Beneficial effects of EGb761 and vitamin E on haloperidol-induced vacuous chewing movements in rats: Possible involvement of S100B mechanisms.

Tardive dyskinesia (TD) is a serious side effect induced by the long-term administration of typical antipsychotics. The pathophysiology of TD remains unclear, but experimental evidence suggests that neurodegeneration caused by free radicals may play an important role in TD development. S100B is considered a potential biomarker of structural neural and glial damage. This study investigated S100B expression in TD-related brain regions and assessed the effect of antioxidants Gingko biloba leaf extract (EGb761) and vitamin E (VE) on S100B in TD rats. A total of 32 rats were randomly divided into 4 study groups: saline control (saline), haloperidol alone group (Hal), EGb761-haloperidol (EGb-Hal), and vitamin E-haloperidol (VE-Hal). Rats were treated with haloperidol intraperitoneal injections (2mg/kg/day) each day for 5 weeks. EGb761 (50mg/kg/day) and VE (20mg/kg/day) were then administered during a 5-week withdrawal period. We performed behavioral assessments and immunohistochemically analyzed S100B expression in four TD-related brain regions. Our findings demonstrated that haloperidol administration led to a progressive increase in VCMs and in S100B expression in all four brain regions. Both EGb761 and VE reversed these changes, and there were no group differences between the EGb761 and VE groups. Our results indicated that long-term administration of haloperidol may induce VCMs and increase S100B expression in TD-related brain regions, and S100B may be a significant biomarker related to TD pathophysiology. Moreover, the antioxidant capacity of EGb761 and VE coupled with the possible neuroprotective effects of S100B may account for their success in improving the symptoms of haloperidol-induced TD.

Effects of dendritic cell-activated and cytokine-induced killer cell therapy on 22 children with acute myeloid leukemia after chemotherapy.

The efficiency of dendritic cell-activated and cytokine-induced killer cell (DC-CIK) therapy on children with acute myeloid leukemia (AML) after chemotherapy was investigated. Mononuclear cells were collected from children achieving complete remission after chemotherapy, cultured in vitro and transfused back into the same patient. Interleukin-2 (IL-2) was injected subcutaneously every other day 10 times at the dose of 1 × 10(6) units. Peripheral blood lymphocyte subsets and minimal residual disease (MRD) were detected by flow cytometry. Function of bone marrow was monitored by methods of morphology, immunology, cytogenetics and molecular biology. The side effects were also observed during the treatment. The average follow-up period for all the 22 patients was 71 months and relapse occurred in two AML patients (9.1%). The percentage of CD3(+)/CD8(+) cells in peripheral blood of 15 patients at the 3rd month after DC-CIK treatment (36.73% ± 12.51%) was dramatically higher than that before treatment (29.20% ± 8.34%, P < 0.05). The MRD rate was >0.1% in 5 patients before the treatment, and became lower than 0.1% 3 months after the treatment. During the transfusion of DC-CIK, side effects including fever, chills and hives appeared in 7 out of 22 (31.82%) cases but disappeared quickly after symptomatic treatments. There were no changes in electrocardiography and liver-renal functions after the treatment. MRD in children with AML can be eliminated by DC-CIK therapy which is safe and has fewer side effects.

The effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) on negative symptoms of schizophrenia and the follow-up study.

In this double-blind, randomized controlled study, we assessed the therapeutic effects of high-frequency left dorsolateral prefrontal cortex (DLPFC) repetitive transcranial magnetic stimulation (rTMS) on negative symptoms of schizophrenia. For the study, 117 patients with prominent negative symptoms were randomized to a 20-day course of either active rTMS applied to the left DLPFC (n = 78) or sham rTMS (n = 39). The primary outcome measures were the Positive and Negative Symptom Scale (PANSS) and the Scale for the Assessment of Negative Symptoms (SANS). Secondary outcomes included the Clinical Global Impressions Scale (CGI) and the Udvalg for Kliniske Under sogelser (UKU) Side Effect Rating Scale. We found that treatment with high-frequency rTMS for 6 weeks significantly improved negative symptoms in the active group as compared to the sham group. However, active rTMS was not correlated with significant improvement in the CGI severity of illness scale (CGI-S). The improvement of negative symptoms persisted to the 24-week follow-up assessment. These results indicate that there is a lasting beneficial effect of rTMS on negative symptoms in absence of decrease in CGI scores. We conclude that rTMS may serve as a relatively noninvasive treatment that alleviates negative symptoms in patients with schizophrenia.

