Glutamate Receptor Interacting Protein 1 Regulates CD4(+) CTLA-4 Expression and Transplant Rejection.

PDZ domains are common 80- to 90-amino-acid regions named after the first three proteins discovered to share these domains: postsynaptic density 95, discs large, and zonula occludens. PDZ domain-containing proteins typically interact with the C-terminus of membrane receptors. Glutamate receptor interacting protein 1 (GRIP1), a seven-PDZ domain protein scaffold, regulates glutamate receptor surface expression and trafficking in neurons. We have found that human and mouse T cells also express GRIP1. T cell-specific GRIP1(-/-) mice >11 weeks old had prolonged cardiac allograft survival. Compared with wild-type T cells, in vitro stimulated GRIP1(-/-) T cells had decreased expression of activation markers and increased apoptotic surface marker expression. Surface expression of the strong T cell inhibitory molecule cytotoxic T lymphocyte antigen-4 (CTLA-4) was increased on GRIP1(-/-) T cells from mice >11 weeks old. CTLA-4 increases with T cell stimulation and its surface expression on GRIP1(-/-) T cells remained high after stimulation was removed, indicating a possible internalization defect in GRIP1-deficient T cells. CTLA-4-blocking antibody treatment following heart transplantation led to complete rejection in T cell GRIP1(-/-) mice, indicating that increased CTLA-4 surface expression contributed to the extended graft survival. Our data indicate that GRIP1 regulates T cell activation by regulating CTLA-4 surface expression.

Economic costs associated with moderate and late preterm birth: a prospective population-based study.

OBJECTIVE: We sought to determine the economic costs associated with moderate and late preterm birth. DESIGN: An economic study was nested within a prospective cohort study. SAMPLE: Infants born between 32(+0) and 36(+6)  weeks of gestation in the East Midlands of England. A sample of infants born at ≥37 weeks of gestation acted as controls. METHODS: Data on resource use, estimated from a National Health Service (NHS) and personal social services perspective, and separately from a societal perspective, were collected between birth and 24 months corrected age (or death), and valued in pounds sterling, at 2010-11 prices. Descriptive statistics and multivariable analyses were used to estimate the relationship between gestational age at birth and economic costs. MAIN OUTCOME MEASURES: Cumulative resource use and economic costs over the first two years of life. RESULTS: Of all eligible births, 1146 (83%) preterm and 1258 (79%) term infants were recruited. Mean (standard error) total societal costs from birth to 24 months were £12 037 (£1114) and £5823 (£1232) for children born moderately preterm (32(+0) -33(+6)  weeks of gestation) and late preterm (34(+0) -36(+6)  weeks of gestation), respectively, compared with £2056 (£132) for children born at term. The mean societal cost difference between moderate and late preterm and term infants was £4657 (bootstrap 95% confidence interval, 95% CI £2513-6803; P < 0.001). Multivariable regressions revealed that, after controlling for clinical and sociodemographic characteristics, moderate and late preterm birth increased societal costs by £7583 (£874) and £1963 (£337), respectively, compared with birth at full term. CONCLUSIONS: Moderate and late preterm birth is associated with significantly increased economic costs over the first 2 years of life. Our economic estimates can be used to inform budgetary and service planning by clinical decision-makers, and economic evaluations of interventions aimed at preventing moderate and late preterm birth or alleviating its adverse consequences. TWEETABLE ABSTRACT: Moderate and late preterm birth is associated with increased economic costs over the first 2 years of life.

Experiences with maternal and perinatal death reviews in the UK--the MBRRACE-UK programme.

Established in 1952, the programme of surveillance and Confidential Enquiries into Maternal Deaths in the UK is the longest running such programme worldwide. Although more recently instituted, surveillance and confidential enquiries into perinatal deaths are also now well established nationally. Recent changes to funding and commissioning of the Enquiries have enabled both a reinvigoration of the processes and improvements to the methodology with an increased frequency of future reporting. Close engagement with stakeholders and a regulator requirement for doctors to participate have both supported the impetus for involvement of all professionals leading to greater potential for improved quality of care for women and babies.

Neonatal intensive care outcomes and resource utilisation of infants born <26 weeks in the former Trent region: 2001-2003 compared with 1991-1993.

