Shucui Jiang

Effects of 12 Weeks of Supported Treadmill Training on Functional Ability and Quality of Life in Progressive Multiple Sclerosis: A Pilot Study

OBJECTIVE To examine the effects of body-weight supported treadmill training (BWSTT) on functional ability and quality of life in patients with progressive multiple sclerosis (MS) of high disability. DESIGN Before-after trial. SETTING Exercise rehabilitation research center. PARTICIPANTS Patients with progressive MS (N=6; 5 primary progressive, 1 secondary progressive) with high disability (mean±SD expanded disability status scale, [EDSS]=6.9±1.07). All participants completed the trial. INTERVENTIONS Subjects completed 36 sessions of BWSTT (30-min sessions, 3×wk) over 12 weeks. MAIN OUTCOME MEASURES Outcome measures included functional ability assessed by EDSS and Multiple Sclerosis Functional Composite (MSFC). Quality of life and fatigue were assessed by the MS Quality of Life-54 (MSQoL-54) and the Modified Fatigue Impact Scale (MFIS), respectively. All tests were administered at baseline and after 12 weeks of training. RESULTS All participants progressively improved training intensity; treadmill walking speed increased (34%; P<.001), and percent body weight support was reduced (42%; P<.001). A significant improvement in both physical (P=.02) and mental (P=.01) subscales of the MSQoL-54 was found. Fatigue was nonsignificantly reduced by 31% (P=.22); however, a large effect size (ES) was noted (ES=-.93). Functional ability remained stable with nonsignificant improvements in MSFC (P=.35; ES=.23) and EDSS (P=.36; ES=-.08) scores. CONCLUSIONS Twelve weeks of BWSTT produces beneficial effects on quality of life and potentially reduces fatigue in patients with primary progressive MS of high disability level. Larger trials will be required to confirm these findings and to evaluate further the effects of BWSTT in progressive MS.

Neurotrophic effects of extracellular guanosine.

Central nervous system (CNS) astrocytes release guanosine extracellularly, that exerts trophic effects. In CNS, extracellular guanosine (GUO) stimulates mitosis, synthesis of trophic factors, and cell differentiation, including neuritogenesis, is neuroprotective, and reduces apoptosis due to several stimuli. Specific receptor-like binding sites for eGUO in the nervous system may mediate its effects through both MAP kinase and PI3-kinase signalling pathways. Extracellular guanine (eGUA) also exerts several effects; the trophic effects of eGUO are likely regulated by conversion of eGUO to eGUA by a membrane located purine nucleoside phosphorylase (ecto-PNP) and by conversion of eGUA to xanthine by guanine deaminase.

Rehabilitation in primary and metastatic brain tumours: impact of functional outcomes on survival.

Patientswith brain tumours have majordisabilities and guarded prognosisbut may benefit from inpatient rehabilitation.The objectives were tocompare functional outcomes inpatients with glioblastoma multiforme(GBM), brain metastasesand other brain tumours, and todetermine predictors of survival. Demographic, clinical,functional, and survival data werecollected for 63 patients.Kaplan-Meier and Cox regression wereused for survival analyses. Functional Independence Measure(FIM™) scores improved fromadmission to discharge for patientswith GBM, brain metastases andother tumours. Estimated mediansurvival was 141 days for brainmetastases, 214 days for GBM and439 days for other tumours. Lowadmission dexamethasone doseand high FIM™ gain predictedbetter survival in GBM. For brainmetastases, high FIM™ gain, lowdexamethasone dose and no organmetastases were positive prognosticfactors. Patientswith primary and metastatic braintumours achieved functional gainsafter rehabilitation. High functionalimprovement is a significantpredictor of longer survival inbrain metastases and GBM. Thisstudy has implications for rehabilitationin the post-acute managementof patients who have disabilitiesdue to brain tumours.ObjectivesPatientswith brain tumours have majordisabilities and guarded prognosisbut may benefit from inpatient rehabilitation.The objectives were tocompare functional outcomes inpatients with glioblastoma multiforme(GBM), brain metastasesand other brain tumours, and todetermine predictors of survival.MethodsDemographic, clinical,functional, and survival data werecollected for 63 patients.Kaplan-Meier and Cox regression wereused for survival analyses.ResultsFunctional Independence Measure(FIM™) scores improved fromadmission to discharge for patientswith GBM, brain metastases andother tumours. Estimated mediansurvival was 141 days for brainmetastases, 214 days for GBM and439 days for other tumours. Lowadmission dexamethasone doseand high FIM™ gain predictedbetter survival in GBM. For brainmetastases, high FIM™ gain, lowdexamethasone dose and no organmetastases were positive prognosticfactors.ConclusionsPatientswith primary and metastatic braintumours achieved functional gainsafter rehabilitation. High functionalimprovement is a significantpredictor of longer survival inbrain metastases and GBM. Thisstudy has implications for rehabilitationin the post-acute managementof patients who have disabilitiesdue to brain tumours.

