Biomedical subjects

J Brotchi

Publications and source records attributed to J Brotchi.

At least 19 recordsLinked to original sources

PubMed2007

Controlled delivery of glial cell line-derived neurotrophic factor by a single tetracycline-inducible AAV vector.

An autoregulated tetracycline-inducible recombinant adeno-associated viral vector (rAAV-pTet(bidi)ON) utilizing the rtTAM2 reverse tetracycline transactivator (rAAV-rtTAM2) was used to conditionally express the human GDNF cDNA. Doxycycline, a tetracycline analog, induced a time- and dose-dependent release of GDNF in vitro in human glioma cells infected with rAAV-rtTAM2 serotype 2 virus. Introducing the Woodchuck hepatitis virus posttranscriptional regulatory element (WPRE) downstream to the rtTAM2 coding sequence, resulted in a more rapid induction and a higher basal expression level. In vivo, 8 weeks after a single injection of the rAAV-rtTAM2-GDNF vector encapsidated into AAV serotype 1 capsids in the rat striatum, the GDNF protein level was 60 pg/mg tissue in doxycycline-treated animals whereas in untreated animals, it was undistinguishable from the endogenous level ( approximately 4 pg/mg tissue). However, a residual GDNF expression in the uninduced animals was evidenced by a sensitive immunohistochemical staining. As compared to rAAV1-rtTAM2-GDNF, the rAAV1-rtTAM2-WPRE-GDNF vector expressed a similar concentration of GDNF in the induced state (with doxycycline) but a basal level (without doxycycline) approximately 2.5-fold higher than the endogenous striatal level. As a proof for biological activity, for both vectors, downregulation of tyrosine hydroxylase was evidenced in dopaminergic terminals of doxycycline-treated but not untreated animals. In conclusion, the rAAV1-rtTAM2 vector which expressed biologically relevant doses of GDNF in the striatum in response to doxycycline with a basal level undistinguishable from the endogenous striatal level, as measured by quantitative ELISA assay, constitutes an interesting tool for local conditional transgenesis.

Animals↗

PubMed2006

[A brief history and a few remarks about classifications of aneurysmal subarachnoid hemorrhages and scales of follow-up].

A brief history of the most current scales of aneurysmal subarachnoid hemorrhage and follow-up is presented. Advantages and inaccuracies of these scales are discussed. The World Federation of Neurological Surgeons (WFNS) classification is recommended as the most objective and reliable although some critics exist about its use in particular conditions. The grading of the follow-up is also analyzed. Here, the Glasgow Outcome Scale (GOS) is the most common employed and promoted in a first approach in spite of its briefness. Secondary functional and neuropsychological examination at 6 or 12 months is to be recommended to enable a more accurate evaluation. In conclusion, the WFNS scales for subarachnoid hemorrhage and follow-up is proposed as the best way to allow comparison between work of different centers.

Glasgow Outcome Scale↗

PubMed2006

Endovascular treatment of intracranial aneurysms with a branch arising from the sac.

BACKGROUND AND PURPOSE: The endovascular treatment (EVT) of intracranial aneurysms is no more limited by the presence of a branch at the neck or by the neck width. Saccular aneurysms with a branch arising from the sac, however, are mostly candidates for surgery rather than embolization. We prospectively evaluated the feasibility and safety of the EVT in such cases. METHODS: Between May and November 2004, 9 consecutive patients with a saccular aneurysm that presents a branch arising from the sac were treated by embolization. There were 7 women and 2 men (mean age, 58 years). Six patients presented with a subarachnoid hemorrhage (SAH), and 3 were asymptomatic. All patients were treated by selective coiling with (n = 6) or without (n = 3) the remodeling technique. Clinical outcome was assessed with a modified Glasgow Outcome Scale at 3 months. RESULTS: EVT was successfully performed in all patients and resulted in 7 excellent outcomes and 2 deaths related to SAH complications. The arterial branch could be preserved in 7 cases and intentionally occluded in 2. Neither embolic nor ischemic complication occurred in the vascular territory of the involved branch. Angiographic results showed 5 neck remnants, 2 incomplete occlusions, and 2 complete occlusions. No rebleeding occurred. CONCLUSION: Our study, though limited by its small patient population, suggests that saccular intracranial aneurysms with a branch arising from the sac may be treated by endovascular approach with excellent clinical results; however, larger series with long-term follow-up are mandatory to confirm these preliminary results mostly in terms of anatomic stability.

