevant to the UK. A further study was then carried out using a self-administered anonymous questionnaire to explore the perspectives of parents and health professionals towards the quality of life of children with congenital heart defects. The findings from a structured review of the medical literature regarding parental experiences were linked with those from a focus group of parents of children with congenital heart defects. RESULTS: Current newborn screening policy comprises a clinical examination at birth and 6 weeks, with specific cardiac investigations for specified high-risk children. Routine data are lacking, but under half of affected babies, not previously identified antenatally or because of symptoms, are identified by current newborn screening. There is evidence that screen-positive infants do not receive timely management. Pulse oximetry and echocardiography, in addition to clinical examination, are alternative newborn screening strategies but their cost-effectiveness has not been adequately evaluated in a UK setting. In a population of 100,000 live-born infants, the model predicts 121 infants with life-threatening congenital heart defects undiagnosed at screening, of whom 82 (68%) and 83 (69%) are detected by pulse oximetry and screening echocardiography, respectively, but only 39 (32%) by clinical examination alone. Of these, 71, 71 and 34, respectively, receive a timely diagnosis. The model predicts 46 (0.5%) false-positive screening diagnoses per 100,000 infants with clinical examination, 1168 (1.3%) with pulse oximetry and 4857 (5.4%) with screening echocardiography. The latter includes infants with clinically non-significant defects. Total programme costs are predicted of pound 300,000 for clinical examination, pound 480,000 for pulse oximetry and pound 3.54 million for screening echocardiography. The additional cost per additional timely diagnosis of life-threatening congenital heart defects ranges from pound 4900 for pulse oximetry to pound 4.5 million for screening echocardiography. Including clinically significant congenital heart defects gives an additional cost per additional diagnosis of pound 1500 for pulse oximetry and pound 36,000 for screening echocardiography. Key determinants for cost-effectiveness are detection rates for pulse oximetry and screening echocardiography. Parents and health professionals place similar values on the quality of life outcomes of children with congenital heart defects and both are more averse to neurological than to cardiac disability. Adverse psychosocial effects for parents are focused around poor management and/or false test results. CONCLUSIONS: Early detection through newborn screening potentially can improve the outcome of congenital heart defects; however the current programme performs poorly, and lacks monitoring of quality assurance, performance management and longer term outcomes. Pulse oximetry is a promising alternative newborn screening strategy but further evaluation is needed to obtain more precise estimates of test performance and to inform optimal timing, diagnostic and management strategies. Although screening echocardiography is associated with the highest detection rate, it is the most costly strategy and has a 5% false-positive rate. Improving antenatal detection of congenital heart defects increases the cost per timely postnatal diagnosis afforded by any newborn screening strategy but does not alter the relative effects of the strategies. An improvement of timely management of screen positive infants is essential. Further research is required to refine the detection rate and other aspects of pulse oximetry, to evaluate antenatal screening strategies more directly, and to investigate the psychosocial effects of newborn screening for congenital heart defects.