Cell-Type-Dependent Thyroid Hormone Effects on Glioma Tumor Cell Lines

Purpose. The present study investigated the potential effects of long-term T3 treatment on glioma tumor cell lines. Thyroid hormone action on cell growth, differentiation and survival during development may be of therapeutic relevance Methods and Results 1321N1 cell line, an astrocytoma grade II, and U87MG, a glioblastoma grade IV, were exposed for 2 and 4 days in medium deprived of T3 and in medium containing 1 nM T3. T3 promoted re-differentiation in both cell lines. However, T3 increased cell proliferation in 1321N1 (2 days) which declined thereafter (4 days) while in U87MG resulted in suppression of cell proliferation. At the molecular level, a 2.9 fold increase in the expression of TRα1 receptor was observed in U87MG versus 1321N1, P < 0.05. TRβ1 receptor was undetectable. These changes corresponded to a distinct pattern of T3-induced kinase signaling activation; T3 had no effect on ERK activation in both cell lines but significantly increased phospho-Akt levels in 1321N1. Conclusion. In conclusion, T3 can re-differentiate glioma tumor cells, whereas its effect on cell proliferation appears to be dependent on the type of tumor cell line with aggressive tumors being more sensitive to T3. TRα1 receptor may, at least in part, be implicated in this response

Vision Threatening Raised Intracranial Pressure Associated with Recreational Nitrous Oxide Use

Nitrous oxide is used as an anaesthetic and analgesic agent in the medical setting and is known to cause raised intracranial pressure. The use of nitrous oxide recreationally for the drug’s euphoric and relaxant properties has been linked to multiple neurological and psychiatric sequelae including neuropathy, myelopathy, and psychosis. We describe a case of a young person who declared heavy nitrous oxide use resulting in vision-threatening papilloedema secondary to raised intracranial pressure. He underwent emergency lumbar drainage alongside high-dose acetazolamide and parenteral vitamin B12 injections. To our knowledge, there have yet to be other reports of cases where heavy nitrous oxide use has caused secondary pseudotumor cerebri syndrome

An Evaluation of the Tolerability and Feasibility of Combining 5-Amino-Levulinic Acid (5-ALA) with BCNU Wafers in the Surgical Management of Primary Glioblastoma.

Background Glioblastoma (GBM) is the commonest primary malignant brain tumour in adults and effective treatment options are limited. Combining local chemotherapy with enhanced surgical resection using 5-aminolevulinic acid (5-ALA) could improve outcomes. Here we assess the safety and feasibility of combining BCNU wafers with 5-ALA-guided surgery. Methods We conducted a multicentre feasibility study of 5-ALA with BCNU wafers followed by standard-of-care chemoradiotherapy (chemoRT) in patients with suspected GBM. Patients judged suitable for radical resection were administered 5-ALA pre-operatively and BCNU wafers at the end resection. Post-operative treatment continued as per routine clinical practice. The primary objective was to establish if combining 5-ALA and BCNU wafers is safe without compromising patients from receiving standard chemoRT. Results Seventy-two patients were recruited, sixty-four (88.9%) received BCNU wafer implants, and fifty-nine (81.9%) patients remained eligible following formal histological diagnosis. Seven (11.9%) eligible patients suffered surgical complications but only two (3.4%) were not able to begin chemoRT, four (6.8%) additional patients did not begin chemoRT within 6 weeks of surgery due to surgical complications. Eleven (18.6%) patients did not begin chemoRT for other reasons (other toxicity (n = 3), death (n = 3), lost to follow-up/withdrew (n = 3), clinical decision (n = 1), poor performance status (n = 1)). Median progression-free survival was 8.7 months (95% CI: 6.4-9.8) and median overall survival was 14.7 months (95% CI: 11.7-16.8). Conclusions Combining BCNU wafers with 5-ALA-guided surgery in newly diagnosed GBM patients is both feasible and tolerable in terms of surgical morbidity and overall toxicity. Any potential therapeutic benefit for the sequential use of 5-ALA and BCNU with chemoRT requires further investigation with improved local delivery technologies

Cytokine secretion in glioblastoma patients

Gliomas are the most common primary tumours of the central nervous system with a lethality rate approaching 80% in the first year of glioblastoma diagnosis. Their highly invasive nature renders local therapies such as surgery and radiation ineffective; whereas novel approaches such as immunotherapy are being actively studied as possible adjuncts in the treatment of patients with malignant gliomas.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Cytokine secretion in glioblastoma patients

Gliomas are the most common primary tumours of the central nervous system with a lethality rate approaching 80% in the first year of glioblastoma diagnosis. Their highly invasive nature renders local therapies such as surgery and radiation ineffective; whereas novel approaches such as immunotherapy are being actively studied as possible adjuncts in the treatment of patients with malignant gliomas.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Cytokine secretion in glioblastoma patients

