It has been shown previously that S-100β levels in serum correspond with the severity of central nervous system (CNS) trauma. It also has been suggested that S-100β in CNS tissue is involved in neuroprotection and neuroregeneration. We have previously shown that administration of quercetin results in improved motor function in an animal model of spinal cord trauma.

Mid-thoracic spinal cord compression injury was produced in adult maleWistar rats. Serum and tissue samples were acquired from quercetin-treated animals (25 μmol / kg) and saline controls at 6, 12 and 24 hours after the trauma. S-100β levels were measured using a luminometric assay in the damaged tissue and in the serum of the animals.

The increase in serum S-100β levels seen in saline controls after spinal cord trauma was ameliorated in the quercetin-treated animals at all time points, although the difference to saline controls became statistically significant only at 24 hrs after the trauma. Compared to tissue S-100β levels in healthy animals, values were significantly decreased in saline controls at all three time points, while they were decreased at 6 hrs and increased at both 12 and 24 hrs in quercetin-treated animals. At all three time points tissue S-100β levels were significantly higher in quercetin-treated animals than in saline controls.

Administration of quercetin results in modification of S-100β levels in the setting of experimental spinal cord trauma. The kinetic patterns of the S-100β fluctuations in serum and tissue suggest that post-traumatic administration of quercetin decreases the extent of CNS injury.

According to a recent proposal for revised diagnostic criteria for Alzheimer disease, the diagnosis could be made even in the absence of impairment of social function or daily life activities, provided positivity of one or more abnormal biomarkers. The use of the new proposed diagnostic criteria raises ethical issues and needs to be carefully evaluated.

We describe two clinical cases of prodromal Alzheimer's disease and discuss the diagnosis disclosure, taking into consideration several issues: (i) the issue of the boundary between well founded research procedures and clinical practice, (ii) the issue of the fuzziness of the concepts of scientific evidence and scientific uncertainty, (iii) the issue of patient's autonomy and patient's best interest, and (iv) the issue of the patients' specific personal and social context.

The degree of informativeness of the proposed diagnostic criteria for the single patient is already such as to deserve high regard in making the diagnosis and in the diagnosis disclosure process. During the disclosure process, the physician needs to take into account both what is known and what it is not sufficiently known. The patient's personal and environmental conditions should drive the physician to partial or full diagnostic disclosure, or delay communication.

We proposed two different diagnosis disclosure processes, on the basis of the common neurological features and of the different global clinical situations, socio-personal contexts and attitudes towards the communication of the diagnosis.

We previously reported that Arsenic trioxide (ATO) can inhibit glioma growth both in vitro and in vivo. While the use of ATO alone for solid tumor treatment sometimes was found to be ineffective which may be due to the protective pathways including heat shock proteins (HSPs) response induced by ATO. In this study, we modified HSPs expression to investigate whether HSPs had some effect on ATO induced glioma cell death.

Trypan bule exclusion assay, mitochondrial membrane potential (MMP) Assay, and SubG1 detection were used to evaluate cell viability and western-blot was employed to detect HSPs and some apoptosis markers expression induced by ATO. Heat pre-treatment, HSPs inhibitor, or Heat Shock factor-1 (HSF1) knockdown by SiRNA was employed to modify HSPs levels.

It was showed that KNK437 (HSPs inhibitor) or HSF1 knockdown significantly enhanced cell death, MMP disruption, JNK phosphorylation and caspase-3 cleavage induced by ATO, which was accompanied by abrogation of HSPs induction, while heat pre-treatment with clear HSPs induction had strong protection on the effects mentioned above.

Those data suggested that HSPs play protective roles on ATO induced cell death in glioma. Inhibition of HSPs may have a synergistic effect with ATO on glioma treatment.

Ubiquitin proteasome system dysfunction is believed to play an important role in the development of Parkinson's disease (PD), and almost all studies till now have mainly focused on the susceptibility of dopaminergic neurons to proteasome inhibition. However, in fact, there are many other types of neurons such as cholinergic ones involved in PD. In our present study, we attempt to figure out what effect the failure of ubiquitin proteasome function would execute on cholinergic cells in culture.

