Lijun Hou

Cholesterol Levels and Risk of Hemorrhagic Stroke A Systematic Review and Meta-Analysis

Background and Purpose— Cholesterol levels are inconsistently associated with the risk of hemorrhagic stroke. The purpose of this study is to assess their relationships using a meta-analytic approach. Methods— We searched PubMed and Embase for pertinent articles published in English. Only prospective studies that reported effect estimates with 95% confidential intervals (CIs) of hemorrhagic stroke for ≥3 categories of cholesterol levels, for high and low comparison, or for per 1 mmol/L increment of cholesterol concentrations were included. We used the random-effects model to pool the study-specific results. Results— Twenty-three prospective studies were included, totaling 1 430 141 participants with 7960 (5.6%) hemorrhagic strokes. In high versus low analysis, the summary relative risk of hemorrhagic stroke was 0.69 (95% CI, 0.59–0.81) for total cholesterol, 0.98 (95% CI, 0.80–1.19) for high-density lipoprotein cholesterol, and 0.62 (95% CI, 0.41–0.92) for low-density lipoprotein cholesterol. In dose–response analysis, the summary relative risk of hemorrhagic stroke for 1 mmol/L increment of total cholesterol was 0.85 (95% CI, 0.80–0.91), for high-density lipoprotein cholesterol was 1.11 (95% CI, 0.99–1.25), and for low-density lipoprotein cholesterol was 0.90 (95% CI, 0.77–1.05). The pooled relative risk for intracerebral hemorrhage was 1.17 (95% CI, 1.02–1.35) for high-density lipoprotein cholesterol. Conclusions— Total cholesterol level is inversely associated with risk of hemorrhagic stroke. Higher level of low-density lipoprotein cholesterol seems to be associated with lower risk of hemorrhagic stroke. High-density lipoprotein cholesterol level seems to be positively associated with risk of intracerebral hemorrhage.

Efficacy of Modafinil on Fatigue and Excessive Daytime Sleepiness Associated with Neurological Disorders: A Systematic Review and Meta-Analysis

Background Modafinil is a novel wake-promoting agent approved by the FDA ameliorating excessive daytime sleepiness (EDS) in three disorders: narcolepsy, shift work sleep disorder and obstructive sleep apnea. Existing trials of modafinil for fatigue and EDS associated with neurological disorders provided inconsistent results. This meta-analysis was aimed to assess drug safety and effects of modafinil on fatigue and EDS associated with neurological disorders. Methods A comprehensive literature review was conducted in order to identify published studies assessing the effects of modafinil on fatigue and EDS associated with neurological disorders. Primary outcomes included fatigue and EDS. Secondary outcomes included depression and adverse effects. Findings Ten randomized controlled trials were identified including 4 studies of Parkinson’s disease (PD), 3 of multiple sclerosis (MS), 2 of traumatic brain injury (TBI) and 1 of post-polio syndrome (PPS). A total of 535 patients were enrolled. Our results suggested a therapeutic effect of modafinil on fatigue in TBI (MD -0.82 95% CI -1.54 - -0.11 p=0.02, I2=0%), while a beneficial effect of modafinil on fatigue was not confirmed in the pooled studies of PD or MS. Treatment results demonstrated a clear beneficial effect of modafinil on EDS in patients with PD (MD -2.45 95% CI -4.00 - -0.91 p=0.002 I2=14%), but not with MS and TBI. No difference was seen between modafinil and placebo treatments in patients with PPS. Modafinil seemed to have no therapeutic effect on depression. Adverse events were similar between modafinil and placebo groups except that more patients were found with insomnia and nausea in modafinil group. Conclusions Existing trials of modafinil for fatigue and EDS associated with PD, MS, TBI and PPS provided inconsistent results. The majority of the studies had small sample sizes. Modafinil is not yet sufficient to be recommended for these medical conditions until solid data are available.

