Cerebral Palsy

In previous studies we found that intrastriatal DCG-IV administration, an agonist for group II metabotropic glutamate receptor: i) protected striatal dopaminergic terminals against MPP(+)-induced neurotoxicity (Matarredona et al., 2001); ii) selectively destroyed striatal GABAergic neurons (Venero et al., 2002) and iii) induced early robust up-regulation of brain-derived neurotrophic factor (BDNF) in nigral dopaminergic neurons afferents in a target-dependent manner (Rite et al., 2005). Considering that BDNF protein is anterogradely transported to dopaminergic nerve endings, an autocrine role of BDNF could account for the neuroprotective effect of DCG-IV against the MPP(+)-induced toxicity of dopaminergic terminals. To test this possibility, we first performed a previous insult with quinolinic acid (QA) to specifically damage the striatal GABAergic neuronal cell bodies in order to remove the nigral BDNF target. Fourteen days later, we explored the potential in vivo neuroprotective action of DCG-IV against MPP(+)-induced toxicity on striatal dopaminergic nerve terminals by in vivo microdialysis. Integrity of GABAergic system was evaluated by glutamic acid decarboxylase (GAD) in situ hybridization. We demonstrate that previous striatal target ablation with QA prevented the neuroprotective effect of DCG-IV perfusion against the MPP(+)-induced neurotoxicity on dopaminergic terminals. Our results strongly suggest an important autocrine neuroprotective role of BDNF on striatal dopaminergic nerve terminals. In addition, we found an unexpected regulatory response of surviving striatal GABAergic neurons in terms of high levels of GAD mRNA expression.

Copyright © 2010. Published by Elsevier Ltd.

Reznik O, Skvortsov A, Loginov I, Ananyev A, Bagnenko S, Moysyuk Y. Kidney from uncontrolled donors after cardiac death with one?h warm ischemic time: resuscitation by extracorporal normothermic abdominal perfusion "in situ" by leukocytes-free oxygenated blood.?Clin Transplant 2010 DOI: 10.1111/j.1399-0012.2010.01333.x© 2010 John Wiley & Sons A/S. Abstract:? The availability of brain death donors is restricted by many factors. Use of uncontrolled donors after cardiac death could be a promising perspective, but the limiting factor in uncontrolled donation after cardiac death is the warm ischemic time. The purpose of our work was to develop an in situ kidney preservation protocol with application of the extracorporal normothermic abdominal perfusion for organ resuscitation in uncontrolled donors after cardiac death. The main attention was paid to the elimination of leukocytes as the key damaging factor from modified donor oxygenated blood circulating in the device. In 2009, we had 10 uncontrolled donors with warm ischemic time from 45 to 92?min; a normothermic extracorporal perfusion device was applied, providing preservation and restoration of kidney after ischemic damage. In 6 out of 20 kidney recipients, graft function was recovered immediately. All kidney grafts are functioning, and to the end of the third month, the average creatinine was 118.5?±?19.9?mM. Treatment of ischemically damaged kidney by normothermic extracorporal perfusion with leukocyte depletion before procurement seems to be a challenging protocol for expanding donors' pool and demands further study.

© 2010 John Wiley & Sons A/S.

Objective: The clock drawing test (CDT) is a quick and easy to administer test that has traditionally shown parietal lobe dysfunction. The aim of this study was to correlate performance on the CDT with the presence of acute traumatic cerebral injuries sustained after traumatic brain injury (TBI). Methods: A retrospective study was conducted on 170 patients with TBI of all severity admitted to an acute care setting. These patients sustained different types of injuries (epidural haematoma, subdural haematoma, subarachnoid haemorrhage, intraparenchymal haematoma and brain oedema) in different sites (frontal, temporal, parietal, occipital lobes, bilateral and right or left hemisphere). Results: The CDT total score was significantly lower for subjects presenting subarachnoid haemorrhage (4.80?±?3.34 vs 7.04?±?3.14, t(168df)?=?4.477, p?<?0.001) and for those presenting brain oedema (4.50?±?3.06 vs 6.69?±?3.38, t(168df)?=?4.214, p?<?0.001), parietal injury (5.15?±?3.17 vs 6.42?±?3.52, t(168df)?=?2.416, p?=?0.017) or bilateral injuries (5.28?±?3.31 vs 6.62?±?3.44, t(168df)?=?2.569, p?=?0.011) compared to those who did not. Conclusion: This study provides empirical evidence of the relationship between TBIs and results on the CDT, supporting previous studies done with other populations.

OBJECT: This report summarizes the treatments and outcomes of a large series of patients with pediatric head injuries (PHIs), who were admitted to a tertiary pediatric trauma center at the University of Mississippi Medical Center from January 1, 2003 through December 31, 2006.

METHODS: Data were retrieved from the Department of Neurosurgery’s Brain Trauma Registry (BTR) on patients who are ?16 years old. Data include Glasgow Coma Scale (GCS) and injury severity scores (ISS) on admission and Glasgow Outcome Scale (GOS) scores at 6 months follow-up.