We treated cholinergic cells in culture with various doses of lactacystin. Then MTT assay was used to evaluate the cellular viability and the Annexin V-PI method was used to detect apoptosis. Both cellular soluble and insoluble polyubiquitinated proteins were detected by western blot. Furthermore, the mitochondrial membrane potential was analyzed using JC-1 and the intracellular production of reactive oxygen species (ROS) was determined using the fluorescent probe CM-H2DCFDA.

We found that low doses of lactacystin were enough to induce significant apoptotic cell death, disturb the mitochondrial membrane potential, and cause oxidative stress. We also found that the amounts of polyubiquitinated proteins dramatically increased with high doses, although the loss of cells did not increase accordingly.

Our results suggest that cholinergic cells are sensitive to ubiquitin proteasome system dysfunction, which exerts its toxic effect by causing mitochondrial dysfunction and subsequent oxidative stress, not through polyubiquitinated proteins accumulation.

Despite optimal medical therapy, a sizeable number of patients continue to have persistent seizures. We evaluated the association of pretreatment and treatment variables with unfavorable seizure outcome.

Patients with follow-up over 12 years in the Nepal Epilepsy Association were evaluated. Patients having seizures for at least a year and already on polytherapy after failure of two monotherapy trials were considered having unfavourable outcome. Variables under study were: age, sex, duration and frequency of seizures prior to treatment, type of seizure, neurological status, Computed Tomography (CT) finding, and failure of first anti-epileptic drug (AED). Bivariate analysis was done with Chi-square and Fisher exact tests. Potential interaction between variables was studied with a logistic regression analysis.

Out of a total 529 consecutive patients, 490 were included in the study. Unfavorable seizure outcome was seen in 26.8% of patients. Among 284 patients who remained viable for analysis, bivariate analysis showed significant association of unfavorable outcome with frequency of seizure (p 0.01), abnormal neurological status (p 0.01) and failure of first AED (p 0.00), while no significant association was seen with age at onset (p 0.45), sex (p 0.47), duration of seizure (p 0.43), type of seizure (p 0.12), and presence of CT abnormality (p 0.46). The fitted regression model portended an unfavorable prognosis with failure of first AED and abnormal neurological status, however, failed to show significant association with frequency of seizure.

Failure of first AED trial and associated neurological deficits are significant predictors of unfavorable seizure outcome.

Cognitive impairment can add to the burden of disease in patients with multiple sclerosis (MS). The aim of this study was to assess the relative importance of diffusion tensor imaging (DTI) indices derived from normal appearing white matter (NAWM) and grey matter (NAGM) in determining cognitive dysfunction in MS patients.

Sixty two MS patients [51 female, mean age= 41 (sd=9.6) years, median expanded disability status scale (EDSS)=2.5] meeting modified McDonald criteria for MS underwent neuropsychological testing using the Neuropsychological Screening Battery for MS (NSBMS) and magnetic resonance imaging (MRI, 1.5T GE) that included DTI sequences. Total T1 hypointense and T2 hyperintense lesion volumes were obtained using semi-automated software. Lesion volumes were subtracted from whole-brain parenchyma to obtain measures of NAWM and NAGM. Fractional anisotropy (FA) of NAWM and mean diffusivity (MD) of NAGM were obtained.

Cognitive impairment was present in 11 patients (18%). These patients had higher EDSS scores, were less educated, and were more likely to have secondary progressive MS. They also had higher hypointense (p=0.001) and hyperintense (p=0.004) lesion volumes, greater NAWM atrophy (p=0.007), lower FA of total NAWM (p=0.003), and higher MD of total NAGM (p=0.015). Using a logistic regression analysis, and after controlling for demographic and disease-related differences between groups, FA of NAWM emerged as a significant predictor of cognitive impairment adding to the variance derived from lesion and atrophy data.

This study underlies the important role of normal-appearing brain tissue in the pathogenesis of MS-related cognitive impairment.

There is currently little information on the genetic epidemiology of Alzheimer disease (AD) among North American Aboriginal populations. No cases of familialAD (FAD) in these populations have been published to date.

Here, we describe a large North American Aboriginal kindred with early onset FAD (EOFAD) in which genetic testing was done.

A novel Presenilin 1 (PS1) gene mutation (L250F) has been identified. In contrast to the three previously reported families with PS1 codon 250 mutations, affected members of this kindred demonstrate neither myoclonus nor seizures. Furthermore, the identification of a PS1 mutation in a North American Aboriginal kindred presents several unique challenges with respect to knowledge transfer and continuity of care in a geographically remote and culturally distinct community.