Gliomas are the most common primary tumours of the central nervous system with a lethality rate approaching 80% in the first year of glioblastoma diagnosis. Their highly invasive nature renders local therapies such as surgery and radiation ineffective; whereas novel approaches such as immunotherapy are being actively studied as possible adjuncts in the treatment of patients with malignant gliomas. A number of factors have been proposed to play a role in glioma immune escape, including their poor immunogenicity since they do not express specific glioma antigens; their location within the CNS, which is considered to be an immune-privileged organ and some indications that glioma cells are capable of releasing various immunosuppressive cytokines, which inhibit the cytotoxic function of T cells. Cytokines are multifunctional pleiotropic proteins, which are involved in intercellular communication and cellular activation, and they may exert their effects in the CNS both directly and indirectly. Since they may originate either from peripheral immune organs, and cross the blood-brain barrier or they may be produced by the neuronal cells within the CNS, their properties are both immunoregulatory and neuromodulatory. This thesis investigated gliomas for the expression of cytokines and implicated their expression in the malignancy and the angiogenesis of the tumours. Cytokine secretion was evaluated from isolated peripheral blood mononuclear cells (PBMCs) of 33 patients with malignant gliomas (grade IV) immediately before surgery, in parallel with a control group of 23 age-matched individuals, and in 5 primary glioma cell cultures using the sensitive ELISPOT methodology. Thi cytokines tumour necrosis factor (TNF-a) and interferon (IFN7) were markedly reduced compared to control levels (P=0.01 and P<0.001, respectively). In contrast, Th2 interleukins IL-(4) and IL-(10) were strongly expressed in both peripheral lymphocytes and glioma cell cultures (P<0.05 and P<0.001 respectively). Immunohistochemical localisation of IL-6, IL-8, COX, IL-lO, VEGF (vascular endothelial growth factor) and CD34 expression levels was performed in formalin-fixed paraffin-embedded tissue sections taken from 23 patients. Microvessels highlighted by means of anti-CD34 irnmunohistochemistry were enumerated with computer assisted image analysis. IL-6 was identified immunohistochemically in all specimens and showed an elevation in expression as necrosis grade increased (p=O.00S). IL-6 was also increased as the histological grade of the tumour increased (p0.020). IL-S expression was detected in all cases of gliomas with a mean of 19.5% of the cells. Expression was not related to either necrosis grade or increase in tumour grade. COX immunoreactivity was detected in all cases with an average of 29.1% positive cells. However, COX immunoreactivity was not significantly correlated with either necrosis or tumour grade. VEGF immunoreactivity occurred in 58.3% of cells and demonstrated a positive correlation with tumour grade (pzr0.035). The expression level of IL-10 was low both in terms of staining intensity and percentage of positive cells, and did not correlate with either necrosis or histological grade. CD34 immunoreactivity indicated that vascular volumetric parameters were not affected by either tumour or by necrosis grade. The expression of soluble CD95 as measured using a specific ELISA was not significantly (p>0.05) reduced in the serum of 43 glioma patients compared to normal levels. In conclusion, these results indicate that patients harbouring malignant gliomas exhibit a broad suppression of cell-mediated immunity possibly due to the marked dysregulation in their cytokinetic profile. Glial tumours seem to induce a Thi (stimulatory) to Th2-type (inhibitory) cytokine shift which further supports humoral immunity at the expense of cell-mediated immune responses, contributing to the inefficient anti-tumour responses generated in these patients

Factors controlling the expression of central progesterone receptors

Progesterone, a steroid hormone is closely associated with a variety of behavioural and neuroendocrine functions. Studies were undertaken to identify the control of progesterone receptor (PR) expression in avian brain tissue. In the first study, glial cells taken from newly hatched ring doves (Streptopelia risoria) were cultured in vitro to examine their subsequent development and to identify those cells which expressed PR. Astrocytes, identified using an antibody against glial fibrillary acidic protein (GFAP) and oligodendrocytes, marked with an antibody to galactocerebroside (GaIC), were observed in culture 5 days after preparation. Over a period of 25 days both the astrocytes and oligodendrocytes altered in form from a protoplasmic to a filamentous morphology. PR expression, using a specific monoclonal antibody against the hinge region of the chicken oviduct progesterone receptor, occurred in both of these cell types and the immunostaining was essentially nuclear. However, PR-immunoreactivity (PRir) in oligodendrocytes was more pronounced when compared to PR-it in astrocytes. In a subsequent study glial cells were cultured with estrogen added to the medium. The development and differentiation of the glial cells was not effected, although a significant difference was observed in the intensity of PR immunofluorescence. The intensity of PR immunofluorescence was greater in those cells treated with estrogen. Addition of tamoxifen failed to influence PR expression, however the length of time of culture with this estrogen antagonist was probably too short. An in situ immunocytochemical study was performed to localise the distribution of astrocytes in the newly hatched ring dove brain. Astrocytes were identified as being distributed throughout the brain with a greater density in the peripheral and ventricular areas. Studies to immunolocalise oligodendrocytes in situ were unsuccessful. A second series of studies examined the distribution of PR-jr in the chicken (Gallus domesticus) brain and to quantify changes in expression during a period of high plasma estrogen concentration (laying) and one of low plasma estrogen concentration (brooding). Cell nuclei containing progesterone receptor were largely restricted to the medial and basal hypothalamic area with the highest density occurring in the preoptic area and the lateral hypothalamus. The distribution of cells containing PR-ir demonstrated a similar pattern in both laying and brooding birds. The number of PR-ir cells was consistently lower in brooding birds than in laying. The intensity of PR expression was also greater in laying birds compared to brooding birds, however, due to the small sample size this did not reach statistical significance. These studies have demonstrated that progesterone receptors are localised in the avian brain and that in both young and adult birds, PR expression is sensitive to the presence of estrogen

