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1.  Elevated Serum Vascular Cell Adhesion Molecule-1 Is Associated with Septic Encephalopathy in Adult Community-Onset Severe Sepsis Patients 
BioMed Research International  2014;2014:598762.
Background and Aim. Septic encephalopathy (SE) is a common complication of severe sepsis. Increased concentrations of circulating soluble adhesion molecules are reported in septic patients. This study aimed to determine whether serum adhesion molecules are associated with SE. Methods. Seventy nontraumatic, nonsurgical adult patients with severe sepsis admitted through ER were evaluated. Serum adhesion molecules were assessed for their relationship with SE, and compared with other clinical predictors and biomarkers. Results. Twenty-three (32.8%) patients had SE. SE group had higher in-hospital mortality (40% versus 11%, P = 0.009) and their sVCAM-1, sICAM-1, and lactate levels on admission were also higher than non-SE group. By stepwise logistic regression model, sVCAM-1, age, and maximum 24-hours SOFA score were independently associated with septic encephalopathy. The AUC analysis of ROC curve of different biomarkers showed that sVCAM-1 is better to predict SE. The sVCAM-1 levels in the SE group were significantly higher than those of the non-SE group at three time periods (Days 1, 4, and 7). Conclusions. Septic encephalopathy implies higher mortality in nontraumatic, nonsurgical patients with severe sepsis. VCAM-1 level on presentation is a more powerful predictor of SE in these patients than lactate concentration and other adhesion molecules on admission.
doi:10.1155/2014/598762
PMCID: PMC4032707  PMID: 24883317
2.  Clinical features and predictive factors of intraventricular rupture in patients who have bacterial brain abscesses 
Background
Intraventricular rupture of brain abscesses (IVRBA) remains a catastrophic and fatal complication of bacterial brain abscess (BBA). However, no information has been reported about the risk factors that are predictive of intraventricular rupture.
Methods
This study was undertaken to determine the potential risk factors that are predictive of intraventricular ruptures in patients with BBA but without intraventricular rupture when arriving at the hospital. A comparison is also made between patients who already have IVRBA at the time of admission (initial IVRBA) and those who have the episode during hospitalisation (subsequent IVRBA).
Results
62 patients, including 45 who had initial IVRBA and 17 who had subsequent IVRBA, were examined. Stepwise logistic regression analysis showed that the adjusted risk of intraventricular rupture during hospitalisation for patients with multiloculated brain abscesses had an odds ratio (OR) of 4.2 (95% confidence interval (CI) 1.24 to 14.3; p = 0.02) compared with those without multiloculated brain abscesses (referent); a reduction of 1 mm in the distance between the ventricle and brain abscesses would increase the rupture rate by 10% (p = 0.006, OR 0.9, 95% CI 0.83 to 0.97).
Conclusion
This study shows that if the abscess is deep seated, multiloculated and close to the ventricle wall, a reduction of 1 mm in the distance between the ventricle and brain abscesses will increase the rupture rate by 10%. Despite aggressive medical and surgical management shown in this series, many patients continue to progress poorly.
doi:10.1136/jnnp.2006.097808
PMCID: PMC2117635  PMID: 17012340
3.  Clinical Features Associated with Frozen Shoulder Syndrome in Parkinson's Disease 
Parkinson's Disease  2015;2015:232958.
Background. Frozen shoulder syndrome is a common musculoskeletal disease of idiopathic Parkinson's disease (PD) that causes long-term pain and physical disability. A better understanding of the associated factors can help identify PD patients who will require prevention to improve their quality of life. Methodology. This prospective study evaluated 60 shoulders of 30 PD patients. Correlation analysis was used to evaluate the relationships between clinical factors and shoulder sonography findings. Results. Frozen shoulder syndrome was found in 14 of 30 PD patients affecting 19 shoulders, including bilateral involvement in five and unilateral involvement in nine. There was a significant positive correlation between the parameters of sonography findings and frozen shoulder syndrome (i.e., thickness of bicipital effusion and tendon thickness of the subscapularis and supraspinatus) and mean ipsilateral Unified Parkinson's Disease Rating Scale (UPDRS) III and its subscores (tremor, rigidity, and bradykinesia scores). Conclusions. Higher ipsilateral UPDRS and subscores are associated with increased effusion around the biceps tendon, with increased tendon thickness of subscapularis and supraspinatus. Preventing frozen shoulder syndrome in the high-risk PD group is an important safety issue and highly relevant for their quality of life.
doi:10.1155/2015/232958
PMCID: PMC4477225  PMID: 26180653
4.  The Roles of Biomarkers of Oxidative Stress and Antioxidant in Alzheimer's Disease: A Systematic Review 
BioMed Research International  2014;2014:182303.