The aim of this study was to determine the number of annual hospitalizations and overall episodes of care that involve a traumatic brain injury (TBI) by age and gender in the province of Ontario. To provide a more accurate assessment of the prevalence of TBI, episodes of care included visits to the emergency department (ED), as well as admissions to hospital. Mechanisms of injury for overall episodes were also investigated.

Traumatic brain injury cases from fiscal years 2002/03-2006/07 were identified by means of ICD-10 codes. Data were collected from the National Ambulatory Care Reporting System and the Discharge Abstract Database.

The rate of hospitalization was highest for elderly persons over 75 years-of-age. Males generally had higher rates for both hospitalizations and episodes of care than did females. The inclusion of ED visits to hospitalizations had the greatest impact on the rates of TBI in the youngest age groups. Episodes of care for TBI were greatest in youth under the age of 14 and elderly over the age of 85. Falls (41.6%) and being struck by or against an object (31.1%) were the most frequent causes for a TBI.

The study provides estimates for TBI from the only Canadian province that has systematically captured ED visits in a national registry. It shows the importance of tracking ED visits, in addition to hospitalizations, to capture the burden of TBI on the health care system. Prevention strategies should include information on ED visits, particularly for those at younger ages.

Idiopathic intracranial hypertension (IIH) can be an elusive diagnosis, and poor visual outcomes may occur. Currently, the only means of accurately diagnosing and following these patients is with repeated lumbar puncture. Previous work has shown that transcranial doppler measurements of pulsatility correlate accurately with elevated intracranial pressure (ICP). This study is designed to assess whether pulsatility index (PI) correlates with ICP in patients newly diagnosed with IIH.

Seven patients with clinical suspicion of IIH were included in this study. Clinical suspicion was based on history of recurrent headaches and papilledema. All patients had otherwise normal examinations and imaging. Middle cerebral arteries were insonated to obtain average PI values. Cerebrospinal fluid (CSF) was then withdrawn, and closing pressures were recorded. Pulsatility index values were then obtained again, within ten minutes after completing CSF withdrawal. PI values were correlated with ICP values, and pre and post CSF withdrawal values were compared.

All seven patients had elevated opening pressures (average 39 cm H2O, range 27-70). The average closing pressure after approximately 30 cc of CSF withdrawal was 11.9 cm H2O. The average PI before CSF withdrawal was 0.95, which dropped to 0.70 after CSF withdrawal (p = 0.02). The change in ICP was found to be correlated with a change in PI (p = 0.004).

These findings suggest that PI may be useful for following patients with IIH non-invasively. Further study with larger groups and blinded assessments should be useful in better characterizing the accuracy of this technique.

The corpus callosum (CC) is frequently compromised in patients with multiple sclerosis (MS). Structural and functional measurements of the CC may be useful to monitor the progression of the disease. The aim of this pilot study was to determine if bimanual tactile temporal thresholds correlates with CC volume. A tactile temporal threshold is the longest temporal interval that separates the onsets of two tactile stimuli when they are judged by the observer as simultaneous. Judgments to bimanual stimulations require interhemispheric transfer via the CC.

Thresholds were examined in MS patients and matched controls. Magnetic resonance (MR) images were acquired on a 3T MR system within 48 hours of clinical assessment and measurement of thresholds.

Corpus callosum volume was assessed by using a semiautomatic livewire algorithm. The CC volume was smaller (by 21% on average, p < 0.01) and thresholds were higher (by 49% on average, p < 0.03) in MS patients when compared to controls. A significant correlation (r = -0.66, p = 0.01) between CC volume and thresholds emerged for the MS patients.

Measuring treatment benefits of neuroprotective and repair therapies is a well recognized challenge in MS research. The overall findings of this study suggest that these measurements, which involve the transfer of information interhemispherically via the CC, may be promising outcome measures that warrant further scientific exploration to develop a model to measure recovery.

In Parkinson's disease, most of current therapies only provide symptomatic treatment and so far there is no drug which directly affects the disease process.

To investigate the neuroprotective effects of minocycline against long-term rotenone toxicity in primary dopaminergic cell cultures.