Immunological evaluation of cytokines and their role in glioma patients

Τα κακοήθη γλοιώματα είναι οι πιο κοινοί πρωτογενείς όγκοι του κεντρικού νευρικού συστήματος με θνησιμότητα που πλησιάζει το 80% στον πρώτο χρόνο της διάγνωσης τους. Η υψηλή τους διεισδυτικότητα καθιστά τις παρούσες θεραπείες, όπως την χειρουργική εξαίρεση και την ακτινοθεραπεία ανεπαρκείς, ενώ καινούργιες προσεγγίσεις όπως η ανοσοθεραπεία μελετούνται προσεκτικά ως πιθανά βοηθήματα στη θεραπεία των ασθενών με κακοήθη γλοιώματα. Ένας αριθμός παραγόντων έχει προταθεί ότι παίζει σημαντικό ρόλο στην διαφυγή των γλοιωμάτων από το ανοσολογικό σύστημα, μεταξύ των οποίων περιλαμβάνεται η φτωχή τους ανοσογενεσιμότητα, εφ’ όσον δεν εκφράζονται ειδικές ανοσοσφαιρίνες και ειδικά αντισώματα για τα γλοιώματα. Ένας άλλος παράγοντας είναι η θέση τους μέσα στο κεντρικό νευρικό σύστημα (ΚΝΣ), το οποίο θεωρείται ως ένα «ανοσο-προνομιούχο» όργανο του ανθρωπίνου σώματος. Τέλος, ακόμη ένας παράγοντας που συντελεί στη διαφυγή από το ανοσολογικό σύστημα είναι το γεγονός ότι τα γλοιωματικά κύτταρα είναι ικανά να εκκρίνουν ποικίλες ανοσοκατασταλτικές κυτοκίνες, οι οποίες δρουν κατασταλτικά στην κυτταροτοξική δράση των Τ κυττάρων. Οι κυτοκίνες είναι πολυλειτουργικές πρωτεΐνες, οι οποίες εμπλέκονται σε διακυτταρικές επικοινωνίες και κυτταρικές λειτουργίες και οι οποίες μπορούν να δείξουν τις επιδράσεις τους στο ΚΝΣ τόσο άμεσα, όσο και έμμεσα. Οι δράσεις τους είναι τόσο ανοσορυθμιστικές όσο και νευροδιαμορφωτικές, αφού μπορούν να προέρχονται, είτε από περιφερικά όργανα του ανοσολογικού συστήματος και να διαπερνούν στη συνέχεια τον αιμοτοεγκεφαλικό φραγμό, ή να παράγονται από νευρωνικά κύτταρα του ΚΝΣ. Σκοπός της παρούσας μελέτης είναι η διερεύνηση της έκφρασης των κυτοκινών στα γλοιώματα και η πιθανή συμμετοχή τους στην κακοήθεια και στην αγγειογέννεση των όγκων. Η έκκριση των κυτοκινών αξιολογήθηκε σε απομονωμένα μονοπύρηνα κύτταρα του περιφερικού αίματος (PBMCs) 50 ασθενών με κακοήθη γλοιώματα σταδίου IV, άμεσα προεγχειρητικά, συγκριτικά με 50 μάρτυρες. Παράλληλα, μελετήθηκε η έκκριση κυτοκινών σε 10 πρωτογενείς καλλιέργειες με την χρήση της μεθοδολογίας ELISPOT. Οι κυτοκίνες Th1-τύπου, TNFα και IFNγ βρεθήκανε μειωμένες στους ασθενείς σε σχέση με τους μάρτυρες (p=0.01 και p<0.001, αντίστοιχα). Σε αντίθεση, οι κυτοκίνες τύπου Th2 (IL-4 και IL-10) βρεθήκανε να είναι αυξημένες στους ασθενείς σε σχέση με τους μάρτυρες Ανοσολογικός προσδιορισμός των κυτοκινών και ο ρόλος τους στα γλοιώματα II τόσο στα περιφερικά κύτταρα, όσο και στις πρωτογενείς καλλιέργειες (p<0.05, p<0.001 αντίστοιχα). Για τον ανοσοϊστοχημικό καθορισμό των κυτοκινών IL-6, IL-8, COX-2, IL-10, VEGF και CD34 χρησιμοποιήθηκαν 23 ασθενείς από τους οποίους ελήφθησαν ιστοτεμάχια τα οποία μονιμοποιήθηκαν σε φορμαλίνη και εμβυθίστηκαν σε παραφίνη. Η μελέτη των μικροαγγείων πραγματοποιήθηκε με το αντίσωμα anti-CD34 και με τη βοήθεια προγράμματος υπολογιστού. Έκφραση της IL-6 ανιχνεύθηκε σε