CXCL9 induces chemotaxis, chemorepulsion and endothelial barrier disruption through CXCR3-mediated activation of melanoma cells.

BACKGROUND: Metastasis is associated with poor prognosis for melanoma. The formation of metastases is a multi-step process, in which cancer cells can subsequently acquire the potential to intravasate into the blood or lymph vessels, disseminate through the circulation, extravasate through the endothelium and invade the connective tissue. There is increasing evidence that chemokines have a pivotal role in the dissemination and establishment of melanoma metastasis. METHODS: We isolated melanoma cells from melanoma metastasis and performed different migration assays and transendothelial resistance measurements of endothelial monolayers co-cultured with melanoma cells, in order to monitor barrier function and diapedesis and confirmed these results by confocal microscopy. RESULTS: We observed that tumour endothelial cells (ECs) secrete high levels of CXCL9 in all, and CXCL10 in most melanoma metastases. Migration studies revealed that low concentrations of these chemokines induce chemotaxis, whereas high concentrations induce spontaneous migration of melanoma cells (chemokinesis/chemorepulsion) and the disruption of the endothelial barrier, resulting in an accelerated transendothelial migration (TEM). Addition of anti-CXCL9 or anti-CXCR3 antibodies to the co-cultures delayed the TEM of melanoma cells. CONCLUSION: Our data represent novel mechanisms by which tumour cells in melanoma metastases might use the chemokine-expressing endothelium to leave the tumour and eventually to form additional metastases at distinct sites.

Revisiting traditional risk factors for rejection and graft loss after kidney transplantation.

Single-antigen bead (SAB) testing permits reassessment of immunologic risk for kidney transplantation. Traditionally, high panel reactive antibody (PRA), retransplant and deceased donor (DD) grafts have been associated with increased risk. We hypothesized that this risk was likely mediated by (unrecognized) donor-specific antibody (DSA). We grouped 587 kidney transplants using clinical history and single-antigen bead (SAB) testing of day of transplant serum as (1) unsensitized; PRA = 0 (n = 178), (2) third-party sensitized; no DSA (n = 363) or (3) donor sensitized; with DSA (n = 46), and studied rejection rates, death-censored graft survival (DCGS) and risk factors for rejection. Antibody-mediated rejection (AMR) rates were increased with DSA (p < 0.0001), but not with panel reactive antibody (PRA) in the absence of DSA. Cell-mediated rejection (CMR) rates were increased with DSA (p < 0.005); with a trend to increased rates when PRA>0 in the absence of DSA (p = 0.08). Multivariate analyses showed risk factors for AMR were DSA, worse HLA matching, and female gender; for CMR: DSA, PRA>0 and worse HLA matching. AMR and CMR were associated with decreased DCGS. The presence of DSA is an important predictor of rejection risk, in contrast to traditional risk factors. Further development of immunosuppressive protocols will be facilitated by stratification of rejection risk by donor sensitization.

Macrophage inflammatory protein 3alpha is involved in the constitutive trafficking of epidermal langerhans cells.

Certain types of dendritic cells (DCs) appear in inflammatory lesions of various etiologies, whereas other DCs, e.g., Langerhans cells (LCs), populate peripheral organs constitutively. Until now, the molecular mechanism behind such differential behavior has not been elucidated. Here, we show that CD1a(+) LC precursors respond selectively and specifically to the CC chemokine macrophage inflammatory protein (MIP)-3alpha. In contrast, CD14(+) precursors of DC and monocytes are not attracted by MIP-3alpha. LCs lose the migratory responsiveness to MIP-3alpha during their maturation, and non-LC DCs do not acquire MIP-3alpha sensitivity. The notion that MIP-3alpha may be responsible for selective LC recruitment into the epidermis is further supported by the following observations: (a) MIP-3alpha is expressed by keratinocytes and venular endothelial cells in clinically normal appearing human skin; (b) LCs express CC chemokine receptor (CCR)6, the sole MIP-3alpha receptor both in situ and in vitro; and (c) non-LC DCs that are not found in normal epidermis lack CCR6. The mature forms of LCs and non-LC DCs display comparable sensitivity for MIP-3beta, a CCR7 ligand, suggesting that DC subtype-specific chemokine responses are restricted to the committed precursor stage. Although LC precursors express primarily CCR6, non-LC DC precursors display a broad chemokine receptor repertoire. These findings reflect a scenario where the differential expression of chemokine receptors by two different subpopulations of DCs determines their functional behavior. One type, the LC, responds to MIP-3alpha and enters skin to screen the epidermis constitutively, whereas the other type, the "inflammatory" DC, migrates in response to a wide array of different chemokines and is involved in the amplification and modulation of the inflammatory tissue response.