Embryonic mice of 14-days-old were used for preparation of primary dopaminergic cell cultures. On the 6th day in vitro, prepared cultures were treated both with minocycline alone (1, 5, 10 and 20 μM) and concomitantly with rotenone (5 and 20 nM) and minocycline. Cultures were incubated at 37°C for six consecutive days. On Day 12 in vitro culture medium was aspirated and used for measuring lactate dehydrogenase. Cultured cells were fixed in 4% paraformaldhyde and stained immunohistochemically against tyrosine hydroxylase.

Treatment of cultures with 5 and 20 nM of rotenone significantly decreased the survival of tyrosine hydroxylase immunoreactive neurons by 27 and 31% and increased the release of lactate dehydrogenase into the culture medium by 31 and 236%, respectively compared to untreated controls. Minocycline (1, 5, 10 μM) significantly protected tyrosine hydroxylase immunoreactive neurons by 17, 15 and 19% and 13, 22 and 23% against 5 and 20 nM of rotenone, respectively compared to rotenone-treated cultures. Minocycline (only at 10 μM) significantly decreased the release of lactate dehydrogenase by 79% and 133% against 5 and 20 nM of rotenone, respectively.

Minocycline has neuroprotective potential against the progressive loss of tyrosine hydroxylase immunoreactive neurons induced by long-term rotenone toxicity in primary dopaminergic cultures.

Some studies have suggested an association between hypocholesterolemia and intracerebral hemorrhage (ICH). In the SPARCL trial, statin use increased ICH risk. We tested the hypothesis that use of statins affects the volume of spontaneous ICH and contributes to the progression of ICH volume between baseline and follow-up CT scans.

Consecutive cases of spontaneous ICH were reviewed. Secondary causes were excluded. We measured ICH volume on the baseline and follow-up CT scans using the AxBxC/2 method. Multivariate analysis and logistic regression modeling were used. The primary outcome was the ICH volume on the baseline CT scan. Secondary outcomes included volume variation between the baseline and the first follow up CT scans and death.

Of 303 subjects, 71 were taking a statin at the time of the ICH (23%). Statin users were significantly more likely to be younger, to have co-morbidities and take anticoagulant or anti-platelet medication. They also had a higher baseline ICH volume than non-statin users (median 31.2 [10,82.1] ml vs 16 [4,43.8] ml; p=0.006). Adjusting for possible confounders, statins remained associated with an increased ICH volume (p=0.007). There was a significant mean ICH volume progression between the first and second CT scans in statin users (+10.8 vs +0.9 ml; p=0.03; 95% CI: [-1,+22.6] [-2.5,+4.3]). No difference in mortality was seen between the two groups.

Treatment with HMG-CoA reductase inhibitors may be a risk factor for increased ICH volume in spontaneous brain hemorrhages and could contribute to hemorrhage's volume progression.

The safety and effectiveness of intra-arterial thrombolysis (IAT) in comparison to intravenous thrombolysis (IVT) for the treatment of ischemic stroke is uncertain. Our study aims to assess and compare IAT to IVT for clinically relevant outcomes in patients with occlusion of the anterior cerebral circulation.

Patients with acute ischemic stroke were enrolled for either treatment; those whose symptoms occurred within 4.5 hrs after stroke were treated with IVT, whereas those who presented <4.5 hrs but had contraindications to IVT or presented between 4.5 and 6 hrs were treated with IAT. Evaluated endpoints included: disability at 90 days as measured by the modified Rankin Scale (mRS), incidence of mortality, and incidence of symptomatic intracranial haemorrhage.

78 patients with anterior cerebral circulation occlusion were included in the study (55 in IVT, 23 in IAT). After 90 days, 82.6% patients treated with IAT reached independence in comparison to 56.4% in the IVT group (P=0.028, RR=2.66, 95% CI: 1.10-7.04). The incidence of all intracranial haemorrhages in the IAT and IVT groups respectively were 30.4% and 12.7% (P=0.103, RR=2.391, 95% CI: 0.946-6.047); symptomatic intracranial haemorrhage occurred in 8.7% and 9.1% of patients (P=1.00, RR= 0.957, 95% CI: 0.200-4.579), and mortality in 8.7% and 16.4% (P=0.492, RR=1.882, 95% CI: 0.440-8.045).

Results suggest that IAT is more effective than IVT in allowing patients to achieve independence. While inconclusive, the safety of IAT within 6 hrs is comparable to IVT within 4.5 hrs.