Prognostic indicators in metastatic spinal cord compression: using functional independence measure and Tokuhashi scale to optimize rehabilitation planning

Study design:Retrospective, descriptive study.Objective:To determine if patients with metastatic spinal cord compression (MSCC) make significant functional gains through rehabilitation. To study survival and predictors of survival in MSCC. To explore predictive factors for high or low functional gains in MSCC.Setting:Inpatient neuro-oncology rehabilitation ward, Henderson General Hospital, Hamilton, Canada.Methods:Clinical records were examined for 63 inpatients with MSCC. Demographics, treatment of MSCC, length of rehabilitation, admission, and discharge Functional Independence Measure (FIM) scores, Tokuhashi score and survival data were collected. Statistical analyses included nonparametric comparisons, Kaplan–Meier analyses, Cox regression, and exploratory logistic regression.Results:FIM score improved from 83 to 102 (P<0.0001). Estimated median survival from time of rehabilitation was 10.0 months. Kaplan–Meier analysis showed longer survival in patients with high Tokuhashi scores (9–15) compared to low scores (0–8) (P<0.005); and high FIM change (>13) compared to low FIM change (⩽13) (P<0.02). Cox regression revealed that high FIM gain and high Tokuhashi score were prognostic factors. Logistic regression showed Tokuhashi score (odds ratio (OR)=1.30, 95% confidence interval (CI)=1.04–1.62) and length of rehabilitation (OR=1.04, 95% confidence interval (CI)=1.01–1.07) were associated with high FIM gain.Conclusions:Rehabilitation improves functional outcomes in MSCC. Patients who had a high Tokuhashi score and achieved high functional gains after rehabilitation had longer survival. Tokuhashi score and length of rehabilitation were associated with high FIM gain. The Tokuhashi score can help identify patients with good prognosis and potential for improvement during rehabilitation.

Mechanisms and effects of curcumin on spatial learning and memory improvement in APPswe/PS1dE9 mice

Evidence suggests that curcumin, the phytochemical agent in the spice turmeric, might be a potential therapy for Alzheimers disease (AD). Its antioxidant, anti‐inflammatory properties have been investigated extensively. Studies have also shown that curcumin can reduce amyloid pathology in AD. The underlying mechanism, however, is complex and is still being explored. In this study, we used the APPswe/PS1dE9 double transgenic mice, an AD model, to investigate the effects and mechanisms of curcumin in the prevention and treatment of AD. The water maze test indicated that curcumin can improve spatial learning and memory ability in mice. Immunohistochemical staining and Western blot analysis were used to test major proteins in β‐amyloid aggregation, β‐amyloid production, and β‐amyloid clearance. Data showed that, 3 months after administration, curcumin treatment reduced Aβ40, Aβ42, and aggregation of Aβ‐derived diffusible ligands in the mouse hippocampal CA1 area; reduced the expression of the γ‐secretase component presenilin‐2; and increased the expression of β‐amyloid‐degrading enzymes, including insulin‐degrading enzymes and neprilysin. This evidence suggests that curcumin, as a potential AD therapeutic method, can reduce β‐amyloid pathological aggregation, possibly through mechanisms that prevent its production by inhibiting presenilin‐2 and/or by accelerating its clearance by increasing degrading enzymes such as insulin‐degrading enzyme and neprilysin.

