Cerebral Palsy

COVER IMAGE: The cover image depicts the co-staining of DC-SIGN and EEA-1 in dendritic cells and shows the co-localization of the endocytosed ligand with markers of the early endosomal compartments. The image was taken from the article by Cambi et al. (pp. 1923-1929), in which the authors analyze the role of the C-type lectin DC-SIGN in viral entry. The authors show that DC-SIGN is involved in clathrin-dependent HIV-1 internalization by dendritic cells. HUMAN NEONATES PROTECTED BY INTRA-UTERINE CONDITIONING OF gammadelta T CELLS: pp. 1794-1806There is emerging evidence in mice that gammadelta cells acquire “hard-wired” functional competences during development, as opposed to the plastic, context-driven differentiation of conventional alphabeta T cells. Such hard-wired responses might be wellsuited to meeting the precipitous challenge of neonatal pathogen exposure. In this issue, Gibbons et al provide data from human neonates that are highly consistent with this. gammadelta cells were competent to produce IFN immediately upon birth, even 10 weeks preterm, and levels were not substantially changed after one month’s environmental exposure. Moreover, by contrast to alphabeta T cells, neonatal gammadelta cells showed precocious production of several cytokines, suggesting that, as in the mouse, gammadelta cells make disproportionately strong contributions to neonatal immunity. The study also shows that gammadelta cells in preterm babies often have functional defects in TLR3 and TLR7 expression, possibly contributing to the wellestablished problems of premature babies in handling infections such as Herpes. DX5+ CD4+ TREG CAN REGULATE CD8+ T-CELL PRIMING: pp. 1765-1773In recent years, many different T-cell populations with regulatory activities have been described. A novel subset of regulatory CD4(+) T cells, DX5(+)CD4(+) Treg, has potent regulatory capacities in autoimmune disease models such as diabetes and collagen-induced arthritis. In this issue, Han et al. demonstrate a novel role of this enigmatic T-cell population in the regulation of CD8(+) T-cell priming. Vaccination with antigen-loaded mature DC induces CD8(+) T-cell responses. Surprisingly, depletion of CD4(+) cells or vaccination with MHC class II-deficient DC boosted CD8(+) T-cell induction considerably. This was inversely correlated with induction and expansion of DX5(+)CD4(+) T cells. In vitro, DX5(+)CD4(+) T cells were able to inhibit CD8(+) T-cell stimulation. Thus, antigen-presenting mature DC initiate a CD8(+) T-cell response; however, simultaneously induce DX5(+)CD4(+) T cells that can limit the magnitude of the CD8(+) T-cell response. IT NEEDS MORE THAN TWO TO TANGO: pp. 1736-1742In recent years the central role of costimulatory molecules in modifying immune responses became increasingly clear and turned them into attractive targets for therapeutic strategies. In this issue, Polte et al. demonstrate that the absence of CD30, previously shown by the same group to play a crucial role in the development of acute allergic asthma, does not affect the long-term outcome of this disease in a chronic model. This discrepancy between the acute and chronic situation might be explained by the compensation of CD30 function by OX40, another costimulatory molecule, over time. The authors show that it is difficult to directly transfer the knowledge you gain from acute models to chronic models of the same disease. It takes two to activate a T cell but it seems that there are more partners in the stand-by position helping out when one of the activating partners is missing or failing. The activation of the T cells might start as a tango but than might turn into an ensemble dance over time. TNF-alpha IN INTESTINAL INFLAMMATION: NOT JUST A BAD GUY: pp. 1743-1753TNF-alpha plays a central role in the pathogenesis of inflammatory bowel disease (IBD) and treatment of patients with a TNF-specific mAb significantly ameliorates disease. TNF-alpha signals through TNFR1 or TNFR2 with different functional outcomes. Since expression of TNFR2 is upregulated in IBD, selective targeting of TNFR2 may represent a more specific treatment than complete blocking of TNF-alpha. In this issue, Dayer Schneider et al. assessed the role of TNFR2 in the CD4(+) T-cell transfer model of colitis using TNFR2(-/-) or WT mice as donors of colitogenic CD4(+)CD45RB(hi) T cells for transfer into RAG2(-/-) or RAG2(-/-)TNFR2(-/-) recipient mice. Intriguingly, absence of TNFR2 on nonlymphoid cells of the recipient mice does not influence the course of colitis while lack of TNFR2 expression by the colitogenic T cells exacerbates disease. Employing a co-transfer of WT and TNFR2 CD4(+) T cells, the authors further show that the enhanced colitogenic potential of TNFR2(-/-) T cells relates to their increased accumulation in vivo due to a reduced susceptibility to activation-induced cell death. This study demonstrates an unanticipated protective role for TNFR2 mediated signaling during intestinal inflammation. THE POLICEMAN OF THE ABDOMEN NO LONGER UNDER COVER: pp. 1893-1901Therapeutic activation of invariant natural killer T (iNKT) cells can prevent and reverse tumor growth in murine models. Clinical trials involving iNKT cells have been disappointing, however, partly because 100-fold lower NKT cells are found in humans than mice. In this issue, Lynch et al. demonstrate that the human omentum contains large numbers of functional iNKT cells, which are reduced in patients with obesity and malignancy. The omentum is an adipocyte-rich peritoneal fold that surrounds the organs in the abdomen. As well as storing fat, the omentum can act as ‘policeman of the abdomen’ by migrating to sites of inflammation, infection and injury, where it limits the spread of infection and contributes to wound repair. Omental tissue is surgically accessible and omental iNKT cells show potent cytotoxic activity and rapid cytokine secretion. They may therefore have exciting therapeutic potential as antitumor effectors for adoptive immunotherapy.

