Long-term Neurological Function Research Articles

The effect of extracorporeal cardiopulmonary resuscitation on prognosis of adult patients with cardiac arrest: meta-analysis

Objective To evaluate the effect of extracorporeal cardiopulmonary resuscitation(ECPR)and conventional cardiopulmonary resuscitation (CCPR)on survival and neurological function in adult patients with cardiac arrest. Methods The PubMed and Web of Science were searched to collect relevant literature from Jan 1980 to Nov 2015, and two reviewers strictly distinguished the studies, assessed the quality of studies and picked up the valuable data for statistical analysis by using RevMan 5.0. Results A total of 8 studies involving 27 18 patients were included in our review. Of them, 462 patients were treated with ECPR and 2 256 patients were cared with CCPR. The meta analysis showed that the survival discharge rate (OR=2.92, 95%CI: 2.24-3.81, P<0.01), long-term survival rate (OR=2.97, 95%CI: 2.11-4.19, P<0.01) and neurological function status (OR=3.50, 95%CI: 2.36-5.81, P<0.01) of ECPR (n=182) were better than those of CCPR (n=182). In 4 studies, propensity score matching was used to minimize bias and heterogeneity. The meta analysis also showed that the rate of ROSC, survival discharge rate, long-term survival rate and neurological function status in ECPR were superior over CCPR. Conclusions ECPR would be the excellent measures to improve ROSC rate, survival discharge rate, long-term survival rate and neurological outcome in adult victims with cardiac arrest. Key words: Cardiopulmonary resuscitation; ECPR; CCPR; Survival discharged; Neurological function prognosis; Meta analysis

LSKL peptide alleviates subarachnoid fibrosis and hydrocephalus by inhibiting TSP1-mediated TGF-β1 signaling activity following subarachnoid hemorrhage in rats.

Hydrocephalus has been demonstrated to be an independent risk factor for poor outcomes in patients with subarachnoid hemorrhage (SAH). Blockage of cerebrospinal fluid (CSF) flow and drainage is widely considered to play a vital role in communicating hydrocephalus, possibly due to subarachnoid fibrosis. A previous study indicated that transforming growth factor-β1 (TGF-β1), a key fibrogenic factor, is significantly increased in the CSF following SAH, implying a pivotal role in the development of chronic hydrocephalus. To investigate whether LSKL peptide, a small molecular peptide and competitive antagonist for TGF-β1, protects against subarachnoid fibrosis and hydrocephalus after SAH, a two-hemorrhage injection model of SAH was created in Sprague-Dawley rats. LSKL (1 mg/kg) was administered intraperitoneally immediately following the first intravenous injection of blood in the SAH model, with repeated injections of LSKL every 12 h until sacrifice. Thrombospondin-1 (TSP1), TGF-β1, p-Smad2/3, collagen I and pro-collagen I c-terminal propeptide levels were assessed via western blotting and ELISA. Lateral ventricular index, Masson staining and Morris water maze tests were employed to evaluate subarachnoid fibrosis, hydrocephalus and long-term neurological function following SAH. It was found that the LKSL peptide readily crossed the blood brain barrier, was protective against subarachnoid fibrosis, attenuated ventriculomegaly and effectively suppressed hydrocephalus. In addition, the results indicated that the protective effects of the LSKL peptide were achieved via the inhibition of TGF-β1 activity and subsequent Smad2/3 signaling. Importantly, the LSKL peptide may improve long-term neurocognitive deficits after SAH. In conclusion, the LSKL peptide suppresses subarachnoid fibrosis via inhibition of TSP1-mediated TGF-β1 activity, prevents the development of chronic hydrocephalus and improves long-term neurocognitive defects following SAH.

