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In the ongoing quest for hybridizing discrete reasoning with neural nets, there is an increasing interest in neural architectures that can learn how to solve discrete reasoning or optimization problems from natural inputs. In this paper, we introduce a scalable neural architecture and loss function dedicated to learning the constraints and criteria of NP-hard reasoning problems expressed as discrete Graphical Models. Our loss function solves one of the main limitations of Besag's pseudo-loglikelihood, enabling learning of high energies. We empirically show it is able to efficiently learn how to solve NP-hard reasoning problems from natural inputs as the symbolic, visual or many-solutions Sudoku problems as well as the energy optimization formulation of the protein design problem, providing data efficiency, interpretability, and \textit{a posteriori} control over predictions., Comment: 10 pages, 2 figures, 6 tables. Published in IJCAI'2023 proceedings

OBJECTIVE: Published reports on directional deep brain stimulation (DBS) have been limited to small, single-center investigations. Therapeutic window (TW) is used to describe the range of stimulation amplitudes achieving symptom relief without side effects. This crossover study performed a randomized double-blind assessment of TW for directional and omnidirectional DBS in a large cohort of patients implanted with a DBS system in the subthalamic nucleus for Parkinson's disease. MATERIALS AND METHODS: Participants received omnidirectional stimulation for the first three months after initial study programming, followed by directional DBS for the following three months. The primary endpoint was a double-blind, randomized evaluation of TW for directional vs omnidirectional stimulation at three months after initial study programming. Additional data recorded at three- and six-month follow-ups included stimulation preference, therapeutic current strength, Unified Parkinson's Disease Rating Scale (UPDRS) part III motor score, and quality of life. RESULTS: The study enrolled 234 subjects (62 ± 8 years, 33% female). TW was wider using directional stimulation in 183 of 202 subjects (90.6%). The mean increase in TW with directional stimulation was 41% (2.98 ± 1.38 mA, compared to 2.11 ± 1.33 mA for omnidirectional). UPDRS part III motor score on medication improved 42.4% at three months (after three months of omnidirectional stimulation) and 43.3% at six months (after three months of directional stimulation) with stimulation on, compared to stimulation off. After six months, 52.8% of subjects blinded to stimulation type (102/193) preferred the period with directional stimulation, and 25.9% (50/193) preferred the omnidirectional period. The directional period was preferred by 58.5% of clinicians (113/193) vs 21.2% (41/193) who preferred the omnidirectional period. CONCLUSION: Directional stimulation yielded a wider TW compared to omnidirectional stimulation and was preferred by

BackgroundIn the spring of 2020, Belgian authorities enforced a full lockdown period to contain the spread of the SARS-CoV-2 virus. This lockdown drastically disrupted the daily life of autistic individuals’ and that of their families. In the midst of these extraordinary circumstances, we assessed the impact of social restrictions on autistic individuals’ behavior and their parents’ or caregivers’ quality of life; we also sought to identify individual characteristics that may influence such changes.MethodsWe designed an online survey targeting caregivers living with an autistic child or adult. The questionnaire included 125 five-point Likert questions which targeted changes in families’ quality of life and in autistic individuals’ behavior, as well as factors likely to influence the extent and direction of these changes.ResultsWe collected data from 209 French-speaking Belgian respondents. Respondents reported that the lockdown brought about a higher frequency of nonfunctional socio-communicative behaviors, as well as a decrease in families’ quality of life. Parents who had less access to respite care experienced a steeper decrease in their quality of life. Autistic individuals with comorbidities, and whose parents had less access to respite care and implemented fewer rules at home during lockdown were more likely to display nonfunctional socio-communicative behaviors.ConclusionCOVID-19 lockdown restrictions had a negative impact on both autistic individuals and their parents., info:eu-repo/semantics/published

Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are associated with motor impairments, with some children holding a comorbid diagnosis of Developmental Coordination Disorder (DCD). However, DCD is underdiagnosed in these populations and the volume abnormalities that contribute to explaining these motor impairments are poorly understood. In this study, motor abilities as measured by the Developmental Coordination Disorder Questionnaire (DCDQ) were compared between children with ADHD, children with ASD and typically developing (TD) children, aged 8-12 years old. Additionally, the association between the DCDQ scores (general coordination, fine motor/handwriting, control during movement, total) and regional volume abnormalities were explored in 6 regions of interest (pre-central gyrus, post-central gyrus, inferior parietal cortex, superior frontal gyrus, middle frontal gyrus, medial frontal gyrus), within each group and across all participants. Children with ASD and children with ADHD showed impaired motor abilities in all the DCDQ-derived scores compared to TD children. Additionally, most children with ASD or ADHD had an indication or suspicion of DCD. Within the ASD group, coordination abilities were associated with the volume of the right medial frontal gyrus, and within the ADHD group, the total DCDQ score was associated with the volume of the right superior frontal gyrus. This study underlines the importance of routinely checking motor abilities in populations with ASD or ADHD in clinical practise and contributes to the understanding of structural abnormalities subtending motor impairments in these disorders., SCOPUS: ar.j, info:eu-repo/semantics/published

