Addition of adipose tissue-derived mesenchymal stem cells improves empagliflozin therapy for alleviating hyperglycemia--induced neuropathy.

BACKGROUND: We examined the impact of adipose-derived mesenchymal stem cell (ADMSC)-facilitated empagliflozin (EMPA) therapy for alleviating hyperglycemic induced neuropathy [i.e., diabetic neuropathy (DN)]. METHODS: Study constituted N2a cell culture and rats to be classified into groups 1 (sham-operated-control)/2 (DN)/3 (DN + empagliflozin/20 mg/kg/daily orally for 6 weeks since post-day-7 DN induction)/4 (DN + ADMSCs/1.2 × 106 cells by vein transfusion at time intervals of 1/3/5 weeks after DN induction)/5 (DN + empagliflozin + ADMSCs) and sacrificed by day-42 after DN induction. RESULTS: In vitro results showed that, compared to N2a cells, the cellular levels of senescence/DNA-damage and protein expressions of oxidative-stress (OS), apoptotic, autophagic and inflammatory biomarkers were significantly higher in N2a + glucose (25 mM) but were significantly reversed in N2a + glucose + ADMSCs, whereas the cellular levels of mitochondrial cytochrome C and protein levels of anti-oxidants displayed an opposite pattern of OS (all P<0.001). The above-mentioned parameters (i.e., OS/apoptosis/fibrosis/autophagy/DNA-damage) were lowest in N2a cells, highest in N2a + glucose and significantly higher in N2a + glucose + EMPA (50 µM) than in N2a + glucose + EMPA (150 µM) (all P<0.001). By days 7/14/21/28/35/42 after DN induction, the values of thermal paw-withdrawal-latency (TPWL)/mechanical-paw-withdrawal-threshold were highest in group 1 and significantly progressively increased from groups 2/4/3/5 (all P<0.0001). The cellular levels of unmyelinated C- and myelinated A-δ fibers, and protein levels of OS/apoptotic/DNA-damaged/fibrotic/autophagic/inflammatory/pain-facilitated/voltage-gated sodium channel biomarkers in L4-L5 levels of dorsal-root-ganglia exhibited an contradictory manner of TPWL among the groups (all P<0.0001). CONCLUSIONS: Combination of EMPA and ADMSC therapy was superior to either alone for improving outcomes of DN.

Synergic Effect of Early Administration of Probiotics and Adipose-Derived Mesenchymal Stem Cells on Alleviating Inflammation-Induced Chronic Neuropathic Pain in Rodents.

This study investigated the hypothesis that probiotics enhanced the therapeutic effect of adipose-derived mesenchymal stem cells (ADMSCs) on alleviating neuropathic pain (NP) due to chronic constriction injury (CCI) mainly through regulating the microbiota in rats. SD rats (n = 50) were categorized into group 1 (sham-control), group 2 (NP), group 3 (NP + probiotics (i.e., 1.5 billion C.F.U./day/rat, orally 3 h after NP procedure, followed by QOD 30 times)), group 4 (NP + ADMSCs (3.0 × 105 cells) 3 h after CCI procedure, followed by QOD six times (i.e., seven times in total, i.e., mimic a clinical setting of drug use) and group 5 (NP + probiotics + ADMSCs (3.0 × 105 cells)) and euthanized by day 60 after NP induction. By day 28 after NP induction, flow-cytometric analysis showed circulating levels of early (AN-V+/PI−) and late (AN-V+/PI+) apoptotic, and three inflammatory (CD11b-c+, Ly6G+ and MPO+) cells were lowest in group 1 and significantly progressively reduced in groups 2 to 5 (all p < 0.0001). By days 7, 14, 21, 28, and 60 after CCI, the thresholds of thermal paw withdrawal latency (PWL) and mechanical paw withdrawal threshold (PWT) were highest in group 1 and significantly progressively increased in groups 2 to 5 (all p < 0.0001). Numbers of pain-connived cells (Nav1.8+/peripherin+, p-ERK+/peripherin+, p-p38+/peripherin+ and p-p38+/NF200+) and protein expressions of inflammatory (p-NF-κB, IL-1ß, TNF-α and MMP-9), apoptotic (cleaved-caspase-3, cleaved-PARP), oxidative-stress (NOX-1, NOX-2), DNA-damaged (γ-H2AX) and MAPK-family (p-P38, p-JNK, p-ERK1/2) biomarkers as well as the protein levels of Nav.1.3, Nav.1.8, and Nav.1.9 in L4-L5 in dorsal root ganglia displayed an opposite pattern of mechanical PWT among the groups (all p < 0.0001). In conclusion, combined probiotic and ADMSC therapy was superior to merely one for alleviating CCI-induced NP mainly through suppressing inflammation and oxidative stress.