Purpose. Oxidative stress plays an important role in the pathogenesis of Alzheimer's disease (AD). This paper aims to examine whether biomarkers of oxidative stress and antioxidants could be useful biomarkers in AD, which might form the bases of future clinical studies. Methods. PubMed, SCOPUS, and Web of Science were systematically queried to obtain studies with available data regarding markers of oxidative stress and antioxidants from subjects with AD. Results and Conclusion. Although most studies show elevated serum markers of lipid peroxidation in AD, there is no sufficient evidence to justify the routine use of biomarkers as predictors of severity or outcome in AD.
doi:10.1155/2014/182303
PMCID: PMC4053273  PMID: 24949424
5.  The Association among Antioxidant Enzymes, Autoantibodies, and Disease Severity Score in Systemic Lupus Erythematosus: Comparison of Neuropsychiatric and Nonneuropsychiatric Groups 
BioMed Research International  2014;2014:137231.
Background. Antioxidative capacity plays an important role in the severity of systemic lupus erythematosus (SLE), which is characterized by autoantibodies. This study aimed to determine the relationship among autoantibody titers, antioxidative stress reserve, and severity of SLE. Methods. The autoantibody titers, clinical markers, antioxidant enzyme levels, and disease activity index (SLEDAI-2k) of 32 SLE patients and 16 healthy controls were compared. We also compared both the neuropsychiatric (NPSLE) and nonneuropsychiatric (non-NPSLE) groups. Results. Superoxide dismutase in red blood cells was significantly lower in the SLE than in the control group. CRP levels are significant higher in SLE patients than in control group (P = 0.034). Among the autoantibodies, anti-U1RNP (P = 0.008), a-Sm (P = 0.027), and anti-ribosomal p (P = 0.028) significantly negatively correlated with glutathione levels. There has no significant correlation between SLE disease activity indexes (SLEDAI) and levels of C3, C4, and antioxidant enzymes. Conclusions. Erythrocyte superoxide dismutase is significantly lower in both NPSLE and non-NPSLE groups. SLE patients have both higher CRP and autoantibodies level and decreased superoxide dismutase level than the healthy control group.
doi:10.1155/2014/137231
PMCID: PMC4024413  PMID: 24877055
6.  The Association between Autoantibodies and Peripheral Neuropathy in Lupus Nephritis 
BioMed Research International  2014;2014:524940.
Background and Aim. The sensitivity and specificity of biomarkers used for predicting peripheral neuropathy in patients with systemic lupus erythematosus (SLE) and nephritis (SLE-LN) remain unsatisfactory. This study aimed to determine the autoantibodies levels in SLE-LN patients with peripheral neuropathy. Methods. Data of 559 SLE-LN patients were collected retrospectively, including titers of autoantibodies, electrodiagnostic studies, and clinical manifestations. Results. The neurologic manifestations of the SLE-LN patients were diverse and nonspecific. The prevalence rate of peripheral polyneuropathy was 2.68%, of which about 73.33% was mixed sensory-motor polyneuropathy. Numbness and functional gastrointestinal problems were the most prevalent symptoms and these were noted in every subtype of peripheral neuropathy. Among all the serology markers, anti-Ro was significantly associated with neuropathy related to SLE (P = 0.009). Conclusion. Peripheral neuropathy among LN patients is rare and may be easily overlooked. This study demonstrated that positive anti-Ro antibody may imply neuropathy in LN patients. Thus, anti-Ro can be considered a biomarker that should be added to the panel of conventional autoantibodies in LN patients.
doi:10.1155/2014/524940
PMCID: PMC4017733  PMID: 24864250
7.  Serial Serum Leukocyte Apoptosis Levels as Predictors of Outcome in Acute Traumatic Brain Injury 
BioMed Research International  2014;2014:720870.
Background. Apoptosis associates with secondary brain injury after traumatic brain injury (TBI). This study posits that serum leukocyte apoptosis levels in acute TBI are predictive of outcome. Methods. Two hundred and twenty-nine blood samples from 88 patients after acute TBI were obtained on admission and on Days 4 and 7. Serial apoptosis levels of different leukocyte subsets were examined in 88 TBI patients and 27 control subjects. Results. The leukocyte apoptosis was significantly higher in TBI patients than in controls. Brief unconsciousness (P = 0.009), motor deficits (P ≤ 0.001), GCS (P ≤ 0.001), ISS (P = 0.001), WBC count (P = 0.015), late apoptosis in lymphocytes and monocytes on Day 1 (P = 0.004 and P = 0.022, resp.), subdural hemorrhage on initial brain CT (P = 0.002), neurosurgical intervention (P ≤ 0.001), and acute posttraumatic seizure (P = 0.046) were significant risk factors of outcome. Only motor deficits (P = 0.033) and late apoptosis in monocytes on Day 1 (P = 0.037) were independently associated with outcome. A cutoff value of 5.72% of late apoptosis in monocytes was associated with poor outcome in acute TBI patients. Conclusion. There are varying degrees of apoptosis in patients following TBI and in healthy individuals. Such differential expression suggests that apoptosis in different leukocyte subsets plays an important role in outcome following injury.
doi:10.1155/2014/720870
PMCID: PMC4016848  PMID: 24864256
8.  The Association between Serological Biomarkers and Primary Sjogren's Syndrome Associated with Peripheral Polyneuropathy 
BioMed Research International  2014;2014:902492.