The overlap/distinctiveness between Attention-Deficit/Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) has been increasingly investigated in recent years, particularly since the DSM-5 allows the dual diagnosis of ASD and ADHD, but the underlying brain mechanisms remain unclear. Although both disorders are associated with brain volumetric abnormalities, it is necessary to unfold the shared and specific volume abnormalities that could contribute to explain the similarities and differences in the clinical and neurocognitive profiles between ADHD and ASD. In this voxel-based morphometry (VBM) study, regional grey matter volumes (GMV) were compared between 22 children with ADHD, 18 children with ASD and 17 typically developing (TD) children aged 8 to 12 years old, controlling for age and total intracranial volume. When compared to TD children or children with ASD, children with ADHD had a larger left precuneus, and a smaller right thalamus, suggesting that these brain abnormalities are specific to ADHD relative to ASD. Overall, this study contributes to the delineation of disorder-specific structural abnormalities in ADHD and ASD., SCOPUS: ar.j, info:eu-repo/semantics/published

Attention-deficit/hyperactivity (ADHD) and autism spectrum (ASD) disorders often co-occur. In both cases, response inhibition deficits and inhibition-related atypical brain activation have been reported, although less consistently in ASD. Research exploring the overlap/distinctiveness between ADHD and ASD has significantly increased in recent years, but direct comparison of the inhibition-related neuronal correlates between these disorders are scarce in the literature.This study aimed at disentangling the shared and specific inhibitory brain dysfunctions in ASD and ADHD. Using functional magnetic resonance imaging (fMRI), brain activity was compared between children with ADHD, ASD and typically developing (TD) children aged 8-12 during an inhibition stop-signal task, using stringent inclusion criteria. At the behavioural level, only children with ADHD exhibited inhibition deficits when compared to the TD group. Distinct patterns of brain activity were observed during successful inhibition. In children with ADHD, motor inhibition was associated with right inferior parietal activation, whereas right frontal regions were activated in children with ASD. Between-group comparisons disclosed higher middle frontal activation in the ASD group compared to the ADHD and the TD groups. Our results evidence different patterns of activation during inhibition in these two disorders, recruiting different regions of the fronto-parietal network associated to inhibition. Besides brain activity differences, behavioural inhibition deficits found only in children with ADHD further suggest that reactive inhibition is one of the core deficits in ADHD, but not in ASD. Our findings provide further evidence contributing to disentangle the shared and specific inhibitory dysfunctions in ASD and ADHD., SCOPUS: ar.j, info:eu-repo/semantics/published

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BACKGROUND The surgical plethysmographic index (SPI) is one of the available indexes of the nociception- Antinociception (NAN) balance. Individually adjusting the NAN balance to prevent somatic responses to noxious stimulation remains a challenge. OBJECTIVES To assess whether guiding remifentanil administration according to the SPI response to a calibrated noxious stimulus (NANCAL) can blunt the haemodynamic response to tracheal intubation and surgical incision. DESIGN Randomised multicentre study. SETTING Two Belgian university hospitals from January 2014 to April 2015. PATIENTS After ethic review board approval and informed consent, 48 American Society of Anesthesiologists I or II adult patients scheduled for surgery under general anaesthesia were enrolled. INTERVENTIONS Patients were randomly assigned to a SPI group, where remifentanil effect-site concentration was adjusted according to NANCAL, or a control group, where it was fixed at 4 ng ml1. Propofol concentration was always adjusted to maintain the bispectral index close to 40. NANCAL consisted of a 100 Hz, 60mA electrical tetanic stimulation during 30 s at the wrist before tracheal intubation and before surgical incision. MAIN OUTCOME MEASURES The primary endpointwas the efficacy of the NANCAL-guided remifentanil administration to prevent the haemodynamic response to tracheal intubation and surgical incision. The secondary aim was to compare the ability of SPI, analgesia nociception index, pupil diameter and mean arterial pressure response to NANCAL to predict the haemodynamic response to tracheal intubation and surgical incision. RESULTS Our SPI response to NANCAL-based correcting scheme for remifentanil administration was not superior to a fixed remifentanil concentration at blunting the haemodynamic response to tracheal intubation or surgical incision. Among all tested NAN balance indices, only mean arterial pressure had significant predictive ability with regard to the haemodynamic response to surgical, SCOPUS: ar.j, info:eu-repo/semantics/published