Extract of Ginkgo biloba is equivalent to vitamin E in attenuating and preventing vacuous chewing movements in a rat model of tardive dyskinesia.

Free radical-mediated abnormalities may contribute toward the pathogenesis of tardive dyskinesia (TD). Many studies have reported the protective antioxidant and free radical-scavenging activities of extract of Ginkgo biloba (EGb761) against free radical-induced cell damage and dysfunction. This study aimed to compare the efficacy of EGb761 with that of vitamin E for the prevention and treatment of TD in a rat model. We carried out two studies. First, rats were injected with haloperidol (2 mg/kg intraperitoneally) daily for 5 weeks. EGb761 (50 mg/kg/day) or vitamin E (20 mg/kg/day) were then administered for another 5 weeks, and their effects on vacuous chewing movements (VCMs) were compared. Second, we compared 10 weeks of haloperidol alone with 10 weeks of haloperidol plus EGb761 or vitamin E. The administration of haloperidol led to a progressive increase in VCMs, which peaked at week 5. In study one, EGb761 and vitamin E, administered by an oral gavage for 5 weeks during withdrawal from chronic haloperidol treatment, decreased VCMs significantly, showing 83.8 and 91.0% reduction, respectively, compared with the haloperidol-alone group. In study two, the concomitant administration of EGb761 and vitamin E led to significantly fewer VCMs, by 64.4 and 73.9%, respectively, compared with the haloperidol-alone group. There was no significant difference in either study between EGb761 and vitamin E treatment. EGb761 shows promise for the prevention and treatment of TD in a rat model with a magnitude that was similar to that of vitamin E.

Impaired prepulse inhibition of acoustic startle in Chinese patients with first-episode, medication-naïve schizophrenia.

BACKGROUND: Patients with schizophrenia have prominent abnormality in information processing that can be observed by measures of prepulse inhibition (PPI) of acoustic startle reflex and PPI deficits have been considered as a candidate endophenotypic marker of schizophrenia. However, there has been little information on PPI and related measures in Chinese patients with schizophrenia. The research was to explore the deficits of acoustic startle reflex that might exist in Chinese patients with schizophrenia. METHODS: Startle response to acoustic stimuli, habituation, and PPI were examined in 31 Chinese patients with first-episode, medication-naïve schizophrenia and 30 age- and sex-matched healthy Chinese controls. At the same day of startle testing, psychopathological symptoms of the patients were assessed with the Positive and Negative Syndrome Scale (PANSS). RESULTS: Compared with healthy controls, patients exhibited the significant reduction in startle response and PPI deficits at 60 milliseconds (ms) intervals (PPI60, P < 0.05) but not at 30 or 120 ms intervals. Furthermore, there was a relatively strong correlation between PPI60 (P < 0.05) and scores of positive scale of PANSS in patients with schizophrenia. CONCLUSION: Our findings confirmed impaired PPI in Chinese patients with schizophrenia and suggested that a relationship between sensorimotor gating deficits and clinical symptoms of patients with schizophrenia might exist.

Ventral medial prefrontal functional connectivity and emotion regulation in chronic schizophrenia: a pilot study.

People with schizophrenia exhibit impaired social cognitive functions, particularly emotion regulation. Abnormal activations of the ventral medial prefrontal cortex (vMPFC) during emotional tasks have been demonstrated in schizophrenia, suggesting its important role in emotion processing in patients. We used the resting-state functional connectivity approach, setting a functionally relevant region, the vMPFC, as a seed region to examine the intrinsic functional interactions and communication between the vMPFC and other brain regions in schizophrenic patients. We found hypo-connectivity between the vMPFC and the medial frontal cortex, right middle temporal lobe (MTL), right hippocampus, parahippocampal cortex (PHC) and amygdala. Further, there was a decreased strength of the negative connectivity (or anticorrelation) between the vMPFC and the bilateral dorsal lateral prefrontal cortex (DLPFC) and pre-supplementary motor areas. Among these connectivity alterations, reduced vMPFC-DLPFC connectivity was positively correlated with positive symptoms on the Positive and Negative Syndrome Scale, while vMPFC-right MTL/PHC/amygdala functional connectivity was positively correlated with the performance of emotional regulation in patients. These findings imply that communication and coordination throughout the brain networks are disrupted in schizophrenia. The emotional correlates of vMPFC connectivity suggest a role of the hypo-connectivity between these regions in the neuropathology of abnormal social cognition in chronic schizophrenia.

