Cases reports: Unintended anti-doping rule violation after dorzolamide use several months prior to a doping control.

The use of specific medicine up to several months before a doping control is not be reported on the doping control form, while the drug could then still be detectable in urine in case of a very slow elimination. It may lead to a positive test result. For example, dorzolamide, a carbonic anhydrase inhibitor for topical ophthalmic application, has a very slow elimination rate via the renal route (half-life > 4 months). This substance can be a source of unintended anti-doping rule violations.

[Glutamate and malignant gliomas, from epilepsia to biological aggressiveness: therapeutic implications]. / Glutamate et gliomes malins, de l'épilepsie à l'agressivité biologique : implications thérapeutiques.

In this review article, we describe the unrecognized roles of glutamate and glutamate receptors in malignant glioma biology. The neurotransmitter glutamate released from malignant glioma cells in the extracellular matrix is responsible for seizure induction and at higher concentration neuronal cell death. This neuronal cell death will create vacated place for tumor growth. Glutamate also stimulates the growth and the migration of glial tumor cells by means of the activation of glutamate receptors on glioma cells in a paracrine and autocrine manner. The multitude of effects of glutamate in glioma biology supports the rationale for pharmacological targeting of glutamate receptors and transporters in the adjuvant treatment of malignant gliomas in neurology and neuro-oncology. Using the website www.clinicaltrials.gov/ as a reference - a service developed by the National Library of Medicine for the National Health Institute in USA - we have evoked the few clinical trials completed and currently ongoing with therapies targeting the glutamate receptors.

Endoscope-integrated ICG technology: first application during intracranial aneurysm surgery.

Microscopic indocyanine green videoangiography (mICG-VA) has gained wide acceptance during intracranial aneurysm surgery by lowering rates of incomplete clipping and occlusion of surrounding vessels. However, mICG-VA images are limited to the microscopic view and some deeper areas, including the aneurysm sac/neck posterior side, cannot be efficiently assessed as they are hidden by the aneurysm, clips, or surrounding structures. Contrarily, endoscopes allow a wider area of visualization, but neurosurgical endoscopes to date only provided visual data. We describe the first application of endoscope ICG-integrated technology (eICG) applied in an initial case of anterior communicating artery aneurysm clipping. This new technique provided also relevant information regarding aneurysm occlusion and patency of parent and branching vessels and small perforating arteries. eICG-VA provided additional information compared to mICG-VA by magnifying areas of interest and improving the ability to view less accessible regions, especially posterior to the aneurysm clip. Obtaining eICG sequences required currently the microscope to be moved away from the operating field. eICG-VA was only recorded under infrared illumination which prevented tissue handling, but white-infrared light views could be interchanged instantaneously. Further development of angled endoscopes integrating the ICG technology and dedicated filters blocking the microscopic light could improve visualization capacities even further. In conclusion, as a result of its ability to reveal structures around corners, the eICG-VA technology could be beneficial when used in combination with mICG-VA to visualize and confirm vessel patency in areas that were previously hidden from the microscope.

Minimally invasive spinal arthrodesis in osteoporotic population using a cannulated and fenestrated augmented screw: technical description and clinical experience.

We describe a percutaneous or minimally invasive approach to apply an augmentation of pedicle fenestrated screws by injection of the PMMA bone cement through the implant and determine the safety and efficiency of this technique in a clinical series of 15 elderly osteoporotic patients. Clinical outcome and the function were assessed using respectively the Visual Analogue Scale (VAS) score and the Oswestry Disability Index (ODI). Peri- and post-operative complications were monitored during a minimum of 2 years of follow-up. Radiographic follow-up was based on plain fluoroscopic control at 3, 6 and 12 months and every year. In this approach, four steps were considered with care: optimal positioning of the screws, correct alignment of the screw heads, waiting time before the injection of cement, fluoroscopic control of the cement injection. Using these precautions, only 2 minor complications occurred. VAS scores and ODI questionnaires showed a statistically significant improvement up to 13.3 months postoperatively. No radiological complications were observed. Based on this experience, PMMA augmentation technique through the novel fenestrated screws provided an effective and long lasting fixation in osteoporotic patients. Applying this procedure through percutaneous or minimally invasive approach under fluoroscopic control seems to be safe.