Adult↗

PubMed2006

Cystic extramedullary ependymoma.

Intradural extramedullary location of ependymoma is rare. To the best of our knowledge, only 9 cases have been described in the literature. We report a case of a histologically confirmed ependymoma (WHO grade II) presented in the MR imaging as a cystic, nonenhancing thoracic intradural extramedullary lesion compressing the spinal cord. The cystic appearance mimicking an arachnoid cyst at diagnosis and the leptomeningeal dissemination developed later were peculiarities that have never been previously described in relation to these rare tumors.

Aged↗

PubMed2005

[Transsphenoidal approach with low field MRI for pituitary adenoma].

INTRODUCTION: Appropriate evaluation of resection remains one of the major difficulties of surgical treatment of pituitary adenoma. The transsphenoidal approach does not allow direct visual control. Endoscopy provides useful information but may no distinguish well residual adenoma from the pituitary gland. Intraoperative MRI offers new perspectives for assessing the quality of resection. We report our experience with low field intraoperative MRI in surgical treatment of pituitary adenoma. POPULATION: Intraoperative MRI (Polestar N10, 30 patients and Polestar N20, 17 patients) was performed in 45 consecutive patients undergoing surgery for pituitary adenoma. Thirty-seven patients had a macroadenoma. Patients were in the prone position with the head fixed with a three-pin MRI-compatible headholder. METHOD: Coronal T1 MRI scans with enhancement were acquired pre and per operatively. We compared scans and surgical filling (complete removal). If there was a difference, a surgical control was undertaken. RESULTS: Intraoperative images were unavailable for two patients due to small size of the neck and the pituitary glands which were not in the middle in the field of view. For the others, the pituitary glands were in the field of view and the intraoperative scans could be used for comparison. For four patients, there was a discrepancy between surgeon filling and the intraoperative MRI. A control showed no residual adenoma but hemostatic tissue. CONCLUSION: Low field intraoperative MRI is an excellent technique for controlling the size of pituitary adenoma resection.

Adenoma↗

PubMed2005

Co-expression/co-location of S100 proteins (S100B, S100A1 and S100A2) and protein kinase C (PKC-beta, -eta and -zeta) in a rat model of cerebral basilar artery vasospasm.

OBJECT: The cellular events leading to cerebral vasospasm after subarachnoid haemorrhages (SAH) involve a number of members of the protein kinase C (PKC) family. However, whereas calcium is thought to play a number of major roles in the pathophysiology of SAH, a number of PKCs function independently of calcium. We recently emphasized the potential role of the calcium-binding S100 proteins in a 'double haemorrhage' rat model of SAH-induced vasospasm. A number of S100 proteins are known to interfere directly with PKC, or indirectly with PKC substrates. We therefore investigated whether specific S100 proteins and PKCs are co-expressed/co-located in a rat model of SAH-induced vasospasm. METHODS AND RESULTS: SAH-induced vasospasm in rats (by means of a double cisternal injection of autologous blood from a rat femoral artery) distinctly modified the expression levels of calcium-dependent PKC-alpha and PKC-beta and calcium-independent PKC-eta and PKC-zeta in endothelial and smooth-muscle cells. The RNA levels of these four PKC isotypes were determined by quantitative RT-PCR. The present study reveals that, in endothelial cells, the S100B expression/location correlate well with those of PKC-eta, and those of S100A1 with PKC-beta. In smooth-muscle cells S100A2 expression/location correlate with those of PKC-eta, and those of S100B with PKC-zeta. CONCLUSION: The present data argue in favour of a joint action of the S100 protein network and the PKC signalling pathway during cerebral vasospasm.

Animals↗

PubMed2004

Recombinant AAV-mediated gene delivery to the central nervous system.

