In this issue

<正>This issue begins with a meta-analysis by Zhu and colleagues[1]focused on the potential therapeutic effectiveness of the‘psychological placebos’used as control conditions in randomized controlled trials(RCTs)about the usefulness of cognitive behavioral therapy(CBT)in the treatment of generalized anxiety disorder.The unsurprising finding was that relaxation training,nondirective support groups,and similar non-specific interventions had a non-negligible therapeutic effect(compared to a wait list condition)that needs to be     

Atypical antipsychotics,more than just an antipsychotic

Antipsychotics are the prescribed drugs for schizophrenia.The first substance used for antipsychotic purposes appeared in 1952 and it was a general anesthetic:chlorpromazine.The use of this drug was mainly because of its effects on violent behavior instead of sedation in patients,which“controls”the psychotic episodes and prevents psychosis relapse.Since then,pharmaceutical antipsychotics have been developed,producing second-generation or atypical drugs.These drugs arose with the synthesis of clozapine in the late‘50s,which represented(and still represent)the“guide molecule”for the development of these substances,because of its effectiveness on the symptomatology of the disease.     

From pilot studies to confirmatory studies

1. Introduction Pilot studies serve an important role in clinical research. They provide information needed to design large confirmatory studies that aim to provide definitive evidence on the efficacy/effectiveness of novel inter- ventions. In the drug development process, phase I and II studies are used to prepare for the conduct of confirmatory phase III trials, In investigator-initiated studies supported by the government such a long developmental process is usually unfeasible, so pilot studies for these projects typically use smaller samples over shorter periods of time than planned for the main study. As a planning tool, pilot studies can be used for a variety of objectives. First, pilot studies can be used to assess the feasibility of confirmatory studies,     

Huangqi Guizhi Wuwu Decoction for treating diabetic peripheral neuropathy:a meta-analysis of 16 randomized controlled trials

OBJECTIVE:This meta-analysis was performed to systematically assess the efficacy and safety of the Chinese herbal medicine Huangqi Guizhi Wuwu Decoction(HGWWD) for treating diabetic peripheral neuropathy.DATA SOURCES:Six electronic databases,including the Cochrane Library,MEDLINE database,Chinese Biomedical Database,Chinese National Knowledge Infrastructure Database,Chinese Science and Technique Journals Database,and the Wanfang Database,were search ed on the internet for randomized controlled trials published up until 1 December 2015.The search terms included "Chinese herbal medicine","diabetic peripheral neuropathy" and "randomized controlled trials" in Chinese and in English.DATA SELECTION:We included randomized controlled trials using HGWWD/modified HGWWD for the treatment group,without restriction for the control group.We assessed literature quality in accordance with the Cochrane Review Handbook.A random or a fixed effects model was used to analyze outcomes using Rev Man 5.2 software.OUTCOME MEASURES:The primary outcomes were changes in symptoms and nerve conduction velocities.The secondary outcomeswere fasting blood glucose and hemorheological indexes.RESULTS:Sixteen randomized controlled trials,with a total of 1,173 patients,were included.Meta-analysis revealed that the efficacy of HGWWD for diabetic peripheral neuropathy was significantly superior compared with the control treatment(i.e.,control group)(risk ratio = 0.36,95% confidence interval(CI):0.29–0.46,Z =8.33,P 0.00001) Compared with the control group,there was an increase in median motor nerve conduction velocity(mean difference(MD) = 3.46,95%CI:1.88–5.04,Z = 4.30,P 0.01) and median sensory nerve conduction velocity(MD = 3.30,95%CI:2.04–4.56,Z = 5.14,P 0.01).There was also an increase in peroneal motor nerve conduction velocity(MD = 3.22,95%CI:2.45–3.98,Z = 8.21,P 0.01) and peroneal sensory nerve conduction velocity(MD = 3.05,95%CI:2.01–4.09,Z = 5.75,P 0.01) in the treatment groups.No significant difference in fasting blood glucose was found between the treatment groups and the control groups(MD =-0.12,95%CI:-0.42–0.19,Z = 0.76,P = 0.45).Plasma viscosity was significantly decreased after treatment(MD =-0.11,95%CI:-0.21 to-0.02,Z = 2.30,P = 0.02).No significant difference in fibrinogen was detectable(MD =-0.53,95%CI:-1.28–0.22,Z = 1.38,P = 0.17).Four trials reported that treatment groups experienced no adverse reactions.Adverse events were not mentioned in the other 12 trials.No trial reported the incidence of complications,quality of life outcomes,or health economics.CONCLUSION:HGWWD treatment improves diabetic neurologic symptoms and ameliorates nerve conduction velocities.Our study suggests that HGWWD may have significant therapeutic efficacy for the treatment of diabetic peripheral neuropathy.However,the methodological quality of the randomized controlled trials was generally low.Larger and better-designed randomized controlled trials are required to more reliably assess the clinical effectiveness of HGWWD.     