Soluble ST2 is a Useful Biomarker for Grading Cerebral-Cardiac Syndrome in Patients after Acute Ischemic Stroke.

This study tested whether the soluble (s)ST2 is a superb biomarker predictive of moderate to severe cerebral-cardiac syndrome (CCS) (defined as coexisting National Institute of Health Stroke Scale (NIHSS) >8 and left-ventricular ejection fraction (LVEF) <60%) in patients after acute ischemic stroke (IS). Between November 2015 and October 2017, a total of 99 IS patients were prospectively enrolled and categorized into three groups based on NIHSS, i.e., group 1 (NIHSS ≤ 8, n = 66), group 2 (NIHSS = 9-15, n = 14) and group 3 (NIHSS ≥ 16, n = 19), respectively. Blood samples were collected immediately after hospitalization, followed by transthoracic echocardiographic examination. The results showed that the flow cytometric analysis for assessment of inflammatory biomarkers of TLR2+/CD14+cells, TLR4+/CD14+cells, Ly6g+/CD14+cells, and MPO+/CD14+cells, and ELISA assessment for circulatory level of sST2 were significantly higher in groups 2/3 than in group 1 (all p < 0.01). However, these parameters did not show significant differences between groups 2 and 3 (all p > 0.05). The LVEF was significantly lower in group 3 than in group 1 (p < 0.001), but it displayed no difference between groups 1/2 or between groups 2/3. These inflammatory biomarkers ((TLR2+/CD14+cells// TLR4+/CD14+cells// MPO+/CD14+cells) and sST2)) were significantly positively correlated to NIHSS and strongly negatively correlated to LVEF (all p < 0.05). Multivariate analysis demonstrated that both MPO/CD14+cells >20% (p = 0.027) and sST2 ≥ 17,600 (p = 0.004) were significantly and independently predictive of moderate-severe CCS after acute IS. Receiver operating characteristic curve analysis demonstrated that sST2 was the most powerful predictor of CCS with a sensitivity of 0.929 and a specificity of 0.731 (p < 0.001). In conclusion, sST2 is a useful biomarker for prediction of CCS severity in patients after acute IS.

Adipose-derived mesenchymal stem cell-derived exosomes markedly protected the brain against sepsis syndrome induced injury in rat.

This study tested the hypothesis that sepsis syndrome [SS-induced by cecal-ligation and puncture (CLP)]-induced systemic inflammation and brain damage in rats were effectively suppressed by allogenic adipose-derived mesenchymal stem cell-derived exosome (AMSCEXO). SD rats (n = 72) were divided into group 1 [sham-control (SC)], group 2 (SS only) and group 3 (SS + AMSCEXO) and equally euthanized at 6/24/48/72 h after SS induction, respectively. By 6/16/24/72 h, flow cytometric analyses demonstrated the numbers of inflammatory cells (Ly6G+/CD11b/c+), immune (CD3+/CD4+ cells/CD3+/CD8+ cells) and early (AN-V+/PI-)/late (AN-V+/PI+) apoptotic cells in circulation were significantly increased in group 2 than in groups 1 and 3, and significantly increased in group 3 than in group 1, whereas the number of T-reg+ cells was significantly progressively increased from groups 1 to 3 (all P < 0.0001). At 6/16/24/72 h, the numbers of (CD3+/CD4+ cells/CD3+/CD8+ cells/T-reg+ cells) in spleen exhibited an identical pattern of circulation among the three groups (all P < 0.0001). ELISA showed inflammatory mediators (IL-6/TNF-α) in circulating/cerebrospinal fluid at 6/24/72 h displayed an identical trend as the immune cells among the three groups (all P < 0.0001). Microscopic findings demonstrated that the cellular expressions of inflammatory (F4/80+//MMP-9+//CD14+//GFPA+) and brain-damaged (AQP4+/γ-H2AX+) biomarkers at 24/72 h exhibited an identical pattern of immune cells among the three groups (all P < 0.0001). The protein expressions of inflammatory (IL-1ß/MMP-9/TNF-α/NF-κB/TLR2/TLR-4/MyD88/HMGB1), apoptotic (cleaved-caspase3/PARP/mitochondrial-Bax) and oxidative-stress (NOX-1/NOX-2/oxidized protein) biomarkers displayed an identical pattern as the immune cells among the three groups (all P < 0.0001). In conclusion, SS elicited vigorously inflammatory reaction not only in circulation but also in spleen/brain, resulting in serious brain damage.