Various regions of the brain have been successfully transduced by recombinant adeno-associated virus (rAAV) vectors with no detected toxicity. When using the cytomegalovirus immediate early (CMV) promoter, a gradual decline in the number of transduced cells has been described. In contrast, the use of cellular promoters such as the neuron-specific enolase promoter or hybrid promoters such as the chicken beta-actin/CMV promoter resulted in sustained transgene expression. The cellular tropism of rAAV-mediated gene transfer in the central nervous system (CNS) varies depending on the serotype used. Serotype 2 vectors preferentially transduce neurons whereas rAAV5 and rAAV1 transduce both neurons and glial cells. Recombinant AAV4-mediated gene transfer was inefficient in neurons and glial cells of the striatum (the only structure tested so far) but efficient in ependymal cells. No inflammatory response has been described following rAAV2 administration to the brain. In contrast, antibodies to AAV2 capsid and transgene product were elicited but no reduction of transgene expression was observed and readministration of vector without loss of efficiency was possible from 3 months after the first injection. Based on the success of pioneer work performed with marker genes, various strategies for therapeutic gene delivery were designed. These include enzyme replacement in lysosomal storage diseases, Canavan disease and Parkinson's disease; delivery of neuroprotective factors in Parkinson's disease, Huntington disease, Alzheimer's disease, amyotrophic lateral sclerosis, ischemia and spinal cord injury; as well as modulation of neurotransmission in epilepsy and Parkinson's disease. Several of these strategies have demonstrated promising results in relevant animal models. However, their implementation in the clinics will probably require a tight regulation and a specific targeting of therapeutic gene expression which still demands further developments of the vectors.

Animals↗

PubMed2004

[Contribution of PET to the management of patients with low-grade glioma].

BACKGROUND AND PURPOSE: Management of patients with low-grade glioma is a major challenge for the neurosurgeon. When is neurosurgery indicated? Should chemotherapy or radiotherapy be used? Many questions without an answer. We reviewed our experience with 65 patients treated for low-grade glioma who had preoperative PET images (FDG or/and MET). We examined the prognostic value of PET and also determined the sensitivity and the specificity of PET images to predict outcome. METHODS: Sixty-five patients with a FDG or MET PET images were analyzed. We used two visual scales and had complete follow-up data for 63 patients. The free interval was the principal criterion for statistical analysis. The sensitivity and the specificity of PET images was determined. RESULTS: Strong FDG uptake was correlated with a short free interval (p=0.001). Similar results were found with the MET analysis (p=0.0076). We had a PET with MET and FDG for 36 patients. The sensitivity was 66% and the specificity 94% for FDG PET. Sensitivity was 100% and specificity 53% for MET PET. CONCLUSIONS: PET imaging provides a prognostic factor independent from histology. MET PET is the best exam for the follow-up of patients with low-grade glioma and is helpful for separating aggressive from low-grade glioma.

Adult↗

PubMed2004

S100A5: a marker of recurrence in WHO grade I meningiomas.

Some WHO grade I intracranial meningiomas resected from the same sites and with the same quality of resection (Simpson's grading scale) recur, while others do not. The reasons for this variability in occurrence of recurrence have not yet been determined. We therefore investigated the prognostic recurrence value of seven biological markers on a series of completely resected WHO grade I meningiomas. For this purpose, we analysed a series of 33 WHO grade I meningiomas totally resected between 1980 and 1990 (a follow-up of 10 years), including 14 cases of recurrence. The fixed tumour material from each meningioma was submitted to histochemical analyses targeting galectin-3 and its binding sites, the S100A5, S100A6 and S100B proteins, and cathepsin-B and -D. The levels of expression were assessed semi-quantitatively (in terms of the staining intensity and the labelling index) and submitted to uni- and multivariate analyses. Of all the markers investigated, only S100A5 expression can be associated with any significant prognostic value in the matter of recurrence. More particularly, the meningiomas with high levels of S100A5 staining intensity either did not recur, or recurred later than those with a low immunopositive S100A5 intensity (P = 0.004). Cox regression analyses demonstrated that this latter marker was associated with significant prognostic values independent of the patients' ages. Furthermore, the combination of the patients' ages and S100A5 staining intensity permitted the identification of a group with a particularly high risk of recurrence, that is, the patients younger than 55 and with meningiomas exhibiting low S100A5 intensities (P = 0.001). In conclusion, the S100A5 protein could play a role in the recurrence of totally resected WHO grade I meningiomas.