MicroRNAs as diagnostic and therapeutic tools for Alzheimer's disease: advances and limitations

Alzheimer's disease(AD) is the most common age-related, progressive neurodegenerative disease. It is characterized by memory loss and cognitive decline and responsible for most cases of dementia in the elderly. Late-onset or sporadic AD accounts for 95% of cases, with age at onset 65 years. Currently there are no drugs or other therapeutic agents available to prevent or delay the progression of AD. The cellular and molecular changes occurring in the brains of individuals with AD include accumulation of β-amyloid peptide and hyperphosphorylated tau protein, decrease of acetylcholine neurotransmitter, inflammation, and oxidative stress. Aggregation of β-amyloid peptide in extracellular plaques and the hyperphosphorylated tau protein in intracellular neurofibrillary tangles are characteristic of AD. A major challenge is identifying molecular biomarkers of the early-stage AD in patients as most studies have been performed with blood or brain tissue samples(postmortem) at late-stage AD. Subjects with mild cognitive impairment almost always have the neuropathologic features of AD with about 50% of mild cognitive impairment patients progressing to AD. They could provide important information about AD pathomechanism and potentially also highlight minimally or noninvasive, easy-to-access biomarkers. MicroRNAs are dysregulated in AD, and may facilitate the early detection of the disease and potentially the continual monitoring of disease progression and allow therapeutic interventions to be evaluated. Four recent reviews have been published of microRNAs in AD, each of which identified areas of weakness or limitations in the reported studies. Importantly, studies in the last three years have shown considerable progress in overcoming some of these limitations and identifying specific microRNAs as biomarkers for AD and mild cognitive impairment. Further large-scale human studies are warranted with less disparity in the study populations, and using an appropriate method to validate the findings.     

Challenges in developing therapeutic strategies for mild neonatal encephalopathy

There is increasing evidence that infants with mild neonatal encephalopathy(NE) have significant risks of mortality, brain injury and adverse neurodevelopmental outcomes. In the era of therapeutic hypothermia, infants need to be diagnosed within 6 hours of birth, corresponding with the window of opportunity for treatment of moderate to severe NE, compared to the retrospective grading over 2 to 3 days, typically with imaging and formal electroencephalographic assessment in the pre-hypothermia era. This shift in diagnosis may have increased the apparent prevalence of brain damage and poor neurological outcomes seen in infants with mild NE in the era of hypothermia. Abnormal short term outcomes observed in infants with mild NE include seizures, abnormal neurologic examination at discharge, abnormal brain magnetic resonance imaging and difficulty feeding. At 2 to 3 years of age, mild NE has been associated with an increased risk of autism, language and cognitive deficits. There are no approved treatment strategies for these infants as they were not included in the initial randomized controlled trials for therapeutic hypothermia. However, there is already therapeutic creep, with many centers treating infants with mild NE despite the limited evidence for its safety and efficacy. The optimal duration of treatment and therapeutic window of opportunity for effective treatment need to be specifically established for mild NE as the evolution of injury is likely to be slower, based on preclinical data. Randomized controlled trials of therapeutic hypothermia for infants with mild NE are urgently required to establish the safety and efficacy of treatment. This review will examine the evidence for adverse outcomes after mild NE and dissect some of the challenges in developing therapeutic strategies for mild NE, before analyzing the evidence for therapeutic hypothermia and other strategies for treatment of these infants.     