Nutritional Support for Patients Sustaining Traumatic Brain Injury: A Systematic Review and Meta-Analysis of Prospective Studies

Background In traumatic brain injury (TBI), the appropriate timing and route of feeding, and the efficacy of immune-enhancing formulae have not been well established. We performed this meta-analysis aiming to compare the effects of different nutritional support modalities on clinical outcomes of TBI patients. Methods We systematically searched Pubmed, Embase, and the Cochrane Library until October, 2012. All randomized controlled trials (RCTs) and non-randomized prospective studies (NPSs) that compared the effects of different routes, timings, or formulae of feeding on outcomes in TBI patients were selected. The primary outcomes included mortality and poor outcome. The secondary outcomes included the length of hospital stay, the length of ventilation days, and the rate of infectious or feeding-related complications. Findings 13 RCTs and 3 NPSs were included. The pooled data demonstrated that, compared with delayed feeding, early feeding was associated with a significant reduction in the rate of mortality (relative risk [RR] = 0.35; 95% CI, 0.24–0.50), poor outcome (RR = 0.70; 95% CI, 0.54–0.91), and infectious complications (RR = 0.77; 95% CI, 0.59–0.99). Compared with enteral nutrition, parenteral nutrition showed a slight trend of reduction in the rate of mortality (RR = 0.61; 95% CI, 0.34–1.09), poor outcome (RR = 0.73; 95% CI, 0.51–1.04), and infectious complications (RR = 0.89; 95% CI, 0.66–1.22), whereas without statistical significances. The immune-enhancing formula was associated with a significant reduction in infection rate compared with the standard formula (RR = 0.54; 95% CI, 0.35–0.82). Small-bowel feeding was found to be with a decreasing rate of pneumonia compared with nasogastric feeding (RR = 0.41; 95% CI, 0.22–0.76). Conclusion After TBI, early initiation of nutrition is recommended. It appears that parenteral nutrition is superior to enteral nutrition in improving outcomes. Our results lend support to the use of small-bowel feeding and immune-enhancing formulae in reducing infectious complications.

Prognostic Influence and Magnetic Resonance Imaging Findings in Paroxysmal Sympathetic Hyperactivity after Severe Traumatic Brain Injury

Paroxysmal sympathetic hyperactivity (PSH) is a clinical syndrome affecting a subgroup of survivors of severe brain injury. In this study, the prevalence, magnetic resonance imaging (MRI) presentation, influence on the clinical course in the intensive care unit (ICU), and effect on neurological recovery of PSH were prospectively surveyed in 87 patients with severe traumatic brain injury (TBI). Cranial MRI was performed during the first 30 days after injury. The outcome was assessed according to the Glasgow Outcome Scale (GOS). PSH occurred in 18.4% of patients, with a greater incidence among younger patients and those with lower Glasgow Coma Scale (GCS) scores. Patients with PSH had more deep lesions as shown on cranial MRI, significantly longer ICU stays, and worse outcomes. PSH was shown to be common among patients with severe TBI who also had deep intraparenchymal lesions. The mechanism by which PSH influences patient outcomes has yet to be defined, but we believe that it may be mediated by diencephalic-mesencephalic dysfunction or disconnection.

Effect of Methylphenidate in Patients with Cancer-Related Fatigue: A Systematic Review and Meta-Analysis

Background Cancer-related fatigue (CRF) is a common symptom affecting patients with cancer. There are an increasing number of trials examining potential treatments for CRF. Methylphenidate represents one of the most researched drugs and an up-to-date assessment of the evidence for its use is needed. Trials of methylphenidate for CRF provided inconsistent results. This meta-analysis was aimed at assessing the effect and safety of methylphenidate on CRF. Methods We comprehensively searched the Pubmed, EMBASE, PSYCHInfo and the Cochrane databases in order to identify published studies on the effect of methylphenidate on CRF. Primary outcomes included fatigue. Secondary outcomes included depression, cognition and adverse effects. Findings A meta-analysis was conducted on five randomized controlled trials and 498 patients were enrolled. Despite a large placebo effect observed in the studies included, pooled data suggested therapeutic effect of methylphenidate on CRF. Subgroup Analyses showed that the efficacy of methylphenidate on CRF is getting better with prolonging treatment duration, with a MD of −3.70 (95% CI −7.03– −0.37, p = 0.03) for long-time group and a MD of −2.49 (95% CI −6.01–1.03, p = 0.17) for short-time group. In general, there was no impact of methylphenidate on depression and cognition associated with CRF. Adverse events were similar between methylphenidate and placebo groups except that more patients reported vertigo, anxiety, anorexia and nausea in methylphenidate group compared to placebo group. Conclusion Existing trials of methylphenidate on CRF provided limited evidence for the use of methylphenidate to treat CRF. The absolute numbers still remain small, and further confirmation is needed before firm recommendations on their usage and safety can be made in the treatment of CRF.