Adolescent↗

PubMed2004

Efficient early and sustained transduction of human fetal mesencephalon using adeno-associated virus type 2 vectors.

The success of transplantation of human fetal mesencephalic tissue into the putamen of patients with Parkinson's disease (PD) is still limited by the poor survival of the graft. In animal models of fetal transplantation for PD, antiapoptotic agents, such as growth factors or caspase inhibitors, or agents counteracting oxidative stress enhance the survival and reinnervation potential of the graft. Genetic modification of the transplant could allow a local and continuous delivery of these factors at physiologically relevant doses. The major challenge remains the development of strategies to achieve both early and sustained gene delivery in the absence of vector-mediated toxicity. We recently reported that E14 rat fetal mesencephalon could be efficiently tranduced by adeno-associated virus type 2 (AAV2) vectors and that gene expression was maintained until at least 3 months after transplantation in the adult rat striatum. Here we report that an AAV2 vector can mediate the expression of the EGFP reporter gene under the control of a CMV promoter in organotypic cultures of freshly explanted solid fragments of human fetal mesencephalic tissue as early as 3 days to at least 6 weeks postinfection. These results suggest that AAV2 vectors could be used to genetically modify the human fetal tissue prior to transplantation to Parkinson's patients to promote graft survival and integration.

Animals↗

PubMed2004

[Surgical treatment of intramedullary tumors. Experience with 316 cases].

We report our experience on the surgical treatment of 316 intraspinal cord tumors at the time we presented our lecture to the Academy. Our series is based on 124 ependymomas, 76 astrocytomas, 30 hemangioblastomas and 21 cavernomas to focus on the most frequent tumors. Ependymomas were totally removed in 90%, astrocytomas in 40% and hemangioblastomas so as cavernomas in 100% of the cases. We describe our surgical technique so as our results. We confirm that the surgical risks are directly related to the preoperative neurological situation. Handicapped patients are subject to high surgical risks. Complete removal is the aim since surgery is the gold standard treatment. Good quality of life may be expected in most of the patients (approximately 90%) operated with moderate neurological deficit before surgery.

Glioma↗

PubMed2003

Tetracycline-inducible transgene expression mediated by a single AAV vector.

Regulated gene delivery systems are usually made of two elements: an inducible promoter and a transactivator. In order to optimize gene delivery and regulation, a single viral vector ensuring adequate stoichiometry of the two elements is required. However, efficient regulation is hampered by interferences between the inducible promoter and (i) the promoter used to express the transactivator and/or (ii) promoter/enhancer elements present in the viral vector backbone. We describe a single AAV vector in which transcription of both the reverse tetracycline transactivator (rtTA) and the transgene is initiated from a bidirectional tetracycline-responsive promoter and terminated at bidirectional SV40 polyadenylation sites flanking both ITRs. Up to 50-fold induction of gene expression in human tumor cell lines and 100-fold in primary cultures of rat Schwann cells was demonstrated. In addition an 80-fold induction in vivo in the rat brain has been obtained. In vitro, the autoregulatory vector exhibits an induced expression level superior to that obtained using the constitutive CMV promoter. Although extinction of the transgene after removal of tetracycline was rapid (less than 3 days), inducibility after addition of tetracycline was slow (about 14 days). This kinetics is suitable for therapeutic gene expression in slowly progressive diseases while allowing rapid switch-off in case of undesirable effects. As compared to previously described autoregulatory tet-repressible (tetOFF) AAV vectors, the tet-inducible (tetON) vector prevents chronic antibiotic administration in the uninduced state.

Animals↗

PubMed2003

Cathepsin B, D and K expression in adamantinomatous craniopharyngiomas relates to their levels of differentiation as determined by the patterns of retinoic acid receptor expression.