Chronic hepatitis B virus (HBV) infection and HBV-related hepatitis in children remains an unmet medical need, as current treatments are only partially effective, and only in a limited number of affected children. So-called "immunotolerant" children have not shown increased serological responses to available treatments. In cases involving more active disease, serological response has only been obtained in approximately one-third of patients when using interferon, whilst other cases exhibited virological response solely under continuous treatment with nucleoside analogues. Guidelines have recently been established to aid pediatricians in effectively managing this condition. With the available medications, no treatment is so far indicated for immunotolerant children, but only for cases presenting increased alanine aminotransferase (ALT) levels to over 1.5 - 2 times the upper limit of normal for over 6 months, and without spontaneous HB envelope antigen (HBeAg) to antibody (HBeAb) seroconversion. The therapeutic arsenal approved by the Food and Drugs Administration (FDA) and European Medicines Agency (EMA) for children remains limited due to the lack of large-scale clinical trials validating treatments already approved for the adult population. Yet the recent discovery of a specific HBV-cell surface receptor, NTCP, allows for new treatment perspectives regarding the future.

The isolated forearm test (IFT) is the gold standard test of connected consciousness (awareness of the environment) during anaesthesia. The frontal alpha-delta EEG pattern (seen in slow wave sleep) is widely held to indicate anaesthetic-induced unconsciousness. A priori we proposed that one responder with the frontal alpha-delta EEG pattern would falsify this concept. Frontal EEG was recorded in a subset of patients from three centres participating in an international multicentre study of IFT responsiveness following tracheal intubation. Raw EEG waveforms were analysed for power-frequency spectra, depth-of-anaesthesia indices, permutation entropy, slow wave activity saturation and alpha-delta amplitude-phase coupling. Volitional responses to verbal command occurred in six out of 90 patients. Three responses occurred immediately following intubation in patients (from Sites 1 and 2) exhibiting an alpha-delta dominant (delta power >20 dB, alpha power >10 dB) EEG pattern. The power-frequency spectra obtained during these responses were similar to those of non-responders (P>0.05) at those sites. A further three responses occurred in (Site 3) patients not exhibiting the classic alpha-delta EEG pattern; these responses occurred later relative to intubation, and in patients had been co-administered ketamine and less volatile anaesthetic compared with Site 1 and 2 patients. None of the derived depth-of-anaesthesia indices could robustly discrimate IFT responders and non-responders. Connected consciousness can occur in the presence of the frontal alpha-delta EEG pattern during anaesthesia. Frontal EEG parameters do not readily discriminate volitional responsiveness (a marker of connected consciousness) and unresponsiveness during anaesthesia. NCT02248623.

The isolated forearm test (IFT) is the gold standard test of connected consciousness (awareness of the environment) during anaesthesia. The frontal alpha-delta EEG pattern (seen in slow wave sleep) is widely held to indicate anaesthetic-induced unconsciousness. A priori we proposed that one responder with the frontal alpha-delta EEG pattern would falsify this concept. Frontal EEG was recorded in a subset of patients from three centres participating in an international multicentre study of IFT responsiveness following tracheal intubation. Raw EEG waveforms were analysed for power-frequency spectra, depth-of-anaesthesia indices, permutation entropy, slow wave activity saturation and alpha-delta amplitude-phase coupling. Volitional responses to verbal command occurred in six out of 90 patients. Three responses occurred immediately following intubation in patients (from Sites 1 and 2) exhibiting an alpha-delta dominant (delta power >20 dB, alpha power >10 dB) EEG pattern. The power-frequency spectra obtained during these responses were similar to those of non-responders (P>0.05) at those sites. A further three responses occurred in (Site 3) patients not exhibiting the classic alpha-delta EEG pattern; these responses occurred later relative to intubation, and in patients had been co-administered ketamine and less volatile anaesthetic compared with Site 1 and 2 patients. None of the derived depth-of-anaesthesia indices could robustly discrimate IFT responders and non-responders. Connected consciousness can occur in the presence of the frontal alpha-delta EEG pattern during anaesthesia. Frontal EEG parameters do not readily discriminate volitional responsiveness (a marker of connected consciousness) and unresponsiveness during anaesthesia. NCT02248623.