OBJECTIVES: To provide survival data and rates of severe disability at 2 years of corrected age in infants born prior to 26 weeks' gestation in 2001-2003 and to compare these outcomes with an earlier cohort from 1991 to 1993. DESIGN: Population-based prospective cohort study. SETTING: Former Trent region of UK covering a population of approximately five million and around 55 000 births per annum. PARTICIPANTS: The authors identified a 3-year cohort of infants born before 26 weeks' gestation between 1 January 2001 and 31 December 2003 from The Neonatal Survey (TNS). Questionnaires based on the Oxford minimum dataset were completed. MAIN OUTCOME MEASURES: Survival, service use and disability levels were compared between the 2001- 2003 cohort and the cohort from 1991 to 1993. RESULTS: In 2001-2003, 0%, 18% and 35% of live born babies were alive at 2 years without any evidence of severe disability at 23, 24 and 25 weeks' gestation, respectively. Overall, of those children admitted to neonatal care, the proportion with no evidence of severe disability at 2 years corrected age improved from 14.5% in 1991-1993 to 26.5% in 2001-2003. There was an increase in the proportion of children with at least one severe disability, out of total admissions to neonatal unit (8% vs 17%) and of those assessed at 2 years (35% vs 39%). CONCLUSIONS: This study has shown an improvement in survival to discharge in babies admitted for neonatal care. However, this improved survival has been associated with an increase in the proportion of children with at least one severe disability at a corrected age of 2 years.

Predicting neonatal mortality among very preterm infants: a comparison of three versions of the CRIB score.

OBJECTIVE: To validate Clinical Risk Index for Babies (CRIB) and CRIB II mortality prediction scores in a UK population of infants born at

Toxic additives in medication for preterm infants.

BACKGROUND: Little is known about exposure of preterm infants to excipients during routine clinical care. OBJECTIVE: To document excipient exposure in vulnerable preterm babies in a single centre, taking into account chronic lung disease (CLD) as a marker of illness severity. DESIGN: Excipient exposure after treatment with eight oral liquid medications was determined by retrospectively analysing the drug charts of infants admitted to a neonatal unit. SETTING: The Leicester Neonatal Service. PARTICIPANTS: 38 infants born between June 2005 and July 2006 who were less than 30 weeks' gestation and 1500 g in weight at birth and managed in Leicester to discharge. RESULTS: The 38 infants represented 53% of the eligible target group; 7/38 infants had CLD. During their in-patient stay, infants were exposed to over 20 excipients including ethanol and propylene glycol, chemicals associated with neurotoxicity. Infants with CLD were exposed to higher concentrations of these toxins. Infants were also exposed to high concentrations of sorbitol, with some infants being exposed to concentrations in excess of recommended guidelines for maximum exposure in adults. CONCLUSIONS: Preterm infants are commonly exposed to excipients, some of which are potentially toxic. Strategies aimed at reducing excipient load in preterm infants are urgently required.

Antenatal umbilical Doppler abnormalities: an independent risk factor for early onset neonatal necrotizing enterocolitis in premature infants.

BACKGROUND: Necrotizing enterocolitis (NEC) is the most common gastrointestinal (GI) emergency seen in neonatal units. Many factors have been considered as potentially important aetiologically, including gut ischaemia, sepsis and feeding. However, evidence remains equivocal. OBJECTIVE: This study investigated whether preterm babies born to mothers with abnormal antenatal umbilical Dopplers (absent or reversed end diastolic flow--AREDF), that is exposed to antenatal gut ischaemia, are at an identical risk of developing NEC early in life, compared to babies born to mothers with normal Dopplers. METHODS: All preterm (

Socioeconomic inequalities in very preterm birth rates.

AIMS: To investigate the extent of socioeconomic inequalities in the incidence of very preterm birth over the past decade. METHODS: Ecological study of all 549 618 births in the former Trent health region, UK, from 1 January 1994 to 31 December 2003. All singleton births of 22(+0) to 32(+6) weeks gestation (7 185 births) were identified from population surveys of neonatal services and stillbirths. Poisson regression was used to calculate incidence of very preterm birth (22-32 weeks) and extremely preterm birth (22-28 weeks) by year of birth and decile of deprivation (child poverty section of the Index of Multiple Deprivation). RESULTS: Incidence of very preterm singleton birth rose from 11.9 per 1000 births in 1994 to 13.7 per 1000 births in 2003. Those from the most deprived decile were at nearly twice the risk of very preterm birth compared with those from the least deprived decile, with 16.4 per 1000 births in the most deprived decile compared with 8.5 per 1000 births in the least deprived decile (incidence rate ratio 1.94; 95% CI (1.73 to 2.17)). This deprivation gap remained unchanged throughout the 10-year period. The magnitude of socio-economic inequalities was the same for extremely preterm births (22-28 weeks incidence rate ratio 1.94; 95% CI (1.62 to 2.32)). CONCLUSIONS: This large, unique dataset of very preterm births shows wide socio-economic inequalities that persist over time. These findings are likely to have consequences on the burden of long-term morbidity. Our research can assist future healthcare planning, the monitoring of socio-economic inequalities and the targeting of interventions in order to reduce this persistent deprivation gap.

Follow up of infants following discharge from the neonatal unit: structure and process.