Neuroprotective effects of guanosine on stroke models in vitro and in vivo

Deprivation of oxygen and glucose for 5h induces apoptosis in SH-SY5Y neuroblastoma cell cultures. After combined glucose and oxygen deprivation (CGOD) addition of guanosine (100 microM), a non-adenine-based purine nucleoside, significantly reduced the proportion of cells undergoing apoptosis. To determine whether guanosine was also neuroprotective in vivo, we undertook middle cerebral artery occlusion (MCAo) on male Wistar rats and administered guanosine (8mg/kg), intraperitoneally, or saline (vehicle control) daily for 7 days. Guanosine prolonged rat survival and decreased both neurological deficits and tissue damage resulting from MCAo. These data are the first to demonstrate that guanosine protects neurons from the effects of CGOD even when administered 5h after the stimulus, and is neuroprotective in experimental stroke in rats.

Altered distribution and function of A2A adenosine receptors in the brain of WAG/Rij rats with genetic absence epilepsy, before and after appearance of the disease

The involvement of excitatory adenosine A2A receptors (A2ARs), which probably contribute to the pathophysiology of convulsive seizures, has never been investigated in absence epilepsy. Here, we examined the distribution and function of A2ARs in the brain of Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats, a model of human absence epilepsy in which disease onset occurs 2–3 months after birth. In the cerebral areas that are mostly involved in the generation of absence seizures (somatosensory cortex, reticular and ventrobasal thalamic nuclei), A2AR density was lower in presymptomatic WAG/Rij rats than in control rats, as evaluated by immunohistochemistry and western blotting. Accordingly, in cortical/thalamic slices prepared from the brain of these rats, A2AR stimulation with the agonist 2‐[4‐(‐2‐carboxyethyl)‐phenylamino]‐5′‐N‐ethylcarboxamido‐adenosine failed to modulate either cAMP formation, mitogen‐activated protein kinase system, or K+‐evoked glutamate release. In contrast, A2AR expression, signalling and function were significantly enhanced in brain slices from epileptic WAG/Rij rats as compared with matched control animals. Additionally, the in vivo injection of the A2AR agonist CGS21680, or the antagonist 5‐amino‐7‐(2‐phenylethyl)‐2‐(2‐fuyl)‐pyrazolo‐(4,3‐c)1,2,4‐triazolo(1,5‐c)‐pyrimidine, in the examined brain areas of epileptic rats, increased and decreased, respectively, the number/duration of recorded spontaneous spike–wave discharges in a dose‐dependent manner during a 1–5 h post‐treatment period. Our results support the hypothesis that alteration of excitatory A2AR is involved in the pathogenesis of absence seizures and might represent a new interesting target for the therapeutic management of this disease.

Activation of P2X(7) receptors stimulates the expression of P2Y(2) receptor mRNA in astrocytes cultured from rat brain.

Under pathological conditions brain cells release ATP at concentrations reported to activate P2X7 ionotropic receptor subtypes expressed in both neuronal and glial cells. In the present study we report that the most potent P2X7 receptor agonist BzATP stimulates the expression of the metabotropic ATP receptor P2Y2 in cultured rat brain astrocytes. In other cell types several kinds of stimulation, including stress or injury, induce P2Y2 expression that, in turn, is involved in different cell reactions. Similarly, it has recently been found that in astrocytes and astrocytoma cells P2Y2 sites can trigger neuroprotective pathways through the activation of several mechanisms, including the induction of genes for antiapoptotic factors, neurotrophins, growth factors and neuropeptides. Here we present evidence that P2Y2 mRNA expression in cultured astrocytes peaks 6 h after BzATP exposure and returns to basal levels after 24 h. This effect was mimicked by high ATP concentrations (1 mM) and was abolished by P2X7-antagonists oATP and BBG. The BzATP-evoked P2Y2 receptor up-regulation in cultured astrocytes was coupled to an increased UTP-mediated intracellular calcium response. This effect was inhibited by oATP and BBG and by P2Y2siRNA, thus supporting evidence of increased P2Y2 activity. To further investigate the mechanisms by which P2X7 receptors mediated the P2Y2 mRNA up-regulation, the cells were pre-treated with the chelating agent EGTA, or with inhibitors of mitogen-activated kinase (MAPK) (PD98059) or protein kinase C, (GF109203X). Each inhibitor significantly reduced the extent to which BzATP induced P2Y2 mRNA. Both BzATP and ATP (1 mM) increased ERK1/2 activation. P2X7-induced ERK1/2 phosphorylation was unaffected by pre-treatment of astrocytes with EGTA whereas it was inhibited by GF109203X. Phorbol-12-myristate-13-acetate (PMA), an activator of PKCs, rapidly increased ERK1/2 activation. We conclude that activation of P2X7 receptors in astrocytes enhances P2Y2 mRNA expression by a mechanism involving both calcium influx and PKC/MAPK signalling pathways.