info:eu-repo/semantics/published

Current treatment of inherited liver inborn errors of metabolism in children consists in appropriate diet and drugs and, for unstable patients, final orthotopic liver transplantation. Unfortunately, liver transplantation remains not easily available because of organ shortage and imposes inherent risks and lifelong immunosuppressive therapy. Therefore alternative treatments are required. Hepatocytes transplantation and its limitations led to consider innovative alternative such as transplantation of adult derived human liver stem cells (ADLHSC). These cells present high proliferative capacity, good resistance to cryopreservation and ability to differentiate into hepatocyte-like cells displaying mature hepatocyte functions. AIM: Biodistribution of ADHLSC had never been assessed after infusion through the portal vein in patients. This information is required to determine the safety of the method. METHODS: ADHLSC were efficiently labelled with 111-Indium DTPA radiotracer and SPECT imaging was used for the acquisition of whole body imaging to document short term biodistribution of ADHLSC. RESULTS: Following infusion through the portal vein, ADHLSC diffused homogenously throughout the liver and remained strictly within the targeted organ. Images were acquired until 5 days after infusion. At that time, no signal was observed in any other organs except the liver. Urinary excretion of 111-Indium DTPA was also monitored. CONCLUSION: For the first time, we documented the short term biodistribution of ADHLSC within the liver after infusion through the portal vein.

Cancer is a complex network of tumor cells and host cells. Tumor cells, by secreting and expressing different proteins, permanently communicate with the stroma and the host surrounding tissues, leading to remodeling of the extra-cellular matrix and further invasiveness or humoral immune response against tumor-associated antigens. Acute comprehension of those two aspects of tumor progression is crucially needed in order to dissect metastasis processes and to identify biomarkers, allowing targeted therapies or early diagnosis of this lethal disease. In the first part of our work, we identified circulating autoantibodies as biomarkers of tumor growth and metastasis development. First, we showed the influence of radiotherapeutic and chemotherapeutic treatments on circulating anti-GRP78 antibodies. Indeed, while chemotherapy induces a decrease in the anti-GRP78 antibodies titer, radiotherapy appeared to increase it, drawing the attention to the therapeutic status of cancer patients recruited in studies aiming to identify new autoantibodies as cancer biomarkers. Second, we documented that hypoxia allows to identify new potential biomarkers that would not have been identified otherwise. Hypoxia is one of the most common features of solid tumors. Integrating this characteristic in our conditions of SERPA, we were able to identify six proteins which induce a humoral immune response in tumor-bearing mice. Thus, on a translational research perspective, this part of our work provides new insights to improve the serological proteome analysis but also the interpretation of the data. Our studies also led to the identification of unsuspected mammary tumor-associated antigens and the possible use of corresponding autoantibodies to detect early stages of the disease. The second part of our work was dedicated to the study of the secretome of tumors cells and to the systemic effects it induces in a syngenic model of melanoma tumors. We focused our attention on the endothelial progenito, (FARM 3) -- UCL, 2011

Since tumor growth is highly dependent on the formation of new blood vessels, angiogenesis inhibitors have become important players in anticancer treatments. Although less cytotoxic than conventional chemotherapy, most of the available antiangiogenic agents may provoke severe adverse effects which can limit their use. The design of new antiangiogenic strategies therefore requires integrating an early evaluation of possible interference with quiescent endothelial cells and nontumor angiogenesis. Here, we describe such a novel antiangiogenic approach based on the in vivo delivery by gene electrotransfer of a negative regulator of angiogenesis, namely, sFlt1. We found that this soluble variant of the vascular endothelial growth factor receptor 1 (Flt1, also known as VEGFR1), which acts as a VEGF trap, differentially influences tumor and postischemic hind limb angiogenesis in mice. sFlt1 gene electrotransfer in tibial cranial muscle leads to high sFlt1 protein expression and secretion, leading to a significant delay in the growth of syngeneic tumors but not altering the revascularization of ischemic peripheral tissue. The higher sensitivity of tumor-bearing animals toward sFlt1 trapping effects (vs ischemia-recovering animals) might be explained by a distinct pattern of VEGF release, as shown by VEGF measurements in plasma and tissue. In conclusion, our data support sFlt1 gene electrotransfer as a novel and safe modality to target VEGF-driven tumor angiogenesis and to maintain unaltered the recovery potential of ischemic tissues.