Voltage-dependent K+ channels as oncotargets in malignant gliomas.

Because both imipramine and citalopram have been commonly used to treat depression, which commonly occurs in glioma patients, it would be interesting to conduct large epidemiological studies to investigate the actual benefit that these two drugs would provide for malignant glioma patients when delivered during their glioma treatment. Such large-scale epidemiological studies have recently revealed the actual benefit provided by digoxin, a Na+/K+ ATPase inhibitor used to treat heart failure, in prostate cancer patients treated for both prostate cancer and heart failure.

Long-term follow-up survey reveals a high yield, up to 30% of patients presenting newly detected aneurysms more than 10 years after ruptured intracranial aneurysms clipping.

The need to pursue long-term follow-up in patients treated for a ruptured aneurysm remains debated. New aneurysms development is a crucial element to consider but remains scarcely analyzed especially after a mean follow-up longer than 10 years. Our study was designed to provide rates of newly developed aneurysms in patients who have undergone prior clipping who were not followed with serial imaging. Patients were included if they were (1) treated more than 10 years ago by clipping of a ruptured aneurysm, (2) independent at time of discharge, (3) presently younger than 65 years, and if (4) they agreed to undergo a late digital subtraction angiography (DSA) control or to transmit results of a recent one performed elsewhere. Twenty patients were included with a mean delay between aneurysm treatment and late DSA of 18.0 years (10-26.5 years). Out of these patients, six (30%) harbored new aneurysms. Of these six individuals, four (66.6%) presented multiple aneurysms with a total of 15 newly discovered aneurysms. Aneurysm sizes ranged from 1 to 10 mm. One patient suffered from a de novo aneurysm rupture. Multiple aneurysms at the time of the first hemorrhage were a risk factor in developing de novo aneurysm (p=0.0175). In conclusion, based on a 30% rate of new aneurysm formation in patients clipped more than a decade ago, close screening on a very long-term perspective is encouraged. This study suggests aneurysm formation to be a continuous process.

Long-term in vitro treatment of human glioblastoma cells with temozolomide increases resistance in vivo through up-regulation of GLUT transporter and aldo-keto reductase enzyme AKR1C expression.

Glioblastoma (GBM) is the most frequent malignant glioma. Treatment of GBM patients is multimodal with maximum surgical resection, followed by concurrent radiation and chemotherapy with the alkylating drug temozolomide (TMZ). The present study aims to identify genes implicated in the acquired resistance of two human GBM cells of astrocytic origin, T98G and U373, to TMZ. Resistance to TMZ was induced by culturing these cells in vitro for months with incremental TMZ concentrations up to 1 mM. Only partial resistance to TMZ has been achieved and was demonstrated in vivo in immunocompromised mice bearing orthotopic U373 and T98G xenografts. Our data show that long-term treatment of human astroglioma cells with TMZ induces increased expression of facilitative glucose transporter/solute carrier GLUT/SLC2A family members, mainly GLUT-3, and of the AKR1C family of proteins. The latter proteins are phase 1 drug-metabolizing enzymes involved in the maintenance of steroid homeostasis, prostaglandin metabolism, and metabolic activation of polycyclic aromatic hydrocarbons. GLUT-3 has been previously suggested to exert roles in GBM neovascularization processes, and TMZ was found to exert antiangiogenic effects in experimental gliomas. AKR1C1 was previously shown to be associated with oncogenic potential, with proproliferative effects similar to AKR1C3 in the latter case. Both AKR1C1 and AKR1C2 proteins are involved in cancer pro-proliferative cell chemoresistance. Selective targeting of GLUT-3 in GBM and/or AKR1C proteins (by means of jasmonates, for example) could thus delay the acquisition of resistance to TMZ of astroglioma cells in the context of prolonged treatment with this drug.

Cervical vertebral artery rerouting: a technique for releasing kinks and restoring endovascular access.