Communicating with the non-dominant hemisphere Implications for neurological rehabilitation

Aphasic syndromes usually result from injuries to the dominant hemisphere of the brain. Despite the fact that localization of language functions shows little interindividual variability, several brain areas are simultaneously activated when language tasks are undertaken. Mechanisms of language recovery after brain injury to the dominant hemisphere seem to be relatively stereotyped, including activations of perilesional areas in the acute phase and of homologues of language areas in the non-dominant hemisphere in the subacute phase, later returning to dominant hemisphere activation in the chronic phase. Plasticity mechanisms reopen the critical period of language development, more specifically in what leads to disinhibition of the non-dominant hemisphere when brain lesions affect the dominant hemisphere. The non-dominant hemisphere plays an important role during recovery from aphasia, but currently available rehabilitation therapies have shown limited results for efficient language improvement. Large-scale randomized controlled trials that evaluate well-defined interventions in patients with aphasia are needed for stimulation of neuroplasticity mechanisms that enhance the role of the non-dominant hemisphere for language recovery. Ineffective treatment approaches should be replaced by more promising ones and the latter should be evaluated for proper application. The data generated by such studies could substantiate evidence-based rehabilitation strategies for patients with aphasia.     

Xingnao Kaiqiao needling method for acute ischemic stroke: a meta-analysis of safety and efficacy

OBJECTIVE: To evaluate the effectiveness and safety of the Xingnao Kaiqiao needling method for treating acute ischemic stroke.DATA SOURCES: We retrieved relevant randomized controlled trials involving Xingnao Kaiqiao acupuncture for treatment of acute ischemic stroke. The China National Knowledge Infrastructure, Weipu Information Resources System, Wanfang Medical Data System, Chinese Biomedical Literature Database, Cochrane Library, and Pub Med were searched from June 2006 to March 2016.DATA SELECTION: We analyzed randomized and semi-randomized clinical controlled trials that compared Xingnao Kaiqiao acupuncture with various control treatments, such as conventional drugs or other acupuncture therapies, for treatment of acute ischemic stroke. The quality of articles was evaluated according to the Cochrane Handbook for Systematic Reviews of Interventions(Version 5.1), and the study was carried out using Cochrane system assessment methods. Rev Man 5.2 was used for the meta-analysis of the included studies.OUTCOME MEASURES: The mortality rate, disability rate, activities of daily living(Barthel Index), and clinical efficacy were observed.RESULTS: Twelve studies met the inclusion criteria for this review. The meta-analysis showed that between Xingnao Kaiqiao acupuncture and the control treatment, Xingnao Kaiqiao acupuncture reduced the disability rate [risk ratio(RR) = 0.51, 95% confidence interval(CI) = 0.27–0.98, z = 2.03, P 0.05], elevated the activities of daily living(weighted mean difference = 12.23, 95% CI: 3.66–20.08, z = 2.80, P 0.005), and had greater clinical efficacy(RR = 1.61, 95% CI: 1.23–2.09, z = 3.53, P 0.0004). However, there was no significant difference in mortality rate(RR = 0.61, 95% CI: 0.15–2.45, z = 0.70, P 0.05). CONCLUSION: The Xingnao Kaiqiao needling method is effective and safe for acute ischemic stroke. However, there was selective bias in this study, and the likelihood of measurement bias is high. Thus, more high-quality randomized controlled trials are needed to provide reliable evidence of the efficacy and safety of Xingnao Kaiqiao acupuncture in the treatment of acute ischemic stroke.     

Recent advancements in noninvasive brain modulation for individuals with autism spectrum disorder

Autism spectrum disorder is classified as a spectrum of neurodevelopmental disorders with an unknown definitive etiology.Individuals with autism spectrum disorder show deficits in a va riety of areas including cognition,memory,attention,emotion recognition,and social skills.With no definitive treatment or cure,the main interventions for individuals with autism spectrum disorder are based on behavioral modulations.Recently,noninvasive brain modulation techniques including repetitive transcranial ...     