όλα τα δείγματα και έδειξε μια αύξηση στην έκφραση σε σχέση με το επίπεδο νέκρωσης (p=0.005). Η έκφραση της IL-6 παρουσίασε παράλληλη αύξηση με το στάδιο κακοήθειας (p=0.020). Η έκφραση της IL-8 ήτανε αυξημένη σε όλα τα δείγματα. Η έκφρασή της όμως δεν σχετίζεται με το στάδιο νέκρωσης, ούτε με το στάδιο κακοήθειας. Η κυτοκίνη COX ανιχνεύθηκε σε όλα τα δείγματα. Επίσης η COX δεν παρουσίασε θετική συσχέτιση με την αύξηση του βαθμού κακοήθειας αλλά και με τον βαθμό της νέκρωσης. Η ανοσοδραστηκότητα της πρωτεΐνης VEGF ανιχνεύθηκε σε 58,3% των κυττάρων και παρουσίασε θετική συσχέτιση με το βαθμό κακοήθειας του όγκου (p=0.035). Η έκφραση των επιπέδων της IL-10 παρουσιάστηκαν χαμηλά τόσο σε επίπεδο έντασης της χρώσης, όσο και σε ποσοστό θετικών κυττάρων και δεν παρουσίασε καμία θετική συσχέτιση με τον βαθμό νέκρωσης και βαθμό κακοήθειας. Η ανοσοδραστικότητα της CD34 έδειξε ότι οι αγγειακοί ογκομετρικοί παράμετροι δεν επηρεάζονται από τον όγκο όυτε από το βαθμό της νέκρωσης. Η έκφραση της διαλυτής CD95 μετρήθηκε με τη βοήθεια της ELISA, η οποία εμφανίστηκε μειωμένη και δεν ήτανε στατιστικά σημαντική (p>0.05) σε σχέση με τα φυσιολογικά επίπεδα. Συμπερασματικά, τα αποτελέσματα της παρούσας μελέτης δηλώνουν ότι οι ασθενείς με κακοήθη γλοιώματα εμφανίζουν, ευρεία καταστολή της κυτταρικής ανοσίας πιθανόν εξαιτίας της έντονης απορύθμισης του κυτοκινετικού τους προφίλ. Έτσι φαίνεται ότι τα γλοιώματα προάγουν μια αλλαγή από την Th1 (διεγέρτες) σε Th2 (καταστολείς) κυτταρική απάντηση, έκφραση των κυτοκινών που υποστηρίζει μια προώθηση της χυμικής ανοσίας σε βάρος της κυτταρικής ανοσίας, συμβάλλοντας κατ’ αυτόν τον τρόπο σε μια ανεπαρκή ικανότητα του οργανισμού να καταπολεμά τα γλοιώματα

What is New and Innovative in Emergency Neurosurgery? Emerging Diagnostic Technologies Provide Better Care and Influence Outcome: A Specialist Review

The development of emergency medical services and especially neurosurgical emergencies during recent decades has necessitated the development of novel tools. Although the gadgets that the neurosurgeon uses today in emergencies give him important help in diagnosis and treatment, we still need new technology, which has rapidly developed. This review presents the latest diagnostic tools, which offer precious help in everyday emergency neurosurgery practice. New ultrasound devices make the diagnosis of haematomas easier. In stroke, the introduction of noninvasive new gadgets aims to provide better treatment to the patient. Finally, the entire development of computed tomography and progress in radiology have resulted in innovative CT scans and angiographic devices that advance the diagnosis, treatment, and outcome of the patent. The pressure on physicians to be quick and effective and to avoid any misjudgement of the patient has been transferred to the technology, with the emphasis on developing new systems that will provide our patients with a better outcome and quality of life