BACKGROUND: The endovascular treatment of intracranial aneurysms can be hampered by the tortuosity of extracranial vessels. Percutaneous or surgical vessel puncture can resolve the problem of inaccessibility. OBJECTIVE: We describe rerouting of a kinked vertebral artery (VA) to restore transfemoral endovascular access to an aneurysm. CASE REPORT: A 63-year-old woman presented with progressive hemiparesis. Magnetic resonance imaging demonstrated a left fusiform vertebrobasilar aneurysm with mass effect on the brainstem. The patient was found to have a dominant left VA on angiography with a severe kink in its V1 segment. Tight loops of this segment prevented catheter progression past V1 during endovascular treatment. INTERVENTION: The left VA was rerouted from its subclavian origin to the C5 transverse foramen through a combined lateral and supraclavicular approach. Release of the VA off the C6 transverse process and C6 and C7 cranial nerve roots permitted unfolding of the VA. The excess length of the VA, initially present between the subclavian artery and the C6 transverse process, was spread over a longer distance. The tight angles present preoperatively were converted into a harmonious curvature. The rerouted VA was attached to surrounding soft tissue to maintain its position. The patient's postoperative course was uneventful. Endovascular treatment of the aneurysm was performed 15 days later. CONCLUSION: The VA rerouting technique can be used successfully in patients in whom tight loops in the VA prevent endovascular access to intracranial vessels.

Long-term temozolomide treatment induces marked amino metabolism modifications and an increase in TMZ sensitivity in Hs683 oligodendroglioma cells.

Gliomas account for more than 50% of all primary brain tumors. The worst prognosis is associated with gliomas of astrocytic origin, whereas gliomas with an oligodendroglial origin offer higher sensitivity to chemotherapy, especially when oligodendroglioma cells display 1p19q deletions. Temozolomide (TMZ) provides therapeutic benefits and is commonly used with radiotherapy in highly malignant astrocytic tumors, including glioblastomas. The actual benefits of TMZ during long-term treatment in oligodendroglioma patients have not yet been clearly defined. In this study, we have investigated the effects of such a long-term TMZ treatment in the unique Hs683 oligodendroglioma model. We have observed increased TMZ sensitivity of Hs683 orthotopic tumors that were previously treated in vitro with months of progressive exposure to increasing TMZ concentrations before being xenografted into the brains of immunocompromised mice. Whole-genome and proteomic analyses have revealed that this increased TMZ sensitivity of Hs683 oligodendroglioma cells previously treated for long periods with TMZ can be explained, at least partly, by a TMZ-induced p38-dependant dormancy state, which in turn resulted in changes in amino acid metabolism balance, in growth delay, and in a decrease in Hs683 oligodendroglioma cell-invasive properties. Thus, long-term TMZ treatment seems beneficial in this Hs683 oligodendroglioma model, which revealed itself unable to develop resistance against TMZ.

Synergistic neuroprotective effects of C3a and C5a receptor blockade following intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is associated with neurological injury that may be ameliorated by a neuroprotective strategy targeting the complement cascade. We investigated the role of C5a-receptor antagonist (C5aRA) solely and in combination with C3a-receptor antagonist (C3aRA) following ICH in mice. METHODS: Adult male C57BL/6J mice were randomized to receive vehicle, C5aRA alone or C3aRA and C5aRA 6 and 12 h after ICH, and every 12 h thereafter. A double injection technique was used to infuse 30 microL of autologous whole blood into the right striatum. A final group of mice received a sham procedure consisting only of needle insertion followed by vehicle injections. Brain water content and flow cytometry analysis for leukocyte and microglia infiltration and activation in both hemispheres were measured on day 3 post ICH. Neurological dysfunction was assessed using a Morris water-maze (MWM), a 28-point scale, and a corner test at 6, 12, 24, 48 and 72 h after ICH induction. RESULTS: Neurological deficits were present and comparable in all three cohorts 6 h after ICH. Animals treated with C5aRA and animals treated with combined C3aRA/C5aRA demonstrated significant improvements in neurological function assessed by both the corner turn test and a 28-point neurological scale at 24, 48 and 72 h relative to vehicle-treated animals. Similarly, C5aRA and C3aRA/C5aRA-treated mice demonstrated better spatial memory retention in the Morris water-maze test compared with vehicle-treated animals (C3aRA/C5aRA: 23.4+/-2.0 s p< or =0.0001 versus vehicle: 10.0+/-1.7 s). Relative to vehicle-treated mice, the brain water content in C3aRA/C5aRA-treated mice was significantly decreased in the ipsilateral cortex and ipsilateral striatum (ipsilateral cortex: C3aRA/C5aRA: 0.755403+/-0.008 versus 0.773327+/-0.003 p=0.01 striatum: 0.752273+/-0.007 versus 0.771163+/-0.0036 p=0.02). C5aRA-treated mice and C3aRA/C5aRA-treated mice had a decreased ratio of granulocytes (CD45(+)/CD11b(+)/Ly-6G(+)) in the hemorrhagic versus non-hemorrhagic hemispheres relative to vehicle-treated animals (C5aRA: 1.78+/-0.36 p=0.02 C3aRA/C5aRA: 1.59+/-0.22 p=0.005 versus vehicle: 3.01). CONCLUSIONS: While administration of C5aRA alone provided neuroprotection, combined C3aRA/C5aRA therapy led to synergistic improvements in neurofunctional outcome while reducing inflammatory cell infiltration and brain edema. The results of this study indicate that simultaneous blockade of the C3a and C5a receptors represents a promising neuroprotective strategy in hemorrhagic stroke.

