Efficacy and Safety of Stem Cell Therapies for Patients with Stroke: a Systematic Review and Single Arm Meta-Analysis

BACKGROUND AND OBJECTIVES: Stem cell-based therapy is a potential new approach in the treatment of stroke. However, the efficacy and safety of these treatments are not yet fully understood. Therefore, we performed a meta-analysis of available single-arm studies using stem cell-based therapy in patients with stroke. METHODS: We searched MEDLINE, EMBASE, and the Cochrane database for studies of stem cell therapy in patients with stroke from its inception through July 2014. The articles included in the search were restricted to the English language, studies with at least 5 patients, and those using cell-based therapies for treating stroke. RESULTS: Fourteen studies included in the meta-analysis. The pooled mean difference in National Institutes of Health Stroke Scale (NIHSS) scores from baseline to follow-up points was 5.7 points (95%CI: -8.2 to -3.2, I2=91.5%) decreased. Also the pooled mean difference in modified Bathel index (BI) score was increased by 31.5 points (95%CI: 35.6~14.9, I2=52.7%) and the pooled incidence rate to achieve on modified Rankin score (mRS)< or =2 was 40% (95% CI: 30%~51%, I2=35.4%) at follow-up points. The pooled incidence rates of death, seizure, and infection were 13% (95%CI, 8~23%), 15% (95%CI, 8~25%), and 15% (95%CI, 8~23%), respectively. CONCLUSIONS: The published data suggest that stem cell-based therapy for patients with stroke can be judged as effective based on single arm clinical studies. However, clinical benefits of stem cell therapy for patients with stroke need further investigation and reevaluation to test the clinical efficacy.

Supra-Additive Neuroprotection by Renexin, a Mixed Compound of Ginkgo Biloba Extract and Cilostazol, Against Apoptotic White Matter Changes in Rat after Chronic Cerebral Hypoperfusion

BACKGROUND AND PURPOSE: White-matter (WM) lesions are known to potentiate cognitive impairment in poststroke patients. The present study was designed to assess whether Ginkgo biloba extract (GB) and cilostazol, which were evaluated alone and in a combination formula (Renexin), can attenuate the WM lesions and cognitive decline caused by chronic hypoperfusion in the rat. METHODS: Animals were divided into five treatment groups: cilostazol (25 mg/kg/day), GB (20 mg/kg/day), Renexin (25 mg/kg/day cilostazol + 20 mg/kg/day GB), vehicle, and sham. The animals received the treatments orally 1 day after bilateral common carotid artery occlusion [two-vessel occlusion (2VO); except for the sham group, which underwent the surgery but the arteries were not occluded], and then the same dose every day for 21 days thereafter. Prior to sacrificing the rats, repetitive eight-arm radial maze testing was performed to examine their cognitive abilities. After drug administration and cognitive testing, brain tissues were isolated for Kluver-Barrera and terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick end-labeling (TUNEL) staining, immunohistochemical assessment of glial fibrillary acidic protein (GFAP) and CD11b (OX-42), and to assay free-radical scavenging activity. RESULTS: We found that the significant WM lesions induced by 2VO was ameliorated significantly by treatment with cilostazol, GB, and Renexin, in association with increased TUNEL-positive cells. In addition, chronic cerebral hypoperfusion caused a large increase in the degree of GFAP and OX-42 immunoreactivity and free-radical activity in the optic tract. These abnormalities were significantly reversed by the three drugs, but most prominently by Renexin, suggesting a markedly enhanced or supra-additive effect of cilostazol and GB when administered together. CONCLUSIONS: Significant attenuation of cytoarchitectural damage and apoptotic cell death was found with GB and cilostazol, but a markedly enhanced effect was seen for treatment with their combination in the WM of rat brains after bilateral occlusion of the common carotid arteries. We suggest that combination therapy with GB and cilostazol provides enhanced neuroprotective effects and induces subsequent cognitive improvement in patients with chronic ischemic conditions.

Anorectal Manometric Dysfunctions in Newly Diagnosed, Early-Stage Parkinson's Disease

BACKGROUND AND PURPOSE: Anorectal dysmotility is common in advanced Parkinson's disease (PD), but there have been few evaluations in newly diagnosed PD patients. METHODS: We conducted anorectal manometric evaluations in 19 newly diagnosed, drug-naive, early-stage PD patients. All of the PD patients were questioned regarding the presence of anorectal symptoms. RESULTS: Anorectal manometry was abnormal in 12 of the 19 patients. These abnormalities were more common in patients with more severe anorectal symptoms, as measured using a self-reported scale. However, more than 40% of patients with no or minimal symptoms also exhibited manometric abnormalities. CONCLUSIONS: These results suggest that anorectal dysmotility manifests in many early-stage PD patients, which this represent evidence for the involvement of neuronal structures in such nonmotor manifestations in PD.

