Cerebral Palsy

The immunologic treatment of cancer has long been heralded as a targeted molecular therapeutic with the promise of eradicating tumor cells with minimal damage to surrounding normal tissues. However, a demonstrative example of the efficacy of immunotherapy in modulating cancer progression is still lacking for most human cancers. Recent breakthroughs in our understanding of the mechanisms leading to full T-cell activation, and recognition of the importance of overcoming tumor-induced immunosuppressive mechanisms, have shed new light on how to generate effective anti-tumor immune responses in humans, and sparked a renewed and enthusiastic effort to realize the full potential of cancer immunotherapy. The immunologic treatment of invasive malignant brain tumors has not escaped this re-invigorated endeavor, and promising therapies are currently under active investigation in dozens of clinical trials at several institutions worldwide. This review will focus on some of the most important breakthroughs in our understanding of how to generate potent anti-tumor immune responses, and some of the clear challenges that lie ahead in achieving effective immunotherapy for the majority of patients with malignant brain tumors. A review of immunotherapeutic strategies currently under clinical evaluation, as well as an outline of promising novel approaches on the horizon, is included to provide perspective on the active and stalwart progress toward effective immunotherapy for the treatment of malignant brain tumors.

OBJECTIVE:: To test the hypothesis that hyporesponsiveness to ghrelin due to reduced growth hormone (GH) contributes to the aging-related hyperinflammatory state in sepsis. SUMMARY BACKGROUND DATA:: Sepsis and septic shock are a serious problem, particularly in the geriatric population. Ghrelin is an endogenous ligand for the GH secretagogue receptor 1a (GHSR1a, ie, ghrelin receptor). The decline in GH with age is directly associated with many adverse changes that occur with aging. However, the role of GH, ghrelin, and GHSR1a in the age-associated vulnerability to sepsis remains unknown. METHODS:: Male Fischer 344 rats (young: 3 months; aged: 24 months) were used. Plasma GH levels, ghrelin receptor expression, and neuronal activity in the parasympathostimulatory nuclei of the brain stem in normal young and aged animals were measured. Endotoxemia was induced by intravenous injection of lipopolysaccharide (LPS, 15 mg/kg BW). RESULTS:: While LPS-induced release of proinflammatory cytokines from macrophages isolated from aged rats decreased, LPS injection resulted in an in vivo hyperinflammatory state. GH levels were lower in aged rats, which was associated with lower expression of GHSR1a in the dorsal vagal complex and a decrease in parasympathostimulatory neuronal activity. GHSR1a antagonist elevated LPS-induced cytokine release in young rats. GH increased GHSR-1a expression in the dorsal vagal complex in aged rats. Coadministration of ghrelin and GH, but not ghrelin alone or GH alone, markedly reduced cytokine levels and organ injury after endotoxemia in aged rats, which was associated with significantly elevated parasympathostimulatory neuronal activity. CONCLUSIONS:: These findings suggest that the reduced central (brain) responsiveness to ghrelin due to the decreased GH, plays a major role in producing the hyperinflammatory state, resulting in severe organ injuries and high mortality after endotoxemia in aged animals. Ghrelin and GH can be developed as a novel therapy for sepsis in the geriatric population.

INTRODUCTION: Transplantation procedures using intraparenchymal injection of stem cells result in tissue injury in addition to associated surgical risks. Intravenous injection of mesenchymal stem cells gives engraftment to lesions, but the method has low efficiency and specificity. In traumatic brain injuries (TBI), there is a transient breakdown of the blood-brain barrier and an inflammatory response, which increase migration of cells from blood to parenchyma. The aim of this investigation was to analyze the effect of intra-arterial administration on cellular engraftment. METHODS: Experimental TBI was produced in a rat model. Endovascular technique was used to administer human mesenchymal stem cells in the ipsilateral internal carotid artery. Evaluation of engraftment and side effects were performed by immunohistochemical analysis of the brain and several other organs. The results were compared to intravenous administration of stem cells. RESULTS: Intra-arterial transplantion of mesenchymal stem cells resulted in central nervous system (CNS) engraftment without thromboembolic ischemia. We observed a significantly higher number of transplanted cells in the injured hemisphere after intra-arterial compared to intravenous administration both 1 day (p < 0.01) and 5 days (p < 0.05) after the transplantation. Some cells were also detected in the spleen but not in the other organs analyzed. CONCLUSION: Selective intra-arterial administration of mesenchymal stem cells to the injured CNS is a minimally invasive method for transplantation. The method is significantly more efficient than the intravenous route and causes no side effects in the current model. The technique can potentially be used for repeated transplantation to the CNS after TBI and in other diseases.