The Correlation between Severity of Neurological Impairment and Left Ventricular Function in Patients after Acute Ischemic Stroke.

Despite left ventricular (LV) dysfunction increases the risk of incidental acute ischemic stroke (AIS), the association between LV function and severity of neurological deficits after AIS remains unclear. Between November 2015 and October 1017, a total of 99 AIS patients were prospectively enrolled and categorized into two groups based on National Institute of Health Stroke Scale (NIHSS). The AIS patients with NIHSS <6 were allocated into Group 1 (n = 50) and those with NIHSS ≥6 were into Group 2 (n = 49). Echocardiography was performed within 5 days after AIS to assess chamber size, left ventricular ejection fraction (LVEF) and valvular regurgitation. Besides, two inflammatory biomarkers, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), were evaluated on admission. The results showed Group 2 had significantly higher value of NLR and PLR (all p-values < 0.01) but lower LVEF (p = 0.001) and frequency of mitral regurgitation (p = 0.021) than Group 1. The NIHSS and modified Rankin scale were significantly negatively correlated with LVEF, whereas both were significantly positively correlated with NLR and PLR (all p-values < 0.02). Multivariate analysis showed LVEF <65%, aging and inflammation were significantly associated with NIHSS ≥6 (all p-values < 0.01). In conclusion, the AIS patients with NIHSS ≥6 had lower LVEF but more clinically dominant mitral regurgitation and higher NLR and PLR compared to those with NIHSS <6.

Intra-carotid arterial transfusion of autologous circulatory derived CD34+ cells for old ischemic stroke patients - a phase I clinical trial to evaluate safety and tolerability.

This phase I clinical trial tested the hypothesis that circulatory CD34+ cell therapy might be safe for old ischemic stroke (IS) (defined as IS>6 months) patients and also to evaluate the neurological function after the therapy. Nine old IS patients (with mean IS interval: 8.6 ± 6.4 years) were consecutively enrolled and received intra-carotid artery transfusion of circulatory-derived autologous CD34+ cells (3.0×107 cells/patient) into the ipsilateral brain infarct area at catheterization room by Catheter Looping Technique, after subcutaneous G-CSF injection (5 µg/kg twice a day for 4 days). The results showed that procedural safety was 100% with all patients uneventfully discharged. The circulating number of EPCs and angiogenesis (i.e., by Matrigel assay) were significantly higher at post than at prior to G-CSF treatment (all P<0.001). Time courses (0/5/10/30 minutes) of blood samplings from right-internal jugular vein exhibited significantly increased in levels of SDF-1α and EPCs numbers in time points of 5/10/30 minutes than in the baseline (0 minute) (all P<0.05). Barthel index was increased (defined as ≥5 scores) in 44.4% (4/9) and CASI score was notably improved (all P<0.01) at 6-month follow-up after the cell therapy as compared to the baseline. No recurrent IS or any tumorigenesis was found in these patients with a mean follow-up time interval of 16.5 ± 6.2 months. All of these patients remain survive and are followed up at outpatient department. In conclusion, CD34+ cell therapy is safe and might offer some benefit to old IS patients.

Melatonin attenuated brain death tissue extract-induced cardiac damage by suppressing DAMP signaling.