Background and Aim. The sensitivity and specificity of biomarkers used for predicting peripheral neuropathy of Sjogren's syndrome (SJS) patients remain unsatisfactory. This study aimed to determine the prognostic value of circulating autoantibodies levels in SJS patients with peripheral neuropathy. Methods. Two hundred and fifty serological positive (either anti-Ro or anti-La positive) SJS patients' data were collected retrospectively. The titers of autoantibodies, electrophysiology reports, and clinical manifestation were reviewed. Results. The prevalence rate of peripheral neuropathy is 7.2% in our study. Regarding classification of peripheral neuropathy, 12 had mixed sensorimotor polyneuropathy, six had cranial neuropathy. After stepwise logistic regression analysis, anti-β2 glycoprotein I (aβ2GP I) and perinuclear anti-neutrophil cytoplasmic antibody (p-ANCA) were significantly associated with peripheral neuropathy in serology positive SJS (P = 0.01, P = 0.046, resp.). Conclusion. The occurrence of peripheral neuropathy among SJS patients is not frequent and easily overlooked. Our study demonstrated that aβ2GP I and p-ANCA levels may imply the danger of the occurrence of neuropathy in SJS patients, and they can be considered a biomarker that should be added to the panel of conventional autoantibody in SJS patients.
doi:10.1155/2014/902492
PMCID: PMC4005097  PMID: 24822219
9.  Peripheral Leukocyte Apoptosis in Patients with Parkinsonism: Correlation with Clinical Characteristics and Neuroimaging Findings 
BioMed Research International  2014;2014:635923.
Apoptosis of both brain neurons and peripheral blood leukocyte is believed to be an important biomarker for evaluating the functional status of Parkinson's disease (PD). However, their correlation remains unknown. A better understanding of the pathophysiology of neurodegeneration is essential for the treatment and prevention of PD. The present study demonstrated that leukocyte apoptosis is significantly higher in PD patients and is associated with central dopamine neuron loss by using 99mTc-TRODAT-1 SPECT. The leukocyte apoptosis and striatal dopamine transporter uptake ratios were further associated with increased severity and longer duration of disease. The interaction between brain and systemic inflammation may be responsible for the neurodegenerative disease progression.
doi:10.1155/2014/635923
PMCID: PMC3984850  PMID: 24795890
10.  Increasing trend of fluconazole-non-susceptible Cryptococcus neoformans in patients with invasive cryptococcosis: a 12-year longitudinal study 
BMC Infectious Diseases  2015;15:277.
Background
This study aimed to investigate the rate of fluconazole-non-susceptible Cryptococcus neoformans in Southern Taiwan for the period 2001–2012 and analyze the risk factors for acquiring it among patients with invasive cryptococcosis.
Methods
All enrolled strains were isolated from blood or cerebrospinal fluid samples of the included patients. If a patient had multiple positive results for C. neoformans, only the first instance was enrolled. Susceptibility testing was performed using the Clinical and Laboratory Standards Institutes M27-A3 broth micro-dilution method. The MIC interpretative criteria for susceptibility to fluconazole were ≤8 μg/ml. A total of 89 patients were included. Patients (n = 59) infected by fluconazole-susceptible strains were compared with those (n = 30) infected by non-susceptible strains. The patients’ demographic and clinical characteristics were analyzed.
Results
The rate of fluconazole-non-susceptible C. neoformans in the study period significantly increased over time (p < 0.001). The C. neoformans isolated in 2011–2012 (odds ratio: 10.68; 95 % confidence interval: 2.87-39.74; p < 0.001) was an independent predictive factor for the acquisition of fluconazole-non-susceptible C. neoformans.
Conclusions
The rate of fluconazole-non-susceptible C. neoformans has significantly increased recently. Continuous and large-scale anti-fungal susceptibility tests for C. neoformans are warranted to confirm this trend.
doi:10.1186/s12879-015-1023-8
PMCID: PMC4509779  PMID: 26194004
Cryptococcus neoformans; Invasive cryptococcosis; Susceptibility; Fluconazole; Risk factors
11.  Structural deficits and cognitive impairment in tuberculous meningitis 
BMC Infectious Diseases  2015;15:279.
Background
Chronic neuropsychological sequelae may occur in patients with tuberculous meningitis (TBM). The impact of structural abnormalities on the clinical performance of patients with TBM is unknown. This study applied the Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra (DARTEL) voxel-based morphometry (VBM) to determine if gray matter deficits in TBM are associated with acute presentations and chronic cognitive impairment.