Neural stem cells exist in the mammalian developing and adult nervous system. Recently, tremendous interest in the potential of neural stem cells for the treatment of neurodegenerative diseases and brain injuries has substantially promoted research on neural stem cell self-renewal and differentiation. Multiple cell-intrinsic regulators coordinate with the microenvironment through various signaling pathways to regulate neural stem cell maintenance, self-renewal, and fate determination. This review focuses on essential intracellular regulators that control neural stem cell maintenance and self-renewal in both embryonic brains and adult nervous system. These factors include the orphan nuclear receptor TLX, the high-mobility-group DNA binding protein Sox2, the basic helix-loop-helix transcription factor Hes, the tumor suppressor gene Pten, the membrane-associated protein Numb, and its cytoplasmic homolog Numblike. The aim of this review is to summarize our current understanding of neural stem cell regulation through these important stem cell regulators. J. Cell. Physiol. (c) 2009 Wiley-Liss, Inc.

INTRODUCTION: Uncontrolled massive bleeding is often the cause of death of polytraumatized patients. Massive haemorrhage in polytrauma is the consequence of severe tissue and blood vessel damage or the development of posttraumatic coagulopathy. Most often, it is the combination of the two causes. Coagulopathy arises in early stages of trauma and it is an independent predictor of mortality of polytraumatized patients, however, its timely correction can significantly result in the reduction of mortality rate in trauma. CASE OUTLINE: We present a 15-year old male patient who fell from 11 m height and sustained injuries of the right lobe of liver, with partial avulsion and lacerations on the diaphragmal and visceral side of the right lobe. He also sustained brain injuries with presence of blood content in the right lateral chamber, numerous haemorrhagic spots and contusions in frontoparietal region and diffuse brain oedema of the right side of the hemisphere. A partial right sided hepatectomy was performed using the surgical techniques of haemostasis (ligation, tamponade, compression, embolisation), circulatory volume resuscitation (crystalloids and colloids), resuscitation of blood and blood components and the application of antifibrynolitics, as well as oxigenotherapy (endotracheal intubation and mechanical ventilation, with high inspiratory fractions of oxygen). Considering massive transfusions, the type and character of injury and visible oozing, as well as the fact that conventional methods did not stop the bleeding, recombinant activated factor VII (rFVIIa) was given intraoperatively, which resulted in successful reduction and finally the cecession of bleeding. CONCLUSION: Until today, there are numerous references about successful application of rFVIIa in uncontrolled bleedings in trauma when previously applied conventional methods of haemostasis were not sufficient. We are presenting a case of successful use of rFVIIa in our hospital accompanied by usual surgical measures and reanimation of a severely injured patient with massive bleeding. Based on our experience and available references, in case of timely diagnosis and adequate therapy, such as conventional treatment methods and the use of rFVIIa, uncontrolled bleedings in polytrauma have better prognosis.

Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPAR) and inflammatory processes have been related to ischemia-induced damage, but there are few studies addressing their response in different brain areas. Here we compare AMPAR expression after ischemia in several brain areas (hippocampus, cerebral cortex and caudate-putamen) in an attempt to correlate it with their different vulnerabilities. We found outstanding decreases in GluR1 and GluR2 mRNA levels after global ischemia and 48 hours reperfusion (I/R) in all the areas studied, however, protein levels maintained in some areas such as CA3, suggesting different post-transcriptional control in different areas of the brain. To characterize the inflammatory response in these areas, we measured the mRNA levels of CD11b/CD18 membrane integrin (a reactive microglia marker), which showed an important but similar up-regulation in all brain areas studied, which was confirmed by immunohistochemistry. We conclude that the down-regulation of AMPAR gene expression following I/R does not explain differences in the vulnerability of different areas. Additionally, our data indicate that the level of inflammation is independent of the vulnerability of the different brain areas and does not explain differences in the AMPAR expression observed in the brain areas studied.

Fenamate NSAIDs are inhibitors of cyclooxygenases, antagonists of non-selective cation channels, subtype-selective modulators of GABA(A) receptors, weak inhibitors of glutamate receptors and activators of some potassium channels. These pharmacological actions are all implicated in the pathogenesis of ischemic stroke. The aim of this study was to investigate the hypothesis that the fenamate, mefenamic acid, is neuroprotective in an in vitro and in vivo model of stroke. Embryonic rat hippocampal neurons were cultured and maintained for up to 14 days in vitro. At 9 or 14 days, cells were exposed to glutamate (5muM) or glutamate (5muM) plus mefenamic acid (10-100muM) or the control agent, MK-801 (10muM) for 10mins. 24hours later, cell death was determined by measuring lactate dehydrogenase (LDH) levels in the culture media. In vivo, male Wistar rats (300-350g) were subjected to 2hours middle cerebral artery occlusion (MCAO) followed by 24hours reperfusion. Animals received either a single iv dose of MFA (10 or 30mg/kg), or MK-801 (2mg/kg) or saline prior to MCAO or, 4 equal doses of MFA (20mg/kg) at 1 hour intervals beginning 1 hour prior to MCAO. Ischemic damage was then assessed 24hours after MCAO. In vitro, mefenamic acid (10-100muM) and MK-801 (10muM) significantly reduced glutamate-evoked cell death compared with control cultures. In vivo, MFA (20mg/kg x 4) significantly reduced infarct volume, total ischemic brain damage and edema by 53% (p</= 0.02), 41% (p</= 0.002) and 45% (p</= 0.002) respectively. Furthermore, mefenamic acid reduced cerebral edema when measured as a function of brain water content. MK-801 was also neuroprotective against MCAO brain injury. This study demonstrates a significant neuroprotective effect by a fenamate NSAID against glutamate-induced cell toxicity, in vitro and against ischemic stroke in vivo. Further experiments are currently addressing the mechanism(s) of this neuroprotection.