Effects of Aromatherapy on Depression, Anxiety and the Autonomic Nervous System in Breast Cancer Patients Undergoing Adjuvant Radiotherapy / 한국호스피스완화의료학회지

PURPOSE: The study was designed to verify effects of aromatherapy on depression, anxiety and the autonomic nervous system in breast cancer patients who are undergoing adjuvant radiotherapy. METHODS: Data were collected from November 2006 through March 2007 at the C university hospital in Seoul. The study included 33 patients and they were assigned to three groups. Group I had aroma oil inhalation for 2 minutes per time, three times a day for six weeks whereas Group II and a control group inhaled aroma oil for 2 minutes per time, once a day for six weeks. For Groups I and II, a mixture of lemon, lavender, rosewood and rose essential oils were used while control group inhaled tea tree oil. RESULTS: Depression was significantly decreased in patients in the experimental groups only. In Groups I and II patients, anxiety level was lower than that in control patients. Patients in Groups I and II also showed stronger physical resistance to stress than control group patients. CONCLUSION: Aromatherapy should be considered as a method that can significantly decrease depression in breast cancer patients who are undergoing adjuvant radiotherapy.

A Study on Management and Report of Adverse Event in Clinical Trials

BACKGROUND: This research is to identify the difficulties occuring in the course of managing the adverse events and the adverse event related standard operating procedure in the regulation of each institutional review board. METHODS: In order to identify the issues of the management of adverse events of each institution, this research surveyed the IRB administrators in fifty two university hospitals nation-wide. This survey is conducted among one chairman and one IRB member from the IRB members per each IRB who have experience in reviewing adverse events. The survey also includes investigators and sponsors who engage in reporting adverse events. RESULTS: The result of this survey demonstrates that the objects and the terms of adverse event reports provided by the Standard Operating Procedure and the KGCP of each institution are not very different from each other. However, according to the survey, any cases reported to the IRBs, although they are not specified as the object of reports in the institution, have been reviewed by the IRB members. To sum up the results of the survey, the major issues include ambiguous regulations on adverse event reports and reviews, the use of different report formats for each institution, and the difficulty with evaluating the causal relationship with Investigational Product. CONCLUSION: It is necessary to develop concrete and specified guidelines on the objects and the terms of reports, the standard for the causal relationship and the adequate measures for adverse events after review and to standardize the format of adverse event reporting.

The Study of Education and Qualification for the Maintenance of Clinical Research Associate (CRA) Professionalism

BACKGROUND: The aim of the current study is to investigate perspectives on the quality and validity of the current clinical research associate (CRA) education program. The trainee program of other healthcare professions including medical doctors, registered nurses, and pharmacists, has been already reviewed as an advance research. Thus, the current study evaluates the CRA education system to assist in building a more suitable CRA education infrastructure in the future. METHODS: A questionnaire was handed out to CRAs with at least 3 months working experience among 30 pharmaceutical corporations, and 10 Contract Research Organizations (CROs) affiliated with the Korean Pharmaceutical Association and the Korean Clinical Research Committee. A total of 118 questionnaires were utilized for data analysis. RESULTS: The poll shows that 93.2 % of the survey participants consider the role of a CRA as a specialized healthcare profession and 58.6 % of those respondents reason that becoming a CRA requires specialized knowledge. 95.9 % of survey participants attend a CRA trainee program for the maintenance of CRA professionalism. The respondents are inclined to attend the Government hosted CRA education program. 59.3 % of survey participants answered that implementing a CRA qualification system is necessary to establish a CRA specialty validation. CONCLUSION: The current study demonstrates the importance of qualification and what is necessary for being a CRA. The study result will provide a guideline for those who wish to become a CRA as part of their career. In addition, the result will also be used in developing an improved CRA education program in the future.

