Cerebral Palsy

Electrical stimulation (ES) has been found to aid repair of nerve injuries and have been shown to increase and direct neurite outgrowth during stimulation. However, the effect of ES on peripheral remyelination after nerve damage has been investigated less well, and the mechanism underlying its action remains unclear. In the present study, the crush-injured sciatic nerves in rats were subjected to 1 hr of continuous ES (20 Hz, 100 musec, 3 V). Electron microscopy and nerve morphometry were performed to investigate the extent of regenerated nerve myelination. The expression profiles of P0, Par-3, and brain-derived neurotrophic factor (BDNF) in the injuried sciatic nerves and in the dorsal root ganglion neuron/Schwann cell cocultures were examined by Western blotting. Par-3 localization in the sciatic nerves was determined by immunohistochemistry to demonstrate Schwann cell polarization during myelination. We reported that 20-Hz ES increased the number of myelinated fibers and the thickness myelin sheath at 4 and 8 weeks postinjury. P0 level in the ES-treated groups, both in vitro and in vivo, was enhanced compared with the controls. The earlier peak of Par-3 in the ES-treated groups indicated an earlier initiation of Schwann cell myelination. Additionally, ES significantly elevated BDNF expression in nerve tissues and in cocultures. ES on the site of nerve injury potentiates axonal regrowth and myelin maturation during peripheral nerve regeneration. Furthermore, the therapeutic actions of ES on myelination are mediated via enhanced BDNF signals, which drive the promyelination effect on Schwann cells at the onset of myelination. (c) 2010 Wiley-Liss, Inc.

Cumulative evidence shows a protective role for adenosine A1 receptors (A1R) in hypoxia/ischemia; A1R stimulation reduces neuronal damage, whereas blockade exacerbates damage. The signal transduction pathways may involve the mitogen-activated protein kinase (MAPK) pathways and serine/threonine kinase (AKT), with cell survival depending on the timing and degree of upregulation of these cascades as well as the balance between pro-survival and pro-death pathways. Here, we show in vitro that extracellular signal-regulated kinase (ERK1/2) and phosphatidylinositol 3-kinase (PI3-K/AKT) activation is dependent on A1R stimulation, with further downstream effects that promote neuronal survival. Phosphorylated ERK1/2 (p-ERK) and AKT (p-AKT) as well as Bcl-2 are upregulated in anoxic neuronally enriched primary cultures from turtle brain. This native upregulation is further increased by the selective A1R agonist 2-chloro-N-cyclopentyladenosine (CCPA), whereas the selective antagonist 8-cyclopentyl-1,3-dihydropylxanthine (DPCPX) decreases p-ERK and p-AKT expression. Conversely, A1R antagonism resulted in increases in phosphorylated JNK (p-JNK), p38 (p-p38), and Bax. As pathological and adaptive changes occur simultaneously during anoxia/ischemia in mammalian neurons, the turtle provides an alternative model to analyze protective mechanisms in the absence of evident pathologies.Journal of Cerebral Blood Flow & Metabolism advance online publication, 21 July 2010; doi:10.1038/jcbfm.2010.109.

The ability of captopril and losartan treatment to restore cerebral blood flow (CBF) autoregulation after intracerebral hemorrhagic stroke (HS) was assessed in Kyoto-Wistar stroke-prone hypertensive rats (SHRsp). Laser Doppler techniques assessed CBF autoregulation in the middle cerebral artery (MCA) perfusion domain and a pressure myograph was used to measure pressure-dependent constriction (PDC) in isolated MCAs before and after stroke and after 13, 33, and 63 days of poststroke captopril or losartan treatment. The treatments did not lower blood pressure (BP) and equally suppressed plasma aldosterone after HS. The HS development was associated with the loss of CBF autoregulation, high CBF, increased CBF conductance to elevations in BP, and the loss of PDC in the MCAs. Both treatments restored these functions to prestroke levels within 13 days. The PDC and CBF autoregulation subsequently deteriorated after 63 days of captopril treatment while being maintained at prestroke levels over all durations of losartan treatment. The SHRsp subjected to 35 days of poststroke losartan treatment exhibited less blood-brain barrier (BBB) disruption and brain herniation than captopril-treated SHRsp. The superior ability of losartan to restore CBF autoregulation and myogenic function may have contributed to the more effective attenuation of cerebral damage after HS.Journal of Cerebral Blood Flow & Metabolism advance online publication, 21 July 2010; doi:10.1038/jcbfm.2010.110.

