Spinal epidural hematoma: not always an obvious diagnosis.

Spinal epidural hematoma (SEH) is a rare neurosurgical emergency. SEH is characterized by an archetypal clinical presentation including abrupt spinal pain followed more or less rapidly by various degrees of neurological deficit. The diagnosis of SEH, often based on a clinical presumption, represents a clinical challenge. Several reports have outlined missed or delayed diagnosis due to unusual and confusing onsets or unawareness of this diagnosis by physicians. Therefore, physicians should keep in mind the possibility of SEH in their differential diagnosis when confronted with patients complaining of sudden onset of acute spinal pain with or without neurological sign, because the impact of a delayed diagnosis can be disabling catastrophic neurological sequelae. We suggest that SEH is a dynamic disease, which occurs in patients with an abnormal vasculature structural degenerative change. The bleeding is probably of multifactorial origin incriminating veins as well as arteries. Therefore, we proposed a classification of SEH, according to the most probable etiology whatever the associated factors, in six groups: spontaneous, secondary, iatrogenic, traumatic, recurrent, and idiopathic SEH.

Human glioblastoma stem-like cells are more sensitive to allogeneic NK and T cell-mediated killing compared with serum-cultured glioblastoma cells.

Glioblastoma multiforme (GBM) is the most dramatic primary brain cancer with a very poor prognosis because of inevitable disease recurrence. The median overall survival is less than 1 year after diagnosis. Cancer stem cells have recently been disclosed in GBM. GBM stem-like cells (GSCs) exhibit resistance to radio/chemotherapeutic treatments and are therefore considered to play an important role in disease recurrence. GSCs are thus appealing targets for new treatments for GBM patients. In this study, we show that GBM cells with stem cell characteristics are resistant to lysis mediated by resting natural killer (NK) cells because of the expression of MHC class I molecules. However, GSCs are killed by lectin-activated NK cells. Furthermore, in experiments using the therapeutic antibody CetuximAb, we show that GSCs are sensitive to antibody-mediated cytotoxicity. We confirm the sensitivity of GSC to cytotoxicity carried out by IL2-activated NK cells and tumor-specific T cells. More importantly, we show that GSCs are more sensitive to NK and T cell-mediated lysis relatively to their corresponding serum-cultured GBM cells obtained from the same initial tumor specimen. Altogether, these results demonstrate the sensitivity of GSC to immune cell cytotoxicity and, therefore, strongly suggest that GSCs are suitable target cells for immunotherapy of GBM patients.

Decision making during preoperative surgical planning.

OBJECTIVE: This study analyzes decision making during preoperative surgical planning through two cognitive indicators: conflict and cognitive control. BACKGROUND: Planning is a critical stage in naturalistic decision making, and there is some evidence suggesting that this activity depends on the level of expertise and the demands of the task. The specificity of surgery resides in the necessity to cope with (potential) conflicts between the purpose of the surgical intervention and the biological laws governing the patient's body. METHOD: Six neurosurgeons (two board-certified neurosurgeons, two chief residents, and two residents) described the operative procedure envisaged on nine surgical cases of increasing surgical complexity. A detailed analysis of one surgical case described by one expert was performed. Moreover, we measured the number of conflicts and controls reported by each surgeon. RESULTS: Two experts were the only ones for which the report of conflicts increased with surgical complexity (respectively, 75% and 73% of the conflict variance predicted by complexity). The two experts significantly activated a higher proportion of knowledge-based control (respectively, 43% and 38%) than did intermediates and residents. The residents significantly activated more motor skill-based controls (respectively, 40% and 44%) than did intermediates and experts. CONCLUSION: It seems that expert surgical decision making to cope with task demands is significantly associated with conflict monitoring. Knowledge-based control to regulate conflict is mainly produced by experts. APPLICATION: Conflicts and controls analyzed through verbal reports can be used as relevant indicators to highlight critical moments in decision making that potentially require assistance from information systems.

Hearing loss attributable to a cerebellopontine-angle arachnoid cyst in a child.