Assessing the relationship between brain tissue oxygenation and neurological dysfunction in critically ill patients: study protocol

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; Acute and chronic neurological complications amongst survivors of critical illness is common, however, the underlying etiology of this neurological dysfunction is unknown. This is the first study to use near-infrared spectroscopy to non-invasively measure brain tissue oxygenation, as a surrogate marker of cerebral perfusion, and correlate these values with subsequent neurological dysfunction. We will test the hypothesis that poor cerebral oxygenation during the first 24 hours of critical illness is correlated with acute and chronic neurological complications.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; This single-centre prospective observational study will be performed in a 33-bed medical/surgical intensive care unit (ICU). Adult patients are eligible for enrolment if they are admitted to the ICU within 24 hours, require mechanical ventilation, and/or vasopressor support. For 24 hours, cerebral oxygenation levels will be measured with the FORESIGHT oximeter; vital signs and tissue oxygenation will be captured with data monitoring software. Participants will be screened daily for delirium with the confusion assessment method-ICU. Long-term neurological function will be assessed with the Repeatable Battery for the Assessment of Neuropsychological Status and the kinesiological instrument for normal and altered reaching movements (KINARM) robot.&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Conclusions:&lt;/strong&gt; This study will provide novel information regarding the determinants of cerebral oxygenation during the acute phase (i.e. 24 hours) of critical illness, and its potential relationship with subsequent neurological complications. Should a relationship exist between cerebral oxygenation and neurological complications, future studies will be aimed at using brain tissue oxygenation as a therapeutic target to prevent acute and chronic neurological dysfunction.&lt;/p&gt;&lt;p class="abstract"&gt; &lt;/p&gt;&lt;p&gt;Clinical Trial Registration:&lt;strong&gt; &lt;/strong&gt;This trial is registered on clinicaltrials.gov (Identifier: NCT02344043), retrospectively registered January 8, 2015.&lt;/p&gt;

Progesterone exerts neuroprotective effects and improves long-term neurologic outcome after intracerebral hemorrhage in middle-aged mice

In this study, we examined the effect of progesterone on histopathologic and functional outcomes of intracerebral hemorrhage (ICH) in 10- to 12-month-old mice. Progesterone or vehicle was administered by intraperitoneal injection 1 hour after collagenase-induced ICH and then by subcutaneous injections at 6, 24, and 48 hours. Oxidative and nitrosative stress were assayed at 12 hours post-ICH. Injury markers were examined on day 1, and lesion was examined on day 3. Neurologic deficits were examined for 28 days. Progesterone posttreatment reduced lesion volume, brain swelling, edema, and cell degeneration and improved long-term neurologic function. These protective effects were associated with reductions in protein carbonyl formation, protein nitrosylation, and matrix metalloproteinase-9 activity and attenuated cellular and molecular inflammatory responses. Progesterone also reduced vascular endothelial growth factor expression, increased neuronal-specific Na+/K+ ATPase ɑ3 subunit expression, and reduced protein kinase C–dependent Na+/K+ ATPase phosphorylation. Furthermore, progesterone reduced glial scar thickness, myelin loss, brain atrophy, and residual injury volume on day 28 after ICH. With multiple brain targets, progesterone warrants further investigation for its potential use in ICH therapy.

Inhibition of microRNA-210 provides neuroprotection in hypoxic–ischemic brain injury in neonatal rats

Perinatal hypoxic–ischemic encephalopathy (HIE) is associated with high neonatal mortality and severe long-term neurologic morbidity. Yet the mechanisms of brain injury in infants with HIE remain largely elusive. The present study determined a novel mechanism of microRNA-210 (miR-210) in silencing endogenous neuroprotection and increasing hypoxic–ischemic brain injury in neonatal rats. The study further revealed a potential therapeutic effect of miR-210 inhibition using complementary locked nucleic acid oligonucleotides (miR-210-LNA) in 10-day-old neonatal rats in the Rice–Vannucci model. The underlying mechanisms were investigated with intracerebroventricular injection (i.c.v) of miR-210 mimic, miR-210-LNA, glucocorticoid receptor (GR) agonist and antagonist. Luciferase reporter gene assay was conducted for identification of miR-210 targeting GR 3′untranslated region. The results showed that the HI treatment significantly increased miR-210 levels in the brain, and miR-210 mimic significantly decreased GR protein abundance and exacerbated HI brain injury in the pups. MiR-210-LNA administration via i.c.v. 4h after the HI insult significantly decreased brain miR-210 levels, increased GR protein abundance, reduced HI-induced neuronal death and brain infarct size, and improved long-term neurological function recovery. Of importance, the intranasal delivery of miR-210-LNA 4h after the HI insult produced similar effects in decreasing HI-induced neonatal brain injury and improving neurological function later in life. Altogether, the present study provides evidence of a novel mechanism of miR-210 in a neonatal HI brain injury model, and suggests a potential therapeutic approach of miR-210 inhibition in the treatment of neonatal HIE.