We tested the hypothesis that melatonin prevents brain death (BD) tissue extract (BDEX)-induced cardiac damage by suppressing inflammatory damage-associated molecular pattern (DAMP) signaling in rats. Six hours after BD induction, levels of a DAMP component (HMGB1) and inflammatory markers (TLR-2, TLR-4, MYD88, IκB, NF-κB, IL-1ß, IFN-γ, TNF-α and IL-6) were higher in brain tissue from BD animals than controls. Levels of HMGB1 and inflammatory markers were higher in BDEX-treated H9C2 cardiac myoblasts than in cells treated with healthy brain tissue extract. These increases were attenuated by melatonin but re-induced with luzindole (all P < 0.001). Additional male rats (n = 30) were divided into groups 1 (negative control), 2 (healthy brain tissue extract implanted in the left ventricular myocardium [LVM]), 3 (BDEX-LVM), 4 (BDEX-LVM + melatonin), and 5 (BDEX-LVM + melatonin + luzindole). Collagen deposition/fibrosis and LVM levels of MTR2, HMGB1, inflammatory markers, oxidative stress, apoptosis, mitochondrial damage and DNA damage were highest in group 3, lowest in groups 1 and 2, and higher in group 5 than in group 4. Heart function and LVM levels of MTR1 and anti-inflammatory, mitochondrial-integrity and anti-oxidative markers exhibited a pattern opposite that of the inflammatory markers in the five groups (all P < 0.0001). These results indicate melatonin inhibits BDEX-induced cardiac damage by suppressing the DAMP inflammatory axis.

Amitriptyline and Sexual Function: A Systematic Review Updated for Sexual Health Practice.

Amitriptyline is an old drug but is still prevalently used as the first-line treatment for a variety of common diseases. Surprisingly, knowledge of sexual risks with amitriptyline comes from only one clinical trial and several case reports from three decades ago. In the current study, a systematic review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) related to amitriptyline and sexual dysfunction (SD) was performed. The frequency, gender-difference, types, disease-specificity and time course of SD, and the relationship between SD and nonsexual adversity were studied. A total of 14 publications, including 8 qualified randomized clinical trials, were eligible. The frequency of SD in overall, male and female patients was 5.7, 11.9 and 1.7%, respectively. SD was six-fold higher in men than women. The frequency of SD was 6.9% in depressive patients compared with 0.8% in non-depressive patients ( p = .008), and gradually decreased at 8 weeks after treatment ( p = .02). Amitriptyline impacted arousal and libido more than orgasm and ejaculation in male patients but mainly libido in female patients. SD was significantly correlated with insomnia linearly whereas somnolence and nausea dually. Therefore, amitriptyline-associated SD mainly occurs in depressive and male patients, disturbs each phase of the sexual response cycle in men but mainly libido in women, gradually decreases under long-term treatment, and can be predicted by the co-existence of insomnia, somnolence or nausea during treatment. Clinicians should caution and tailor the gender and disease vulnerability of amitriptyline in their practice.

Topiramate-associated sexual dysfunction: A systematic review.

INTRODUCTION: Sexual pharmacotoxicity renders patients with epilepsy at a risk for sexual dysfunction (SD). This study is aimed to analyze the relationship between sexual function and topiramate to avoid topiramate-associated SD. METHODS: A systematic review following the PRISMA guidelines was performed to elucidate any SD occurrence in patients receiving topiramate. RESULTS: A total of 17 publications were reviewed. Based on limited polytherapy observational studies, the frequency of self-reported topiramate-associated SD, libido disorder, and orgasmic disorder in patients with polytherapy was 9.0%, 9.0%, and 2.6%, respectively (grade C evidence). Female patients mainly had anorgasmia, whereas male patients principally had erectile dysfunction. The daily dose of topiramate in patients with SD was within the recommended dose. Sexual adversity usually occurred from 4weeks after topiramate use but favorably subsided without eventful complications after topiramate substitution or dose reduction in all patients. CONCLUSIONS: Topiramate can elicit different patterns of SD, especially anorgasmia in women and erectile dysfunction in men, even with a therapeutic dose. Detailed drug education and careful monitoring are necessary to maximize sexual health, especially in persons undergoing polytherapy and with other risks for SD. Moreover, a rapid response, such as substitution or reduction of the dose, is suggested when SD occurs during its use.