Although hearing loss in newborns and infants is predominantly due to malformations and infections, there are other situations which may compromise hearing quality in later stages, including posterior-fossa arachnoid cysts (ACs). We report the case of an 8-year-old girl who presented with hearing loss linked to a pontocerebellar-angle AC which had been diagnosed and treated when she was 14 months old. The pathophysiology of this late AC complication is discussed. This case reminds us that a close follow-up with audiologic monitoring and/or brain stem auditory evoked response is necessary in children with posterior-fossa AC because modern neuroradiological imaging methods do not inform about cerebral and nerve functions, although they provide excellent morphological details of ACs and have improved the ease and accuracy of their early diagnosis. Therefore, surgery should be performed before complete hearing loss occurs; however, in hearing-impaired patients, it remains unclear which surgical treatment is most appropriate.

Diagnosis of childhood astrocytomas.

BACKGROUND: Astrocytomas are the most common brain tumours, accounting for 28 - 50% of all primary CNS tumours. Diagnosis of CNS tumours remains difficult because the varied and nonspecific presentations of CNS tumours in childhood. Objectives/method: The clinical presentations of CNS astrocytomas vary with their sites of location; therefore, a period of uncertainty often precedes diagnosis, and approximately 42% of patients with an intracranial process make several visits to various physicians between the onset and diagnosis. However, on clinical suspicion of a brain tumour, a wide range of neuroimaging techniques may be used to assess the diagnosis of paediatric brain lesions. In this review the authors, for ease of presentation, describe the clinical presentations of supratentorial, infratentorial and spinal cord astrocytomas as well as their radiological and pathological features, and discuss their differential diagnoses. RESULTS/CONCLUSIONS: Understanding and mastering the numerous imaging features of several subtypes of primary brain tumours affecting children, in addition to radiological features of non-tumoural disorders, remains a significant challenge and demands increased awareness of the paediatric brain diseases.

Gliomagenesis and neural stem cells: Key role of hypoxia and concept of tumor "neo-niche".

Gliomas represent the most common primary brain tumors and the most devastating pathology of the central nervous system. Despite progress in conventional treatments, the prognosis remains dismal. Recent studies have suggested that a glioma brain tumor may arise from a "cancer stem cell". To understand this theory we summarize studies of the concepts of neural stem cell, and its specialized microenvironment, namely the niche which can regulate balanced self-renewal, differentiation and stem cell quiescence. We summarize the molecular mechanism known or postulated to be involved in the disregulation of normal stem cells features allowing them to undergo neoplasic transformation. We seek data pointing out the key role of hypoxia in normal homeostasis of stem cells and in the initiation, development and aggressiveness of gliomas. We develop the concept of tumor special microenvironment and we propose the new concept of neo-niche, surrounding the glioma, in which hypoxia could be a key factor to recruit and deregulate different stem cells for gliogenesis process. Substantial advances in treatment would come from obtaining better knowledge of molecular impairs of this disease.

Neurotrophin-directed differentiation of human adult marrow stromal cells to dopaminergic-like neurons.

Marrow-isolated adult multilineage inducible (MIAMI) cells were differentiated in vitro to neuronal cells in a neurotrophin-dependent fashion. After induction, the cells revealed electrophysiological features similar to those observed in mature neurons. Primary early passage human MIAMI cells without any type of co-cultures with other cell types were used. The developmental program involved a multi-step process requiring the concerted action of brain-derived neurotrophic factor, nerve growth factor and depended on neurotrophin-3, after basic fibroblast growth factor withdrawal. MIAMI-derived neuron-like cells sequentially expressed the neuronal markers, developed a complex neurite outgrowth and arborization, and acquired electrophysiological characteristics similar to those observed in mature neurons. The young and old MIAMI-derived neuronal cells developed both inward and outward currents upon depolarization, similar to those observed in normal neurons. These results represent the earliest evidence that neurotrophin-3 can direct the differentiation of non-neural stem cells from human adult bone marrow stroma to neuron-like cells in vitro. Supplementing the aforementioned multi-step process with sonic hedgehog, fibroblast growth factor 8, and retinoic acid increased the expression of molecules involved in dopaminergic differentiation and of tyrosine hydroxylase, the rate limiting enzyme of dopamine synthesis. MIAMI cells from young and old individuals represent autologous human cell populations for the treatment of disorders of the skeletal and nervous systems and for applications in cell therapy and reparative medicine approaches.