Risk Factors Associated with Sleep Disturbance following Traumatic Brain Injury: Clinical Findings and Questionnaire Based Study

Background Sleep disturbance is very common following traumatic brain injury (TBI), which may initiate or exacerbate a variety of co-morbidities and negatively impact rehabilitative treatments. To date, there are paradoxical reports regarding the associations between inherent characteristics of TBI and sleep disturbance in TBI population. The current study was designed to explore the relationship between the presence of sleep disturbance and characteristics of TBI and identify the factors which are closely related to the presence of sleep disturbance in TBI population. Methods 98 TBI patients (72 males, mean age ± SD, 47 ± 13 years, range 18-70) were recruited. Severity of TBI was evaluated based on Glasgow Coma Scale (GCS). All participants performed cranial computed tomography and were examined on self-reported sleep quality, anxiety, and depression. Results TBI was mild in 69 (70%), moderate in 15 (15%) and severe in 14 (15%) patients. 37 of 98 patients (38%) reported sleep disturbance following TBI. Insomnia was diagnosed in 28 patients (29%) and post-traumatic hypersomnia in 9 patients (9%). In TBI with insomnia group, 5 patients (18%) complained of difficulty falling asleep only, 8 patients (29%) had difficulty maintaining sleep without difficulty in initial sleep and 15 patients (53%) presented both difficulty falling asleep and difficulty maintaining sleep. Risk factors associated with insomnia were headache and/or dizziness and more symptoms of anxiety and depression rather than GCS. In contrast, GCS was independently associated with the presence of hypersomnia following TBI. Furthermore, there was no evidence of an association between locations of brain injury and the presence of sleep disturbance after TBI. Conclusion Our data support and contribute to a growing body of evidence which indicates that TBI patients with insomnia are prone to suffer from concomitant headache and/or dizziness, report more symptoms of anxiety and depression and severe TBI patients are likely to experience hypersomnia.

Up-regulation of USP2a and FASN in gliomas correlates strongly with glioma grade

Gliomas are the most common neoplasms in the central nervous system. The lack of efficacy of glioma therapies necessitates in-depth studies of glioma pathology, especially of the underlying molecular mechanisms that transform normal glial cells into tumor cells. Here we report that a deubiquitinating enzyme, ubiquitin-specific protease 2a (USP2a), and its substrate, fatty acid synthase (FASN), are over-expressed in glioma tissue. Using real-time quantitative polymerase chain reaction (PCR), Western blot and immunohistochemistry, we examined the expression and cellular distribution of USP2a and FASN in human glioma tissues. The expression patterns of USP2a and FASN correlated with the pathologic and clinical characteristics of the patients. Real-time PCR analysis showed that the expression levels of USP2a and its substrate FASN were higher in high-grade (World Health Organization [WHO] grades III and IV) glioma tissues than in low-grade (WHO grades I and II) glioma tissues. Western blot analysis indicated that the average optical densitometry ratio of USP2a and its substrate FASN in high-grade gliomas was higher than in low-grade gliomas. Moreover, statistical analysis of grade-classified glioma samples showed that the level of USP2a and FASN expression increased with the elevation of the WHO grade of glioma. USP2a protein expression was detected in the nucleus of glioma tissues and an increase in expression was significantly associated with the elevation of the WHO grade of glioma by immunohistochemistry. These findings expand our understanding of the molecular profiling of glioma and could shed light on new diagnostic criteria for gliomas.

Clinical features and functional recovery of traumatic isolated oculomotor nerve palsy in mild head injury with sphenoid fracture

OBJECT The aim of this study was to provide information about long-term functional outcome in patients with isolated oculomotor nerve palsy following minor head injury and to discuss surgical treatment of these patients, especially those with accompanying sphenoid fracture. METHODS A retrospective analysis was made of 26 patients with traumatic isolated oculomotor nerve palsy. The severity of oculomotor nerve palsy and the functional recovery were evaluated based on extraocular muscle movement, eyelid movement, and pupil size. On average, patients were evaluated 3.6 days after the initial injury, and the average follow-up period was 14.2 months (range 3 months-2 years). RESULTS Twenty men and six women were enrolled in this study. The most common cause of trauma was motor vehicle accident in 17 (65.4%) of 26. Among all the recorded symptoms, internal ophthalmoplegia was most frequently seen. The recovery rates of ptosis, external ophthalmoplegia, and internal ophthalmoplegia were 95% (19 of 20 patients), 83.3% (15 of 18 patients), and 50% (13 of 26 patients), respectively. The 6 patients with sphenoid fracture underwent surgical decompression of the superior orbital fissure, after which all patients experienced recovery from ptosis and external ophthalmoplegia and 66.7% (4 of 6 patients) recovered from internal ophthalmoplegia. CONCLUSIONS Limited eye movement may be a major factor that negatively affects functional recovery after mild head injury. Sphenoid fracture might be one of the potential mechanisms involved in traumatic isolated oculomotor nerve palsy after mild head injury. Surgical decompression should be considered when there is evidence of bone compression of the superior orbital fissure.