Institutional Review Board (IRB) Mutual Recognition Program and Its Feasibility in Korea

BACKGROUND: The use of Cooperative Institutional Review Board (Co-IRB) has become subject to continuous discussion. As a result, leading mainly by the Korea Association of Institutional Review Boards (KAIRB), "IRB mutual recognition program (MR-IRB)" was proposed. However operational methods of the program are still controversial. The object of this research is to examine domestically feasible scope and operation methods of MR-IRB by conducting survey. METHODS: 71 survey data was collected from chairman or specialist of each IRB and 29 IRB members of one institution running Central IRB was included. RESULTS: 76.5 % of respondents selected phase 3 multi-national, multi-center clinical Sponsor Initiated Trial as a suitable subject of MR-IRB, but only 50 % supported Investigator initiated trials, and answered early-stage clinical trials such as phase 1 clinical trials or biological agent trials are unsuitable due to relatively insufficient knowledge on risk level. In order to operate MR-IRB, standardized review criteria and agreement of institutions in building mutual trust is essential. Also it was learned from the survey that the most desirable way to adopt MR-IRB is to be initiated by the representing organization such as KAIRB based on mutual trust from institutional agreement. CONCLUSION: MR-IRB was recognized as one of Co-IRB. A suitable subjects of MR-IRB were preferred the phase 3 multi-national, multi-center clinical sponsor initiated trials to all kinds of clinical trials. This study suggests that based on real operation experience from MR-IRB pilot study, further study should be conducted to analyze pros and cons of MR-IRB and identify domestically eligible model to facilitate MR-IRB.

Crossed Cerebellar Diaschisis in Complex Partial Status Epilepticus

Crossed cerebellar diaschisis has been described mostly in hemispheric stroke and supratentorial tumors with positron-emission tomography (PET) and single photon emission computed tomography (SPECT). Rarely it has been described with brain diffusion-weighted MRI of status epilepticus. We report a patient with status epilepticus, who developed MRI abnormalities in the cerebral cortex and contralateral cerebellum. EEG abnormalities correlated anatomically with the cerebral cortex of image change. An aggressive medication resulted in seizure control, reversal of neurologic deficit, and improvement or resolution of the MRI and EEG abnormalities in 3 weeks. We concluded that both localization and resolution of lesions may be explained by reversible excitotoxic cell damage due to seizure-related excessive synaptic activity.

Crossed Cerebellar Diaschisis in Complex Partial Status Epilepticus / 대한간질학회지

Crossed cerebellar diaschisis has been described mostly in hemispheric stroke and supratentorial tumors with positron-emission tomography (PET) and single photon emission computed tomography (SPECT). Rarely it has been described with brain diffusion-weighted MRI of status epilepticus. We report a patient with status epilepticus, who developed MRI abnormalities in the cerebral cortex and contralateral cerebellum. EEG abnormalities correlated anatomically with the cerebral cortex of image change. An aggressive medication resulted in seizure control, reversal of neurologic deficit, and improvement or resolution of the MRI and EEG abnormalities in 3 weeks. We concluded that both localization and resolution of lesions may be explained by reversible excitotoxic cell damage due to seizure-related excessive synaptic activity.

Citicoline Protects Against Cognitive Impairment in a Rat Model of Chronic Cerebral Hypoperfusion

BACKGROUND AND PURPOSE: Cerebral white matter (WM) lesions are frequently observed in human cerebrovascular diseases, and are believed to be responsible for cognitive impairment. Various neuroprotective agents can suppress this type of WM or neuronal damage. In this study, we investigated whether citicoline, a drug used to treat acute ischemic stroke, can attenuate WM lesions and cognitive decline caused by chronic hypoperfusion in the rat. METHODS: Animals were divided into immediate- and delayed-treatment groups. Those in the immediate-treatment group received a sham operation, citicoline (500 mg/kg/day), or phosphate buffered saline (PBS) treatment. Citicoline or PBS was administered intraperitoneally for 21 days after occluding the bilateral common carotid arteries. Rats in the delayed-treatment group were intraperitoneally administered with either 500 mg/kg/day citicoline or PBS for 21 days beginning on the 8th day after the operation. From the 17th day of administration, the rats were placed in an eight-arm radial maze to examine their cognitive abilities. After completing the administration, tissues were isolated for Kluver-Barrera and the terminal deoxynucleotidyl transferase biotin-dUTP nick end labelling (TUNEL) staining. RESULTS: In the immediate-treatment group, cognitive functions were preserved in the citicoline-treated group, and WM damage and TUNEL-positive cells differed significantly between the citicoline- and PBS-treated animals. In the delayed-treatment group, there was no decrease in WM damage and TUNEL-positive cells, but cognitive improvement was evident for citicoline treatment relative to PBS treatment. CONCLUSIONS: These results show that citicoline can prevent WM damage and aid cognitive improvement, even after a certain extent of disease progression. Citicoline might be useful in patients with acute ischemic stroke as well as in chronic stroke accompanied with cognitive impairment.