Prognostication of cardiac arrest survivors using low apparent diffusion coefficient cluster volume

IntroductionWe developed a new neuroprognostication method for cardiac arrest (CA) using the relative volume of the most dominant cluster of low apparent diffusion coefficient (ADC) voxels and tested its performance in a multicenter setting. MethodsAdult (>15 years) out-of-hospital CA patients from three different facilities who underwent an MRI 12h after resuscitation were retrospectively analyzed. Patients with unknown long-term prognosis or poor baseline neurologic function were excluded. Average ADCs (mean and median), LADCV (relative volume of low-ADC voxels) and DC-LADCV (relative volume of most dominant cluster of low-ADC voxels) were extracted using different thresholds between 400 and 800×10−6mm2s−1 at 10×10−6mm2s−1 intervals. Area under the receiver operating characteristic curve (AUROC) and sensitivity for poor outcome (6-month cerebral performance category score >2) while maintaining 100% specificity were measured. Results110 patients were analyzed. Average ADCs showed fair performance with an AUROC of 0.822 (95% confidence interval [CI], 0.744–0.900) for the mean and 0.799 (95% CI, 0.716–0.882) for the median. LADCV showed better performance with a higher AUROC (maximum, 0.925) in an ADC threshold range of 400 to 690×10−6mm2s−1. DC-LADCV showed the best performance with a higher AUROC (maximum, 0.955) compared with LADCV in an ADC threshold range of 600 to 680×10−6mm2s−1. DC-LADCV had a high sensitivity for poor outcomes (>80%) in a wide threshold range from 400 to 580×10−6mm2s−1 with a maximum of 89.2%. ConclusionsQuantitative analysis using DC-LADCV showed impressive performance in determining the prognosis of out-of-hospital CA patients in a multicenter setting.

Abstract 12374: Apparent Diffusion Coefficient Predictors of Outcome in Cardiac Arrest Survivors

Objective: Various methods of quantitative apparent diffusion coefficient (ADC) analysis has been suggested as useful for prognostication of comatose cardiac arrest (CA) patients. We developed a new computerized prognostication method using relative volume of most dominant cluster of low-ADC voxels and tested its performance in multicenter setting. Method: Adult (&gt;15 years) out-of-hospital CA patients from three different facilities with MRI taken after 12 hours after resuscitation were retrospectively analyzed. Patients with unknown long-term prognosis or poor baseline neurologic function were excluded. Average ADCs (mean and median), LADCV (relative volume of low-ADC voxels) and DC-LADCV (relative volume of most dominant cluster of low-ADC voxels) were extracted using different thresholds from 400 to 800х10–6 mm2/s at 10х10–6 mm2/s intervals. Area under the receiver operating characteristic curve (AUROC) and sensitivity for poor outcome (6-month cerebral performance category score &gt; 2) while maintaining 100% specificity were measured. Results: 110 patients were analyzed. Average ADCs showed fair performance with AUROC of 0.822 (95% confidence interval [CI], 0.744-0.900) for mean and 0.799 (95% CI, 0.716-0.882) for median ADC. LADCV showed better performance with higher AUROC (maximum, 0.925) in ADC threshold range from 400 to 690х10–6mm2/s. DC-LADCV showed the best performance with higher AUROC (maximum, 0.955) compared to LADCV in ADC threshold range of 600 to 680х10–6 mm2/s. It had high sensitivity for poor outcome (&gt;80%) in wide threshold range from 400 to 580х10–6 mm2/s with maximum of 89.2%. Interpretation: Computerized quantitative analysis using DC-LADCV showed impressive performance in prognostication of out-of-hospital CA patients in multicenter setting.

