Vertebrobasilar ischemia after cervical spine manipulation: A case report

INTRODUCTION: The most serious accidents after cervical spine manipulation are vertebrobasilar ischemia. Their incidence is underestimated. Their risk of apparition is lower if the contraindications are respected and if they are realised according to suitable practice. CASE REPORT: Mrs B, 39 years old, was an active smoker and had migraine for 10 years ago. One day, she presented an unusual headache associated with neck pain that was treated by a cervical spine manipulation. Seven hours after, she developed an alternate syndrome with a right sensory motor defect, a cerebellar syndrome, a pyramidal syndrome and a left defect of cranial nerves. The arteriography showed a thrombosis of the basilar trunk and a dissection of the left vertebral artery. A thrombolysis "in situ" was realized six hours and a half after the onset of the neurological defects. After eight months of rehabilitation, there were still a paralysis of the right upper limb, of the cranial nerves and a cerebellar syndrome but the patient was able to walk with two crutches and can eat by herself. DISCUSSION: Several risk factors were present in this case and there was also a major contraindication to manipulations: unusual acute occipital headache. Given the long period between the onset of neurological symptoms and the confirmation of the diagnosis, intravenous thrombolysis could not be done. Unfortunately, after eight months, important neurological sequels persisted. In order to avoid this type of accident after cervical manipulations, it is necessary to realize a strict medical examination and to implement the recommendations from the French society of manual and orthopaedic osteopathic medicine (Société fran?aise de médecine manuelle orthopédique et ostéopathique [SOFMMOO]).     

SLIT2/ROBO signaling in tumor-associated microglia and macrophages drives glioblastoma immunosuppression and vascular dysmorphia

SLIT2 is a secreted polypeptide that guides migration of cells expressing Roundabout 1 and 2 (ROBO1 and ROBO2) receptors. Herein, we investigated SLIT2/ROBO signaling effects in gliomas. In patients with glioblastoma (GBM), SLIT2 expression increased with malignant progression and correlated with poor survival and immunosuppression. Knockdown of SLIT2 in mouse glioma cells and patient-derived GBM xenografts reduced tumor growth and rendered tumors sensitive to immunotherapy. Tumor cell SLIT2 knockdown inhibited macrophage invasion and promoted a cytotoxic gene expression profile, which improved tumor vessel function and enhanced efficacy of chemotherapy and immunotherapy. Mechanistically, SLIT2 promoted microglia/macrophage chemotaxis and tumor-supportive polarization via ROBO1- and ROBO2-mediated PI3K-γ activation. Macrophage Robo1 and Robo2 deletion and systemic SLIT2 trap delivery mimicked SLIT2 knockdown effects on tumor growth and the tumor microenvironment (TME), revealing SLIT2 signaling through macrophage ROBOs as a potentially novel regulator of the GBM microenvironment and immunotherapeutic target for brain tumors.     

De novo microdeletions of chromosome 6q14.1-q14.3 and 6q12.1-q14.1 in two patients with intellectual disability - further delineation of the 6q14 microdeletion syndrome and review of the literature

Interstitial 6q deletions can cause a variable phenotype depending on the size and location of the deletion. 6q14 deletions have been associated with intellectual disability and a distinct pattern of minor anomalies, including upslanted palpebral fissures with epicanthal folds, a short nose with broad nasal tip, anteverted nares, long philtrum, and thin upper lip. In this study we describe two patients with overlapping 6q14 deletions presenting with developmental delay and characteristic dysmorphism. Molecular karyotyping using array CGH analysis revealed a de novo 8.9 Mb deletion at 6q14.1-q14.3 and a de novo 11.3 Mb deletion at 6q12.1-6q14.1, respectively. We provide a review of the clinical features of twelve other patients with 6q14 deletions detected by array CGH analysis. By assessing all reported data we could not identify a single common region of deletion. Possible candidate genes in 6q14 for intellectual disability might be FILIP1, MYO6, HTR1B, and SNX14.     

Resistance of hepatitis C virus to NS3-4A protease inhibitors: mechanisms of drug resistance induced by R155Q, A156T, D168A and D168V mutations

BACKGROUND/AIMS: One of the main issues in the development of antiviral therapy is the emergence of drug-resistant viruses. In the case of hepatitis C virus (HCV), selection of drug-resistant mutants was evidenced by in vitro studies on protease inhibitors (PIs); for example, BILN-2061, VX-950 and SCH-6. Four mutations in the HCV protease (R155Q, A156T, D168A and D168V) have been identified in vitro in the HCV replicon system that confer resistance to BILN-2061 (a reference inhibitor). However, the molecular mechanism of drug resistance is still unknown. The aim of this study is to unravel, using an molecular modelling strategy, the structural basis of such molecular mechanism of HCV resistance to PIs. We focused on protease mutations conferring HCV resistance to BILN-2061 and described for the first time such mechanism at a molecular level. METHODS: The structures of drug-resistant NS3 proteases were obtained by mutation of selected residues (R155Q, A156T, D168A and D168V) and the ternary complexes formed between NS3-4A and BILN-2061 were optimized using GenMol software (www.3dgenoscience.com; Genoscience, Marseille, France). RESULTS: Two mechanisms were evidenced for viral resistance to BILN-2061. A 'direct' resistance mechanism is based on contacts between the mutated R155Q and A156T protease residues and its inhibitor. In the 'indirect' resistance mechanism, the mutated D168A/V residue is not in close contact with the drug itself but interacts with other residues connected to the drug. CONCLUSIONS: These data provide new insights in the understanding of the mechanisms of HCV drug escape, and may allow predicting potential cross-resistance phenomenon with other PIs. This approach can be used as a basis for future rational PI drug design candidates.     

Validating a bimodal intravascular ultrasound (IVUS) and near-infrared fluorescence (NIRF) catheter for atherosclerotic plaque detection in rabbits

Coronary artery disease is characterized by atherosclerotic plaque formation. Despite impressive advances in intravascular imaging modalities, in vivo molecular plaque characterization remains challenging, and different multimodality imaging systems have been proposed. We validated an engineered bimodal intravascular ultrasound imaging (IVUS) / near-infrared fluorescence (NIRF) imaging catheter in vivo using a balloon injury atherosclerosis rabbit model. Rabbit aortas and right iliac arteries were scanned in vivo after indocyanine green (ICG) injection, and compared to corresponding ex vivo fluorescence and white light images. Areas of ICG accumulation were colocalized with macroscopic atherosclerotic plaque formation. In vivo imaging was performed with the bimodal catheter integrating ICG-induced fluorescence signals into cross-sectional IVUS imaging. In vivo ICG accumulation corresponded to ex vivo fluorescence signal intensity and IVUS identified plaques.OCIS codes: (170.0110) Imaging systems, (110.7170) Ultrasound, (170.6280) Spectroscopy, fluorescence and luminescence, (170.2150) Endoscopic imaging