Cytokines regulate proteolysis in major histocompatibility complex class II-dependent antigen presentation by dendritic cells.

Endo/lysosomal proteases control two key events in antigen (Ag) presentation: the degradation of protein Ag and the generation of peptide-receptive major histocompatibility complex (MHC) class II molecules. Here we show that the proinflammatory cytokines tumor necrosis factor alpha and interleukin (IL)-1beta rapidly increase the activity of cathepsin (cat) S and catB in human dendritic cells (DCs). As a consequence, a wave of MHC class II sodium dodecyl sulfate stable dimer formation ensues in a catS-dependent fashion. In contrast, the antiinflammatory cytokine IL-10 renders DCs incapable of upregulating catS and catB activity and in fact, attenuates the level of both enzymes. Suppressed catS and catB activity delays MHC class II sodium dodecyl sulfate stable dimer formation and impairs Ag degradation. In DCs exposed to tetanus toxoid, IL-10 accordingly reduces the number of MHC class II-peptide complexes accessible to tetanus toxoid-specific T cell receptors, as analyzed by measuring T cell receptor downregulation in Ag-specific T cell clones. Thus, the control of protease activity by pro- and antiinflammatory cytokines is an essential feature of the Ag presentation properties of DCs.

Epidermal Langerhans cells from normal human skin bind monomeric IgE via Fc epsilon RI.

Human epidermal Langerhans cells (LC) bearing IgE are found in disease states associated with hyperimmunoglobulinemia E. When studying the mechanism(s) underlying this phenomenon, immunohistology revealed that a majority of epidermal LC from normal skin of healthy individuals can specifically bind monomeric IgE. IgE binding to LC could neither be prevented by preincubation of the tissue with monoclonal antibodies (mAb) against either Fc epsilon RII/CD23 or Fc gamma RII/CD32, nor by the addition of lactose. However, binding could be entirely abrogated by preincubation with the anti-Fc epsilon RI alpha mAb 15-1, which interferes with IgE binding to Fc epsilon RI alpha gamma transfectants. These observations indicated that IgE binding to epidermal LC is mediated by Fc epsilon RI rather than by CD23, CD32, or the D-galactose-specific IgE-binding protein. This assumption gained support from our additional findings that: (a) the majority of LC exhibited distinct surface immunolabeling with the anti-Fc epsilon RI alpha mAbs 15-1 and 19-1, but not with any of eight different anti-Fc epsilon RII/CD23 mAbs; and (b) transcripts for the alpha, beta, and gamma chains of Fc epsilon RI could be amplified by polymerase chain reaction from RNA preparations of LC-enriched, but not of LC-depleted, epidermal cell suspensions. In view of the preeminent role of Fc epsilon RI crosslinking on mast cells and basophils in triggering the synthesis and release of mediators of allergic reactions, the demonstration of this receptor on epidermal LC may have important implications for our understanding of allergic reactions after epicutaneous contact with allergens.

Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages.

A plexus of lymphatic vessels guides interstitial fluid, passenger leukocytes, and tumor cells toward regional lymph nodes. Microvascular endothelial cells (ECs) of lymph channels (LECs) are difficult to distinguish from those of blood vessels (BECs) because both express a similar set of markers, such as CD31, CD34, podocalyxin, von Willebrand factor (vWF), etc. Analysis of the specific properties of LECs was hampered so far by lack of tools to isolate LECs. Recently, the 38-kD mucoprotein podoplanin was found to be expressed by microvascular LECs but not BECs in vivo. Here we isolated for the first time podoplanin(+) LECs and podoplanin(-) BECs from dermal cell suspensions by multicolor flow cytometry. Both EC types were propagated and stably expressed VE-cadherin, CD31, and vWF. Molecules selectively displayed by LECs in vivo, i.e., podoplanin, the hyaluronate receptor LYVE-1, and the vascular endothelial cell growth factor (VEGF)-C receptor, fms-like tyrosine kinase 4 (Flt-4)/VEGFR-3, were strongly expressed by expanded LECs, but not BECs. Conversely, BECs but not LECs expressed VEGF-C. LECs as well as BECs formed junctional contacts with similar molecular composition and ultrastructural features. Nevertheless, the two EC types assembled in vitro in vascular tubes in a strictly homotypic fashion. This EC specialization extends to the secretion of biologically relevant chemotactic factors: LECs, but not BECs, constitutively secrete the CC chemokine receptor (CCR)7 ligand secondary lymphoid tissue chemokine (SLC)/CCL21 at their basal side, while both subsets, upon activation, release macrophage inflammatory protein (MIP)-3alpha/CCL20 apically. These results demonstrate that LECs and BECs constitute stable and specialized EC lineages equipped with the potential to navigate leukocytes and, perhaps also, tumor cells into and out of the tissues.