Methods
Seventeen patients with TBM who discontinued their anti-TB therapy for more than six months, and 17 age-, sex-, and education-matched healthy subjects were enrolled. Differences in gray matter volume (GMV) between patients and healthy controls were investigated using DARTEL-VBM to determine structural abnormalities. Disease severity during the acute stage was scored by clinical profiles and conventional imaging findings. Correlations among chronic structural deficits, cognitive impairment, and initial disease severity were assessed.
Results
The patients with TBM had worse neuropsychological subtest performances than the healthy controls. Compared to the controls, the patients showed smaller GMVs in the right thalamus, right caudate nucleus, right superior and middle temporal gyrus, right precuneus, and left putamen (p < 0.001). The smaller GMVs in the right thalamus, right superior temporal gyrus, right precuneus, left putamen, and right caudate nucleus (p < 0.05) were further associated with worse cognitive function. More severe initial disease also correlated with smaller GMVs in the right caudate nucleus (p < 0.05).
Conclusion
Multiple domain cognitive impairment may persist in patients with chronic TBM even after appropriate treatment. Worse initial disease severity may contribute to the vulnerability of brain tissue to damage, with subsequent neuropsychological consequences.
doi:10.1186/s12879-015-1011-z
PMCID: PMC4510907  PMID: 26198732
Tuberculous meningitis; Cognitive deficits; Magnetic resonance imaging; Voxel-based morphometry
12.  Resting State-fMRI with ReHo Analysis as a Non-Invasive Modality for the Prognosis of Cirrhotic Patients with Overt Hepatic Encephalopathy 
PLoS ONE  2015;10(5):e0126834.
Background
To investigate the relationships among regional activity abnormalities, clinical disease severity, and prognosis in cirrhotic patients with overt hepatic encephalopathy (OHE) using resting-state functional magnetic resonance imaging (rs-fMRI).
Methods
Regional homogeneity (ReHo) values of 12 cirrhotic patients with OHE and 12 age- and sex-matched healthy volunteers were calculated from rs-fMRI. Two-sample t-test was performed on individual ReHo maps between the two groups. The relationships between ReHo variation, disease severity, and prognosis were analyzed.
Results
Cirrhotic patients with OHE had significantly low ReHo values in the left middle cingulum, bilateral superior temporal, left inferior orbito-frontal, right calcarine, left inferior frontal gyrus, left post-central, left inferior temporal, and left lingual areas, and high ReHo in the right superior frontal, right inferior temporal, right caudate, and cerebellum. There was significant group difference in the right superior temporal lobe (p=0.016) and crus1 of the left cerebellum (p=0.015) between survivors and non-survivors in the OHE group. Worse Glasgow Coma Scale was associated with increased local connectivity in the left cerebellar crus I (r= -0.868, p=0.001).
Conclusions
Information on the functional activity of cirrhotic patients with OHE suggests the use of rs-fMRI with ReHo analysis as a non-invasive prognosticating modality.
doi:10.1371/journal.pone.0126834
PMCID: PMC4431841  PMID: 25973853
13.  Long-Term Neuropsychological Sequelae in HIV-Seronegative Cryptococcal Meningoencephalitis Patients with and without Ventriculoperitoneal Shunts: A Cine MRI Study 
Behavioural Neurology  2015;2015:356476.
Background. Hydrocephalus in cryptococcal meningoencephalitis is most commonly managed with a ventriculoperitoneal shunt. This study applied cine magnetic resonance imaging (MRI) to evaluate initial disease severity on long-term cerebrospinal fluid (CSF) flow dynamics and associated neuropsychological sequelae in cryptococcal meningoencephalitis patients with and without ventriculoperitoneal shunts. Methods. Eighteen human immunodeficiency virus-seronegative cryptococcal meningoencephalitis patients (10 with shunts versus 8 without shunts) were compared with 32 age- and sex-matched healthy volunteers. All subjects underwent complete neurologic examination and neuropsychological testing. Cine MRI was conducted to evaluate CSF flow parameters. Initial CSF laboratory analysis and imaging findings were correlated with present CSF flow parameters and neuropsychological scores. Results. Patients without shunts had higher average flow than controls, suggesting chronic hydrocephalus. Initial Evans ratios and CSF glucose levels were associated with CSF peak velocity and flow. Worsening CSF flow parameters correlated with decreased neuropsychological performance. Conclusions. CSF flow parameter differences between the cryptococcal meningoencephalitis patients both with and without ventriculoperitoneal shunts could be detected by cine MRI and correlated with acute stage disease severity and chronic stage neuropsychological results. Cine MRI is useful for assessing the chronic hydrocephalus that may lead to neuropsychological deficits in cryptococcal meningoencephalitis patients.
doi:10.1155/2015/356476
PMCID: PMC4407401  PMID: 25948879
14.  Erythropoietin improves long-term neurological outcome in acute ischemic stroke patients: a randomized, prospective, placebo-controlled clinical trial 
Critical Care  2015;19(1):49.