Cognitive Impairment in Essential Tremor without Dementia

BACKGROUND AND PURPOSE: Several clinical studies have demonstrated that patients with essential tremor (ET) may have cognitive deficits; however, there are no published data regarding detailed neuropsychological assessments of ET without dementia. We therefore conducted a case-control study of cognitive function in patients with ET. METHODS: The cohort for this study comprised 34 consecutive patients with ET without dementia and 33 age-matched controls, all of who completed a dementia-screening questionnaire and underwent a detailed neuropsychological investigation. RESULTS: Severe impairments were observed in most domains for the ET group compared to the controls, including attention, part of language function, verbal memory, and frontal executive functions. CONCLUSIONS: Our results support the finding that the subclinical cognitive deficits characterized by attention, verbal memory impairments, and executive dysfunction are a clinical feature of ET. In addition, our results also support the finding that age at examination and educational status are the most important risk factors associated with cognitive deficits in patients with ET.

ERRATUM: Citicoline Protects Against Cognitive Impairment in a Rat Model of Chronic Cerebral Hypoperfusion

The publisher wishes to apologise for incorrectly displaying the second author's academic degree. We correct the second author's academic degree from MS to AD.

Differential Expression of Activating Transcription Factor-2 and c-Jun in the Immature and Adult Rat Hippocampus Following Lithium-Pilocarpine Induced Status Epilepticus

PURPOSE: Lithium-pilocarpine induced status epilepticus (LPSE) causes selective and age-dependent neuronal death, although the mechanism of maturation-related injury has not yet been clarified. The activating transcription factor-2 (ATF-2) protein is essential for the normal development of mammalian brain and is activated by c-Jun N-terminal kinase (JNK). It induces the expression of the c-jun gene and modulates the function of the c-Jun protein, a mediator of neuronal death and survival. Therefore, we investigated the expression of c-Jun and ATF-2 protein in the immature and adult rat hippocampus to understand their roles in LPSE-induced neuronal death. MATERIALS AND METHODS: Lithium chloride was administrated to P10 and adult rats followed by pilocarpine. Neuronal injury was assessed by silver and cresyl violet staining, performed 72 hours after status epilepticus. For evaluation of the expression of ATF-2 and c-Jun by immunohistochemical method and Western blot, animals were sacrificed at 0, 4, 24, and 72 hours after the initiation of seizure. RESULTS: Neuronal injury and expression of c-Jun were maturation-dependently increased by LPSE, whereas ATF-2 immunoreactivity decreased in the mature brain. Since both c-Jun and ATF-2 are activated by JNK, and targets and competitors in the same signal transduction cascade, we could speculate that ATF-2 may compete with c-Jun for JNK phosphorylation. CONCLUSION: The results suggested a neuroprotective role of ATF-2 in this maturation-related evolution of neuronal cell death from status epilepticus.

Toxoplasmosis Showing Atypical Brain Lesion in an Immunocompetent Patient With Complex Partial Seizure

Toxoplasma gondii is a protozoan parasite that typically manifests as multiple brain lesions of varying sizes. Toxoplasmosis usually causes neurological complications in immunocompromised patients while it is mostly asymptomatic in healthy subjects. A 19-year-old Peruvian woman presented with seizure, and MRI of the brain disclosed a nodular lesion in the left parietal lobe. This case of toxoplasmosis in an immunocompetent patient required extensive differential diagnoses and treatments.

Life-Threatening Anaphylactoid Reaction in an Acute Ischemic Stroke Patient With Intravenous rt-PA Thrombolysis, Followed by Successful Intra-Arterial Thrombolysis

An anaphylactoid reaction to recombinant tissue plasminogen activator (rt-PA) is an uncommon but fatal complication. A 39-year-old man was admitted within 1 hour of the onset of a right hemispheric stroke. He was not taking any specific medication, including angiotensin-converting enzyme (ACE) inhibitors. A systemic anaphylactoid reaction developed immediately after rt-PA infusion. However, the symptoms were improved after treatment with a steroid and antihistamine. Subsequent intra-arterial thrombolytic therapy resulted in complete recanalization and clinical improvement. To our knowledge, this is the first report of a life-threatening anaphylactoid reaction after rt-PA treatment followed by successful intra-arterial thrombolytic therapy in a patient who had not taken an ACE inhibitor.