AIMS: To investigate the potential predictive value of cathepsins B, D and K in a series of 51 adamantinomatous craniopharyngiomas. While almost always benign, craniopharyngiomas exhibit a high propensity to recur postsurgically and biological markers are therefore needed to predict their recurrence. We have previously demonstrated the potential predictive value of retinoic acid receptors (RARs) (Lefranc et al., J. Neurosurg. 2003; 98; 145-153). METHODS AND RESULTS: Computer-assisted microscopy was used to determine quantitatively the immunohistochemical levels of expression of the alpha, beta and gamma RAR subtypes and cathepsins B, D and K. The levels of expression of cathepsin D and of cathepsin B correlated significantly with the levels of expression of RARbeta. The levels of expression of cathepsin K correlated significantly with the levels of expression of RARgamma. CONCLUSIONS: Recurrent adamantinomatous craniopharyngiomas are characterized by low levels of RARbeta and high levels of RARgamma. The tendency to recurrence seems, at least partly, to relate to the fact that (i) craniopharyngiomas with low levels of RARbeta express low levels of cathepsin D, and (ii) craniopharyngiomas with high levels of RARgamma express high levels of cathepsin K.

Adolescent↗

PubMed2002

AAV2 vectors mediate efficient and sustained transduction of rat embryonic ventral mesencephalon.

The success of transplantation of human embryonic mesencephalic tissue to treat parkinsonian patients is limited by the poor survival of the transplant. We show that an AAV2 vector mediates efficient expression of the egfp reporter gene in organotypic cultures of freshly explanted solid fragments of rat embryonic ventral mesencephalon (VM). We observed early and sustained transgene expression (4 days to > or = 6 weeks). Furthermore, rAAV-infected rat embryonic VM transplanted in the adult striatum continued to express EGFP for > or = 3 months. More than 95% of the transduced cells were neurons. Dopaminergic neurons were transduced at low frequency at earlier time points. This method of gene delivery could prove useful to achieve local, continuous secretion of neurotrophic factors at physiologically relevant doses to treat Parkinson's disease.

Animals↗

PubMed2002

Neuroprotective gene therapy for Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disease characterised by a progressive loss of the dopaminergic neurones in the substantia nigra pars compacta. Accumulating evidence indicates that apoptosis contributes to neuronal cell death in PD patients' brain. Excitotoxicity, oxidative stress, and mitochondrial respiratory failure are thought to be the key inducers of the apoptotic cascade. Even though the initial cause and the mechanism of degeneration are poorly understood, neuroprotection can be achieved by interfering with neuronal cell death either directly or by preventing neuronal dysfunction. Potential agents for neuroprotection are neurotrophic factors, inhibitors of apoptosis or anti-oxidative agents. However, the existence of the blood-brain barrier precludes systemic delivery of these factors. In situ gene delivery provides strategies for local and sustained administration of protective factors at physiologically relevant doses. Viral vectors mediating stable gene expression in the central nervous system exist and are still under development. Efficacy of these vectors has repeatedly been demonstrated in the animal models both ex vivo and in vivo. Ex vivo gene delivery could furthermore be combined with cell replacement therapies by transplanting genetically modified cells compensating for the lost neuronal cell population in order to provide neuroprotection to both the grafted cells and degenerating host neurones. However, several aspects of gene transfer, such as uncontrolled diffusion, axonal transport, unpredictable site of integration and immunological responses, still raise safety concerns and justify further development of viral and non-viral vectors as well as genetic elements with tightly controlled gene expression. Various relevant animal models for Parkinson's disease are available for the evaluation of gene therapy strategies. These include induction of cell death in specific neurone population through administration of toxins either directly in the brain or systemically, as well as transgenic mice expressing human disease-associated mutations.

Animals↗

PubMed2002

[Pineal region surgery. Experience in 22 patients].

BACKGROUND AND PURPOSE: Different approaches to the pineal region are described in the literature with high mortality and morbidity. We report our experience with two different approaches (occipitoparietal or infratentorial supracerebellar approaches) for pineal region. METHODS: Between 1986 and 1997, 25 operations were performed in 22 patients. Preoperative work-up included a CT-scan with conventional angiography (for older patients), magnetic resonance imaging with angiographic study (angio-MRI) for the others. Two different approaches, the occipitoparietal (n=14) or the infratentorial supracerebellar (n=8) ones, were used. Three patients had a stereotactic biopsy, followed by a total resection for one of them. RESULTS: The mortality and morbidity induced by the approaches were low compared to the series of the literature. Only 2 patients were worsened by the surgery: Patient 4 developed hemianopsia after an occipitoparietal approach and patient 21 temporary Parinaud syndrome after resection of a teratoma by supracerebellar infratentorial approach. One patient improved his neurological status but died on the 10th postoperative day from pulmonary embolism. CONCLUSIONS: Total or partial resection of well-defined pineal region lesions by direct neurosurgical approaches can be achieved in most cases with low morbidity. The choice among the two surgical occipitoparietal or infratentorial supracerebellar approaches depends on the size and the location of the lesion in the pineal area, its relation to the ventricular system, the median line and the splenium. Angiographic sequences in magnetic resonance with study of the deep veins are helpful in this respect.