Low oxygen tension inhibits osteogenic differentiation and enhances stemness of human MIAMI cells.

We recently reported the isolation of a unique subpopulation of human stromal cells from bone marrow (BM) termed marrow-isolated adult multilineage inducible (MIAMI) cells, capable of differentiating in vitro into mature-like cells from all three germ layers. The oxygen tension (pO2) in BM ranges from 1 to 7%, which prompted us to examine the role of pO2 in regulating the capacity of MIAMI cells both to self-renew and maintain their pluripotentiality (stemness) or to progress toward osteoblastic differentiation. MIAMI cells were grown under low-pO2 conditions (1, 3, 5, and 10% oxygen) or air (21% oxygen). The proliferation rate of cells exposed to 3% oxygen (3 days) increased, resulting in cell numbers more than threefold higher than those of cells exposed to air (at 7 days). In cells grown under osteoblastic differentiation conditions, the expression of the osteoblastic markers osteocalcin, bone sialoprotein, osterix, and Runx2 and alkaline phosphatase activity was upregulated when incubated in air; however, it was blocked at low (3%) pO2. Similarly, biomineralization of long-term cell cultures was high under osteoblastic differentiation conditions in air but was undetectable at low (3%) pO2. In contrast, low pO2 upregulated mRNAs for OCT-4, REX-1, telomerase reverse transcriptase, and hypoxia-inducible factor-1 alpha, and increased the expression of SSEA-4 compared to air. Moreover, the expression of embryonic stem cell markers was sustained even under osteogenic culture conditions. Similar results were obtained using commercially available marrow stromal cells. We hypothesize a physiological scenario in which primitive MIAMI cells self-renew while localized to areas of low pO2 in the bone marrow, but tend to differentiate toward osteoblasts when they are located closer to blood vessels and exposed to higher pO2. Our results strongly suggest that maintaining developmentally primitive human cells in vitro at low pO2 would be more physiological and favor stemness over differentiation.

Marrow-isolated adult multilineage inducible (MIAMI) cells, a unique population of postnatal young and old human cells with extensive expansion and differentiation potential.

We report here the isolation of a population of non-transformed pluripotent human cells from bone marrow after a unique expansion/selection procedure. This procedure was designed to provide conditions resembling the in vivo microenvironment that is home for the most-primitive stem cells. Marrow-adherent and -nonadherent cells were co-cultured on fibronectin, at low oxygen tension, for 14 days. Colonies of small adherent cells were isolated and further expanded on fibronectin at low density, low oxygen tension with 2% fetal bovine serum. They expressed high levels of CD29, CD63, CD81, CD122, CD164, hepatocyte growth factor receptor (cMet), bone morphogenetic protein receptor 1B (BMPR1B), and neurotrophic tyrosine kinase receptor 3 (NTRK3) and were negative for CD34, CD36, CD45, CD117 (cKit) and HLADR. The embryonic stem cell markers Oct-4 and Rex-1, and telomerase were expressed in all cultures examined. Cell-doubling time was 36 to 72 hours, and cells have been expanded in culture for more than 50 population doublings. This population of cells was consistently isolated from men and women of ages ranging from 3- to 72-years old. Colonies of cells expressed numerous markers found among embryonic stem cells as well as mesodermal-, endodermal- and ectodermal-derived lineages. They have been differentiated to bone-forming osteoblasts, cartilage-forming chondrocytes, fat-forming adipocytes and neural cells and to attachment-independent spherical clusters expressing genes associated with pancreatic islets. Based on their unique characteristics and properties, we refer to them as human marrow-isolated adult multilineage inducible cells, or MIAMI cells. MIAMI cells proliferate extensively without evidence of senescence or loss of differentiation potential and thus may represent an ideal candidate for cellular therapies of inherited or degenerative diseases.