BACKGROUND: Despite the discovery of novel inhibitors of tumor angiogenesis, protein-based antiangiogenic cancer therapy suffers some limitations that antiangiogenic gene therapy could overcome. We investigated whether intra-tumoral electrotransfer of three angiogenic plasmids could inhibit tumor growth and metastasis. METHODS: Plasmids encoding recombinant disintegrin domain of ADAM-15 (RDD), thrombospondin 1 (TSP-1), and the soluble isoform of the VEGF receptor 1 (sFlt-1) were injected into B16F10 melanoma-bearing C57BL/6 mice followed by electroporation. Tumor volume was measured daily using a digital caliper. Metastasis was monitored by in vivo bioluminescence after surgical removal of the primary luciferase-encoding B16F10 tumor 5days after intra-tumoral electrotransfer. Markers of vascularization and cell proliferation were quantified by immunohistochemistry. RESULTS: Intra-tumoral electrotransfer of the antiangiogenic plasmids induced a significant inhibition of tumor growth, doubling of mean survival time and long-term survivors (∼40% vs 0% in control). When the tumor was removed by surgery after intra-tumoral plasmid electrotransfer, a significant decrease in tumor metastasis was observed leading to long-term tumor-free survival especially after treatment with pRDD plasmid (84% vs 0% in control). Unlike pTSP-1 and psFlt-1, pRDD significantly decreased cell proliferation in B16F10 primary tumors which express αvβ3 and α5β1 integrins. No effect of antiangiogenic plasmid electrotransfer on normal skin blood flow was detected. CONCLUSION: The intra-tumoral electrotransfer of the three antiangiogenic plasmids is a promising method for the treatment of melanoma. The plasmid encoding RDD seems to be particularly effective due to its direct antitumoral activity combined with angiogenesis suppression, and its marked inhibition of metastasis.

The clinical outcome of melanoma depends on the local and distant spread of the disease at the time of diagnosis, as the estimated 5-year survival rate is about 100% for superficial melanoma diagnosed early, but less than 10% for melanoma that has disseminated to major organs such as lungs. There is a crucial need for new effective methods for the detection and the characterization of melanomas. In the pre-clinical setting, this will help to understand the factors that contribute to the malignancy while the transfer into the clinic will contribute to an early effective treatment of patients. Melanoma lesions can be detected by electron paramagnetic resonance (EPR) using paramagnetic properties of melanin pigments. As part of the development of EPR imaging to characterize melanomas, we evaluated in the present study the usefulness of EPR to report on the extension of lung metastases by comparing the method with bioluminescence imaging using B16 melanoma cells expressing luciferase. B16 melanoma cells were injected subcutaneously or intravenously in C57/BL6 mice. The primary tumors or the lung colonization by melanoma cells was measured after several delay periods to obtain several degrees of invasiveness. The animals were measured in-vivo with bioluminescence after i.v. injection of luciferin. The primary tumors or lungs were then excised. After freeze-drying, the content of melanin in lungs was measured and imaged by EPR at 9 GHz. We observed a direct relationship between the EPR intensity and the bioluminescence intensity. Another tumor model (KHT sarcoma), non-pigmented but expressing luciferase, was used to confirm that the EPR signal was directly linked to the melanin pigment present in the tumors. Copyright © 2011 John Wiley & Sons, Ltd.

Tumor progression is associated with the release of signaling substances from the primary tumor into the bloodstream. Tumor-derived cytokines are known to promote the mobilization and the recruitment of cells from the bone marrow, including endothelial progenitor cells (EPC). Here, we examined whether such paracrine influence could also influence the capacity of EPC to interfere with circulating metastatic cells. We therefore consecutively injected EPC prestimulated by tumor-conditioned medium (EPC-CM) and luciferase-expressing B16 melanoma cells to mice. A net decrease in metastases spreading (vs. nonstimulated EPC) led us to carry out a 2-dimensional difference gel electrophoresis (2D-DIGE) proteomic study to identify possible mediators of EPC-driven protection. Among 33 proteins exhibiting significant changes in expression, secreted protein, acidic and rich in cysteine (SPARC) presented the highest induction after EPC exposure to CM. We then showed that contrary to control EPC, SPARC-silenced EPC were not able to reduce the extent of metastases when injected with B16 melanoma cells. Using adhesion tests and the hanging drop assay, we further documented that cell-cell interactions between EPC-CM and melanoma cells were promoted in a SPARC-dependent manner. This interaction led to the engulfment of melanoma cells by EPC-CM, a process prevented by SPARC silencing and mimicked by recombinant SPARC. Finally, we showed that contrary to melanoma cells, the prometastatic human breast cancer cell line MDA-MB231-D3H2 reduced SPARC expression in human EPC and stimulated metastases spreading. Our findings unravel the influence of tumor cells on EPC phenotypes through a SPARC-driven accentuation of macrophagic capacity associated with limitations to metastatic spread.