EPO-cyclosporine combination therapy reduced brain infarct area in rat after acute ischemic stroke: role of innate immune-inflammatory response, micro-RNAs and MAPK family signaling pathway.

This study tested the hypothesis that erythropoietin (EPO) and cyclosporine (CsA) could effectively reduce brain infarct area (BIA) in rat after acute ischemic stroke (AIS) through regulating inflammation, oxidative stress, MAPK family signaling and microRNA (miR-223/miR-30a/miR-383). Adult male Sprague-Dawley rats (n = 48) were equally divided into group 1 (sham control), group 2 (AIS), group 3 [AIS+EPO (5,000 IU/kg at 0.5/24/48 h, subcutaneous)] and group 4 [AIS+CsA (20.0 mg/kg at 0.5/24/48 h, intra-peritoneal)]. By 72 h, histopathology showed that BIA was largest in group 2 and smallest in group 1, and significantly larger in group 4 than group 3 (all P<0.0001). The three microRNAs expressed were higher in group 2 than in the other three groups (all P<0.04); between these three latter groups there were no significant differences. The protein expressions of MAPK family [phosphorylated (p)-ERK1/2, p-p38/p-JNK], inflammatory (iNOS/MMP-9/TNF-α/NF-κB/IL-12/MIP-1α/CD14/CD68/Ly6g), apoptotic (caspase-3/PARP/mitochondrial-Bax), oxidative-stress (NOX-1/NOX-2/oxidized protein) and mitochondrial-damaged (cytosolic cytochrome-C) biomarkers exhibited an identical pattern to BIA findings (all P<0.0001). The cellular expressions of brain edema (AQP4+), inflammation (CD11+/glial-fibrillary-acid protein+), and cellular damage (TUNEL assay/positive Periodic acid-Schiff stain) biomarkers exhibited an identical pattern, whereas the cellular-integrity markers (neuN+/MAP2+/doublecorin+) exhibited an opposite pattern to BIA (all P value <0.001). EPO-CsA therapy markedly reduced BIA mainly by suppressing the innate immune response to inflammation, oxidative stress, microRNAs (miR-223/miR-30a/miR-383) and MAPK family signaling.

Cheiro-pedal syndrome: A revisit of etiology, localization and outcome.

OBJECTIVE: Cheiro-pedal syndrome (CPS) is an incomplete sensory disorder confined to hand and foot and is generally considered a benign entity. However, knowledge comes from case report or case series only. The aim of this study is to clarify the etiology, localization and outcome of CPS. PATIENT AND METHOD: A total of 21 CPS patients from our database and another 9 patients from literature were reviewed. CPS was classified into 4 types, namely unilateral and ipsilateral (Type I), bilateral (Type II), incomplete bilateral (Type III), and crossed (Type IV). RESULTS: They were 20 men and 10 women; including 20 Type I patients, 9 Type II patients, 1 Type III patients, and 0 Type IV patient. Vascular disorders, non-vascular cervical disorder and polyneuropathy were the responsible causes in 18 patients, 7 patients, and 2 patients, respectively. Etiology was unknown in another 3 patients. Lesions were located at brain parenchyma in 16 patients, and cervical cord above C5 level in 9 patients. Disable motoroparesis occurred between 4days to 2 months in two-third of deteriorated patients. In three patients, their lesions were detected only on recurrence or exacerbation of CPS 4 months to 2 years later. Recovery, residual deficit and deterioration ensued in 44%, 28% and 28% patients, respectively. A 33.3% of brain involvement patients and 100.0% of spinal involvement patients terminated to residual deficit or deterioration. The sensitivity and specificity of prediction for deterioration was 77.8% and 100%, respectively, by type II or III CPS. CONCLUSION: CPS is actually not a benign neurological disorder but a sensory alarm sign. A thorough examination of brain parenchyma and cervical spinal cord is urgent for identifying any treatable or preventable pathological lesions to reduce harmful consequence, especially in case of type II or III CPS.

The prognostic values of leukocyte Rho kinase activity in acute ischemic stroke.

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.

Levels of circulating neopterin in patients with severe carotid artery stenosis undergoing carotid stenting.