Reviewing high risk infants after discharge to provide ongoing clinical care and to monitor later outcomes is an important role for neonatologists and paediatricians. Clinical need is the primary reason for such follow up but the process does provide additional opportunities, for example collecting information on later outcomes is vital for health care commissioning, and to determine the longer term effects of new medical treatments. Parents welcome the early identification of any problems in their infant and the opportunity for early intervention may improve outcomes in some circumstances. However, depending on the model adopted, follow up can be costly and this expenditure must be justified by considering the benefits obtained.

Developmental outcome in newborn infants treated for acute respiratory failure with extracorporeal membrane oxygenation: present experience.

OBJECTIVE: To describe the later health status of newborn infants who received extracorporeal membrane oxygenation (ECMO) for acute respiratory failure in the era after the UK ECMO trial. DESIGN: Prospective follow up study of newborn infants who received ECMO at a single centre between January 1997 and January 2001. SETTING: Departments of ECMO and Paediatric Intensive Care, University Hospitals of Leicester. PATIENTS: All babies who received ECMO within 14 days of birth. INTERVENTIONS: Neurodevelopment screening using the schedule for growing skills-II (SGS-II) assessment tool. MAIN OUTCOME MEASURES: Survival at 12 months of age by disease and functional development at follow up. RESULTS: A total of 145 neonates received ECMO for treatment of respiratory failure. Of these, 108 (75%) were alive at 1 year of age. There were no deaths in children treated for respiratory failure secondary to meconium aspiration syndrome (73/145). Ninety three (86% of survivors) infants attended a follow up visit at 11-19 months postnatal age. Eighty two were classed as normal, seven as having "impairment", and four as having "severe disability". CONCLUSIONS: Most newborn infants with acute respiratory failure treated with ECMO will have a normal neurodevelopment screening assessment at 11-19 months of postnatal age. There is no evidence to suggest that changes in neonatal practice since the UK ECMO trial have led to changes in outcome of infants undergoing ECMO therapy.

Neonatal disease severity scoring systems.

Illness severity scores have become widely used in neonatal intensive care. Primarily this has been to adjust the mortality observed in a particular hospital or population for the morbidity of their infants, and hence allow standardised comparisons to be performed. However, although risk correction has become relatively commonplace in relation to audit and research involving groups of infants, the use of such scores in giving prognostic information to parents, about their baby, has been much more limited. The strengths and weaknesses of the existing methods of disease severity correction in the newborn are presented in this review.

The potential impact on costs and staffing of introducing clinical networks and British Association of Perinatal Medicine standards to the delivery of neonatal care.

OBJECTIVE: To produce models to estimate the impact of introducing clinical networks and the 2001 BAPM standards to the delivery of neonatal care. DESIGN: Prospective observational study using a geographically defined population and data collected by questionnaire on staffing levels and cot availability. SETTING: Trent Health Region UK. SUBJECTS: All infants born to Trent resident mothers at or before 32 weeks gestation between 1 January 1998 and 31 December 1999. Staffing numbers and cot availability for neonatal care in 2001. METHODS: A modelling exercise was carried out using information for all neonatal admissions for Trent resident infants. Three models were investigated: (a). the current care provision; (b). a network where three lead centres provided the intensive care for the region and the remaining units provided either high dependency or special care alone; (c). a network where six lead centres provided the intensive care for the region and the remaining units provided either high dependency or special care alone. Overall costings, staffing levels, and cot requirements were calculated for each model. Data on staffing levels and cot availability were used to calculate current care provision costings. RESULTS: The current cost of running the service is approximately pound 33.35 million, although a proportion of nursing posts are currently unfilled. Estimates for the introduction of a three centre model meeting BAPM 2001 standards range from pound 37.31 to pound 43.40 million. Equivalent figures for the six centre model were: pound 36.32 to pound 42.62 million. Approximately 370 and 230 babies a year would be involved in transfer in the three and six centre models respectively. This is in contrast with 374 and 368 urgent transfers that actually took place in 1998 and 1999 respectively. CONCLUSION: The costs associated with the introduction of managed clinical networks and meeting BAPM standards of care are not excessive, especially when considered against the likely implementation timetable of perhaps 7-10 years. Attracting and retaining sufficient staff will pose the major challenge.

Contour integration and cortical processing.

Our understanding of visual processing in general, and contour integration in particular, has undergone great change over the last 10 years. There is now an accumulation of psychophysical and neurophysiological evidence that the outputs of cells with conjoint orientation preference and spatial position are integrated in the process of explication of rudimentary contours. Recent neuroanatomical and neurophysiological results suggest that this process takes place at the cortical level V1. The code for contour integration may be a temporal one in that it may only manifest itself in the latter part of the spike train as a result of feedback and lateral interactions. Here we review some of the properties of contour integration from a psychophysical perspective and we speculate on their underlying neurophysiological substrate.