BACKGROUND: Despite the discovery of novel inhibitors of tumor angiogenesis, protein-based antiangiogenic cancer therapy suffers some limitations that antiangiogenic gene therapy could overcome. We investigated whether intra-tumoral electrotransfer of three angiogenic plasmids could inhibit tumor growth and metastasis. METHODS: Plasmids encoding recombinant disintegrin domain of ADAM-15 (RDD), thrombospondin 1 (TSP-1), and the soluble isoform of the VEGF receptor 1 (sFlt-1) were injected into B16F10 melanoma-bearing C57BL/6 mice followed by electroporation. Tumor volume was measured daily using a digital caliper. Metastasis was monitored by in vivo bioluminescence after surgical removal of the primary luciferase-encoding B16F10 tumor 5days after intra-tumoral electrotransfer. Markers of vascularization and cell proliferation were quantified by immunohistochemistry. RESULTS: Intra-tumoral electrotransfer of the antiangiogenic plasmids induced a significant inhibition of tumor growth, doubling of mean survival time and long-term survivors (∼40% vs 0% in control). When the tumor was removed by surgery after intra-tumoral plasmid electrotransfer, a significant decrease in tumor metastasis was observed leading to long-term tumor-free survival especially after treatment with pRDD plasmid (84% vs 0% in control). Unlike pTSP-1 and psFlt-1, pRDD significantly decreased cell proliferation in B16F10 primary tumors which express αvβ3 and α5β1 integrins. No effect of antiangiogenic plasmid electrotransfer on normal skin blood flow was detected. CONCLUSION: The intra-tumoral electrotransfer of the three antiangiogenic plasmids is a promising method for the treatment of melanoma. The plasmid encoding RDD seems to be particularly effective due to its direct antitumoral activity combined with angiogenesis suppression, and its marked inhibition of metastasis.

Early detection of tumor-specific autoantibodies (auto-Abs) has the potential to be used for cancer screening and diagnosis. Whether auto-Ab may be useful to track metastatic progression or response to treatment is, however, largely unknown. To address these issues, the serological proteome was analyzed in an invasive but treatment-responsive mouse tumor model. Among 40 serum-reactive proteins identified by multiplex analysis, we chose to focus on glucose-regulated protein 78 (GRP78), a chaperone protein involved in the endoplasmic reticulum stress response. We first validated GRP78 as a protein overexpressed and mislocalized in tumor cells. We then documented that an increase in GRP78 auto-Ab titer preceded the detection of a palpable tumor mass, correlated with metastatic progression, and was influenced by the onset of tumor neovascularization. We also found that chemotherapy and radiotherapy, both leading to inhibition of tumor growth, oppositely influenced the anti-GRP78 immune response. Whereas radiation increased the concentration of GRP78 auto-Ab by three-fold, the auto-Ab titer was reduced in response to bolus or metronomic administration of cyclophosphamide. Finally, we established a decrease in auto-Ab-producing B lymphocytes in response to chemotherapy and the overexpression of GRP78 together with a strong immunoglobulin response in irradiated tumors. In conclusion, we identified GRP78 auto-Ab as an early marker of tumor and metastatic progressions. However, the multiple influences of anticancer treatments on the humoral immune system calls for caution when exploiting such auto-Ab as markers of the tumor response.

Sudden epileptic falls are frequently reported in continuous spike-waves during slow sleep (CSWS) syndrome. Inhibitory seizures are usually considered as the underlying mechanism. However, published polygraphic recordings are rare. We report the case of a 22 month-old boy suffering from a symptomatic CSWS syndrome associated with a perinatal stroke involving the right middle cerebral artery territory. He presented with psychomotor regression and daily multiple falls related to myoclonic-atonic seizures. Neurophysiological examination showed secondary generalized myoclonus systematically correlated with a bilateral spike spreading from the right central area. This confirms that positive myoclonus, in addition to negative myoclonus, may be responsible for epileptic falls in CSWS syndrome. [Published with video sequences].

