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.

Synthetic lethality of yeast slt mutations with U2 small nuclear RNA mutations suggests functional interactions between U2 and U5 snRNPs that are important for both steps of pre-mRNA splicing.

A genetic screen was devised to identify Saccharomyces cerevisiae splicing factors that are important for the function of the 5' end of U2 snRNA. Six slt (stands for synthetic lethality with U2) mutants were isolated on the basis of synthetic lethality with a U2 snRNA mutation that perturbs the U2-U6 snRNA helix II interaction. SLT11 encodes a new splicing factor and SLT22 encodes a new RNA-dependent ATPase RNA helicase (D. Xu, S. Nouraini, D. Field, S. J. Tang, and J. D. Friesen, Nature 381:709-713, 1996). The remaining four slt mutations are new alleles of previously identified splicing genes: slt15, previously identified as prp17 (slt15/prp17-100), slt16/smd3-1, slt17/slu7-100, and slt21/prp8-21. slt11-1 and slt22-1 are synthetically lethal with mutations in the 3' end of U6 snRNA, a region that affects U2-U6 snRNA helix II; however, slt17/slu7-100 and slt21/prp8-21 are not. This difference suggests that the latter two factors are unlikely to be involved in interactions with U2-U6 snRNA helix II but rather are specific to interactions with U2 snRNA. Pairwise synthetic lethality was observed among slt11-1 (which affects the first step of splicing) and several second-step factors, including slt15/prp17-100, slt17/slu7-100, and prp16-1. Mutations in loop 1 of U5 snRNA, a region that is implicated in the alignment of the two exons, are synthetically lethal with slu4/prp17-2 and slu7-1 (D. Frank, B. Patterson, and C. Guthrie, Mol. Cell. Biol. 12:5179-5205, 1992), as well as with slt11-1, slt15/prp17-100, slt17/slu7-100, and slt21/prp8-21. These same U5 snRNA mutations also interact genetically with certain U2 snRNA mutations that lie in the helix I and helix II regions of the U2-U6 snRNA structure. Our results suggest interactions among U2 snRNA, U5 snRNA, and Slt protein factors that may be responsible for coupling and coordination of the two reactions of pre-mRNA splicing.

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.

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.

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.

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.

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.

Phase reversal discrimination.

In the Fourier representation of space, the parameter of phase plays a crucial role. In this study, several experiments were performed involving discrimination of various phase relations of fundamental (2 c/deg) to second harmonic (4 c/deg) at low contrast levels. The results were consistent with a model involving four "channels", each optimally sensitive to one of the following phase relations: + cosine (bright bar), -cosine (dark bar), +sine (left edge), and -sine (right edge).

Contour integration across depth.

In order to investigate the extent of the local connections subserving contour integration across depth, we measured performance for detecting the continuity of a path of Gabor elements distributed in depth and embedded in a three-dimensional field of random background elements. The results show that performance cannot be explained in terms of monocular performance and that contour information is not limited to single disparity planes. Path detection does indeed involve the integration of information across different, very disparate depth planes. The rules which emerge are in general similar to that already described in the two-dimensional case in as far as orientation and disparity are important. Unlike the two-dimensional case, three-dimensional integration operates over relatively large three-dimensional distances.

Sparse coding with an overcomplete basis set: a strategy employed by V1?

The spatial receptive fields of simple cells in mammalian striate cortex have been reasonably well described physiologically and can be characterized as being localized, oriented, and bandpass, comparable with the basis functions of wavelet transforms. Previously, we have shown that these receptive field properties may be accounted for in terms of a strategy for producing a sparse distribution of output activity in response to natural images. Here, in addition to describing this work in a more expansive fashion, we examine the neurobiological implications of sparse coding. Of particular interest is the case when the code is overcomplete--i.e., when the number of code elements is greater than the effective dimensionality of the input space. Because the basis functions are non-orthogonal and not linearly independent of each other, sparsifying the code will recruit only those basis functions necessary for representing a given input, and so the input-output function will deviate from being purely linear. These deviations from linearity provide a potential explanation for the weak forms of non-linearity observed in the response properties of cortical simple cells, and they further make predictions about the expected interactions among units in response to naturalistic stimuli.

Visual sensitivity, blur and the sources of variability in the amplitude spectra of natural scenes.

A number of researchers have suggested that in order to understand the response properties of cells in the visual pathway, we must consider the statistical structure of the natural environment. In this paper, we focus on one aspect of that structure, namely, the correlational structure which is described by the amplitude or power spectra of natural scenes. We propose that the principle insight one gains from considering the image spectra is in understanding the relative sensitivity of cells tuned to different spatial frequencies. This study employs a model in which the peak sensitivity is constant as a function of frequency with linear bandwith increasing (i.e., approximately constant in octaves). In such a model, the "response magnitude" (i.e., vector length) of cells increases as a function of their optimal (or central) spatial frequency out to about 20 cyc/deg. The result is a code in which the response to natural scenes, whose amplitude spectra typically fall as 1/f, is roughly constant out to 20 cyc/deg. An important consideration in evaluating this model of sensitivity is the fact that natural scenes show considerable variability in their amplitude spectra, with individual scenes showing falloffs which are often steeper or shallower than 1/f. Using a new measure of image structure (the "rectified contrast spectrum" or "RCS") on a set of calibrated natural images, it is shown that a large part of the variability in the spectra is due to differences in the sparseness of local structure at different scales. That is, an image which is "in focus" will have structure (e.g., edges) which has roughly the same magnitude across scale. That is, the loss of high frequency energy in some images is due to the reduction of the number of regions that contain structure rather than the amplitude of that structure. An "in focus" image will have structure (e.g., edges) across scale that have roughly equal magnitude but may vary in the area covered by structure. The slope of the RCS was found to provide a reasonable prediction of physical blur across a variety of scenes in spite of the variability in their amplitude spectra. It was also found to produce a good prediction of perceived blur as judged by human subjects.