AIMS: The association between an elevated serum neopterin level and the development of coronary artery complex lesions has been extensively assessed; however, the correlation between the serum neopterin level and the development of carotid artery stenosis has seldom been reported. This study tested whether this biomarker is increased in patients with severe carotid artery stenosis(≥70%) undergoing carotid artery(CA) stenting and investigated independent predictors of an increased circulating neopterin level. METHODS: Fifty patients with severe CA stenosis(CAS) undergoing CA stenting were consecutively enrolled in this study from January 2009 through December 2011. The serum neopterin levels of age- and gender-matched acute ischemic stroke(AIS) patients(n=120) and control subjects(CS)(n=33) were also measured. A blood sample was prospectively collected from each patient in the catheterization room. RESULTS: The serum levels of neopterin were significantly higher in the CAS patients than in the AIS patients or CS and significantly higher in the AIS patients than in the CS(all p＜0.001). An analysis of the variables of 170 patients(CAS＋AIS) demonstrated that age, a previous history of stroke and severe CAS were significantly correlated with an increased serum level of neopterin(all p＜0.005). A multivariate binary logistic regression analysis of the severe CAS patients(n=50) demonstrated that age and the creatinine level were independent predictors of a high neopterin level(neopterin level ≥16.52 ng/dL, i.e., according to the median value of neopterin)(all p＜0.05). CONCLUSIONS: The circulating neopterin levels are significantly higher in patients with severe CAS than in those with AIS. The presence of CAS, age and the creatinine level were significantly correlated with an increased serum neopterin level.

Association between MIF gene polymorphisms and carotid artery atherosclerosis.

Atherosclerosis is a chronic inflammatory disorder. Macrophage migration inhibitory factor (MIF) is a potent cytokine that plays an important role in the regulation of immune responses. Polymorphisms including five- to eight-repeat CATT variants ((CATT)(5-8)) and G-173C in the promoter region of the MIF gene are associated with altered levels of MIF gene transcription. The purpose of the study is to investigate the relationship between promoter polymorphisms of the MIF gene and the severity of carotid artery atherosclerosis (CAA). The severity of CAA was assessed in 593 individuals with a history of ischemic stroke by using sonographic examination, and the MIF promoter polymorphisms of these individuals were genotyped. The carriage of (CATT)7 (compared to genotypes composed of (CATT)5, (CATT)6, or both), carriage of C allele (compared to GG), and carriage of the haplotype (CATT)7-C (compared to genotypes composed of (CATT)5-G, (CATT)6-G, or both) were significantly associated with an increase in the severity of CAA. We conclude that polymorphisms in the MIF gene promoter are associated with CAA severity in ischemic stroke patients. These genetic variants may serve as markers for individual susceptibility to CAA.

Montreal cognitive assessment in assessing clinical severity and white matter hyperintensity in Alzheimer's disease with normal control comparison.

PURPOSE: Use Taiwanese version of the Montreal Cognitive Assessment (MoCA) in evaluating patients in different stages of Alzheimer's disease (AD) and correlate with white matter change. METHODS: Ninety-seven normal controls (NC), 52 very-mild AD (clinical dementia rating [CDR] = 0.5), 48 mild AD (CDR = 1) and 38 moderate AD (CDR = 2) patients were enrolled for the MoCA, Mini- Mental State Examination (MMSE) and the Cognitive Assessment Screening Instrument (CASI). White matter hyperintensities (WMHs) on brain MRI were visually rated and classified as deep or periventricular WMHs. RESULTS: In NC group, education (ß = 0.326) but not age (ß = -0.183, p = 0.069), was significantly related to MoCA score. However, while we added two points to the AD patients with less than 6 years education, the effects of education disappeared as compared with those of 7 years of education. For all educational levels, the cutoff value of MoCA for very-mild AD was 22/23 (sensitivity = 82.7%, specificity = 87.6%). No significant differences were found in the areas under the curves that differentiated NC from the patients with AD for MoCA and MMSE (differences = 0.008, p = 0.490), or for MoCA and CASI (differences = 0.023, p = 0.082). Total WMHs, frontal deep and periventricular WMHs were inversely correlated with the attention and delayed-recall subdomain. CONCLUSION: The MoCA is a good clinical tool for screening very-mild stage AD if the educational effects are carefully considered. The correlation between the executive subdomains with the frontal WMHs also makes it a useful tool for detecting subtle WMHs.