Hypoxia is a common feature in tumors associated with an increased resistance of tumor cells to therapies. In addition to O(2) diffusion-limited hypoxia, another form of tumor hypoxia characterized by fluctuating changes in pO(2) within the disorganized tumor vascular network is described. Here, we postulated that this form of intermittent hypoxia promotes endothelial cell survival, thereby extending the concept of hypoxia-driven resistance to the tumor vasculature. We found that endothelial cell exposure to cycles of hypoxia reoxygenation not only rendered them resistant to proapoptotic stresses, including serum deprivation and radiotherapy, but also increased their capacity to migrate and organize in tubes. By contrast, prolonged hypoxia failed to exert protective effects and even seemed deleterious when combined with radiotherapy. The use of hypoxia-inducible factor-1alpha (HIF-1alpha)-targeting small interfering RNA led us to document that the accumulation of HIF-1alpha during intermittent hypoxia accounted for the higher resistance of endothelial cells. We also used an in vivo approach to enforce intermittent hypoxia in tumor-bearing mice and found that it was associated with less radiation-induced apoptosis within both the vascular and the tumor cell compartments (versus normoxia or prolonged hypoxia). Radioresistance was further ascertained by an increased rate of tumor regrowth in irradiated mice preexposed to intermittent hypoxia and confirmed in vitro using distinctly radiosensitive tumor cell lines. In conclusion, we have documented that intermittent hypoxia may condition endothelial cells and tumor cells in such a way that they are more resistant to apoptosis and more prone to participate in tumor progression. Our observations also underscore the potential of drugs targeting HIF-1alpha to resensitize the tumor vasculature to anticancer treatments.

The objective of this study was to describe the clinical course of acute transverse myelitis in children, to identify prognostic factors, and to compare our findings with published data Twenty-four children, aged 2 to 14 years and admitted with a diagnosis of acute transverse myelitis, were studied. Clinical features and results of investigations were collected at admission and during the course of the disease. Motor, sphincter, and global outcomes were compared with those in the main adult and pediatric series. During the initial phase, the most common presenting symptoms were pain (88%) and fever (58%). Motor loss preceded sphincter dysfunction in two thirds of patients and became bilateral in half of the patients. When maximal deficit was achieved (plateau), the patients presented a combination of sensory, motor, and sphincter dysfunctions without radicular involvement The motor loss consistently involved the lower limbs but was inconsistent and moderate in the upper limbs. The mean duration of the plateau was 1 week. The recovery phase was characterized by a progressive improvement of all deficits. Sphincter dysfunction improved more slowly than did the other deficits. A full recovery was achieved by 31% of the patients; minimal sequelae were present in 25% and mild to severe sequelae in 44%. An unfavorable outcome was associated with complete paraplegia (P = .03) and/or a time to maximal deficit shorter than 24 hours (P = .005). A favorable outcome was associated with a plateau shorter than 8 days (P = .03), the presence of supraspinal symptoms (P = .01), and a time to independent walking shorter than 1 month (P = .01). The course of acute transverse myelitis in children proceeds through three stages, an initial phase, a plateau, and a recovery phase, each characterized by specific clinical features. The global outcome was favorable in 56% of patients. Several prognostic factors were identified.

Les retards mentaux liés au chromosome X

No effective treatment has been demonstrated for patients with acute transverse myelopathy. In a multicentre controlled study, 12 children with severe acute transverse myelopathy were treated with intravenous methylprednisolone (IVMP) and compared with a historical group of 17 patients. The treatment had a significant effect on the proportion of patients walking independently at 1 month and on the proportion with full recovery at 1 year, with no differences in the frequency of complications between the two groups.

No effective treatment has been demonstrated for patients with acute transverse myelopathy. In a multicentre controlled study, 12 children with severe acute transverse myelopathy were treated with intravenous methylprednisolone (IVMP) and compared with a historical group of 17 patients. The treatment had a significant effect on the proportion of patients walking independently at 1 month and on the proportion with full recovery at 1 year, with no differences in the frequency of complications between the two groups., SCOPUS: ar.j, info:eu-repo/semantics/published

No effective treatment has been demonstrated for patients with acute transverse myelopathy. In a multicentre controlled study, 12 children with severe acute transverse myelopathy were treated with intravenous methylprednisolone (IVMP) and compared with a historical group of 17 patients. The treatment had a significant effect on the proportion of patients walking independently at 1 month and on the proportion with full recovery at 1 year, with no differences in the frequency of complications between the two groups., SCOPUS: ar.j, info:eu-repo/semantics/published