The role of polyamine metabolism in neuronal injury following cerebral ischemia.

Stroke is a leading cause of morbidity and mortality in the US, with secondary damage following the initial insult contributing significantly to overall poor outcome. Prior investigations have shown that the metabolism of certain polyamines such as spermine, spermidine, and putrescine are elevated in ischemic parenchyma, resulting in an increase in their metabolite concentration. Polyamine metabolites tend to be cytotoxic, leading to neuronal injury in the penumbra following stroke and expansion of the area of infarcted tissue. Although the precise mechanism is unclear, the presence of reactive aldehydes produced through polyamine metabolism, such as 3-aminopropanal and acrolein, have been shown to correlate with the incidence of cerebral vasospasm, disruption of oxidative metabolism and mitochondrial functioning, and disturbance of cellular calcium ion channels. Regulation of the polyamine metabolic pathway, therefore, may have the potential to limit injury following cerebral ischemia. To this end, we review this pathway in detail with an emphasis on clinical applicability.

C3a receptor antagonist attenuates brain injury after intracerebral hemorrhage.

Neuroprotective therapy targeting the complement cascade may reduce injury associated with intracerebral hemorrhage (ICH). We investigated the role of C3a-receptor antagonist (C3aRA) after ICH in mice. Autologous whole blood was infused into the right striatum of mice that were treated with C3aRA or vehicle, using both a pre- and postinjury dosing regimen. Hematoma volume, brain water content, and inflammatory cell profile were assessed at 72 h post-ICH. Neurologic dysfunction was assessed by evaluating both spatial memory and sensorimotor capacity. Animals pretreated with C3aRA showed significantly improved neurologic function, brain water content, and granulocyte infiltration relative to vehicle-treated animals when assessed at 72 h. There was no significant difference in hemorrhagic/nonhemorrhagic ratio of microglial activation among all groups. Hematoma volumes were also not significantly different between C3aRA-treated and vehicle-treated animals. Administration of C3aRA beginning 6 h postinjury afforded significant amelioration of neurologic dysfunction as well as a reduction in brain water content. Treatment with C3aRA improved neurologic outcome while reducing inflammatory cell infiltration and brain edema formation after experimental ICH in mice. Results of this study suggest that the C3a receptor may be a promising target for therapeutic intervention in hemorrhagic stroke.

Monocyte chemoattractant protein-1 predicts outcome and vasospasm following aneurysmal subarachnoid hemorrhage.

OBJECT: Despite efforts to elucidate both the molecular mechanism and the clinical predictors of vasospasm after aneurysmal subarachnoid hemorrhage (ASAH), its pathogenesis remains unclear. Monocyte chemoattractant protein-1 (MCP-1) is a chemokine that has been firmly implicated in the pathophysiology of vasospasm and in neural tissue injury following focal ischemia in both animal models and human studies. The authors hypothesized that MCP-1 would be found in increased concentrations in the blood and cerebrospinal fluid (CSF) of patients with ASAH and would correlate with both outcome and the occurrence of vasospasm. METHODS: Seventy-seven patients who presented with ASAH were prospectively enrolled in this study between July 2001 and May 2002. Using an enzyme-linked immunosorbent assay, MCP-1 levels were measured in serum daily and in CSF when available. The mean serum and CSF MCP-1 concentrations were calculated for each patient throughout the entire hospital stay. Neurological outcome was evaluated at discharge or 14 days posthemorrhage using the modified Rankin Scale. Vasospasm was evaluated on angiography. RESULTS: The serum MCP-1 concentrations correlated with negative outcome such that a 10% increase in concentration predicted a 25% increase in the probability of a poor outcome, whereas the serum MCP-1 levels did not correlate with vasospasm. Concentrations of MCP-1 in the CSF, however, proved to be significantly higher in patients with angiographically demonstrated vasospasm. CONCLUSIONS: These findings suggest a role for MCP-1 in neurological injury and imply that it may act as a biomarker of poor outcome in the serum and of vasospasm in the CSF.