Infusions of recipient-derived cytokine-induced killer cells of donor origin eradicated residual disease in a relapsed leukemia patient after allo-hematopoietic stem cell transplantation.

A female patient diagnosed with acute myelocytic leukemia M5a (AML-M5a) relapsed 986 days after her allogeneic peripheral blood stem cell transplantation (allo-PBSCT) from an unrelated male donor with matched human leukocyte antigen (HLA). Three re-induction chemotherapies were administered, and partial remission was achieved. The patient was given repetitive infusion of cytokine-induced killer (CIK) cells expanded from recipient peripheral mononuclear cells of full donor chimerism due to loss of contact of quondam donor for donor lymphocyte infusion (DLI) and rejection of second transplantation. The patient achieved complete cytogenetical remission. This strategy might overcome the obstacle of donor unavailability and present an appealing new therapeutic alternative to donor-recruited adoptive immunotherapy for relapsed disease at post-transplantation.

Brain-derived neurotrophic factor levels and its Val66Met gene polymorphism predict tardive dyskinesia treatment response to Ginkgo biloba.

BACKGROUND: Tardive dyskinesia (TD) has no well-accepted treatments or known pathophysiology, but low brain-derived neurotrophic factor (BDNF) may play an important role in its pathophysiology. Ginkgo biloba (EGb-761) is a potent antioxidant that has neuroprotective effects mediated through enhancing BDNF levels. We hypothesized that treatment with EGb-761 would increase serum BDNF levels and reduce TD, particularly among schizophrenia patients who have the BDNF valine 66 to methionine (Val66Met) genotype (Val/Val). METHODS: Serum BDNF levels and genotyping for the BDNF gene Val66Met polymorphism were assessed in Chinese schizophrenic patients with (n = 368) and without (n = 563) TD as well as healthy control subjects (n = 546). About half of the TD patients (n = 157) then participated in a double-blind, randomized, placebo-control 12-week treatment with 240 mg per day of EGb-761. Serum BDNF levels were measured again at posttreatment. Clinical efficacy was determined using the Abnormal Involuntary Movement Scale (AIMS). RESULTS: TD patients had lower BDNF levels than the non-TD patients and healthy controls. EGb-761 treatment improved symptoms of TD and increased BDNF levels compared with placebo treatment. Moreover, the improvement of AIMS total score correlated with the increase in BDNF levels. Furthermore, improvement in the AIMS score was greatest in those with the Val/Val allele and lowest with the Met/Met allele. CONCLUSIONS: The BDNF system may be implicated in the pathophysiology of TD and its improvement with antioxidant treatment. Furthermore, patients with the genetic potential for greater BDNF release (Val/Val at 66) may obtain a greater reduction in TD from EGb-761 treatment.

Effects of risperidone and haloperidol on superoxide dismutase and nitric oxide in schizophrenia.

Oxidative stress may be involved in the pathophysiology of schizophrenia. No double-blind study has compared the effects of typical and atypical antipsychotics on both antioxidant enzyme activity and nitric oxide (NO) levels in schizophrenic patients. Seventy-eight inpatients with chronic schizophrenia were randomly assigned to 12 weeks of treatment with 6 mg/day of risperidone or 20 mg/day of haloperidol using a double-blind design. Clinical efficacy was determined using the Positive and Negative Syndrome Scale. Blood superoxide dismutase (SOD) and plasma NO levels were measured in patients and 30 normal controls. Our results showed that following a 2-week washout period, levels of SOD and NO were significantly increased in patients with schizophrenia compared to normal controls. Both risperidone and haloperidol equivalently reduced the elevated blood SOD levels in schizophrenia, but neither medication reduced the elevated plasma NO levels in schizophrenia. Low blood SOD levels at baseline predicted greater symptom improvement during treatment, and greater change in SOD was correlated with greater symptom improvement. These results suggest that both typical and atypical antipsychotic drugs may at least partially normalize abnormal free radical metabolism in schizophrenia, and some free radical parameters at baseline may predict antipsychotic responses of schizophrenic patients.