P2Y2 receptor up-regulation induced by guanosine or UTP in rat brain cultured astrocytes.

Among P2 metabotropic ATP receptors, P2Y2 subtype seems to be peculiar as its upregulation triggers important biological events in different cells types. In non-stimulated cells including astrocytes, P2Y2 receptors are usually expressed at levels lower than P2Y1 sites, however the promoter region of the P2Y2 receptors has not yet been studied and little is known about the mechanisms underlying the regulation of the expression of this ATP receptor. We showed that not only UTP and ATP are the most potent and naturally occurring agonist for P2Y2 sites, but also guanosine induced an up-regulation of astrocyte P2Y2 receptor mRNA evaluated by Northern blot analysis. We also focused our attention on this nucleoside since in our previous studies it was reported to be released by cultured astrocytes and to exert different neuroprotective effects. UTP and guanosine-evoked P2Y2 receptor up-regulation in rat brain cultured astrocytes was linked to an increased P2Y2-mediated intracellular calcium response, thus suggesting an increased P2Y2 activity. Actinomycin D, a RNA polymerase inhibitor, abrogated both UTP and guanosine-mediated P2Y2 up-regulation, thus indicating that de novo transcription was required. The effect of UTP and guanosine was also evaluated in astrocytes pretreated with different inhibitors of signal transduction pathways including ERK, PKC and PKA reported to be involved in the regulation of other cell surface receptor mRNAs. The results show that ERK1-2/MAPK pathway play a key role in the P2Y2 receptor up-regulation mediated by either UTP or guanosine. Moreover, our data suggest that PKA is also involved in guanosine-induced transcriptional activation of P2Y2 mRNA and that increased intracellular calcium levels and PKC activation may also mediate P2Y2 receptor up-regulation triggered by UTP. The extracellular release of ATP under physiological and pathological conditions has been widely studied. On the contrary, little is known about the release of pyrimidines and in particular of UTP. Here we show that astrocytes are able to release UTP, either at rest or during and following hypoxia/hypoglicemia obtained by submitting the cells to glucose-oxygen deprivation (OGD). Interestingly, also P2Y2 receptor mRNA increased by about two-fold the control values when the cultures were submitted to OGD. It has been recently reported that P2Y receptors can play a protective role in astrocytes, thus either guanosine administration or increased extracellular concentrations of guanosine and UTP reached locally following CNS injury may increase P2Y2-mediated biological events aimed at promoting a protective astrocyte response.

A review of the neuro- and systemic inflammatory responses in post concussion symptoms: Introduction of the "post-inflammatory brain syndrome" PIBS

Post-concussion syndrome is an aggregate of symptoms that commonly present together after head injury. These symptoms, depending on definition, include headaches, dizziness, neuropsychiatric symptoms, and cognitive impairment. However, these symptoms are common, occurring frequently in non-head injured controls, leading some to question the existence of post-concussion syndrome as a unique syndrome. Therefore, some have attempted to explain post-concussion symptoms as post-traumatic stress disorder, as they share many similar symptoms and post-traumatic stress disorder does not require head injury. This explanation falls short as patients with post-concussion syndrome do not necessarily experience many key symptoms of post-traumatic stress disorder. Therefore, other explanations must be sought to explain the prevalence of post-concussion like symptoms in non-head injury patients. Many of the situations in which post-concussion syndrome like symptoms may be experienced such as infection and post-surgery are associated with systemic inflammatory responses, and even neuroinflammation. Post-concussion syndrome itself has a significant neuroinflammatory component. In this review we examine the evidence of neuroinflammation in post-concussion syndrome and the potential role systemic inflammation plays in post-concussion syndrome like symptoms. We conclude that given the overlap between these conditions and the role of inflammation in their etiologies, a new term, post-inflammatory brain syndromes (PIBS), is necessary to describe the common outcomes of many different inflammatory insults. The concept of post-concussion syndrome is in its evolution therefore, the new term post-inflammatory brain syndromes provides a better understanding of etiology of its wide-array of symptoms and the wide array of conditions they can be seen in.