RESULTS: The BTR registered 554 patients with accidental and nonaccidental PHIs. Follow-up was complete in 98.2%. Aggressive first-tier management with ventricular drainage was used to lower intracranial pressure. Vasopressors were used only to correct hypotension. Second-tier therapies were used infrequently. Craniectomies (14 patients) were associated with good outcomes (GOS 4-5) in nine patients; hypothermia (six patients) and barbiturate (four patients) therapies were ineffective. All 439 patients with ISS <25 showed good outcomes. Fifteen of 16 patients with GCS >8 and ISS ?25 had good outcomes. In 134 patients with severe PHIs (GCS ?8), all 45 with ISS <25 and 46 with ISS ?25 showed good outcomes. Forty-three patients with GCS ?8 and ISS ?25 had poor outcomes. Of these patients, 38 died; 22 died within 3 days of admission.

CONCLUSIONS: This study indicated that poor outcomes occurred only in PHIs with severe generalized trauma. While 28.4% of patients with GSC ?8 died, more than half of these sustained nonsurvivable injuries. Aggressive medical management with ventricular drainage was the mainstay of therapy.

Ludwig II of Bavaria (Germany) entered the political stage at the age of 18, following the premature death of his father Maximilian II in 1864. At that time, Ludwig was a very handsome, slender young man; he was enthusiastic and had a pronounced taste for fine arts and music, and was admired by the people as a “fairy tale king”. However, already during the first years of his reign, he displayed traits that fulfilled the ICD-10 criteria for schizotypal disorder together with a combined cluster B personality disorder. They became even more pronounced over time. Towards the end of his life, Ludwig developed “imperial madness”, a typical pattern of behavioural excesses including craving for power, splendour, construction, unrestrained spending, excessive eating and sexual exploitation, revenge with a tendency for cruelty, and an inclination for theatrical and sometimes irrational acts. This complex syndrome is usually manifested in excessively egocentric rulers who have almost unlimited power or, in the case of Ludwig II, an overwhelming desire to possess it. His imperial madness was possibly contributed to by an orbitofrontal brain syndrome. One conjecture is that this condition reflected a neurodegenerative process; another is that a primary deficit, initiated by brain damage following a severe bout of meningitis during Ludwig’s babyhood, played a role. In this case, functional compensation by other brain areas may have eventually been counteracted by chronic substance abuse in his thirties. The monarch’s life ended tragically when he was 40 by which time he had become adipose and had lost most of his teeth; meanwhile, he was placed under tutelage, dismissed and detained. Before his death by drowning in Lake Starnberg (suicide? attempted escape??), Ludwig apparently killed his psychiatrist, Bernhard von Gudden, who carelessly served as his sole attendant. Yet Ludwig’s image as the beautiful fairy tale king is still alive in the hearts of successive generations of Bavarians and in the fascination demonstrated by the masses of tourists from throughout the world who visit (against his formerly declared wishes) his “dream castles”.

Oxidative/nitrosative stress plays a crucial role in Parkinson’s disease (PD) by triggering mitochondrial dysfunction. Nitrosative stress is mediated by reactive species such as peroxynitrite (PN) which could damage biomolecules thereby impinging on the cellular machinery. We observed that PN (0-1000 ?M) inhibited brain mitochondrial complex I (CI) activity in a dose-dependent manner with concomitant tyrosine nitration of proteins. We also observed that exposure to PN at low concentrations (62.5-125 ?M) significantly decreased the mitochondrial membrane potential and affected the mitochondrial integrity at higher doses (500-750 ?M) as indicated by the mitochondrial swelling experiment. Therefore, it could be surmised that compounds that prevent such mitochondrial damage might have therapeutic value in neurological conditions such as PD. We previously showed that curcumin could detoxify PN and protect against CI inhibition and protein nitration. However, the therapeutic potential of curcumin is constrained by limited bioavailability. To address this issue and obtain improved antioxidants, three bioconjugates of curcumin (Di-demethylenated piperoyl, di-valinoyl and di-glutamoyl esters) were generated and tested against PN-mediated nitrosative stress and mitochondrial damage. We found that among the bioconjugates, the glutamoyl diester of curcumin showed improved protection against PN-dependent CI inhibition and protein nitration compared to other conjugates. Di-glutamoyl curcumin protected dopaminergic neurons against 1-methyl-4-phenylpyridinium (MPP(+))-mediated neuronal death. These effects were improved compared to curcumin alone suggesting that di-glutamoyl curcumin could be a better neuroprotective agent in neurodegenerative diseases such as PD.