Activated human T lymphocytes express MHC class I heavy chains not associated with beta 2-microglobulin.

We present here the molecular characterization of a new activation-induced surface structure on human T lymphocytes, termed LA45, with high homology (93% at protein level) to MHC class I molecules. Antigen modulation and sequential immunoprecipitation experiments revealed that LA45 and HLA class I proteins do not crossreact with the corresponding antibodies. Furthermore, LA45 is not associated with beta 2-m. On the other hand, we could show that the separation of HLA-A,B,C and beta 2m molecules, induced by SDS-denaturation, leads to a conformational change in the heavy chain in such a way that it becomes reactive with LA45. The 90/45 kD LA45 proteins thus appear to be non-beta 2m-associated MHC class I alpha chains that are selectively expressed by activated but not by resting human T lymphocytes.

Expression of functional high affinity immunoglobulin E receptors (Fc epsilon RI) on monocytes of atopic individuals.

Suggestive evidence indicates that immunoglobulin E (IgE)-dependent activation of mononuclear phagocytes plays an important pathogenic role in allergic tissue inflammation. Prevailing opinion holds that low affinity IgE receptors are the relevant IgE-binding structures on monocytes/macrophages and that functional events occurring after cross-linking of membrane-bound IgE on these cells are mediated by these receptors. Here we demonstrate that peripheral blood monocytes can bind monomeric IgE via the high affinity IgE receptor (Fc epsilon RI) and that Fc epsilon RI expression on these cells is upregulated in atopic persons. Further, we demonstrate that, upon monocyte adherence to substrate, bridging of monocyte Fc epsilon RI is followed by cell activation. We propose that direct interaction of multivalent allergen with Fc epsilon RI(+)-bound IgE on mononuclear phagocytes results in cell signaling via Fc epsilon RI and that the biological consequences of this event may critically influence the outcome of allergic reactions.

Rapid improvement in the acuity of infants after visual input.

Visual acuity was assessed in 28 human infants who had been deprived of all patterned visual input by cataracts in one or both eyes until they were treated at 1 week to 9 months of age. Immediately after treatment, acuity was no better than that of normal newborns. Acuity improved significantly over the next month, with some improvement apparent after as little as 1 hour of visual input. Unlike findings at older ages, the pattern of results was the same for eyes treated for monocular and for binocular deprivation. The results indicate that patterned visual input is necessary for the postnatal improvement of human visual acuity and that the onset of such input initiates rapid functional development.

Processes that determine the interplay of root exudation, methane emission and yield in rice agriculture.

Rice is the most important staple food for half of the world's population, but also accounts for about 10% of all anthropogenic CH4 emissions. In spite of a wealth of information on the mechanistic basis and the importance of the rice plant in mediating these emissions, the significance of root exudation for CH4 emissions and the processes that determine root exudation are not well understood. Root exudates derive from photosynthate allocated to the root and subjected to root anabolic and catabolic processes. Key processes in roots that determine the extent of root exudation and, hence, CH4 emission from rice agriculture, include (i) deviation of metabolites from root anabolic and catabolic pathways facilitating root exudation, but also (ii) xylem loading and transport of potential root exudates for reallocation to the leaves, and (iii) xylem loading of sucrose in roots for its transport into reproductive organs, both suppressing root exudation. These processes are modulated by plant development and metabolic requirements resulting from different functions of root exudation. In the present report the interplay of root exudation, CH4 emission and yield are discussed.

Reproducibility of length measurements of the lower limb by using EOS™.