The purpose of this study was to determine the value of galactography-guided, stereotactic, vacuum-assisted breast biopsy (VABB) for the assessment of intraductal breast lesions and its potential as a therapeutic tool that could eliminate the need for surgical excision. Eighteen patients (median age 64 years, range 37-80) with nipple discharge and galactography-verified intraductal lesions underwent galactography-guided, stereotactic, 11-gauge VABB followed by surgery. Histopathology findings from VABB and subsequent surgery were compared. Underestimation and false-negative rates were assessed. After VABB, histopathology revealed invasive ductal carcinoma (IDC) in three (17%), ductal carcinoma in situ (DCIS) in six (33%), high-risk lesions in six (33%) and benign lesions in three (17%) cases. After surgical biopsy, histopathology confirmed the previously established diagnosis in 11 lesions (61%). The underestimation rate for high-risk lesions and DCIS was 50% (6/12). The false-negative rate was 7% (1/14). Histopathology examination after surgery showed that not a single lesion had been completely removed at VABB. Galactography-guided VABB is a feasible diagnostic tool. However, its value as a therapeutic procedure is limited because of the high number of underestimated and missed lesions and because of the histopathological detection of lesions’ remnants in every case. Surgical excision should be the therapeutic gold standard in cases of pathological nipple discharge and galactography abnormalities.

INTRODUCTION: Central pontine myelinolysis (CPM) is almost always described in association with a disturbance in sodium homeostasis, most commonly rapid correction of chronic hyponatremia. It has only rarely been described in patients with disturbances of serum osmolality in the absence of abnormal serum sodium concentrations. METHODS: Case report. RESULTS: A 93 year-old-man developed marked gait ataxia 2 days after the diagnosis and treatment of hyperosmolar hyperglycemia. MRI demonstrated a symmetric lesion in the central pons consisting of increased T2 signal intensity and restricted diffusion, consistent with CPM. Calculated serum osmolality on admission was 344 mOsm/kg and fell to 300 mOsm/Kg over 20 h. Serum sodium concentration stayed between 137 and 140 mEq/l throughout the admission. One month after admission, his ataxia had nearly completely resolved and the MRI changes had improved. CONCLUSION: CPM can develop in the setting of hyperosmolar hyperglycemia without abnormalities of sodium homeostasis. This supports the theory that the pathogenesis of CPM is dependent on a relatively hypertonic insult, which may occur independently of sodium abnormalities. CPM can present as isolated gait ataxia. Clinical manifestations of the disorder may show significant improvement despite a dramatic initial presentation.

Objective. To determine the precision with which intrapartum metabolic acidemia and hypoxic-ischemic encephalopathy (HIE) in term and near-term infants can be identified by neonatal brain imaging. Study design. This is a case-control study whose inclusion criteria were neonates born at >/=34 weeks gestation with a cord gas at delivery, suspected neurological abnormalities, and computed tomography (CT) or magnetic resonance (MR) imaging of the brain. Neonates with chromosomal and major congenital malformations were excluded. Brain imaging for neonates with and without metabolic acidemia (pH < 7.0 and base deficit > 12 mM) at birth and HIE were retrospectively reviewed by a neuroradiologist blinded to their clinical course and compared. Results. There were 54 neonates admitted to the NICU at a single university hospital between 1992 and 2006 that met these inclusion criteria of which 27 had metabolic acidemia at birth. There were 16 diagnosed clinically as having HIE at the time of neonatal discharge, 13 from the acidemic group and 3 from the nonacidemic group. Radiological signs of basal ganglia injury were significantly more common in neonates with metabolic acidemia (29.6%, 3.7%, p = 0.02) and HIE (37.5%, 7.9%, p = 0.01). Logistic regression corrected for gestational age showed that radiological signs of basal ganglia injury could identify the presence of HIE with area under the ROC curve of 0.71, sensitivity 37.5%, specificity 92.1%, positive predictive value 66.7%, and negative predictive value of 77.8%. Conclusion. Radiological signs of basal ganglia injury on early neonatal imaging are associated with metabolic acidemia and HIE, but is not precise enough to serve as a gold standard in the identification of these conditions.