The goal of this study was to optimize intraoperative neuropathology consultations by studying trends and sources of diagnostic error. We hypothesized that errors in intraoperative diagnoses would have sampling, technical, and interpretive sources. The study also audited diagnostic strengths, weaknesses and trends associated with increasing experience. We hypothesized that errors would decline and that the accuracy of “qualified” diagnoses would improve with experience.

The pathologist's first 100 cases (P1), second 100 (P2), and most recent 100 (P3, after ten years in practice) formed the data set. Intraoperative diagnoses were scored as correct, minor error or major error using the final diagnosis as the gold-standard. Incorrect diagnoses were re-examined by two reviewers to identify sources of error.

Among the 300 cases there were 22 errors with 11 in P1, 9 in P2 and 2 in P3. Sampling contributed to 17 errors (77%), technical factors to 7 (32%) and interpretive factors to 16 (73%). Improvement in diagnostic accuracy between P1 and P2 (p=0.8143), or P2 and P3 (p=0.0582) did not reach significance. However, significant improvement was found between P1 and P3 (p=0.0184).

The present study was a practical and informative audit for the pathologist and trainees. It reaffirmed the accuracy of intraoperative neuropathology diagnoses and informed our understanding of sources of error. Most errors were due to a combination of sampling, technical and interpretive factors. A significant improvement in diagnostic proficiency was observed with increasing experience.

Growing evidence shows that the deregulation of the circadian clock plays an important role in the development of malignant tumors, including gliomas. However, the molecular mechanisms of genes controlling circadian rhythm in glioma cells have not been explored.

Using reverse transcription polymerase chain reaction and immunohistochemistry techniques, we examined the expression of two important clock genes, Per1 and Per2, in 33 gliomas.

In this study, out of 33 gliomas, 28 were Per1-positive, and 23 were Per2-positive. The expression levels of Per1 and Per2 in glioma cells were significantly different from the surrounding non-glioma cells (P<0.01). The difference in the expression rate of Per1 and Per2 in high-grade (grade III and IV) and low-grade (grade 1 and II) gliomas was insignificant (P>0.05). While there was no difference in the intensity of immunoactivity for Per2 between high-grade gliomas and low-grade gliomas (r=-0.330, P=0.061), the expression level of Per1 in highgrade gliomas was significantly lower than that in low-grade gliomas(r=-0.433, P=0.012).

In this study, we found that the expression of Per1 and Per2 in glioma cells was much lower than in the surrounding non-glioma cells. Therefore, we suggest that disturbances in Per1 and Per2 expression may result in the disruption of the control of normal circadian rhythm, thus benefiting the survival of glioma cells. Differential expression of circadian clock genes in glioma and non-glioma cells may provide a molecular basis for the chemotherapy of gliomas.

Neuropsychiatric symptoms are increasingly recognised as a significant problem in patients with Parkinson's disease (PD). These symptoms may be due to ‘sensitisation’ following repeated levodopa treatment or a direct effect of dopamine on the disease state. The levodopa-treated MPTP-lesioned marmoset was used as a model of neuropsychiatric symptoms in PD patients. Here we compare the time course of levodopa-induced motor fluctuations and neuropsychiatric-like behaviors to determine the relationship between duration of treatment and onset of symptoms.

Marmosets were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (2.0 mg/kg s.c.) for five days, resulting in stable parkinsonism. Levodopa (15 mg/kg and benserazide, 3.75 mg/kg) p.o. b.i.d. was administered for 30 days. Animals were evaluated for parkinsonian disability, dyskinesia and on-time (motor fluctuations) and neuropsychiatric-like behaviors on Day 0 (prior to levodopa) and on Days 1, 7, 13, 27 and 30 of treatment using post hoc DVD analysis by a trained rater, blind to the treatment day.

The neuropsychiatric-like behavior rating scale demonstrated high interrater reliability between three trained raters of differing professional backgrounds. As anticipated, animals exhibited a progressive increase in levodopa-induced motor fluctuations, dyskinesia and wearing-off, that correlated with the duration of levodopa therapy. In contrast, levodopa-induced neuropsychiatric-like behaviors were present on Day 1 of levodopa treatment and their severity did not correlate with duration of treatment.

The data suggest that neuropsychiatric disorders in PD are more likely an interaction between levodopa and the disease state than a consequence of sensitisation to repeated dopaminergic therapy.