BACKGROUND: Lower-limb discrepancy following total hip arthroplasty is the third-most common reason for patient dissatisfaction in orthopaedic surgery. Therefore, accurate planning and evaluation methods are mandatory. The main aim of this study was to evaluate the reliability of the EOS™ system by establishing and comparing the reproducibility of lower-limb automatic and manual 3D measurements. We hypothesized that the reproducibility of the lower-limb measurements is similar regardless of the method used and with an agreement higher than 0.95 for the length parameters. MATERIALS AND METHODS: This study utilized an EOS radiological database of 112 patients. Two independent observers performed two rounds of lower-limb measurements twice, either in manual 3D or automatic 3D mode. The intra- and inter-observer reproducibility was evaluated by the calculation of the intra-class coefficient for each measurement method. The methods were then compared. RESULTS: The intra- and inter-observer reproducibility for length measurements found with the manual and automatic 3D methods was always > 0.98. There was no significant difference in the reproducibility between the two measurement modes, with the exception of the offset, hip-knee-shaft, and neck-shaft angles. CONCLUSION: Our results indicate a very good reproducibility of EOS™ length measurement, regardless of the method used. Automated 3D mode is preferred for the collection of angular and offset measurements. Furthermore, manual mode measurements are not affected by surgical history. Level of evidence IV.

In situ wavelength calibration system for the X-ray Imaging Crystal Spectrometer (XICS) on W7-X.

An in situ wavelength calibration system for the X-ray Imaging Crystal Spectrometer (XICS) on W7-X has been developed to provide routine calibration between plasma shots. XICS is able to determine plasma flow profiles by measuring the Doppler shift of x-ray line emission from highly charged impurity species. A novel design is described that uses an x-ray tube with a cadmium anode placed in front of the diffracting spherically bent crystal. This arrangement provides calibration lines over the full detector extent for both the Ar16+ and Ar17+/Fe24+ spectrometer channels. This calibration system can provide a relative wavelength accuracy of 3 × 10-7 Å across the full spatial extent of the detector, which corresponds to 50 m/s in the W7-X system. An absolute wavelength calibration of 1 × 10-5 Å is expected, corresponding to 1 km/s, based on the current known accuracy of the calibration wavelength and the achievable measurement of the absolute positioning of the hardware. This calibration system can be used to independently calibrate XICS systems on both stellarators and tokamaks, without the need for special plasma conditions often used for calibration, such as locked modes on tokamaks. Experimental and simulated results are shown along with expected results, and the complete design of the calibration hardware that is to be installed in the W7-X XICS system.

Anti-FcepsilonRIalpha autoantibodies in autoimmune-mediated disorders. Identification of a structure-function relationship.

Anti-FcepsilonRIalpha autoantibodies (autoAbs) occur and may be of pathogenetic relevance in a subset of chronic urticaria (CU) patients. To analyze the prevalence and magnitude of the humoral anti-FcepsilonRIalpha response in cohorts of CU patients compared with individuals suffering from classic skin- related (auto)immune diseases, we developed an ELISA system for the measurement of anti-FcepsilonRIalpha autoAbs in nonfractionated serum samples. Results obtained using this assay correlated well with those generated by Western blotting. We found IgG anti-FcepsilonRIalpha autoreactivity in 38% of CU patients but not in atopic dermatitis patients, psoriatics, or healthy individuals. We frequently detected anti-FcepsilonRIalpha autoAbs in pemphigus vulgaris (PV, 39%), dermatomyositis (DM, 36%), systemic lupus erythematosus (SLE, 20%), and bullous pemphigoid (BP, 13%). While the autoAb titers in DM, SLE, BP, and PV were similar to those encountered in CU patients, only anti-FcepsilonRIalpha+ CU serum specimens displayed pronounced histamine-releasing activity. The anti-FcepsilonRIalpha autoAbs in CU patients belong predominantly to the complement-fixing subtypes IgG1 and IgG3, whereas in DM, PV, and BP, they were found to be mainly of the IgG2 or IgG4 subtype. Complement-activating properties of anti-FcepsilonRIalpha autoAbs can indeed be of pathogenetic relevance, because C5a receptor blockade on basophils as well as decomplementation reduced drastically the histamine-releasing capacity of most anti-FcepsilonRIalpha-reactive CU sera. As a consequence, therapeutic efforts in CU should aim at altering not only the quantity but also the complement-activating properties of IgG anti-FcepsilonRIalpha autoAbs.

Serum IgG autoantibodies directed against the alpha chain of Fc epsilon RI: a selective marker and pathogenetic factor for a distinct subset of chronic urticaria patients?