Ubiquitin-specific protease 2a stabilizes MDM4 and facilitates the p53-mediated intrinsic apoptotic pathway in glioblastoma

The mouse double minute 4 (MDM4) oncoprotein may inhibit tumorigenesis by regulating the apoptotic mediator p53. Ubiquitin-specific protease 2a (USP2a) is a deubiquitinating enzyme that protects MDM4 against degradation, so USP2-MDM4 interaction may be a key determinant of the malignant potential of human cancers. MDM4 and USP2a, as well as the MDM4-USP2a complex, were more highly expressed in glioblastoma multiforme tissue samples from patients with good prognosis compared with patients with poor prognosis. Analysis of the prognostic parameters indicated that MDM4 expression was positively correlated with an increased likelihood for survival. Compared with the poor prognosis patients, mitochondria from good prognosis glioma patients contained higher levels of both MDM4 and the proapoptotic protein p53Ser46(P). In U87MG glioma cell line, the overexpression of MDM4 enhanced ultraviolet (UV)-induced cytochrome c release and apoptosis. In contrast, MDM4 knockdown decreased mitochondrial p53Ser46(P) levels and rescued cells from UV-induced apoptosis. The expression of MDM4 and USP2a were positively correlated with each other. MDM4-USP2a complexes were found only in the cytoplasmic fraction, whereas the mitochondrial fraction contained MDM4-p53Ser46(P) and MDM4-Bcl-2 complexes. Overexpression of USP2a increased p53 and p53Ser46(P) levels in the mitochondria, whereas simultaneous MDM4 knockdown completely reversed this effect. UV-induced apoptosis was reduced by USP2a knockdown but restored by the simultaneous overexpression of MDM4. This apoptotic response was reduced by knockdown of p53 but not p21. Our results suggest that USP2a binds to and stabilizes MDM4; thus in turn, it enhances the mitochondrial localization of p53 and promotes apoptosis in glioma cells.

Risk factors related to dysautonomia after severe traumatic brain injury.

BACKGROUND Dysautonomia after severe traumatic brain injury (TBI) is a clinical syndrome affecting a subgroup of survivors and is characterized by episodes of autonomic dysregulation and muscle overactivity. The purpose of this study was to determine the incidence of dysautonomia after severe TBI in an intensive care unit setting and analyze the risk factors for developing dysautonomia. METHODS A consecutive series of 101 patients with severe TBI admitted in a major trauma hospital during a 2-year period were prospectively observed to determine the effects of age, sex, mode of injury, hypertension history, admission systolic blood pressure, fracture, lung injury, admission Glasgow Coma Scale (GCS) score, injury severity score, emergency craniotomy, sedation or analgesia, diffuse axonal injury (DAI), magnetic resonance imaging (MRI) scales, and hydrocephalus on the development of dysautonomia. Risk factors for dysautonomia were evaluated by using logistic regression analysis. RESULTS Seventy-nine of the 101 patients met inclusion criteria, and dysautonomia was observed in 16 (20.3%) of these patients. Univariate analysis revealed significant correlations between the occurrence of dysautonomia and patient age, admission GCS score, DAI, MRI scales, and hydrocephalus. Sex, mode of injury, hypertension history, admission systolic blood pressure, fracture, lung injury, injury severity score, sedation or analgesia, and emergency craniotomy did not influence the development of dysautonomia. Multivariate logistic regression revealed that patient age and DAI were two independent predictors of dysautonomia. There was no independent association between dysautonomia and admission GCS score, MRI scales, or hydrocephalus. CONCLUSIONS Dysautonomia frequently occurs in patients with severe TBI. A younger age and DAI could be risk factors for facilitating the development of dysautonomia.