A mouse model of intracerebral hemorrhage using autologous blood infusion.

The development of controllable and reproducible animal models of intracerebral hemorrhage (ICH) is essential for the systematic study of the pathophysiology and treatment of hemorrhagic stroke. In recent years, we have used a modified version of a murine ICH model to inject blood into mouse basal ganglia. According to our protocol, autologous blood is stereotactically infused in two stages into the right striatum to mimic the natural events of hemorrhagic stroke. Following ICH induction, animals demonstrate reproducible hematomas, brain edema formation and marked neurological deficits. Our technique has proven to be a reliable and reproducible means of creating ICH in mice in a number of acute and chronic studies. We believe that our model will serve as an ideal paradigm for investigating the complex pathophysiology of hemorrhagic stroke. The protocol for establishing this model takes about 2 h.

Neurologic assessment of somatosensory dysfunction following an experimental rodent model of cerebral ischemia.

The modified adhesive removal (sticky-tape) test is an assessment of somatosensory dysfunction following cerebral ischemia in rats. This test is less time consuming than the original protocol by virtue of requiring minimal pre-training. We present a detailed protocol describing how to conduct the modified adhesive removal (sticky-tape) test. Following right middle cerebral artery occlusion (rMCAo) using an intraluminal filament, animals undergo the modified sticky-tape test (MST) on post-operative days 1, 3, 7 and 10. For the test, a non-removable tape sleeve is placed around the animal's paw and the time to remove the stimulus is measured. The time spent attending to this stimulus is also recorded. Animals undergoing MST for the first time demonstrate nearly-uniform excellent performance. However, following rMCAo, the ratio of left to right performance on the MST is significantly different at all time points. In short, the MST accurately assesses neurological dysfunction in rodents, not only with minimal pre-training, but also with accurate localization to the side of injury.

Factors affecting the health-related quality of life of patients with cervical dystonia and the impact of botulinum toxin type A injections.

The purpose of this study was to analyze the health-related quality of life (HRQL) of patients with cervical dystonia (CD) and the impact of botulinum toxin A (BTX-A) therapy in these patients. The authors recruited 101 patients with CD, all previously treated with BTX-A. Both before and 4 weeks after injection of BTX-A the patients were assessed using the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), a Visual Analogue Scale for pain (VAS: 0-100%), the Short Form 36 health survey questionnaire (SF-36), and the Montgomery-Asberg Depression Rating Scale (MADRS). A control group of 84 healthy volunteers was also evaluated. The patients? baseline SF-36 scores were worse in all the domains when compared with those of the controls. Depression was found in 47.5% of the patients. Improvements were noticed 4 weeks after the single BTX-A injections in all the SF-36 domains, and in the VAS, TWSTRS and MADRS scores. The TWSTRS results did not correlate with any of the SF-36 subscores. Stepwise backward regression analysis revealed depression as the main predictor of poor HRQL, as well as female sex, poor financial situation, and living alone. On contrary, longer treatment with BTX-A was associated with better scores. Cervical dystonia has a marked impact on HRQL and treatment with BTX-A injections has a beneficial effect, seen both in objective and in subjective measures. Depression in CD patients is a main predictor of worse HRQL.

[A case of a giant cavernoma located in the temporal region]. / Przypadek olbrzymiego naczyniaka jamistego plata skroniowego.

We present a case of a 21-year-old female with a giant cavernoma (5 cm x 3.1 cm x 3.6 cm) located in the left temporal region. Giant cavernomas are very rarely diagnosed. In our research we wanted to focus on the occurrence of these vascular malformations and diagnostic problems related to this matter.