Introduction
Mortality and disability following ischemic stroke (IS) remains unacceptably high with respect to the conventional therapies. This study tested the effect of erythropoietin (EPO) on long-term neurological outcome in patients after acute IS. This study aimed to evaluate the safety and efficacy of two consecutive doses of EPO (5,000 IU/dose, subcutaneously administered at 48 hours and 72 hours after acute IS) on improving the 90-day combined endpoint of recurrent stroke or death that has been previously reported. A secondary objective was to evaluate the long-term (that is, five years) outcome of patients who received EPO.
Methods
This was a prospective, randomized, placebo-controlled trial that was conducted between October 2008 and March 2010 in a tertiary referral center. IS stroke patients who were eligible for EPO therapy were enrolled into the study.
Results
The results showed that long-term recurrent stroke and mortality did not differ between group 1 (placebo-control; n = 71) and group 2 (EPO-treated; n = 71).
Long-term Barthel index of <35 (defining a severe neurological deficit) was lower in group 2 than group 1 (P = 0.007). Multiple-stepwise logistic-regression analysis showed that EPO therapy was significantly and independently predictive of freedom from a Barthel index of <35 (P = 0.029). Long-term major adverse neurological event (MANE; defined as: death, recurrent stroke, or long-term Barthel index < 35) was lower in group 2 than group 1 (P = 0.04). Log-Rank test showed that MANE-free rate was higher in group 2 than group 1 (P = 0.031). Multiple-stepwise Cox-regression analysis showed that EPO therapy and higher Barthel Index at day 90 were independently predictive of freedom from long-term MANE (all P <0.04).
Conclusion
EPO therapy significantly improved long-term neurological outcomes in patients after IS.
Trial registration
ISRCTN71371114. Registered 10 October 2008.
doi:10.1186/s13054-015-0761-8
PMCID: PMC4349661  PMID: 25888250
15.  Investigation of the caspase-dependent mitochondrial apoptotic pathway in mononuclear cells of patients with systemic lupus erythematosus 
Background
This study aimed to explore the role of apoptosis initiators, caspase-9, caspase-10, mitochondrial anti-viral signaling protein (MAVS), and interferon regulatory factor 7 (pIRF7), in patients with systemic lupus erythematosus (SLE).
Methods
Leukocyte apoptosis was determined by flow cytometry, including annexin V, APO2.7, and 7-amino-actinomycin D (7-AAD) on each subtype of leukocyte in 35 patients with SLE, 15 disease controls, and 17 volunteer normal controls. Levels of caspase-9, caspase-10, MAVS, and pIRF7 in mononuclear cells and the disease activity index (SLEDAI) in the SLE patients were determined. Correlation among intracellular adaptor proteins and caspase levels were calculated.
Results
The SLE patients had higher APO2.7 in total leukocyte, lymphocyte, and monocytes, and higher late apoptosis markers in total leukocytes and neutrophils than normal controls (all p < 0.05). Disease activity was positively associated with the APO2.7 of CD19+ cells in SLE, but negatively associated with MAVS and caspase-9 levels (all p < 0.05). Markers of viral infection and anti-virus transcription factors like MDA5, MAVS, and pIRF7 were significantly higher in SLE patients than in disease controls (p < 0.05). Caspase-9 and caspase-10 levels positively correlated with MAVS and pIRF7 in SLE patients (p < 0.05).
Conclusions
The disease activity of SLE is positively associated with APO2.7 level of CD19+ cells but negatively associated with MAVS and caspase-9 levels, which all point to a mitochondrial pathway.
doi:10.1186/s12967-014-0303-1
PMCID: PMC4226892  PMID: 25370148
Caspase; Leukocyte apoptosis; Systemic lupus erythematosus; Interferon
16.  Predictors and long-term outcome of seizures in human immuno-deficiency virus (HIV)-negative cryptococcal meningitis 
BMC Neurology  2014;14:208.
Background
Seizures are one of the most important neurologic complications of human immuno-deficiency virus (HIV)-negative cryptococcal meningitis. A better understanding of the risk associated factors can help predict those who will require treatment.
Methods
This 22-year retrospective study enrolled 180 patients. Prognostic variables independently associated with seizures or fatality were analyzed using stepwise logistic regression.
Results
Twenty-eight patients with HIV-negative cryptococcal meningitis had seizures, including 13 with early seizures and 15 with late seizures. The mean time interval from HIV-negative cryptococcal meningitis to first seizure in the early and late seizure groups were 1.5 and 51.4 days, respectively. Nine out of the 28 cases (32%) occurred within 24 hours of presentation. The overall mortality rate was 54% (15/28) and two patients progressed to epilepsy.
Conclusions
Patients with seizure have worse outcomes and longer hospitalization. Most first seizures occur within one year after the diagnosis of HIV-negative cryptococcal meningitis.
doi:10.1186/s12883-014-0208-x
PMCID: PMC4203868  PMID: 25307800
Outcome; Risk factors; Seizures; HIV-negative cryptococcal meningitis
17.  Longitudinal Brain White Matter Alterations in Minimal Hepatic Encephalopathy before and after Liver Transplantation 
PLoS ONE  2014;9(8):e105887.