Cifu DX, Cohen SI, Lew HL, Jaffee M, Sigford B: The history and evolution of traumatic brain injury rehabilitation in military service members and veterans.The field of traumatic brain injury has evolved since the time of the Civil War in response to the needs of patients with injuries and disabilities resulting from war. The Department of Veterans Affairs and the Defense and Veterans Brain Injury Center have been in the forefront of the development of the interdisciplinary approach to the rehabilitation of soldiers with traumatic brain injury, particularly those injured from the recent conflicts in Iraq and Afghanistan. The objectives of this literature review are to examine how the casualties resulting from major wars in the past led to the establishment of the current model of evaluation and treatment of traumatic brain injury and to review how the field has expanded in response to the growing cohort of military service members and veterans with TBI.

This study analyzedretrospectively the clinical efficacy of combinedtherapy consisting of high-dose methotrexate(MTX), administered at a dose of 4 g/m2 every 2 weeks(maximum of 4 courses), followed by whole-brain irradiation for newly diagnosed primary central nervous system lymphoma(PCNSL)patients. Fifteen patients(median age: 59 years old; range: 26- 79)were diagnosed by histological examinations or imaging techniques in our hospital. Of 15 patients, 12(6: complete response; 6: partial response)achieved objective response, and the response rate was 80%(95% CI, 51. 9-95. 7%). The median follow-up time was 20(range: 3-81)months, and the 3-year survival rate was 76%. The overall survival time was 71 months(95% CI, 23. 7-118. 3 months), and the progression free survival was 15 months(95% CI, 0-43. 8 months). The major toxicity(grade>/=3)of high-dose MTX included cytopenia(20%), acute respiratory distress syndrome(6. 7%), and liver damage(6. 7%). No patient evidenced complicated leukoencephalopathy in the follow-up time. The combinedtherapy of high-dose MTX followed by whole-brain irradiation showed a substantial antitumor efficacy in PCNSL patients. Prospective studies are required to determine the suitable treatment schedule for MTX and irradiation.

Cell replacement therapy has been tested clinically in Parkinson’s disease (PD) and Huntington’s disease (HD), epilepsy, spinal cord injury, and stroke. The clinical outcomes have been variable, perhaps partly because of the differing levels of preclinical, basic experimental evidence that was available prior to the trials. The most promising results have been seen in PD trials, with encouraging ones in HD. A common feature of most trials is that they have concentrated on the biological and technical aspects of transplantation without presupposing that the outcomes might be influenced by events after the surgery. The growing evidence of plasticity demonstrated by the brain and grafts in response to environmental and training stimuli such as rehabilitation interventions has been mostly neglected throughout the clinical application of cell therapy. This review suggests that a different approach may be required to maximize recovery: postoperative experiences, including rehabilitation with explicit behavioral retraining, could have marked direct as well as positive secondary effects on the integration and function of grafted cells in the host neural system. The knowledge gained about brain plasticity following brain damage needs to be linked with what we know about promoting intrinsic recovery processes and how this can boost neurobiological and surgical strategies for repair at the clinical level. With proof of principle now established, a rich area for innovative research with profound therapeutic application is open for investigation.

Objective: Deep hypothermia is used as a neuroprotectant during cardiac surgery utilizing deep hypothermic circulatory arrest (DHCA), although the ideal rewarming strategy is not known yet. Some of the neuroprotective properties of hypothermia seem to be mediated by Nuclear Factor Kappa B (NFkappaB) as an important transcription factor. The current study was designed to investigate the effect of the rewarming rate on histologic outcome and cerebral NFkappaB expression one day following DHCA in rats. Methods: With IRB approval, 20 rats were cannulated for cardiopulmonary bypass (CPB), cooled to a rectal temperature of 15-18 degrees C, subjected to 45min of DHCA and randomly assigned to either a slow (40 min) or a fast (20 min) rewarming protocol. At 24 hours post DHCA, the number of eosinophilic neurons was analyzed with hematoxylin and eosin (HE) staining, and NFkappaB expression immunohistochemically. The two experimental groups were compared with untreated control rats. Results: HE staining showed more eosinophilic neurons in the motor cortex following fast rewarming (60 [15-388]) compared to slow rewarming (15 [10-21]) (p<0.05). Neuronal expression of NFkappaB was increased in the fast rewarming group in both brain areas, the motor cortex (fast: 258 [135-393]; slow: 165 [80-212]; control: 73 [44-111]) as well as the hippocampus (fast: 243 [209-314]; slow: 202 [187-239]; control: 86 [68-108]) (p<0.05). Hyperthermic episodes were strictly avoided. Conclusions: Fast rewarming with strict avoidance of hyperthermia after DHCA in rats was accompanied by pronounced histologic damage and accentuated cerebral NFkappaB expression.