[Comparisons of clinical features of chronic aplastic anemia and myelodysplastic syndrome in children].

OBJECTIVE: This study compared the differences in clinical features between chronic aplastic anemia (CAA) and myelodysplastic syndrome (MDS) in children in order to provide a basis for the differential diagnosis of the two diseases. METHODS: A retrospective study of 23 cases of CAA and 9 cases of MDS from September 2007 to September 2010 was performed. The clinical data including routine blood test results, reticulocyte counts, serum lactate dehydrogenase level, serum ferritin level, cytological examination of bone marrow, bone marrow CD34+ cell counts, bone marrow chromosome and FISH test results were compared between the CAA and MDS groups. RESULTS: Neutrophils, reticulocytes, and serum ferritin and lactate dehydrogenase levels increased in the MDS group compared with those in the CAA group. There were significant differences in bone marrow blast cell counts and dyshematopoiesis phenomena of three lines blood cells between the CAA and MDS groups. The bone marrow CD34+ cell counts and the rate of chromosomal abnormalities detected in bone marrow cytogenetic analysis in the MDS group were significantly higher than those in the CAA group. CONCLUSIONS: There are differences in the results of laboratory examinations and morphological and cytogenetic examinations of bone marrow between the children with CAA and MDS. The differences are useful to the differential diagnosis of the two diseases.

Dysfunction in different phases of working memory in schizophrenia: evidence from ERP recordings.

The present study combined a time-locked paradigm and high-time-resolution event-related potential (ERP) recordings to examine different phases of working memory, including early visual processing and late memory-related processes of encoding, maintenance, and retrieval, in 67 adults with schizophrenia and 46 healthy controls. Alterations in ERP components were correlated with task performance. Patients performed significantly worse in the working memory task than healthy subjects, although all subjects' accuracy exceeded 80%. During encoding, the N1 and P2 component amplitudes were lower while the P300 amplitude was higher in schizophrenic patients compared to healthy controls. There were no differences between groups with respect to the mean amplitudes of the negative slow waves in the early stage (the first 400 ms) of the maintenance phase. However, in the next 500-ms time window, the patients exhibited a more negative deflection in the middle fronto-central region than the control group. Likewise, a similar pattern was observed in the second 500-ms period in the middle fronto-central region, although the effect was marginally significant. There were no differences between groups in the remaining 1000 ms. During retrieval, the P1, N1 and P2 amplitudes were lower while the P300 amplitude and latency were higher in schizophrenic patients. The present results indicate early visual deficits in the working memory task in adults with schizophrenia. Impairments in the maintenance phase were confined to the late rehearsal stage. The increased P300 amplitude at the fronto-central electrode sites along with the poorer behavioral performance suggests that schizophrenic patients have an inefficient working memory system.

[Expression and clinical significance of COX-2 and BCL-2 in distal transitional mucosa adjacent to rectal carcinoma].

OBJECTIVE: To investigate the expression of COX-2 and BCL-2 in transitional mucosa adjacent to rectal carcinoma, and to determine whether precursor event exists in the transitional mucosa. METHODS: Mucin histochemical method (HID/AB) was used to determine the distal mucosa 2 cm away from rectal carcinoma in 54 patients with rectal cancer. Immunohistochemical method was employed to detect the expression of BCL-2 and COX-2 in the rectal cancer specimen, transitional mucosa (TM), non-transitional mucosa (NTM), and 20 cases of normal rectal mucosa. Student's t-test and Chi-square test were preformed. RESULTS: Nineteen patients with positive TM were found. COX-2 expression was identified in 81.5% of cancer tissue, 21.1% of TM, 17.1% of NTM, and 10.0% in normal mucosa. BCL-2 protein was found in 77.8% of cancer tissue, 21.1% of TM, 22.9% of NTM, and 5.0% of normal mucosa. The expressions of COX-2 and BCL-2 in TM were significantly different from tumor tissue[(0.737±0.895) versus (3.519±1.998), and (0.632±0.955) versus (2.833±1.756), all P<0.01]. However, there were no significant differences between TM and NTM or normal mucosa. CONCLUSIONS: Expressions of COX-2 and BCL-2 are non-specific in the transitional mucosa at the distal rectum. Evidence is not available in TM being precursor lesion.