Decorin alleviated chronic hydrocephalus via inhibiting TGF-β1/Smad/CTGF pathway after subarachnoid hemorrhage in rats

Chronic hydrocephalus is one of the severe complications after subarachnoid hemorrhage (SAH). However, there is no efficient treatment for the prevention of chronic hydrocephalus, partially due to poor understanding of underlying pathogenesis, subarachnoid fibrosis. Transforming growth factor-β1(TGF-β1) is a potent fibrogenic factor implicated in wide range of fibrotic diseases. To investigate whether decorin, a natural antagonist for TGF-β1, protects against subarachnoid fibrosis and chronic hydrocephalus after SAH, two-hemorrhage-injection SAH model was conducted in 6-week-old rats. Recombinant human decorin(rhDecorin) (30ug/2ul) was administered before blood injection and on the 10th day after SAH. TGF-β1, p-Smad2/3, connective tissue growth factor (CTGF), collagen I and pro-collagen I c-terminal propeptide were assessed via western blotting, enzyme-linked immunosorbent assay, radioimmunoassay and immunofluorescence. And neurobehavioral tests and Morris water maze were employed to evaluate long-term neurological functions after SAH. We found that SAH induced heightened activation of TGF-β1/Smad/CTGF axis, presenting as a two peak response of TGF-β1 in cerebrospinal fluid, elevation of TGF-β1, p-Smad2/3, CTGF, collagen I in brain parenchyma and pro-collagen I c-terminal propeptide in cerebrospinal fluid, and increased lateral ventricle index. rhDecorin treatment effectively inhibited up-regulation of TGF-β1, p-Smad2/3, CTGF, collagen I and pro-collagen I c-terminal propeptide after SAH. Moreover, rhDecorin treatment significantly reduced lateral ventricular index and incidence of chronic hydrocephalus after SAH. Importantly, rhDecorin improved neurocognitive deficits after SAH. In conclusion, rhDecorin suppresses extracellular matrix accumulation and following subarachnoid fibrosis via inhibiting TGF-β1/Smad/CTGF pathway, preventing development of hydrocephalus and attenuating long-term neurocognitive defects after SAH.

Dietary supplementation with omega-3 polyunsaturated fatty acids robustly promotes neurovascular restorative dynamics and improves neurological functions after stroke

Stroke is a devastating neurological disease with no satisfactory therapies to preserve long-term neurological function, perhaps due to the sole emphasis on neuronal survival in most preclinical studies. Recent studies have revealed the importance of protecting multiple cell types in the injured brain, such as oligodendrocytes and components of the neurovascular unit, before long-lasting recovery of function can be achieved. For example, revascularization in the ischemic penumbra is critical to provide various neurotrophic factors that enhance the survival and activity of neurons and other progenitor cells, such as oligodendrocyte precursor cells. In the present study, we hypothesized that chronic dietary supplementation with fish oil promotes post-stroke angiogenesis, neurogenesis, and oligodendrogenesis, thereby leading to long-term functional improvements. Mice received dietary supplementation with n-3 PUFA-enriched fish oil for three months before and up to one month after stroke. As expected, dietary n-3 PUFAs significantly increased levels of n-3 PUFAs in the brain and improved long-term behavioral outcomes after cerebral ischemia. n-3 PUFAs also robustly improved revascularization and angiogenesis and boosted the survival of NeuN/BrdU labeled newborn neurons up to 35days after stroke injury. Furthermore, these pro-neurogenic effects were accompanied by robust oligodendrogenesis. Thus, this is the first study to demonstrate that chronic dietary intake of n-3 PUFAs is an effective prophylactic measure not only to protect against ischemic injury for the long term but also to actively promote neurovascular restorative dynamics and brain repair.

U0126 attenuates cerebral vasoconstriction and improves long-term neurologic outcome after stroke in female rats.