Lithium-induced glomerular toxicity is an infrequent occurrence in pediatric patients. We report a 13-year-old patient presenting with clinical and laboratory evidence of renal insufficiency after long-term lithium use. Biopsy revealed membranous glomerulonephropathy. Discontinuation of the lithium treatment resulted in resolution of the symptoms and laboratory abnormalities. Other alkali metals have been implicated as risk factors for membranous glomerulonephropathy. To the best of our knowledge, this is the first reported case of lithium-induced glomerulonephropathy in a pediatric patient.

OBJECTIVE:: To summarize the practical operation of temporary pacemakers in common use pertinent to the intensivist caring for the postcardiac patient. Pacemaker therapy is commonly required in the postoperative period after congenital cardiac surgery. DATA SYNTHESIS:: Monitoring the hemodynamic status and availability of equipment for resuscitation is always important in any patient requiring a temporary pacemaker. Two important scenarios to consider in the pediatric intensive care unit are: 1) the patient in whom pacing has been initiated to optimize cardiac function; and 2) the patient without demonstrable spontaneous electrical activity or with extreme bradycardia. A number of different models of temporary pacemaker are available. Management of the child requiring cardiac pacing requires an understanding of the indications for pacing, a thorough knowledge of the available pacemaker, and an ability to troubleshoot problems. CONCLUSIONS:: As the most common arrhythmias post congenital cardiac surgery involve either rate or conduction abnormalities, temporary pacemaker systems are a common form of electrical therapy in the postoperative period.

Background: In up to 20% of patients with renal cell cancer (RCC) an inflammatory response consisting of low-grade fever, weight loss and an elevated ESR and CRP may occur with modest granulocytosis and thrombocytosis. Clinical and experimental data suggest a pathogenic role for tumour-derived cytokine production, especially interleukin-6. Case report: A 79-year-old female with RCC presented with low-grade fever, weight loss and overt granulocytosis and thrombocytosis. Radiological examination revealed a right-sided renal tumour. During nephrectomy a gradient between the IL-6 levels in the renal artery and vein was demonstrated, providing direct evidence for in vivo production of IL-6 by the tumour affected kidney, which was confirmed by the demonstration of IL -6 in the tumour cells by immunohistochemical staining and in the supernatant of the homogenised tumour. Cytogenetic examination revealed complex abnormalities including a gain of chromosome 7. In addition we demonstrated production of IL-1α, IL-1β, IL-8 and ICAM-1 in the tumour with systemic elevated levels of IL-6 and IL-8 with secondary increased serum G-CSF and TPO levels. Conclusion: We have provided direct evidence for the production of pro-inflammatory cytokines by renal cancer cells in a patient with RCC and a profound inflammatory response, with a central role of IL-6, probably due to a gain of chromosome 7. The extreme granulocytosis and thrombocytosis may have resulted from the secondary systemic production of G-CSF and TPO.