Cerebral hypothermia reduces brain injury and improves behavioral recovery after hypoxia-ischemia (HI) at birth. However, using current enrolment criteria many infants are not helped, and conversely, a significant proportion of control infants survive without disability. In order to further improve treatment we need better biomarkers of injury. A ‘true’ biomarker for the phase of evolving, ‘treatable’ injury would allow us to identify not only whether infants are at risk of damage, but also whether they are still able to benefit from intervention. Even a less specific measure that allowed either more precise early identification of infants at risk of adverse neurodevelopmental outcome would reduce the variance of outcome of trials, improving trial power while reducing the number of infants unnecessarily treated. Finally, valid short-term surrogates for long term outcome after treatment would allow more rapid completion of preliminary evaluation and thus allow new strategies to be tested more rapidly. Experimental studies have demonstrated that there is a relatively limited ‘window of opportunity’ for effective treatment (up to about 6-8h after HI, the ‘latent phase’), before secondary cell death begins. We critically evaluate the utility of proposed biochemical, electronic monitoring, and imaging biomarkers against this framework. This review highlights the two central limitations of most presently available biomarkers: that they are most precise for infants with severe injury who are already easily identified, and that their correlation is strongest at times well after the latent phase, when injury is no longer ‘treatable’. This is an important area for further research. Copyright © 2010. Published by Elsevier Ltd.

OBJECTIVE: To compare the clinical efficacy and safety of nephrectomy versus radical nephrectomy for renal cell carcinoma (RCC). METHODS: A total of 134 patients with renal carcinoma without metastasis in lymphatic system and distant sites were recruited. In random, 69 cases of renal cell carcinoma were elected for nephrectomy and the others radical nephrectomy. The operating time, blood loss, fasting time, postoperative hospital stay, information of tumor recurrence and metastasis, survival time without tumor, survival rate and perioperative complication were compared between two groups. RESULTS: In cases of nephrectomy, the operating time ranged from 60 – 135 minutes and blood loss 70 – 100 ml. In 4 cases, membrana pleuroperitonealis was damaged. The fasting time ranged from 6 – 24 hours and postoperative hospital stay 5 – 8 days; the staging of all 69 cases was detected; follow-up studies ranged from 5 – 15 years, finding 1 case tumor metastasis in adrenal body and 1 case recurrent tumor in cases of radical nephrectomy, operating time ranged from 105 – 185 minutes and blood loss 150 – 2000 ml. Membrana pleuroperitonealis was breached in 3 cases. The fasting time ranged from 12 – 90 hours and postoperative hospital stay 8 – 12 days. The staging of all 65 cases was detected. Follow-up studies of 5 – 15 years revealed 1 case of tumor metastasis in brain and 1 case of recurrent tumor. There was no significant difference in perioperative complication, tumor recurrence, tumor metastasis and survival time without tumor between those two groups (P > 0.05). The blood loss, operating time, fasting and postoperative hospital stay were less than that in radical nephrectomy group (P < 0.05). CONCLUSION: In patients without metastasis in lymphatic system and distant sites, nephrectomy is both effective and safe. It has the advantages of a short operating time, a short postoperative hospital stay and less damage and blood loss than radical nephrectomy.

ABSTRACT: BACKGROUND: Recently, members of the two-pore domain potassium channel family (K2P channels) could be shown to be involved in mechanisms contributing to neuronal damage after cerebral ischemia. K2P3.1-/- animals showed larger infarct volumes and a worse functional outcome following experimentally induced ischemic stroke. Here, we question the role of the closely related K2P channel K2P9.1. METHODS: We combine electrophysiological recordings in brain-slice preparations of wildtype and K2P9.1-/- mice with an in vivo model of cerebral ischemia (transient middle cerebral artery occlusion (tMCAO)) to depict a functional impact of K2P9.1 in stroke formation. RESULTS: Patch-clamp recordings reveal that currents mediated through K2P9.1 can be obtained in slice preparations of the dorsal lateral geniculate nucleus (dLGN) as a model of central nervous relay neurons. Current characteristics are indicative of K2P9.1 as they display an increase upon removal of extracellular divalent cations, an outward rectification and a reversal potential close to the potassium equilibrium potential. Lowering extracellular pH values from 7.35 to 6.0 showed comparable current reductions in neurons from wildtype and K2P9.1-/- mice (68.31+/- 9.80% and 69.92 +/- 11.65%, respectively). These results could be translated in an in vivo model of cerebral ischemia where infarct volumes and functional outcomes showed a none significant tendency towards smaller infarct volumes in K2P9.1-/- animals compared to wildtype mice 24 hours after 60 min of tMCAO induction (60.50 +/- 17.31 mm3 and 47.10 +/- 19.26 mm3, respectively). CONCLUSIONS: Together with findings from earlier studies on K2P2.1-/- and K2P3.1-/- mice, the results of the present study on K2P9.1-/- mice indicate a differential contribution of K2P channel subtypes to the diverse and complex in vivo effects in rodent models of cerebral ischemia.