Sex differences are well known in cerebral ischemia and may impact the effect of stroke treatments. In male rats, the MEK1/2 inhibitor U0126 reduces ischemia-induced endothelin type B (ETB) receptor upregulation, infarct size and improves acute neurologic function after experimental stroke. However, responses to this treatment in females and long-term effects on outcome are not known. Initial experiments used in vitro organ culture of cerebral arteries, confirming ERK1/2 activation and increased ETB receptor-mediated vasoconstriction in female cerebral arteries. Transient middle cerebral artery occlusion (tMCAO, 120 minutes) was induced in female Wistar rats, with U0126 (30 mg/kg intraperitoneally) or vehicle administered at 0 and 24 hours of reperfusion, or with no treatment. Infarct volumes were determined and neurologic function was assessed by 6-point and 28-point neuroscores. ETB receptor-mediated contraction was studied with myograph and protein expression with immunohistochemistry. In vitro organ culture and tMCAO resulted in vascular ETB receptor upregulation and activation of ERK1/2 that was prevented by U0126. Although no effect on infarct size, U0126 improved the long-term neurologic function after experimental stroke in female rats. In conclusion, early prevention of the ERK1/2 activation and ETB receptor-mediated vasoconstriction in the cerebral vasculature after ischemic stroke in female rats improves the long-term neurologic outcome.

Sustained functional improvement by hepatocyte growth factor-like small molecule BB3 after focal cerebral ischemia in rats and mice.

Hepatocyte growth factor (HGF), efficacious in preclinical models of acute central nervous system injury, is burdened by administration of full-length proteins. A multiinstitutional consortium investigated the efficacy of BB3, a small molecule with HGF-like activity that crosses the blood-brain barrier in rodent focal ischemic stroke using Stroke Therapy Academic Industry Roundtable (STAIR) and Good Laboratory Practice guidelines. In rats, BB3, begun 6 hours after temporary middle cerebral artery occlusion (tMCAO) reperfusion, or permanent middle cerebral artery occlusion (pMCAO) onset, and continued for 14 days consistently improved long-term neurologic function independent of sex, age, or laboratory. BB3 had little effect on cerebral infarct size and no effect on blood pressure. BB3 increased HGF receptor c-Met phosphorylation and synaptophysin expression in penumbral tissue consistent with a neurorestorative mechanism from HGF-like activity. In mouse tMCAO, BB3 starting 10 minutes after reperfusion and continued for 14 days improved neurologic function that persisted for 8 weeks in some, but not all measures. Study in animals with comorbidities and those exposed to common stroke drugs are the next steps to complete preclinical assessment. These data, generated in independent, masked, and rigorously controlled settings, are the first to suggest that the HGF pathway can potentially be harnessed by BB3 for neurologic benefit after ischemic stroke.

Use of nerve elongator to repair short-distance peripheral nerve defects: a prospective randomized study.

Repair techniques for short-distance peripheral nerve defects, including adjacent joint flexion to reduce the distance between the nerve stump defects, “nerve splint” suturing, and nerve sleeve connection, have some disadvantages. Therefore, we designed a repair technique involving intraoperative tension-free application of a nerve elongator and obtained good outcomes in the repair of short-distance peripheral nerve defects in a previous animal study. The present study compared the clinical outcomes between the use of this nerve elongator and performance of the conventional method in the repair of short-distance transection injuries in human elbows. The 3-, 6-, and 12-month postoperative follow-up results demonstrated that early neurological function recovery was better in the nerve elongation group than in the conventional group, but no significant difference in long-term neurological function recovery was detected between the two groups. In the nerve elongation group, the nerves were sutured without tension, and the duration of postoperative immobilization of the elbow was decreased. Elbow function rehabilitation was significantly better in the nerve elongation group than in the control group. Moreover, there were no security risks. The results of this study confirm that the use of this nerve elongator for repair of short-distance peripheral nerve defects is safe and effective.

MiR-21 improves the neurological outcome after traumatic brain injury in rats.