Cerebral edema is the common pathogenic mechanism for cognitive impairment in minimal hepatic encephalopathy. Whether complete reversibility of brain edema, cognitive deficits, and their associated imaging can be achieved after liver transplantation remains an open question. To characterize white matter integrity before and after liver transplantation in patients with minimal hepatic encephalopathy, multiple diffusivity indices acquired via diffusion tensor imaging was applied. Twenty-eight patients and thirty age- and sex-matched healthy volunteers were included. Multiple diffusivity indices were obtained from diffusion tensor images, including mean diffusivity, fractional anisotropy, axial diffusivity and radial diffusivity. The assessment was repeated 6–12 month after transplantation. Differences in white matter integrity between groups, as well as longitudinal changes, were evaluated using tract-based spatial statistical analysis. Correlation analyses were performed to identify first scan before transplantation and interval changes among the neuropsychiatric tests, clinical laboratory tests, and diffusion tensor imaging indices. After transplantation, decreased water diffusivity without fractional anisotropy change indicating reversible cerebral edema was found in the left anterior cingulate, claustrum, postcentral gyrus, and right corpus callosum. However, a progressive decrease in fractional anisotropy and an increase in radial diffusivity suggesting demyelination were noted in temporal lobe. Improved pre-transplantation albumin levels and interval changes were associated with better recoveries of diffusion tensor imaging indices. Improvements in interval diffusion tensor imaging indices in the right postcentral gyrus were correlated with visuospatial function score correction. In conclusion, longitudinal voxel-wise analysis of multiple diffusion tensor imaging indices demonstrated different white matter changes in minimal hepatic encephalopathy patients. Transplantation improved extracellular cerebral edema and the results of associated cognition tests. However, white matter demyelination may advance in temporal lobe.
doi:10.1371/journal.pone.0105887
PMCID: PMC4148329  PMID: 25166619
18.  Diffusion Tensor Imaging Study of White Matter Damage in Chronic Meningitis 
PLoS ONE  2014;9(6):e98210.
Tuberculous meningitis (TBM) and cryptococcal meningitis (CM) are two of the most common types of chronic meningitis. This study aimed to assess whether chronic neuro-psychological sequelae are associated with micro-structure white matter (WM) damage in HIV-negative chronic meningitis. Nineteen HIV-negative TBM patients, 13 HIV-negative CM patients, and 32 sex- and age-matched healthy volunteers were evaluated and compared. The clinical relevance of WM integrity was studied using voxel-based diffusion tensor imaging (DTI) magnetic resonance imaging. All of the participants underwent complete medical and neurologic examinations, and neuro-psychological testing. Differences in DTI indices correlated with the presence of neuro-psychological rating scores and cerebrospinal fluid (CSF) analysis during the initial hospitalization. Patients with CM had more severe cognitive deficits than healthy subjects, especially in TBM. There were changes in WM integrity in several limbic regions, including the para-hippocampal gyrus and cingulate gyrus, and in the WM close to the globus pallidus. A decline in WM integrity close to the globus pallidus and anterior cingulate gyrus was associated with worse CSF analysis profiles. Poorer DTI parameters directly correlated with worse cognitive performance on follow-up. These correlations suggest that WM alterations may be involved in the psychopathology and pathophysiology of co-morbidities. Abnormalities in the limbic system and globus pallidus, with their close relationship to the CSF space, may be specific biomarkers for disease evaluation.
doi:10.1371/journal.pone.0098210
PMCID: PMC4043527  PMID: 24892826
19.  Association between Oxidative Stress and Outcome in Different Subtypes of Acute Ischemic Stroke 
BioMed Research International  2014;2014:256879.
Objectives. This study investigated serum thiobarbituric acid-reactive substances (TBARS) and free thiol levels in different subtypes of acute ischemic stroke (AIS) and evaluated their association with clinical outcomes. Methods. This prospective study evaluated 100 AIS patients, including 75 with small-vessel and 25 with large-vessel diseases. Serum oxidative stress (TBARS) and antioxidant (thiol) were determined within 48 hours and days 7 and 30 after stroke. For comparison, 80 age- and sex-matched participants were evaluated as controls. Results. Serum TBARS was significantly higher and free thiol was lower in stroke patients than in the controls on days 1 and 7 after AIS. The level of free thiol was significantly lower in the large-vessel disease than in the small-vessel disease on day 7 after stroke. Using the stepwise logistic regression model for potential variables, only stroke subtype, NIHSS score, and serum TBARS level were independently associated with three-month outcome. Higher TBARS and lower thiol levels in the acute phase of stroke were associated with poor outcome. Conclusions. Patients with large-vessel disease have higher oxidative stress but lower antioxidant defense compared to those with small-vessel disease after AIS. Serum TBARS level at the acute phase of stroke is a potential predictor for three-month outcome.
doi:10.1155/2014/256879
PMCID: PMC4034452  PMID: 24895559
20.  Association between Peripheral Oxidative Stress and White Matter Damage in Acute Traumatic Brain Injury 
BioMed Research International  2014;2014:340936.