Objective To quantify total and regional brain damage in subjects with cerebrotendinous xanthomatosis (CTX) using MR based quantitative measures. Background CTX is a rare inherited disorder characterised by progressive neurological impairment. Appropriate therapy can slow disease progression. Measures of brain volume changes have been used in several neurological disorders due to their value in assessing disease outcome and monitoring patients' evolution. Methods 24 CTX patients underwent conventional MRI to measure total and regional brain volumes. In five CTX patients who started therapy at baseline, clinical and MRI examinations were repeated after 2&emsp14;years. Clinical disability, overall cognitive performance and cerebellar function were evaluated using the modified Rankin Scale (RS), Mini Mental Status Examination (MMSE) and cerebellar functional system score (CB-FSS). Results Measures of normalised brain, cortical and cerebellar volumes were lower in CTX patients than in healthy controls (p<0.01). Instead, there were no differences in normalised white matter volumes between the two groups (p=0.1). At regional analysis, a significant volume decrease was found in each cortical region (p<0.01 for all regions). Normalised cortical volumes correlated closely with age (r=-0.9, p<0.0001), RS (r=-0.65, p<0.001) and MMSE (r=-0.60, p<0.01). Normalised cerebellar volumes correlated closely with CB-FSS scores (r=-0.58, p<0.01). In the five CTX patients followed over time, the annual brain volume decrease was -1.1±0.2%. Conclusions Cortical volume, rather than white matter volume, is diffusely decreased in CTX patients and correlates closely with the patient's clinical status. These data provide evidence for the presence of clinically relevant neuronal-axonal damage in the brains of CTX patients.

Magnetic resonance imaging (MRI) has the potential to aid characterise of disease progression in multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Methods Six patients with probable MSA (mean age (years±SD) was 61±10.4) and 7 with PSP (64.7±5.9&emsp14;years) according to NNIPPS criteria were prospectively recruited for MRI scanning at King's College Hospital. Illness duration at baseline was 5.6±2 (MSA) and 3.72±2.6 (PSP), and at follow-up 8.29±1.7 and 6.58±2.7, respectively; assessment intervals were 2.6±0.2 (MSA) and 2.8±0.3. SIENA was used to estimate local and global brain volume change between MRI at each timepoint, by co-registering and segmenting the images and calculating displacement of the brain/nonbrain boundary. Results Annual global brain atrophy was 1.27±0.6% (MSA) and 1.5±0.7% (PSP). In PSP, localised grey matter atrophy was detected in left superior temporal gyrus, right parahippocampal gyrus, left nucleus dentate, left cerebellar tonsil and right semilunar cerebellum. In MSA, left superior, middle frontal gyrus and right frontopolar regions were affected. Discussion Progressive atrophy was found in frontal and temporal cortices in both disorders; the absence of change in striatum and pallidum may reflect already severely damage at baseline.

Background Biomarkers of a number of pathophysiological processes might improve the clinical diagnosis of stroke and transient ischaemic attack (TIA). Methods We recruited symptomatic patients with suspected stroke or TIA <24&emsp14;h after onset. We measured markers of inflammation, thrombosis; thrombolysis, cardiac dysfunction and cerebral damage. A panel of stroke physicians, neurologists and neuro-radiologists reviewed the clinical features, brain imaging and subsequent course of each patient to make the gold standard diagnosis. We constructed multivariate logistic models to analyse the data. Results We recruited 405 patients with suspected stroke (285 stroke or TIA, 180 mimics) at a median of 7&emsp14;h (IQR 3-19&emsp14;h) after symptom onset. Higher levels of Ln NT pro-BNP (OR 2.2 (95% CI 1.5 to 3.0) 75th to 25th centile) and t-PA (OR 1.6 (1.2 to 2.2)) were associated with a diagnosis of TIA or stroke. Adjustment for neurological impairment and age attenuated these associations. The associations of higher levels of adiponectin (OR 1.8 (1.2 to 2.4)) and IL-10 (OR 1.1 (1.0 to 1.1)) with a diagnosis of mimic were robust to adjustment for neurological impairment, age and infection. A model with eight markers from systematic review had no better diagnostic performance than an emergency department clinician. Conclusion We found no single marker or combination of markers that positively predicted a diagnosis of stroke or TIA independently of neurological impairment and age, or added usefully to the clinical diagnosis.

Anterior temporal lobe resection (ATLR) is an effective treatment for temporal lobe epilepsy (TLE). The structural consequences of ATLR and how these relate to language function after surgery remain unknown. We applied diffusion tensor imaging in 26 left and 20 right TLE patients before and 5&emsp14;months after surgery. We used whole brain analysis techniques to compare preoperative and postoperative data. We observed a 7% decrease in fractional anisotropy (FA) in white matter networks connected to the area of resection, following surgery. We also observed an 8% increase in FA after left ATLR in the ipsilateral frontotemporal white matter. Post-operative tractography seeded from this area suggests that it is part of the ventromedial language network. The mean preoperative and postoperative FA and parallel diffusivity (PaD) in this cluster were significantly correlated with postoperative verbal fluency and naming test scores. Further, the percentage change in PaD in this cluster was correlated with the percentage change in verbal fluency after anterior temporal lobe resection, such that the bigger the increase in PaD, the smaller the fall in language proficiency after surgery. These findings may represent reorganisation in the ventromedial language network in response to ATLR which may damage the more susceptible dorsolateral language pathway. This has important implications for our understanding of brain injury, and the prediction of postoperative language deficits.