Is the spatial deficit in strabismic amblyopia due to loss of cells or an uncalibrated disarray of cells?

We examine two competing explanations for the spatial localization deficit in human strabismic amblyopia, namely neural undersampling and uncalibrated neural disarray. An undersampling hypothesis would predict an associated deficit for contrast discrimination for which we find no evidence in strabismic amblyopia. A neural disarray hypothesis would predict an associated deficit in the degree to which stimuli appear spatially distorted. We find evidence for such a deficit in strabismic amblyopia. We propose that the spatial deficit in strabismic amblyopia is due to a filter-based distortion which is unable to be re-calibrated by higher visual centres.

What's constant in contrast constancy? The effects of scaling on the perceived contrast of bandpass patterns.

"Contrast constancy" refers to the ability to perceive objects as maintaining a constant contrast independent of size or distance. When tested with high contrast sinusoidal gratings, contrast constancy has been shown to hold for a wide range of spatial frequencies, suggesting that sensitivity is constant across the spectrum at suprathreshold. In this study, we show that contrast constancy also holds for relatively broadband patterns. We describe how the frequency spectra of such functions change as the patterns scale in size. In particular, we emphasize how these changes in the spectra depend on whether the functions are localized (coherent phase) or spatially distributed (incoherent phase). In Fourier terms, the scaling properties depend on the phase spectra of the patterns. Contrast constancy is shown to hold for both localized Gabor patches (coherent phase spectra) and bandpass noise patterns (incoherent phase spectra). Constancy holds over a wide range of suprathreshold contrasts; in fact, matching is quite accurate as soon as the pattern is suprathreshold. These results are explained with a model in which mechanism bandwidths increase with frequency (constant in octaves) and peak spectral sensitivity is equal across frequency out to around 16 c/deg. In the case of the Gabor stimuli, perceived contrast is assumed to be mediated by a mechanism centered on the patch. For the bandpass noise, contrast is determined by the average response of units distributed across the stimulus. This model can account for the matching data without assuming that the contrast-response gain of the underlying channels changes with spatial frequency. Neither does the model assume "response pooling". In addition to explaining the experimental results, the model also predicts that perceived contrast will be approximately constant across scale for scenes whose spectra fall as 1/f, as is typical of natural scenes.

Uncalibrated distortions vs undersampling.

In a recent paper of ours [Hess & Field (1993). Vision Research, 33, 2663-2670], we claim that there was a predictable relationship between position errors and contrast errors for an undersampled system. In this paper we re-state our main points. We feel that the response to that paper by Levi and Klein in the accompanying article does not require us to produce changes in our original position. We believe that the data support the notion that the principal causes of the positional errors in the normal periphery and the in the amblyopic visual system are due to uncalibrated distortions in the local signs of visual neurons. We believe that undersampling plays a major role in producing positional errors only in the far periphery at, or very near, the acuity limit. We maintain that our initial studies provide strong evidence that undersampling is insufficient as an explanation for the positional errors in the periphery of normals (Hess & Field, 1993) or the central field of amblyopes [Hess & Field (1994). Vision Research, 34, 3397-3406.

Contour integration in strabismic amblyopia: the sufficiency of an explanation based on positional uncertainty.

Contour integration was measured in a group of strabismic amblyopes to determine if an explanation based solely on positional uncertainty was sufficient to explain performance. The task involved the detection of paths composed of micropatterns with correlated carrier orientations embedded in a field of similar micropatterns of random position and orientation (Field et al. Contour integration by the human visual system; Evidence for a local "association field". Vision Research, 33, 173-193, 1993). The intrinsic positional uncertainty for each amblyopic eye was measured with the same stimulus and it was found that in 10 out of our 11 amblyopic subjects, the reduced performance of the amblyopic eye could be modelled by the normal eye with an equivalent amount of positional uncertainty added to the stimulus. We conclude that the rules by which cellular outputs are combined, at least as reflected by this task, are normal in amblyopia.

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.

Contour integration by the human visual system: evidence for a local "association field".

The Gestalt law of "good continuation" has been used to describe a variety of phenomena demonstrating the importance of continuity in human perception. In this study, we consider how continuity may be represented by a visual system that filters spatial data using arrays of cells selective for orientation and spatial frequency. Many structures (e.g. fractal contours) show a form of redundancy which is well represented by the continuity of features as they vary across space and frequency. We suggest that it is possible to take advantage of the redundancy in continuous, but non-aligned features by associating the outputs of filters with similar tuning. Five experiments were performed, to determine the rules that govern the perception of continuity. Observers were presented with arrays of oriented, band-pass elements (Gabor patches) in which a subset of the elements was aligned along a "jagged" path. Using a forced-choice procedure, observers were found to be capable of identifying the path within a field of randomly-oriented elements even when the spacing between the elements was considerably larger than the size of any of the individual elements. Furthermore, when the elements were oriented at angles up to +/- 60 deg relative to one another, the path was reliably identified. Alignment of the elements along the path was found to play a large role in the ability to detect the path. Small variations in the alignment or aligning the elements orthogonally (i.e. "side-to-side" as opposed to "end-to-end") significantly reduced the observer's ability to detect the presence of a path. The results are discussed in terms of an "association field" which integrates information across neighboring filters tuned to similar orientations. We suggest that some of the processes involved in texture segregation may have a similar explanation.