Magnesium homeostasis is essential for many intracellular processes and depends on the balance of intestinal absorption and renal excretion. Hypomagnesaemia may arise from various disorders. We review the literature on hypomagnesaemia due to the use of proton pump inhibitors, as illustrated by a case of a 76-year-old woman with muscle cramps and lethargy caused by hypomagnesaemia and hypocalcaemia with a low parathyroid hormone level while using esomeprazole, a proton pump inhibitor (PPI). After oral magnesium repletion both abnormalities resolved. Fractional magnesium excretion was low, excluding excessive renal loss. A causal relation with PPI use was supported by the recurrence of hypomagnesaemia after rechallenge. In the past decade our understanding of transcellular magnesium transport was enhanced by the discovery of several gene mutations i.e. transient receptor potential melastin (TR PM) 6 and 7. In this light we discuss the possible aetiology of proton pump inhibitor related hypomagnesaemia.

BACKGROUND: Concern is growing about missed test results, but data assessing their effect on patient safety are limited. OBJECTIVE: To examine the frequency with which computed tomography (CT)-documented dilations of the abdominal aorta are accompanied by evidence in the electronic medical record (EMR) that a clinician recognized the abnormality. DESIGN: Retrospective cohort study. SETTING: 2 hospitals in the Veterans Affairs Health Care System. PATIENTS: Patients with new dilations of the abdominal aorta detected on CT performed in 2003. MEASUREMENTS: Radiology report and EMR evidence that the radiologist notified the clinical service, aneurysm size, and interval between CT and EMR recognition. RESULTS: Computed tomography scans of 4112 patients were reviewed and 440 (11%) aortic dilations were identified, of which 91 were new findings. Radiologists directly notified clinical teams about 5 (5%) new dilations. Clinical teams did not record in the EMR recognition of 53 of 91 (58%) dilations within 3 months of the CT, and 9% of these dilations were 5.5 cm or larger. The median time to recognition of aneurysm in the EMR was 237 days, and no EMR documentation existed for 16 abnormalities (29% of surviving patients) during a mean follow-up of 3.2 years. No evidence indicated that any of the aneurysms ruptured or that patient deaths resulted from the delayed follow-up. Limitation: Clinicians may have recognized some aneurysms but did not document them in the EMR. CONCLUSION: Clinicians neglect to note a substantial proportion of new aortic dilations in the EMR. The findings highlight the need for better strategies to ensure documentation of follow-up of tests. Primary Funding Source: National Institutes of Health.

The t(8:21)(q22;q22) translocation is 1 of the most common chromosomal abnormalities linked to acute myeloid leukemia (AML). AML1-ETO, the product of this translocation, fuses the N-terminal portion of the RUNX transcription factor AML1 (also known as RUNX1), including its DNA-binding domain, to the almost entire transcriptional corepressor ETO (also known as MTG8 or RUNX1T1). This fusion protein acts primarily by interfering with endogenous AML1 function during myeloid differentiation, although relatively few genes are known that participate with AML1-ETO during leukemia progression. Here, we assessed the consequences of expressing this chimera in Drosophila blood cells. Reminiscent of what is observed in AML, AML1-ETO specifically inhibited the differentiation of the blood cell lineage whose development depends on the RUNX factor Lozenge (LZ) and induced increased numbers of LZ(+) progenitors. Using an in vivo RNAi-based screen for suppressors of AML1-ETO, we identified calpainB as required for AML1-ETO-induced blood cell disorders in Drosophila. Remarkably, calpain inhibition triggered AML1-ETO degradation and impaired the clonogenic potential of the human t(8;21) leukemic blood cell line Kasumi-1. Therefore Drosophila provides a promising genetically tractable model to investigate the conserved basis of leukemogenesis and to open avenues in AML therapy.