The oxidative stress is believed to be one of the mechanisms involved in the neuronal damage after acute traumatic brain injury (TBI). However, the disease severity correlation between oxidative stress biomarker level and deep brain microstructural changes in acute TBI remains unknown. In present study, twenty-four patients with acute TBI and 24 healthy volunteers underwent DTI. The peripheral blood oxidative biomarkers, like serum thiol and thiobarbituric acid-reactive substances (TBARS) concentrations, were also obtained. The DTI metrics of the deep brain regions, as well as the fractional anisotropy (FA) and apparent diffusion coefficient, were measured and correlated with disease severity, serum thiol, and TBARS levels. We found that patients with TBI displayed lower FAs in deep brain regions with abundant WMs and further correlated with increased serum TBARS level. Our study has shown a level of anatomic detail to the relationship between white matter (WM) damage and increased systemic oxidative stress in TBI which suggests common inflammatory processes that covary in both the peripheral and central reactions after TBI.
doi:10.1155/2014/340936
PMCID: PMC3996315  PMID: 24804213
21.  The Prognostic Values of Leukocyte Rho Kinase Activity in Acute Ischemic Stroke 
BioMed Research International  2014;2014:214587.
Objective. It has been reported that leukocyte ROCK activity is elevated in patients after ischemic stroke, but it is unclear whether leukocyte ROCK activity is associated with clinical outcomes following acute stroke events. The objective of this study is to investigate if leukocyte ROCK activity can predict the outcomes in patients with acute ischemic stroke. Materials and Methods. We enrolled 110 patients of acute ischemic stroke and measured the leukocyte ROCK activity and plasma level of inflammatory cytokines to correlate the clinical outcomes of these patients. Results. The leukocyte ROCK activity at 48 hours after admission in acute ischemic stroke patients was higher as compared to a risk-matched population. The leukocyte ROCK activity significantly correlated with National Institute of Health Stroke Scale (NIHSS) difference between admission and 90 days after stroke event. Kaplan-Meier survival estimates showed lower stroke-free survival during follow-up period in patients with high leukocyte ROCK activity or plasma hsCRP level. Leukocyte ROCK activity independently predicted the recurrent stroke in patients with atherosclerotic stroke. Conclusions. This study shows elevated leukocyte ROCK activity in patients with ischemic stroke as compared to risk-matched subjects and is an independent predictor for recurrent stroke.
doi:10.1155/2014/214587
PMCID: PMC3955656  PMID: 24716192
22.  Statin therapy reduces oxidized low density lipoprotein level, a risk factor for stroke outcome 
Critical Care  2014;18(1):R16.
Introduction
Statins are reported to have anti-inflammatory and anti-oxidative effects aside from cholesterol-lowering effects. This study aimed to evaluate the effects of statin therapy on oxidized LDL (Ox-LDL) and the clinical outcome of patients with acute ischemic stroke (AIS).
Methods
This prospective study enrolled 120 patients with AIS divided in the statin (n = 55) and non-statin (n = 65) groups. Eighty sex- and age- matched participants were recruited as risk controls. Ox-LDL was measured using a monoclonal antibody-based enzyme-linked immune-sorbent assay at different time points after AIS. The clinical outcomes were analyzed between the statin and non-statin groups.
Results
Plasma Ox-LDL was significantly higher in stroke patients than in the controls (P < 0.001). Plasma Ox-LDL level was significantly reduced in the statin group on day 7 and day 30 compared to the non-statin group (P < 0.01). The plasma Ox-LDL positively correlated with serum total cholesterol, LDL-cholesterol, and hemoglobin A1c (HbA1c). Among the potential risk factors, only National Institutes of Health stroke scale (NIHSS) score and Ox-LDL level on admission were independently associated with 3-month outcome.
Conclusions
Our study demonstrates that statin therapy reduces plasma Ox-LDL level after AIS. Plasma Ox-LDL may be a more powerful predictor than serum LDL, high-sensitivity C-reactive protein or white blood cell counts for stroke outcome. Therefore, assay of plasma Ox-LDL should be added as a predictor among the panel of conventional biomarkers in stroke outcome.
doi:10.1186/cc13695
PMCID: PMC4056016  PMID: 24423248
23.  Long-term effects on carotid intima-media thickness after radiotherapy in patients with nasopharyngeal carcinoma 
Background
Vascular abnormalities are the predominant histologic changes associated with radiation in nasopharyngeal carcinoma (NPC). This study examined if the duration after radiotherapy correlates with the progression of carotid intima-media thickness (IMT) and investigated its relationship with inflammatory markers.