Extract of Ginkgo biloba treatment for tardive dyskinesia in schizophrenia: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Free radicals may be involved in the pathogenesis of tardive dyskinesia (TD). Extract of Ginkgo biloba (EGb) is a potent antioxidant possessing free radical-scavenging activities. The aim of the study was to evaluate the efficacy of EGb-761, a standardized extract given in capsule form, in treating TD in schizophrenia patients. METHOD: Inpatients with DSM-IV-diagnosed schizophrenia and TD (n = 157) in a mainland China Veterans Affairs psychiatric hospital were randomly assigned to 12 weeks of treatment with either EGb-761, 240 mg/d (n = 78) or a placebo (n = 79) in a double-blind manner. Primary outcome measures were (1) change from baseline in the Abnormal Involuntary Movement Scale (AIMS) score and (2) proportion of patients with a ≥ 30% reduction in their AIMS total score at week 12. Secondary outcome measures included the Positive and Negative Syndrome Scale (PANSS) and cognitive performance as measured by the Continuous Performance Test-37 Version and the 3-card Stroop task. Patients were recruited for the study between December 2006 and May 2007. RESULTS: Of the 157 patients who were randomly assigned, 152 (96.8%) completed the study. EGb-761 treatment significantly decreased the AIMS total score in patients with TD compared to those who were given a placebo (2.13 ± 1.75 vs -0.10 ± 1.69; P < .0001), with 40 (51.3%) and 4 (5.1%) patients achieving response in the EGb-761 and placebo treatment groups, respectively. There were no between-group differences in the PANSS total score or cognitive measures from baseline to week 12. CONCLUSIONS: EGb-761 appears to be an effective treatment for reducing the symptoms of TD in schizophrenia patients, and improvement may be mediated through the well-known antioxidant activity of this extract. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00672373.

Superoxide dismutase and cytokines in chronic patients with schizophrenia: association with psychopathology and response to antipsychotics.

OBJECTIVE: Both schizophrenia and oxidative stress have been associated with immune system abnormalities in interleukin-2 and -6 (IL-2; IL-6) and increases in superoxide dismutase (SOD) activity. These abnormalities may improve during antipsychotic drug treatment that reduces symptoms in schizophrenic patients. MATERIALS AND METHODS: Subjects included 30 healthy controls (HC) and 78 schizophrenic (SCH) in-patients who were randomly assigned to 12 weeks of double-blind treatment with risperidone 6 mg/day or haloperidol 20 mg/day. Ratings using the Positive and Negative Syndrome Scale (PANSS) were correlated with blood SOD and serum IL-2 levels. RESULTS: SCH patients who were medication-free for 2 weeks had greater SOD, IL-2, and IL-6 levels than HC. At baseline, these SOD elevations were associated with higher PANSS total scores and the IL-2 elevations with lower PANSS positive symptom scores. The SOD and IL-2 levels in the SCH were also positively correlated. After treatment, PANSS positive symptoms and both SOD and IL-2 showed a significant decrease, but IL-6 showed no change. The SOD and IL-2 reductions were correlated with the reductions in PANSS total score, and SOD reductions also correlated with positive subscore reductions. Females showed these associations more strongly than males. CONCLUSION: Our results suggest that the dysregulation in the cytokine system and oxidative stress in patients with schizophrenia is implicated in clinical symptoms and is improved at least partially with antipsychotic treatment. The stronger associations in females deserve further study and confirmation.

[Therapeutic effects of a combination of high-dose immunoglobulin and cyclosporine A in children with aplastic anemia].