Language is proposed to have developed atop the human analog of the macaque mirror neuron system for action perception and production [Arbib M.A. 2005. From monkey-like action recognition to human language: An evolutionary framework for neurolinguistics (with commentaries and author's response). Behavioral and Brain Sciences, 28, 105-167; Arbib M.A. (2008). From grasp to language: Embodied concepts and the challenge of abstraction. Journal de Physiologie Paris 102, 4-20]. Signed languages of the deaf are fully-expressive, natural human languages that are perceived visually and produced manually. We suggest that if a unitary mirror neuron system mediates the observation and production of both language and non-linguistic action, three prediction can be made: (1) damage to the human mirror neuron system should non-selectively disrupt both sign language and non-linguistic action processing; (2) within the domain of sign language, a given mirror neuron locus should mediate both perception and production; and (3) the action-based tuning curves of individual mirror neurons should support the highly circumscribed set of motions that form the “vocabulary of action” for signed languages. In this review we evaluate data from the sign language and mirror neuron literatures and find that these predictions are only partially upheld.

Several in vivo and in vitro studies have demonstrated the neuroprotective potential of pretreatment with 1alpha,25-dihydroxyvitamin D3 (calcitriol). The aim of the present study was to determine the effectiveness of calcitriol administered in vivo after a brain ischemic episode in the rat model of perinatal asphyxia, or when co-applied with or without delay during 24-h exposure of mouse hippocampal, neocortical and cerebellar neuronal cultures to glutamate on their 7th and 12th day in vitro (7 DIV and 12 DIV, respectively). Calcitriol was also administered after acute exposure of rat cerebellar neurons to glutamate. In 7-day-old rat pups subjected to hypoxia-ischemia, acute application of calcitriol in a single dose of 2 microg/kg, 30 min after termination of the insult, or subchronic, 7-day post-treatment with calcitriol, effectively reduced brain damage. The level of neuroprotection exceeded that achieved by hypoxic preconditioning used as the reference neuroprotective method. The results of in vitro experiments revealed the ability of calcitriol to reduce excitotoxicity in a manner dependent on the origin of the neuronal cells, their stage of maturation in culture and the duration of exposure to the excitotoxic insult before calcitriol application. Calcitriol was neuroprotective when it was administered together with glutamate or even after a delay of up to 6h during 24-h excitotoxic challenge of hippocampal and neocortical, but not cerebellar neuronal cultures. Application of calcitriol to cultured cerebellar granule neurons after acute exposure to glutamate was ineffective. In 12 DIV hippocampal cell cultures, 50 nM calcitriol inhibited glutamate-induced caspase-3 activity, while only 100 nM concentrations were effective in 7 DIV cultures. We ascribe the protective effects of calcitriol to the rapid modulation of mechanisms that are instrumental in the direct anti-apoptotic, neuroprotective action of this compound.

PURPOSE OF REVIEW: Fever in the neurocritical care setting is very common and has a negative impact on outcome of all disease types. Recent advances have made eliminating fever and maintaining normothermia feasible. However, important questions regarding indications and timing remain. The purpose of this review is to analyze the data surrounding the impact of fever across a range of neurologic injuries to better understand the optimal timing and duration of fever control. RECENT FINDINGS: Meta-analyses have demonstrated that fever at onset and in the acute setting after ischemic brain injury, intracerebral hemorrhage, and cardiac arrest have a negative impact on morbidity and mortality. There are data to support that the impact of fever is sustained for longer durations after subarachnoid hemorrhage and traumatic brain injury. However, there are currently no prospective randomized trials demonstrating the benefit of fever control in these patient populations. SUMMARY: The negative impact of fever after neurologic injury is well understood. Prospective randomized trials are needed to determine whether the beneficial impact of secondary injury prevention is outweighed by the potential infectious risk of prolonged fever control.