1000/Symptomatic and pathogenetic treatment of diabetic neuropathy. The role of alpha-lipoic acid

Diabetic neuropathy, the most common form of peripheral neuropathy worldwide, presents in different forms of focal or diffuse neuropathy, including the disabling, or potentially life-threatening clinical entities of painful diabetic neuropathy, autonomic neuropathy, and diabetic foot. The pathogenesis of diabetic neuropathy results from the concurrent action of various intersecting factors of nerve damage, i.e. oxidative stress and mitochondrial dysfunction, inflammation, microangiopathy and ischemia, triggered by hyperglycemia and related biochemical changes. Symptomatic treatment of diabetic neuropathy mainly concerns the therapy of neuropathic pain with antidepressants (tricyclics and serotonin-norepinephrine inhibitors), anticonvulsants (in particular, alpha2delta calcium channel modulator), opioids (oxycodone CR and tramadol), and local treatment and physical therapy. Symptomatic treatment of autonomic neuropathy includes different interventions targeted at the organ systems involved. The management of diabetic foot is directed at the various combined factors resulting in foot ulceration, such as infection, peripheral ischemia, and pressure relief. Various therapeutic approaches pathogenetically oriented have been proposed and investigated in experimental and clinical studies, targeted to the different components involved in the causation of nerve damage. In particular, oxidative stress has been demonstrated to play a central role in the cascade of events triggered by hyperglycemia, thus it appears as an ideal target for a pathogenetic therapeutic approach. Alpha-lipoic acid, a potent lipophilic free radical scavenger, has been used in a series of controlled randomized clinical trials in patients with diabetic neuropathy, with either oral administration or intravenous infusion. Most of the trials demonstrated the efficacy of alpha-lipoic acid on the chief symptoms of diabetic neuropathy, and in particular on neuropathic pain, also indicating that neuropathic deficits may be improved by treatment. Current evidence suggests a possible efficacy of alpha-lipoic acid not only for neuropathic symptoms, but also for modifying the natural history of diabetic neuropathy. The potential role of alpha-lipoic acid in contrasting the progression of diabetic neuropathy is being explored in the NATHAN 1 study, using an oral dose of 600 mg once daily over 4 years in diabetic patients with mild to moderate distal symmetric polyneuropathy, and evaluating the long-term effects with a composite score that combines clinical and neurophysiological assessment.     

区分亚临床抑郁(域下抑郁)与抑郁症残留症状(英文)

The terms‘sub-clinical’or‘subthreshold’are widely used in medicine to label individuals who are in the early stages of a disease process (e.g., cancer,hypertension, etc.) and to identify high-risk populations that need to be monitored or provided with specific preventative interventions or treatments. Because the pathophysiological changes that occur in the sub-clinical stages of a condition are similar to those that occur during the full-blown disease,     

Publication trends in studies examining radix notoginseng as a treatment for ischemic brain injury

Acute ischemic stroke has become a major disease burden with high mortality and morbidity rates. There is a lack of evidence-based medicine confirming the efficacy of common treatments. Panax notoginseng saponins, the main active ingredient of radix notoginseng, have a neuro- protective role in ischemic brain injury, and have been popularized as a maintenance treatment for acute cerebral infarction and its sequelae. We conducted literature searches on the Web of Science, ClinicalTrials.gov, Cochrane Collaboration, CNKI, Wanfang and the China Scientific ＆ Technological Achievements Database and analyzed the experimental and clinical outcomes of studies investigating the use of radix notoginseng in the treatment of ischemic brain injury to improve the understanding of relevant research trends and existing problems. We found that over the past 10 years, China has maintained its interest in Panax notoginseng research, while such studies are scarce on the Web of Science. However, Chinese researchers often focus on the neuroprotective role of radix notoginseng in ischemic brain injury, but there are no large-scale clinical data to confirm its efficacy and safety. There remains a need for more rigorous large-sample randomized controlled clinical trials with long-term follow-up, to determine whether radix notoginseng lowers stroke recurrence and improves patient＇s quality of life.     

Antidepressants for bipolar disorder——A meta-analysis of randomized,double-blind,controlled trials