The expression levels of microRNAs (miRNAs) including miR-21, have been reported to change in response to traumatic brain injury (TBI), suggesting that they may influence the pathophysiological process in brain injury. To analyze the potential effect of miR-21 on neurological function after TBI, we employed the fluid percussion injury rat model and manipulated the expression level of miR-21 in brain using intracerebroventricular infusion of miR-21 agomir or antagomir. We found that upregulation of miR-21 level in brain conferred a better neurological outcome after TBI by improving long-term neurological function, alleviating brain edema and decreasing lesion volume. To further investigate the mechanism underlying this protective effect, we evaluated the impact of miR-21 on apoptosis and angiogenesis in brain after TBI. We found that miR-21 inhibited apoptosis and promoted angiogenesis through regulating the expression of apoptosis- and angiogenesis-related molecules. In addition, the expression of PTEN, a miR-21 target gene, was inhibited and Akt signaling was activated in the procedure. Taken together, these data indicate that miR-21 could be a potential therapeutic target for interventions after TBI.

Isoflurane postconditioning improved long-term neurological outcome possibly via inhibiting the mitochondrial permeability transition pore in neonatal rats after brain hypoxia–ischemia

BackgroundIsoflurane postconditioning induces neuroprotection in neonatal rats after hypoxia/ischemia (HI). Here, we evaluated the possible role of inhibiting the mitochondrial permeability transition pore (mPTP) in isoflurane postconditioning-improved long-term neurological outcome after brain HI. MethodsSeven-day-old Sprague-Dawley rats (n=360) were randomly divided into eight groups (n=45 in each). They underwent or did not undergo left common carotid arterial ligation followed by exposure to 8% oxygen for 2h at 37°C (brain HI). The mPTP opener atractyloside or inhibitor cyclosporin A was injected into the lateral cerebral ventricle. The weight ratio and neuronal density ratio in the ventral posteromedial thalamic nucleus and hippocampal CA3 area of left to right cerebral hemispheres were evaluated at 7 or 35days after brain HI. The changes of mitochondrial optical density (ΔOD540 of mPTP) and the performance in Morris water maze were assessed. ResultsCompared with the control (sham group), brain HI decreased the weight ratio and neuronal density ratio in the ventral posteromedial thalamic nucleus and hippocampal CA3 area (P<0.05). Brain HI also impaired the performance of rats in the Morris water maze and increased the ΔOD540. These effects of brain HI were reduced by isoflurane postconditioning and cyclosporin A. The improvement induced by isoflurane postconditioning was attenuated by atractyloside. ConclusionIsoflurane postconditioning improved long-term neurological functions after brain HI in neonatal rats. Inhibiting the opening of the mPTP may contribute to this protection.

Cavernous Angiomas of the Cauda Equina: Clinical Characteristics and Surgical Outcomes

Cavernous angioma (CA) is a rare hamartomatous vascular lesion, consisting of abnormal, dilated, and packed sinusoidal vascular channels without interposed nervous tissue. CAs of the cauda equina are exceedingly rare and have been previously reported in the literature as case reports. The aim of this study was to discuss the clinical presentation and the outcomes of microsurgery for these rare lesions. We retrospectively reviewed the records of 10 patients who underwent microsurgery for CAs of the cauda equina. All patients had performed pre- and postoperative magnetic resonance imaging (MRI). CAs of the cauda equina generally exhibited mixed intensity on T1- and T2-weighted images. Contrast-enhanced T1-weighted images showed heterogeneous enhancement. The hemosiderin ring which surrounded the cauda equina CA was rare. Gross total resection was achieved in all cases. All patients were followed up, with a mean duration of 41.1 months. Long-term neurological function was improved in nine patients and remained stable in one patient. No recurrence was observed on MRI. CAs should be considered in the differential diagnosis of cauda equina tumors. Because of the excessive vascularity of CAs, en bloc resection is recommended. For symptomatic patients, early surgery should be performed before neurological deficits deteriorate.