OBJECTIVE: To evaluate the therapeutic effects of a combined immunotherapy, high-dose immunoglobulin (HDIG) plus cyclosporine A (CsA) plus prednisone (P), in children with aplastic anemia (AA) and to explore the association of peripheral blood lymphocyte subsets, peripheral blood cells and marrow CD34+ cells with therapeutic effects in AA. METHODS: The clinical data of 46 children with AA and who received the combined immunotherapy of HDIG + CsA + P were retrospectively studied. RESULTS: Of the 46 children with AA, 31 (67.4%) were responded to the combined immunotherapy. The binary logistic regression analysis showed low absolute neutrophil count (B=4.703, p<0.05), low percentage of peripheral blood CD4+ cells (B=0.142, p<0.05) and low ratio of peripheral blood CD4+/CD8+ (B=2.945, p<0.05)were associated with poor therapeutic effects. The ratio of CD34+/karyocytes of bone marrow in children with AA was lower than that in normal individuals, but it was not significantly related to the therapeutic effect. CONCLUSIONS: The combined immunotherapy (HDIG+CsA+P) was effective in children with AA. The absolute neutrophilcount, the percentage of peripheral blood CD4+ and the ratio of peripheral blood CD4+/CD8+ were important prognostic factors in AA.

[The establishment of an animal model of gut-brain interaction in irritable bowel syndrome for the evaluation of visceral sensation, motility and psychological behavior.].

OBJECTIVE: To develop a gut-brain interaction animal model of IBS which combines multiple factors including behavior, visceral sensation and motility. METHODS: Setting up a multifactor interactional animal model (chronic acute combining stress model, CACS) based on a chronic unpredictable mild stress model of depression (CUMS) while combined with wrap restraint stress (WRS), changes of some indexes were recorded including motility (granules of defecating, time of defecating), visceral sensitivity (spontaneous contraction of abdominal striated muscles) and behavior/mind (sucrose consumption, body weight). G protein subunits were measured by Western blot in both hippocampus and prefrontal cortex simultaneously. RESULTS: (1) Compared with the state before stress given, defecating granules increased, defecating time of glassie from rectum shorten, number of abdominal contraction increased, and sucrose consumption decreased in CACS, however, neither significant change was found on defecating behavior in CUMS nor on sucrose consumption in WRS;(2) Compared with the control group, some G protein submits expression decreased in both CACS and CUMS (P < 0.05), while no significant changes of any G protein subunits were found in WRS. CONCLUSION: The CACS animal model was a new, brain-gut interaction model, which can mimic part of human symptoms of IBS very well.

Therapeutic effectiveness of the ALL-XH-99 protocol for childhood acute lymphoblastic leukemia.

OBJECTIVE: The ALL-XH-99 protocol for the treatment of childhood acute lymphoblastic leukemia (ALL) has been performed in the Union Hospital for 10 years. This study aimed to evaluate the therapeutic effectiveness of the protocol for childhood ALL and to investigate the prognostic factors for childhood ALL. METHODS: This is a retrospective study. The eligible patients were treated with the ALL-XH-99 protocol. However a minor modification based on the ALL-XH-99 protocol was performed in this study, i.e., the high-risk patients as the low- and moderate-risk patients were not administered with cranial irradiation. Event-free survival (EFS) was evaluated using the Kaplan-Meier method and the differences of the EFS among groups were compared with the log-rank test. Prognostic factors for childhood ALL were investigated by the stepwise Cox proportional hazard model. RESULTS: One hundred fifteen patients were eligible for the ALL-XH-99 protocol clinical study. The 115 patients consisted of 62 low-risk, 12 moderate-risk and 41 high-risk patients. The overall EFS at 5 years in the 115 patients was 69.0 +/- 5.0%. The 5-year-EFS in the low-risk, moderate-risk and high-risk patients was 82.0 +/- 6.0%, 77.0 +/- 15.0% and 43.0 +/- 11.0%, respectively (P <0.01). Relapse occurred in 16 patients (13.9%) in a median time of 17 months. Without administering cranial irradiation to all of the patients, the incidence of CNS leukemia relapse (2/115, 1.7%) was not higher than that previously reported. Multivariate analysis showed that the risk degree of leukemia, the presence of t (9; 22)/bcr/abl fusion gene and leukocyte count were independent adverse prognostic factors for ALL and their hazard ratio was 1.867, 3.397 and 2.236 respectively. CONCLUSIONS: The therapeutic effectiveness of the ALL-XH-99 protocol for childhood ALL is satisfactory, with an EFS rate comparable to that of the developed countries. t (9; 22)/bcr/abl is the most important adverse independent prognostic factor for childhood ALL. Cranial irradiation may be eliminated to reduce late adverse effects in all of ALL patients.