Repeatability of cellular constituents and cytokine concentration in fluid obtained by non-bronchoscopic bronchoalveolar lavage of infants receiving extracorporeal oxygenation.

BACKGROUND: Since few studies have assessed the repeatability of non-bronchoscopic bronchoalveolar lavage (NB-BAL), we compared cellular counts and cytokine concentrations in fluid obtained by standardised NB-BAL from each side of 20 intubated infants receiving extracorporeal membrane oxygenation (ECMO). METHODS: Total cell counts were obtained from 95 paired lavages and 77 pairs were suitable for differential counts and measurement of cytokine concentrations. RESULTS: Moderate correlation was noted between the two sides for most cell types including total cell counts and percentages of neutrophils and macrophages (R=0.70-0.84) and for cytokine concentrations (IL-8 R=0.78, IL-6 R=0.75, TNF-alpha R=0.64, all p< or =0.001). Using Bland-Altman analysis the mean difference between the two sides approached zero for cellular constituents (total cell counts mean difference 1.7, limits of agreement -187.5 to +190.9 x 10(4)/ml; percentage neutrophils -3.9%, -41.5% to +33.6%; percentage macrophages 3.9%, -33.8% to +41.6%) but tended to be greater on the right for logarithmically transformed cytokine measurements (IL-8: left/right ratio 0.74, limits of agreement 0.12 to 5.45, IL-6: 0.93, 0.09 to 5.87, and TNF-alpha: 0.93, 0.27 to 3.16). Using linear regression with random effects to assess the variability, only the infant's age appeared to influence the cellular results but, for cytokines, only the volume retrieved affected the variability. The magnitude of the measurements, the underlying disease, the operator's experience, days on ECMO, or survival did not affect the variability. CONCLUSION: Measurements obtained by NB-BAL need to be interpreted with caution and strongly suggest that normalisation for the dilutional effects of saline is essential.

UK collaborative randomised trial of neonatal extracorporeal membrane oxygenation: follow-up to age 4 years.

Extracorporeal membrane oxygenation (ECMO) is a supportive intensive-care technique used for babies with acute respiratory failure. We examined morbidity at age 4 years in surviving children recruited to the UK Collaborative ECMO Trial, and provide long-term data on ECMO support compared with contemporary conventional care. The neonatal ECMO policy resulted in improved survival and a favourable outcome. We therefore advocate the safety and efficacy of this intervention.

Sensitivity to contrast histogram differences in synthetic wavelet-textures.

Recent research on texture synthesis suggests that characterisation of those properties of textures to which human observers are sensitive may be provided by the histograms of the coefficients of a wavelet decomposition. In this study we examined the properties of wavelet histograms that affect texture discrimination by measuring observer sensitivity to differences in the wavelet histograms of synthetic textures. The textures, generated via Gabor micropattern synthesis, were broadband, with amplitude spectra that are characteristic of natural images, i.e. 1/f. We measured texture-difference thresholds for three moments of the wavelet histograms -- variance, skew and kurtosis -- by manipulating the contrast, phase, and density, of the Gabor elements used to construct the textures. Observers discriminated more efficiently between textures that had differences in kurtosis, than between textures that had differences in either variance or skew. Performance was compared to two model observers; one used the pixel-luminance histogram, the other used the histogram of the output of wavelet-filters. The results support the idea that the visual system is relatively sensitive to the kurtosis, or 4th moment, of the wavelet histogram of textures. We argue that higher than 4th-order moments will, in practice, become increasingly difficult for the visual system to represent because the lack of a perfect match between the elements and the receptive fields effectively blurs the response histogram, thereby attenuating higher moments.

The roles of polarity and symmetry in the perceptual grouping of contour fragments.

We describe two experiments that investigate the roles of polarity and symmetry in the perceptual grouping of contour fragments. Observers viewed, for one second on each presentation, arrays of oriented, spatial-frequency band-pass, elements, in which a subset of the elements was aligned along a twisting curve. In each of five conditions we measured observers' ability to detect aligned combinations of even- and odd-symmetric elements, of the same and different polarities, against a background of 'noise' elements. As with previous experiments we found that the 'path' could be reliably detected, even when the elements of the path were oriented at angles of up to +/- 60 deg relative to each other. Detection of the path was still possible when the polarity of path elements alternated. However, the probability of detection of the path was raised significantly when the path elements were all of the same polarity. Perceptual grouping of even-symmetric elements was no different to perceptual grouping of odd-symmetric elements. The results provide evidence, that in achieving integration of contour fragments, the visual system uses a process that is to some degree phase selective. We use the results to describe how the visual system may resolve natural contours when they occur against backgrounds that vary over a wide range of intensities. The data presented here have been published in conference-abstract form (Hayes et al., 1993; Field et al., 1997).