Clinical characteristics and surgical outcomes of spinal intramedullary ependymal cysts

Intramedullary ependymal cysts are exceedingly rare lesions, and have been previously reported in the literature as case reports. The aim of this study was to discuss the clinical presentation and the outcomes of microsurgery for these benign lesions. The authors retrospectively reviewed the records of ten patients who underwent microsurgery for intramedullary ependymal cysts. All patients had preoperative and postoperative magnetic resonance imaging. The surgical treatment included gross total resection and biopsy plus a cyst-subarachnoid shunt. The diagnosis of intramedullary ependymal cysts was based on radiological and pathological criteria. All patients were followed up, with a mean duration of 47.6 months. Intramedullary ependymal cysts were hypointense on T1-weighted images and hyperintense on T2-weighted images. Contrast-enhanced T1-weighted images showed no enhancement. Gross total resection was achieved in one case. Biopsy of the cyst wall plus cyst-subarachnoid shunt placement was achieved in nine cases. Long-term neurological function was improved in eight patients. No recurrence was observed on magnetic resonance imaging. Ependymal cysts should be considered in the differential diagnosis of intramedullary cysts. For symptomatic patients, early surgery should be performed before neurological deficits deteriorate. Complete decompression and cyst-subarachnoid shunt placement is the optimal treatment and the outcome may be favorable.

Intramedullary spinal capillary hemangiomas: clinical features and surgical outcomes

Intramedullary capillary hemangiomas are exceedingly rare lesions in the spinal cord, and have been previously reported in the literature as case reports. The authors review their experience in 5 surgically treated patients with intramedullary capillary hemangiomas and discuss the clinical features, radiological findings, and surgical outcomes. Clinical and imaging data of 5 patients with intramedullary spinal capillary hemangiomas treated at a single institution were retrospectively analyzed. There were 4 men and 1 woman, and their ages ranged from 18 to 63 years (mean 47.2 years). The thoracic cord was affected in 4 patients, and the cervicothoracic cord in 1 patient. Four patients underwent a gross-total resection. One patient initially underwent a subtotal removal and then underwent a second surgery due to enlargement of the residual lesion. Long-term neurological function was improved in all patients and MRI showed no tumor recurrence. Capillary hemangiomas should be considered in the differential diagnosis of intramedullary spinal vascular lesions. Complete resection is the treatment of choice for these lesions. When total resection cannot be achieved, subtotal or even partial removal of the tumor is advised and repeat removal of the lesion is indicated when residual tumor regrowth is associated with neurological deterioration.

Insulin-Like Growth Factor-1 and its Derivatives: Potential Pharmaceutical Application for Treating Neurological Conditions

Ischemic brain damage remains a major cause of disability at all ages. This review examines the efficacy, mode of action and mechanisms of insulin-like growth factor (IGF)-1 and its derivatives in animal models of acute brain injury and neurodegenerative conditions, their potential in pharmaceutical developments. IGF-1 reduces cell loss and improves long-term neurological function in animal models. IGF-1 needs to be given within a few hours of the insult. However, the therapeutic window can be extended by mild hypothermia, likely by delaying apoptosis. Nevertheless, the poor central uptake of IGF-1 and its mitogenic potential limit clinical translation. Thus, recent studies have examined related compounds. For example, intravenous infusion of the N-terminal tripeptide of IGF-1 (glycine- proline-glutamate, GPE) can alleviate brain injury and improve long-term function in rats, with a broad effective dose range and a 3-7 hour therapeutic window, but has a short half-life. G-2meth-PE(G-2mPE), a GPE analogue with a longer half-life, is also neuroprotective. GPE/G-2mPE do not interact with IGF receptors and may act by modulating postinjury inflammation, astrogliosis and vascular remodeling. Cyclo-glycyl-proline (cGP), an endogenous diketopiperazine possibly derived from GPE is also neuroprotective. An analogue, cyclo-L-glycyl-L-2-allylproline (NNZ-2591) improves long-term somatosensory-motor function and histology after ischemic injury. Treatment with NNZ-2591 after 6-hypdroxydopamine injection in adult rats improves neurogenesis and long-term motor function. Further, oral administration of NNZ-2591 also prevents scopolamine-induced acute memory impairment. These beneficial effects may mediated by improved neuroplasticity. This review is an updated version of a previous publication in Recent Pat CNS Drug Discov.