While it is well established that acute allergic urticaria is caused by degranulation of skin mast cells occurring after allergen/IgE-dependent cross-linking of high affinity IgE receptors (FcepsilonRI), the pathophysiologic mechanisms operative in chronic urticaria (CU) are less well understood. Some evidence points to the existence of histamine-releasing activity in the serum of CU patients which possibly acts via triggering of FcepsilonRI. In this study, we aimed to better characterize this anti-FcepsilonRIalpha reactivity of CU patients using affinity-purified, IgE-depleted IgG fractions of such individuals (CU-IgG). Using immobilized, recombinant soluble FcepsilonRIalpha as a a reaction target for Western blot studies, we found that 12/32 (37%) CU-IgG serum samples exhibited IgG autoreactivity against FcepsilonRI- alpha. These findings were confirmed by experiments demonstrating that immunoblot-reactive, but not immunoblot-nonreactive, CU-IgG preparations precipitated the FcepsilonRIalpha from FcepsilonRI- alphagamma-transfected cells. No anti-FcepsilonRIalpha reactivity was observed in IgG fractions from atopic dermatitis (AD) patients (0/15) or healthy control individuals (CO:0/15). As opposed to the selective occurrence of IgG anti-Fc epsilon RI alpha autoantibodies in CU patients, IgG anti-IgE antibodies were detected in all groups investigated (CU: 69%; AD: 73%; CO: 26%). While both types of autoantibodies can exhibit histamine-releasing properties, not all of the autoantibodies proved to be functional in vitro. Our results indicate that the occurrence of IgG anti-FcepsilonRIalpha reactivity defines an autoimmune-mediated subentity of CU and provide a basis for the development of new diagnostic procedures and, perhaps, therapeutic strategies for this disease.

Neural correlates of processing facial identity based on features versus their spacing.

Adults' expertise in recognizing facial identity involves encoding subtle differences among faces in the shape of individual facial features (featural processing) and in the spacing among features (a type of configural processing called sensitivity to second-order relations). We used fMRI to investigate the neural mechanisms that differentiate these two types of processing. Participants made same/different judgments about pairs of faces that differed only in the shape of the eyes and mouth, with minimal differences in spacing (featural blocks), or pairs of faces that had identical features but differed in the positions of those features (spacing blocks). From a localizer scan with faces, objects, and houses, we identified regions with comparatively more activity for faces, including the fusiform face area (FFA) in the right fusiform gyrus, other extrastriate regions, and prefrontal cortices. Contrasts between the featural and spacing conditions revealed distributed patterns of activity differentiating the two conditions. A region of the right fusiform gyrus (near but not overlapping the localized FFA) showed greater activity during the spacing task, along with multiple areas of right frontal cortex, whereas left prefrontal activity increased for featural processing. These patterns of activity were not related to differences in performance between the two tasks. The results indicate that the processing of facial features is distinct from the processing of second-order relations in faces, and that these functions are mediated by separate and lateralized networks involving the right fusiform gyrus, although the FFA as defined from a localizer scan is not differentially involved.

Anti-IgE and anti-Fc epsilon RI autoantibodies in clinical allergy.

Autoantibodies recognizing critical effector molecules of type I allergic reactions have been identified. Anti-IgE autoantibodies occur at high frequencies not only in atopic diseases but also in healthy individuals and, depending on their epitope specificities, may promote or prevent the elicitation of allergic symptoms. In contrast, anti-Fc epsilon RI autoantibodies with basophil/mast cell activating properties were selectively found in patients with chronic urticaria, a condition characterized by the continuous degranulation of mast cells. Thus, humoral anti-Fc epsilon RI autoreactivity defines a distinctive subset of chronic urticaria and may well be the causative and pathogenetic principle in this disease.

Orientation dependence of trinucleotide CAG repeat instability in Saccharomyces cerevisiae.

To examine the chromosomal stability of repetitions of the trinucleotide CAG, we have cloned CAG repeat tracts onto the 3' end of the Saccharomyces cerevisiae ADE2 gene and placed the appended gene into the ARO2 locus of chromosome VII. Examination of chromosomal DNA from sibling colonies arising from clonal expansion of strains harboring repeat tracts showed that repeat tracts often change in length. Most changes in tract length are decreases, but rare increases also occur. Longer tracts are more unstable than smaller tracts. The most unstable tracts, of 80 to 90 repeats, undergo changes at rates as high as 3 x 10(-2) changes per cell per generation. To examine whether repeat orientation or adjacent sequences alter repeat stability, we constructed strains with repeat tracts in both orientations, either with or without sequences 5' to ADE2 harboring an autonomously replicating sequence (ARS; replication origin). When CAG is in the ADE2 coding strand of strains harboring the ARS, the repeat tract is relatively stable regardless of the orientation of ADE2. When CTG is in the ADE2 coding strand of strains harboring the ARS, the repeat tract is relatively unstable regardless of the orientation of ADE2. Removal of the ARS as well as other sequences adjacent to the 5' end of ADE2 alters the orientation dependence such that stability now depends on the orientation of ADE2 in the chromosome. These results suggest that the proximity of an ARS or another sequence has a profound effect on repeat stability.