OBJECTIVE： To examine the efficacy and safety of short-term and long-term use of antidepres- sants in the treatment of bipolar disorder. DATA SOURCES： A literature search of randomized, double-blind, controlled trials published until December 2012 was performed using the PubMed, ISI Web of Science, Medline and Cochrane Central Register of Controlled Trials databases. The keywords ＂bipolar disorder, bipolar I disorder, bipolar II disorder, bipolar mania, bipolar depression, cyclothymia, mixed mania and depression, rapid cycling and bipolar disorder＂, AND ＂antidepressant agent, antidepressive agents second- generation, antidepressive agents tricyclic, monoamine oxidase inhibitor, noradrenaline uptake in- hibitor, serotonin uptake inhibitor, and tricyclic antidepressant agent＂ were used. The studies that were listed in the reference list of the published papers but were not retrieved in the above-mentioned databases were supplemented. STUDY SELECTION： Studies selected were double-blind randomized controlled trials assessing the efficacy and safety of antidepressants in patients with bipolar disorder. All participants were aged 18 years or older, and were diagnosed as having primary bipolar disorder. Antidepressants or antidepressants combined with mood stabilizers were used in experimental interventions. Placebos, mood stabilizers, antipsychotics and other antide pressants were used in the control interventions. Studies that were quasi-randomized studies, or used antidepressants in combination with antipsy- chotics in the experimental group were excluded. All analyses were conducted using Review Man- ager 5.1 provided by the Cochrane Collaboration.     

Why psychosis is frequently associated with Parkinson's disease?

Psychosis is a common non-motor symptom of Parkinson’s disease whose pathogenesis remains poorly understood.Parkinson’s disease in conjunction with psychosis has been shown to induce injury to extracorticospinal tracts as well as within some cortical areas.In this study,Parkinson’s disease patients with psychosis who did not receive antipsychotic treatment and those without psychosis underwent diffusion tensor imaging.Results revealed that in Parkinson’s disease patients with psychosis,damage to the left frontal lobe,bilateral occipital lobe,left cingulated gyrus,and left hippocampal white-matter fibers were greater than damage to the substantia nigra or the globus pallidus.Damage to white-matter fibers in the right frontal lobe and right cingulate gyrus were also more severe than in the globus pallidus,but not the substantia nigra.Damage to frontal lobe and cingulate gyrus white-matter fibers was more apparent than that to occipital or hippocampal fiber damage.Compared with Parkinson’s disease patients without psychosis,those with psychosis had significantly lower fractional anisotropy ratios of left frontal lobe,bilateral occipital lobe,left cingulated gyrus,and left hippocampus to ipsilateral substantia nigra or globus pallidus,indicating more severe damage to white-matter fibers.These results suggest that psychosis associated with Parkinson’s disease is probably associated with an imbalance in the ratio of white-matter fibers between brain regions associated with psychiatric symptoms(frontal lobe,occipital lobe,cingulate gyrus,and hippocampus) and those associated with the motor symptoms of Parkinson’s disease(the substantia nigra and globus pallidus).The relatively greater damage to white-matter fibers in psychiatric symptom-related brain regions than in extracorticospinal tracts might explain why psychosis often occurs in Parkinson’s disease patients.     

Large animal ischemic stroke models: replicating human stroke pathophysiology

The high morbidity and mortality rate of ischemic stroke in humans has led to the development of numerous animal models that replicate human stroke to further understand the underlying pathophysiology and to explore potential therapeutic interventions.Although promising therapeutics have been identified using these animal models,with most undergoing significant testing in rodent models,the vast majority of these interventions have failed in human clinical trials.This failure of preclinical translation highlights the critical need for better therapeutic assessment in more clinically relevant ischemic stroke animal models.Large animal models such as non-human primates,sheep,pigs,and dogs are likely more predictive of human responses and outcomes due to brain anatomy and physiology that are more similar to humans-potentially making large animal testing a key step in the stroke therapy translational pipeline.The objective of this review is to highlight key characteristics that potentially make these gyrencephalic,large animal ischemic stroke models more predictive by comparing pathophysiological responses,tissue-level changes,and model limitations.     

Neural grafting for Parkinson's disease: challenges and prospects

Parkinson's disease (PD) is a neurodegenerative condition which causes a characteristic movement disorder secondary to loss of dopaminergic neurons in the substanitia nigra. The motor disorder responds well to dopamine-replacement therapies, though these result in significant adverse effects due to non-physiolog-ical release of dopamine in the striatum, and off-target effects. Cell-based regenerative treatments offer a potential means for targeted replacement of dopamine, in a physiological manner. Dopaminergic neurons for cell-based therapies can be obtained from several sources. Fetal ventral mesencephalon tissue contains dopaminergic neuron progenitors, and has been transplanted into the striatum of PD patients with good results in a number of cases. However, the ethical implications and logistical challenges of using fetal tissue mean that fetal ventral mesencephalon is unlikely to be used in a widespread clinical setting. Induced plu-ripotent stem cells can be used to generate dopaminergic neurons for transplantation, providing a source of autologous tissue for grafting. This approach means that challenges associated with allografts, such as the potential for immune rejection, can be circumvented. However, the associated cost and difficulty in producing a standardized product from different cell lines means that, at present, this approach is not com-mercially viable as a cell-based therapy. Dopaminergic neurons derived from embryonic stem cells offer the most promising basis for a cell-based therapy for Parkinson's disease, with trials due to commence in the next few years. Though there are ethical considerations to take into account when using embryonic tissue, the possibility of producing a standardized, optimized cell product means that this approach can be both effective, and commercially viable.     