Cryptolepine hydrochloride is an indoloquinoline alkaloid isolated from the roots of Cryptolepis sanguinolenta. It is characterized by a multiplicity of host-mediated biological activities, including antibacterial, antiviral, and antimalarial properties. To date, the molecular basis for its diverse biological effects remains largely uncertain. Several lines of evidence strongly suggest that DNA might correspond to its principal cellular target. Consequently, we studied the strength and mode of binding to DNA of cryptolepine by means of absorption, fluorescence, circular, and linear dichroism, as well as by a relaxation assay using DNA topoisomerases. The results of various optical and gel electrophoresis techniques converge to reveal that the alkaloid binds tightly to DNA and behaves as a typical intercalating agent. In DNAase I footprinting experiments it was found that the drug interacts preferentially with GC-rich sequences and discriminates against homo-oligomeric runs of A and T. This study has also led to the discovery that cryptolepine is a potent topoisomerase II inhibitor and a promising antitumor agent. It stabilizes topoisomerase II-DNA covalent complexes and stimulates the cutting of DNA at a subset of preexisting topoisomerase II cleavage sites. Taking advantage of the fluorescence of the indoloquinoline chromophore, fluorescence microscopy was used to map cellular uptake of the drug. Cryptolepine easily crosses the cell membranes and accumulates selectively into the nuclei rather than in the cytoplasm of B16 melanoma cells. Quantitative analyses of DNA in cells after Feulgen reaction and image cytometry reveal that the drug blocks the cell cycle in G2/M phases. It is also shown that the alkaloid is more potent at inhibiting DNA synthesis rather than RNA and protein synthesis. Altogether, the results provide direct evidence that DNA is the primary target of cryptolepine and suggest that this alkaloid is a valid candidate for the development of tumor act

Since tumor necrosis factor alpha (TNF-alpha) is known to be involved in the feto-maternal relationship, this cytokine was studied in Trypanosoma cruzi-infected pregnant BALB/c mice and their fetuses and offspring. Pregnant chronically infected mice displayed significantly higher levels of circulating TNF-alpha than animals either only infected or only pregnant. TNF-alpha was undetectable in sera of uninfected and nonpregnant mice as well as in breast milk obtained from infected and uninfected animals. Fetuses from infected mice exhibited significantly more cells containing TNF-alpha mRNA in their thymus than fetuses from uninfected mothers. When infected 2 months after birth, offspring born to infected and uninfected mothers displayed similar amounts of circulating TNF-alpha during chronic infection, whereas this cytokine was only weakly detectable during the acute phase of the disease. An intravenous injection of lipopolysaccharide during acute infection strongly increased the production of TNF-alpha in offspring born to infected mothers to levels higher than those in progeny from uninfected mice. These results suggest that TNF-alpha is an important cytokine in the feto-maternal relationship during T. cruzi infection and that fetuses and offspring of infected mothers are primed to produce elevated levels of TNF-alpha., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Since tumor necrosis factor alpha (TNF-alpha) is known to be involved in the feto-maternal relationship, this cytokine was studied in Trypanosoma cruzi-infected pregnant BALB/c mice and their fetuses and offspring. Pregnant chronically infected mice displayed significantly higher levels of circulating TNF-alpha than animals either only infected or only pregnant. TNF-alpha was undetectable in sera of uninfected and nonpregnant mice as well as in breast milk obtained from infected and uninfected animals. Fetuses from infected mice exhibited significantly more cells containing TNF-alpha mRNA in their thymus than fetuses from uninfected mothers. When infected 2 months after birth, offspring born to infected and uninfected mothers displayed similar amounts of circulating TNF-alpha during chronic infection, whereas this cytokine was only weakly detectable during the acute phase of the disease. An intravenous injection of lipopolysaccharide during acute infection strongly increased the production of TNF-alpha in offspring born to infected mothers to levels higher than those in progeny from uninfected mice. These results suggest that TNF-alpha is an important cytokine in the feto-maternal relationship during T. cruzi infection and that fetuses and offspring of infected mothers are primed to produce elevated levels of TNF-alpha., Journal Article, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Cell lines were derived from eight individual leukemias induced by X-rays in NFS mice. First typed as null cells (surface immunoglobulin negative, Thy-1 negative), they turned out to have a mixed phenotype with myeloid cytochemical markers, pre-B surface antigens and molecular markers of pro-B lymphocytes. They represent murine models for mixed phenotype (pro-pre-B-myeloid) leukemias., SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: re.j, info:eu-repo/semantics/published

SCOPUS: le.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: le.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: re.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published

SCOPUS: ar.j, info:eu-repo/semantics/published