Mapping the polarity of changes that occur in interrupted CAG repeat tracts in yeast.

To explore the mechanisms by which CAG trinucleotide repeat tracts undergo length changes in yeast cells, we examined the polarity of alterations with respect to an interrupting CAT trinucleotide near the center of the tract. In wild-type cells, in which most tract changes are large contractions, the changes that retain the interruption are biased toward the 3' end of the repeat tract (in reference to the direction of lagging-strand synthesis). In rth1/rad27 mutant cells that are defective in Okazaki fragment maturation, the tract expansions are biased to the 5' end of the repeat tract, while the tract contractions that do not remove the interruption occur randomly on either side of the interruption. In msh2 mutant cells that are defective in the mismatch repair machinery, neither the small changes of one or two repeat units nor the larger contractions attributable to this mutation are biased to either side of the interruption. The results of this study are discussed in terms of the molecular paths leading to expansions and contractions of repeat tracts.

Anterior knee pain and evidence of osteoarthritis of the patellofemoral joint should not be considered contraindications to mobile-bearing unicompartmental knee arthroplasty: a 15-year follow-up.

AIMS: It is not clear whether anterior knee pain and osteoarthritis (OA) of the patellofemoral joint (PFJ) are contraindications to medial unicompartmental knee arthroplasty (UKA). Our aim was to investigate the long-term outcome of a consecutive series of patients, some of whom had anterior knee pain and PFJ OA managed with UKA. PATIENTS AND METHODS: We assessed the ten-year functional outcomes and 15-year implant survival of 805 knees (677 patients) following medial mobile-bearing UKA. The intra-operative status of the PFJ was documented and, with the exception of bone loss with grooving to the lateral side, neither the clinical or radiological state of the PFJ nor the presence of anterior knee pain were considered a contraindication. The impact of radiographic findings and anterior knee pain was studied in a subgroup of 100 knees (91 patients). RESULTS: There was no relationship between functional outcomes, at a mean of ten years, or 15-year implant survival, and pre-operative anterior knee pain, or the presence or degree of cartilage loss documented intra-operatively at the medial patella or trochlea, or radiographic evidence of OA in the medial side of the PFJ. In 6% of cases there was full thickness cartilage loss on the lateral side of the patella. In these cases, the overall ten-year function and 15-year survival was similar to those without cartilage loss; however they had slightly more difficulty with descending stairs. Radiographic signs of OA seen in the lateral part of the PFJ were not associated with a definite compromise in functional outcome or implant survival. CONCLUSION: Severe damage to the lateral side of the PFJ with bone loss and grooving remains a contraindication to mobile-bearing UKA. Less severe damage to the lateral side of the PFJ and damage to the medial side, however severe, does not compromise the overall function or survival, so should not be considered to be a contraindication. However, if a patient does have full thickness cartilage loss on the lateral side of the PFJ they may have a slight compromise in their ability to descend stairs. Pre-operative anterior knee pain also does not compromise the functional outcome or survival and should not be considered to be a contraindication. Cite this article: Bone Joint J 2017;99-B:632-9.

Deficits in the processing of local and global motion in very low birthweight children.

This study evaluated the impact of premature birth on the development of local and global motion processing in a group of very low birthweight (<1500 g), 5- to 8-year-old children. Sensitivity to first- and second-order local motion stimuli and coherence thresholds for global motion in random dot kinematograms were measured. Relative to full-term controls, premature children showed deficits on all three aspects of motion processing. These problems could not be accounted for by stereo deficits, amblyopia, or attentional problems. A history of mild retinopathy of prematurity and/or intraventricular hemorrhage increased risk, but deficits were observed in some children with no apparent ocular or cerebral pathology. It is important to note that, despite the observed group differences, individual profiles of performance did vary; the results suggest that these three forms of motion processing may involve separate neural mechanisms. These findings serve to increase our understanding of the organization and functional development of motion-processing subsystems in humans, and of the impact of prematurity and associated complications on visual development.