Treatment of Lithium-Pilocarpine Induced Status Epilepticus Rat Models According to EEG Stage

BACKGROUND: EEG shows a sequence of progressive changes in status epilepticus (SE). Timely antiepileptic drug treatment is an important factor for the prognosis of SE. Here we investigated the effect of treatment according to EEG staging in a lithium-pilocarpine SE rat model. METHODS: By analyzing the on-going EEG of SE, we injected propofol (PF) or propofol and valproate (PF+VA) on each defined EEG stage [early period, merging stage; middle period, continuous stage; late period, early periodic epileptiform discharges stage (ePED)]. We measured the duration of each stage after the treatment and the number of principal cells at three hippocampal areas (CA1, CA3, dentate gyrus] after SE. RESULTS: Both PF- and PF+VA-treated groups showed lower mortality rate in the merging stage-treated subgroup than in ePED-treated subgroup. Seizure duration was significantly shortened in the merging stage of both PF- (p<0.005) and PF+VA-treated groups than in untreated group (p<0.002). The durations of the continuous stage and ePED were shortened in the merging stage-treated subgroup, but ePED duration did not decrease in ePED-treated subgroup. The shortening of the continuous stage and ePED was more prominent in the PF+VA-treated group than in PF-treated group. Neuronal loss in both PF- and PF+VA-treated groups was so severe that CA1 and CA3 neuronal loss was decreased more markedly in the ePED-treated group than in the merging stage-treated group (p<0.01). CONCLUSIONS: Early therapy based on the defined EEG staging might be an effective option for shortening duration of SE and decreasing neuronal damage at the hippocampus. Early combination therapy adopting PF+VA requires further investigation for new treatment option.

Japanese-B Virus Encephalitis With Biphasic Illness Pattern

Japanese-B virus encephalitis (JE), the most common human endemic and epidemic encephalitis, usually has a uniphasic illness with a variable outcome. A 49-year-old woman with cognitive dysfunction from JE had improved over 3 weeks. Brain MRI revealed multiple lesions in the bilateral thalamus, caudate nuclei and medial temporal lobe. Two weeks after discharge, the patient showed re-aggravation of the cognitive dysfunction and lapsed into coma. We report a patient with JE having showed biphasic illness pattern.

Pure Limb Ataxia as Isolated Manifestation in Lateral Medullary Infarction

Pure limb ataxia without other common symptoms of Wallenberg syndrome has rarely been reported as manifestation of lateral medullary infarction. We describe a patient with lateral medullary infarction who presented with almost isolated right limb(mainly lower limb) ataxia without usual symptoms such as hemibody sensory changes, dysphagia, hoarseness, hiccup, and Horner sign. The brain magnetic resonance image showed small ischemic lesion involving the dorsolateral portion of the medulla oblongata.

The Pattern of Cognitive Impairment Associated with the Motor Subtype in Parkinson's Disease

BACKGROUND: Previous studies have found over-representation of a postural instability and gait difficulty(PIGD) motor subtype in Parkinsons disease with dementia(PD-D). METHODS: One hundred twenty patients with Parkinson's disease(PD) were included in this study. All patients were evaluated by the Unified Parkinson's Disease Rating Scale(UPDRS) and neuropsychological tests. On the basis of the criteria for dementia(DSM-IV) and the results of the neuropsychological assessments, the patients were divided into the following three groups: (1) non-demented(PD-ND), (2) mild cognitive impairment(PD-MCI), and (3) dementia (PD-D). In addition, patients were also grouped into the following two phenotypes based on the UPDRS components: (1) tremor and (2) postural instability gait difficulty(PIGD)-predominant. We also analyzed the clinical characteristics and subtypes of the disease. In addition, the relationship between the cognitive impairments and the parkinsonian motor handicaps was evaluated. RESULTS: There was a significant relationship between cognitive impairment and the motor subtypes. The PIGD group had a higher prevalence of PD-D than the other group. In addition, there were significant correlations between the general cognitive functions and motor handicaps, especially those with axial symptoms. Multiple logistic regression analysis showed that the motor subtype was independently associated with the cognitive decline in PD. CONCLUSION: These findings support that cognitive decline in patients with PD is associated with a specific motor subtype. This association might be explained by the involvement of non-dopaminergic pathways. These results have implications for the clinical management of PD with regard to the motor symptoms and cognition.

Pisa Syndrome in Parkinson's Disease With a Good Response to Dopamine Therapy

No abstract available.