Glial cells in intracerebral transplantation for Parkinson's disease

In the last few decades,intracerebral transplantation has grown from a dubious neuroscientific topic to a plausible modality for treatment of neurological disorders.The possibility for cell replacement opens a new field of perspectives in the therapy of neurodegenerative disorders,ischemia,and neurotrauma,with the most lessons learned from intracerebral transplantation in Parkinson's disease.Multiple animal studies and a few small-scale clinical trials have proven the concept of intracerebral grafting,but still have to provide a uniform and highly efficient approach to the procedure,suitable for clinical application.The success of intracerebral transplantation is highly dependent on the integration of the grafted cells with the host brain.In this process,glial cells are clearly more than passive bystanders.They provide transplanted cells with mechanical support,trophics,mediate synapse formation,and participate in graft vascularization.At the same time,glial cells mediate scarring,graft rejection,and neuroinflammation,which can be detrimental.We can use this information to try to understand the mechanisms behind the glial reaction to intracerebral transplantation.Recognizing and utilizing glial reactivity can move translational research forward and provide an insight not only to post-transplantation events but also to mechanisms of neuronal death and degeneration.Knowledge about glial reactivity to transplanted cells could also be a key for optimization of transplantation protocols,which ultimately should contribute to greater patient benefit.     

In this issue(December 2015)

<正>This issue starts with a meta-analysis by Liu and colleagues~([1])about the effectiveness of adjunctive treatment with metformin to reduce the weight gain associated with clozapine use in patients with schizophrenia.The relatively common occurrence of the metabolic syndrome among individuals taking clozapine~([2])is a major problem for the minority of     

Research progress in rehabilitation treatment of stroke patients A bibliometric analysis

BACKGROUND: Stroke presents as a transient or chronic brain dysfunction and is associated with high morbidity and high mortality. The doctors and scientists would like to argue how to enhance the validity of the rehabilitation treatment and how to further improve the level of treatment on stroke. OBJECTIVE: The aim of this study was to quantitatively analyze the current worldwide progress in research on stroke rehabilitation treatment based on Web of Science database and ClinicalTrial.gov in the past 10 years. METHODS: We conducted a quantitative analysis of clinical trial articles regarding stroke rehabilitation published in English from 2003 to 2013 and indexed in the National Institutes of Health Clinical Trials registry and Web of Science databases. Data were downloaded on March 15, 2013. RESULTS: (1) From 2003 to 2013, 2 654 clinical trials investigating stroke were indexed in ClinicalTrials.gov. There were only 58 clinical trials registered in 2003, and there was a marked increase from 2005. A total of 605 clinical trials on the rehabilitation of stroke were conducted in the past 10 years. (2) The analysis showed that most of the trials in the field were registered by North American institutions. With respect to the Asian countries, China and Taiwan area of China also published a reasonable proportion of the trials, but comparatively speaking, the number of trials is really rare. Most of the interventions were drugs, followed by the devices, and behavioral interventions were ranked third. (3) In the past 10 years, there were 4 052 studies on stroke indexed by Web of Science database. CONCLUSION: From perspective of research progress, we found that the number of clinical trials and papers on stroke rehabilitation has increased significantly in the past 10 years, between them a remarkable positive correlation exists.     

氯氮平使用不足(英文)

I read the piece by Wang and Li[1] with great interest. The issues surrounding the use of clozapine in China and the United States provide an interesting contrast. Wang and Li suggest that clozapine is over-utilized in China both as a first-line treatment and (in low doses) to augment other antipsychotic agents. The situation in the United States is that clozapine is grossly underutilized as a treatment for patients with refractory