Ping Sheng

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.

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.

Knockdown of CDK6 enhances glioma sensitivity to chemotherapy

Chemotherapy is widely used for the treatment of glioma. Given the high resistance of brain neoplasm tissues to chemotherapy, it is important to find new methods to improve the effects of chemotherapy. However, the molecular mechanisms underlying glioma resistance to chemotherapy are largely unknown. Here, we demonstrate that CDK6, a cell cycle regulator, is significantly upregulated in glioma cells, and the increasing expression of CDK6 correlates well with the grades of glioma malignancy. Using shRNA-mediated CDK6 knockdown, we found that the proliferation and survival of tumor cells were dramatically inhibited. Moreover, CDK6 knockdown in the U251 glioma cell line caused significant increase in the apoptosis of U251 cells treated with temozolomide (TMZ). Furthermore, CDK6 knockdown reduced the expression level of drug resistance genes such as MRP and MDR. These data indicate that CDK6 is an important mediator of glioma resistance to chemotherapy. Our findings provide a new strategy for the development of chemotherapy sensitizer.

Coagulation Parameters and Risk of Progressive Hemorrhagic Injury after Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

Intracranial hemorrhage (ICH) after traumatic brain injury (TBI) commonly increases in size and coagulopathy has been implicated in such progression. Our aim is to perform a meta-analysis to assess their relationship. Cochrane library, PubMed, and EMBASE were searched for literatures. Pooled effect sizes and 95% confidential intervals (CIs) were calculated using random-effects model. We included six studies, involving 1700 participants with 540 progressive hemorrhagic injuries (PHIs). Our findings indicate that PT, D-dimer level, and INR value are positively associated with the risk of PHI. Higher level of PLT and Fg seemed to suggest a lower risk of PHI. Among these parameters, higher D-dimer level and INR value would possess more powerful strength in predicting PHI.

The Development of Posttraumatic Stress Disorder after Mild TraumaticBrain Injury in Civilian Populations: A Meta-Analysis

Background: Posttraumatic stress disorder (PTSD) is an anxiety disorder following exposure to a traumatic event. Recent studies demonstrate that mild traumatic brain injury (mTBI) is strongly associated with PTSD among soldiers returning from Iraq. However, the effect of mTBI on development of PTSD in civilian populations is quite controversial. The study is aimed at identifying whether mTBI contributes to an increased risk of PTSD in civilian populations as it happens in the service members. Methods: A comprehensive search of literature was undertaken in order to identify published studies on PTSD associated with mTBI. mTBI was defined according to the American Congress of Rehabilitation Medicine (ACRM). PTSD was operationalized as the presence of symptoms consistent with those defined by the Diagnostic and Statistical Manual of Mental Disorders. The effect of mTBI on the development of PTSD was assessed with odds ratio (OR) with 95% confidence intervals (CIs). Results: The pooled data consisted of 1222 mTBI patients and 1468 general trauma participants. 14% of mTBI patients reported PTSD, and 9% of general trauma patients developed PTSD. Or of the pooled studies indicates a 61% increase in the prevalence of PTSD, suggesting that mTBI might increase the risk of development of PTSD in civilian settings (or 1.61, 95% CI 1.25-2.06. p=0.0002, I2=0%). The occurrence of PTSD was not significantly different among 3-months, 6-months and 12-months follow up subgroups (p=0.28). A sensitivity analysis shows the results are affected by sequential exclusion of study reported by Bryant et al. (2010). When Bryant et al. data were removed, OR of the other six studies demonstrates that the prevalence of PTSD in mTBI and general trauma groups doesn’t significantly differ (OR 1.30, 95% CI 0.88-1.93. p=0.19, I2=0%). The study from Bryant et al contributed 57% of patients to overall data, which was derived from four levels I trauma centers across three states in Australia. Conclusion: Our data indicate that mTBI patients are more prone to develop PTSD than general trauma patients without mTBI in civilian settings.

Identification and expression of a novel MDM4 splice variant in human glioma

The product of the MDMX (or MDM4) gene is structurally related to the MDM2 oncoprotein and is also capable of interacting with the tumor suppressor protein p53. The MDM4 gene is overexpressed in several human tumors, while its product can be detected as various isoforms. This study was aimed to find the presence of aberrant mRNA transcripts of MDM4 in human glioma and their association with the clinicopathological characteristics of glioma patients. 42 glioma tissues were examined for MDM4 mRNA splicing variants by RT-PCR. A total of four distinct transcript sizes (full length-MDM4 851 bp, MDM4-S 783 bp, MDM4-A 701 bp, MDM4-B 540 bp) were detected. In the present study, we first report the novel alternative splicing form of MDM4, MDM4-B (GenBank accession no.KC479043.1). Expression of MDM4-B was present in various stages of human gliomas, but no significant correlation between presence of MDM4-B and malignancy of glioma was observed. The expression level of MDM4-B mRNA detected by real-time PCR was not only significantly associated with tumor stages, but also with p53 mutation and Ki-67 status which are important clinical molecular markers of glioma. Our data indicate that the novel variant MDM4-B may play a role in glioma tumorigenesis or cancer progression.

Effects of Intensive Blood Pressure Reduction on Acute Intracerebral Hemorrhage: A Systematic Review and Meta-analysis

Current opinions about the effect of intensive blood pressure (BP) reduction for acute intracerebral hemorrhage (ICH) are inconsistent. We performed a meta-analysis to evaluate the efficacy and safety of intensive BP reduction for acute ICH by analyzing data from several recent randomized controlled trials (RCTs). There were six eligible studies that met the inclusion criteria, for a total of 4,385 acute ICH patients in this meta-analysis. After analyzing these data, we found differences between intensive and standard BP lowering treatment groups in total mortality rates, unfavorable outcomes, hematoma expansion, neurologic deterioration, and severe hypotension were not significant. Moreover, compared with the standard treatment, the rate of renal adverse event in intensive treatment group was significantly higher. The intensive treatment approach was recommended in the following situations: (1) longer prehospital duration; (2) lower National Institute of Health stroke scale (NIHSS) score; (3) no hypertension history.