When should cardiopulmonary bypass be used in the setting of severe hypothermic cardiac arrest?

A best evidence topic was written according to a structured protocol. The question addressed was regarding the indication and timing of the use of cardiopulmonary bypass (CPB), following severe hypothermic cardiac arrest. A total of 284 papers were found using the reported searches, of which nine represented the best evidence to answer the clinical question. The authors, date, journal, study type, population, main outcome measures and results are tabulated. Reported measures were survival, rewarming speed, incidence of arrhythmia during rewarming, resolution of full neurological function, long-term neurological function, evidence of damage on neurological imaging and venous metabolic parameters in hypothermic patients. The most recent of the best evidence studies, a retrospective comparative study of 68 patients, demonstrated CPB rewarming to be far superior to conventional methods of rewarming, with mortality rates of 15.8 and 53.3%, respectively. Another study of similar size, comparing CPB with extracorporeal membrane oxygenation (ECMO) for rewarming, revealed superior survival rates with ECMO, 75 vs 34%. A systematic review of 68 patients demonstrated an overall survival of 60%, and 80% of survivors returning to a previous level of activity. Two smaller observational studies reported survival rates of 73.1 and 45.5%, respectively. A retrospective study analysing long-term neurological outcomes of survivors reported normal history and physical examination in 93.3%, normal neurovascular ultrasound in 100%, normal neuropsychological findings in 93.3% and normal brain magnetic resonance imaging in 86.7%. A small comparative study demonstrated a significant survival benefit when CPB was preceded with emergency thoracotomy, internal cardiac massage and warm mediastinal irrigation compared with CPB alone. We conclude that, following deep hypothermic circulatory arrest, the urgent use of cardiopulmonary bypass is widely indicated for rewarming where it has been shown to provide good survival and neurological outcomes far superior in comparison with conventional methods of rewarming.

Hyperbaric oxygenation reduces long-term brain injury and ameliorates behavioral function by suppression of apoptosis in a rat model of neonatal hypoxia–ischemia

Neonatal hypoxia–ischemia (HI) produces neurodegeneration and brain injury, and leads to behavioral and cognitive dysfunction. Hyperbaric oxygen (HBO) treatment may potentially be neuroprotective in HI injury. The aim of this study was to examine any neuroprotection by HBO treatment on long-term neurological function in the rat model of neontatal HI. Seven-day-old rats were subjected to HI or sham surgery. HBO treatment was administered (2.5 ATA for 90min) 1h after hypoxia exposure. Sensorimotor (grip test and rota-rod) and cognitive tests (inhibitory avoidance and Morris water maze) were performed at postnatal day 28 to day 60. The extent of brain damage was determined by histological evaluation. Apoptosis, caspase-3 and apoptosis inducing factor (AIF) expression were assessed by immunohistochemistry 12, 24, and 48h after HI. HI-treated animals had significantly worse sensorimotor and cognitive performances than those in the Sham group. HBO treatment led to significant improvements in neurobehavioral functions compared to the HI group, especially for cognitive performances. Morphological evaluation revealed a remarkable recovery of brain injury in the HBO group. Furthermore, the improvements in neurobehavioral impairments were correlated with the reduction in lesion size of the hippocampus and cerebral cortex. The proportion of apoptotic cells significantly increased with time after HI, and HBO significantly inhibited apoptotic cell death. The proportion of caspase-3 positive cells and nuclear AIF translocation increased and peaked at 24h after HI injury. HBO-treated rats showed decreased expression of these proteins compared to HI-treated animals. In conclusion, our results suggested that HBO treatment was effective in promoting long-term functional and histological recovery against neonatal HI brain injury. HBO-induced neuroprotection was associated with suppression of apoptosis by inhibiting caspase-3 and AIF-mediated pathways. Further studies evaluating its associated molecular and cellular mechanism are needed.