Methods
One hundred and five NPC patients post-radiotherapy for more than one year and 25 healthy control subjects were examined by B-mode ultrasound for IMT measurement at the far wall of the common carotid artery (CCA). Surrogate markers including lipid profile, HbA1c, and high sensitive C-reactive protein (hs-CRP) were assessed.
Results
The IMT of CCA was significantly increased in NPC patients and carotid plaque was detected in 38 NPC patients (38/105, 36.2%). Significant risk factors for carotid plaques included age, duration after radiotherapy, and HbA1c levels. Age, duration after radiotherapy, hs-CRP, HbA1c, and platelet count positively correlated with IMT. The cut-off value of age and duration after radiotherapy for the presence of plaque was 52.5 years and 42.5 months, respectively. In NPC subjects, multiple linear regression analysis revealed that age, gender, duration after radiotherapy and platelet counts were independently associated with CCA IMT. After adjustments for age, gender and platelet counts, IMT increased in a linear manner with duration after radiotherapy.
Conclusions
Radiation-induced vasculopathy is a dynamic and progressive process due to late radiation effects. Extra-cranial color-coded duplex sonography can be part of routine follow-up in NPC patients aged ≥50 years at 40 months post-radiotherapy.
doi:10.1186/1748-717X-8-261
PMCID: PMC3827874  PMID: 24196030
Atherosclerosis; Nasopharyngeal carcinoma; Radiotherapy; Risk factors
24.  The association among leukocyte apoptosis, autoantibodies and disease severity in systemic lupus erythematosus 
Background
Both apoptosis and autoantibodies are important factors associated with disease activity in the pathogenesis of systemic lupus erythematosus (SLE). This study tested the hypothesis that increased leukocyte apoptosis is associated with elevated levels of autoantibodies and the disease activity of SLE.
Methods
Leukocyte apoptosis was determined by flow cytometry, including annexin V, APO2.7, and 7-amino-actinomycin D (7-AAD) on each subtype of leukocyte in 23 patients with SLE. Leukocyte apoptosis was also evaluated in nine patients with Sjogren’s syndrome (SJS) and in 20 volunteer subjects. Titers of common autoantibodies and the disease activity index (SLEDAI-2 k) of the SLE patients were also determined.
Results
Except for annexin V and APO 2.7 of monocytes and late apoptosis (annexin V + 7-ADD) of lymphocytes, apoptosis in the total and in subsets of leukocytes were significantly higher in SLE patients than in controls (all p < 0.05, post hoc analysis). The mean percentage of late apoptosis of leukocytes (annexin V + 7-AAD) positively correlated with levels of anti-Ro52/60 (r = 0.513, p < 0.01), anti-La (r = 0.439, p = 0.04), and anti-Mi-2 (r = 0.492, p = 0.02), and inversely correlated with both C3 and C4 levels, although not statistically significant. The percentage of APO2.7 of CD19+ cells positively correlated with SLEDAI-2 K score (p = 0.01).
Conclusions
Leukocyte apoptosis is significantly higher in patients with SLE and correlates well with the levels of several autoantibodies. The APO2.7 of B-lymphocyte (CD19+) cells positively correlates with the disease activity of SLE.
doi:10.1186/1479-5876-11-261
PMCID: PMC3853096  PMID: 24138706
Autoantibodies; Diseases severity score; Leukocyte apoptosis; Systemic lupus erythematosus
25.  Structural and cognitive deficits in chronic carbon monoxide intoxication: a voxel-based morphometry study 
BMC Neurology  2013;13:129.
Background
Patients with carbon monoxide (CO) intoxication may develop ongoing neurological and psychiatric symptoms that ebb and flow, a condition often called delayed encephalopathy (DE). The association between morphologic changes in the brain and neuropsychological deficits in DE is poorly understood.
Methods
Magnetic resonance imaging and neuropsychological tests were conducted on 11 CO patients with DE, 11 patients without DE, and 15 age-, sex-, and education-matched healthy subjects. Differences in gray matter volume (GMV) between the subgroups were assessed and further correlated with diminished cognitive functioning.
Results
As a group, the patients had lower regional GMV compared to controls in the following regions: basal ganglia, left claustrum, right amygdala, left hippocampus, parietal lobes, and left frontal lobe. The reduced GMV in the bilateral basal ganglia, left post-central gyrus, and left hippocampus correlated with decreased perceptual organization and processing speed function. Those CO patients characterized by DE patients had a lower GMV in the left anterior cingulate and right amygdala, as well as lower levels of cognitive function, than the non-DE patients.
Conclusions
Patients with CO intoxication in the chronic stage showed a worse cognitive and morphologic outcome, especially those with DE. This study provides additional evidence of gray matter structural abnormalities in the pathophysiology of DE in chronic CO intoxicated patients.
doi:10.1186/1471-2377-13-129
PMCID: PMC3850907  PMID: 24083408
Carbon monoxide intoxication; Cognitive deficits; Delayed encephalopathy; Magnetic resonance imaging; Voxel-based morphometry

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