Adolescent↗

PubMed2002

[The neurosurgery department].

Opened on November 1st, 2001, the Department of Neurosurgery has progressively grown to become worldwide renown in a few years. All the pathologies are covered, from lumbar disc hernia to intracranial tumors and vascular malformations. But the originality stays into the exceptional environment by the concentration of logistic resources and the ability of clinician and researchers who daily collaborate with the neurosurgical team. The Department of Neurosurgery has a strong reputation in several fields like intraspinal cord tumors or Pet-guided Neurosurgery in stereotactic biopsies, neuronavigation and Gamma Knife and, generally speaking, in the original approach of the treatment and follow-up of brain tumors. Neurodegenerative diseases also benefit of modern approaches trough the Gamma Knife, deep brain stimulation or fetal cell grafting into the brain in Parkinson and soon in Huntington diseases. Last but not least, the arrival for the 25th anniversary of Erasme Hospital of an interventional MRI will allow to follow in real-time the resection of brain tumors with an obvious benefit for the surgical performances and the quality of life of the patients. It will also open a new window for neurosurgical research through combination with functional MRI and Pet-Scan, reinforcing the reputation of Erasme Neurosurgical Department who has been distinguished in 1997 by the World Health Organisation as "WHO Collaborating Center for Research and Training in Neurosurgery" and nominated again in 2002 for a new 4-year period, which is unique in the Neurosurgical World.

Belgium↗

PubMed2001

[Radiosurgery of the brain at the beginning of the 21st century: gamma knife with C-table].

The goal of stereotactic radiosurgery by definition is "the delivery of a single, high dose of radiation allowing the precise and complete destruction of chosen target structures containing healthy and/or pathological cells, without significant concomitant or late radiation damage to adjacent tissues". This effect is obtained by the precise focusing of multiple low energy radiation beams crossing at the target. Three different techniques can be used for radiosurgery: linear accelerator (LINAC) based radiosurgery, Bragg-peak (proton) therapy and Gamma Knife radiosurgery. Leksell Gamma Knife (LGK) is a dedicated neurosurgical device for brain surgery to destroy predetermined intracranial targets through the intact skull. It operates via the radiobiological effect of stereotactically directed, highly focused ionizing gamma-beams of 201 cobalt-60 sources. The LGK offers the best precision of target during irradiation. The mechanical accuracy is about 0.3 mm, which makes it particularly suitable for highly sophisticated neurosurgical interventions. Radiosurgery was originally developed to treat functional neurological disorders, but soon after its introduction cerebral arteriovenous malformations, and brain tumors became the main targets for the technique. Since the first LGK installation at the Sophiahemmet Hospital, Stockholm, Sweden in 1967, over 150,000 patients have already been treated in more than 150 units worldwide. The accumulated clinical experience with the LGK has established this method as the "golden standard" of radiosurgery. In December 1999, a new development, the LGK Model-C was installed at the Centre Gamma Knife, Université Libre de Bruxelles, Hôpital Académique Erasme, Brussels, Belgium. This was followed by completion of two similar units in Krefeld, Germany, and at the Presbyterian University Hospital, Pittsburgh, Pennsylvania, U.S.A. The major innovation in the design of the LGK Model-C is the robotic Automatic Positioning System, which allows computer-controlled automatic and sequential positioning of multiple shots during treatment. Thus all steps of the procedure are performed through an unbroken digital chain, from stereotactic image acquisition to the control of the irradiation sequence. This represents a significant achievement which increases the accuracy and practicality of the treatment. The technical details of the method are described, and the main treatment indications are reviewed.

Brain Neoplasms↗