Serum level and prognostic value of neopterin in patients after ischemic stroke.

BACKGROUND: We hypothesized that serum level of neopterin is significantly predictive of prognostic outcome in patients after acute ischemic stroke (IS). METHODS: Between November 2008 and May 2010, serum levels of neopterin were prospectively collected at 48 h after acute IS in 157 patients. RESULTS: Serum neopterin levels were substantially higher in patients with severe neurological impairment [National institutes of Health Stroke Scale (NIHSS) score ≥12] than in those with NIHSS <12 (p<0.008). Furthermore, Spearman's test showed a strongly positive correlation between neopterin level and NIHSS (p=0.003). Multiple logistic regression analysis demonstrated that serum neopterin level was strongly and independently predictive of NIHSS ≥12 (p=0.002) at 48 h after acute IS and 90-day major adverse clinical outcome (defined as NIHSS≥12, recurrent stroke or death) (p=0.003). CONCLUSION: Serum level of neopterin was notably increased after acute IS. This biomarker was strongly and independently predictive of 90-day unfavorable clinical outcome in patients after acute IS.

Clinical analysis of cheiro-pedal syndrome.

Cheiro-pedal syndrome (CPS) is an incomplete pure sensory disorder confined strictly to simultaneous hand/finger and ipsilateral foot/toe symptoms. However, its clinical significance and pathogenesis are unclear. We present nine patients with typical CPS, and review another seven previously reported patients. Ischemic stroke is the leading cause of CPS in these 16 patients. In 13 patients, the lesions responsible were distributed widely in the brain from the corona radiata to the medulla oblongata whereas in three patients the lesions were found in the cervical spinal cord or peripheral nerves. All patients had a favorable outcome. The close proximity of the cheiral and pedal sensory fibers in the pons, thalamus, internal capsule and the caudal thalamocortical projection increases the vulnerability for CPS. Therefore, the underlying cause of CPS should be investigated rapidly despite it causing only minor symptoms. The pathogenesis of CPS may consist of several interacting factors including preconditioned neuronal damage and proximity of the acral sensory fibers.

Link between lipoprotein-associated phospholipase A2 gene expression of peripheral-blood mononuclear cells and prognostic outcome after acute ischemic stroke.

AIM: To evaluate the potential of the lipoprotein-associated phospholipase A(2) (Lp-PLA(2) level as a biomarker in the prediction of prognostic outcome in patients with acute ischemic stroke (IS). METHODS: From October 2008 to March 2010, 130 patients with acute IS were prospectively enrolled in the study and their medical records were reviewed. A blood sample was collected from each patient 48 hours after acute IS, as well as from 20 healthy volunteers as controls. Messenger-RNA (mRNA) expression of Lp-PLA(2) of peripheral-blood mononuclear cells (PBMNCs) relative to that of ß actin was measured using quantitative reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Patients with acute IS exhibited significantly higher Lp-PLA(2) mRNA expression of PBMNCs than the control group (p <0.0001). Lp-PLA(2) mRNA expression of PBMNCs in patients with a major adverse clinical outcome (MACO) (defined as recurrent stroke or death) within 90 days was significantly higher than in patients without MACO (p=0.006). Furthermore, elevated Lp-PLA(2) mRNA expression was strongly associated with old age, diabetes mellitus, a positive history of significant coronary arterial disease and significant stenosis of the extra-cranial carotid arteries (all p <0.04), and positively correlated with the body mass index, leukocyte count, and serum levels of total cholesterol and low-density lipoprotein cholesterol. Multivariate analysis revealed that Lp-PLA(2) mRNA expression of PBMNCs was a significant independent predictor of MACO within 90 days (p= 0.011). CONCLUSION: Elevated Lp-PLA(2) mRNA expression of PBMNCs seems to be a potential biomarker for predicting an unfavorable outcome in patients with acute IS.

Salt-and-pepper eye pain and brainstem stroke.

BACKGROUND AND PURPOSE: The salt-and-pepper pain is a characteristic sensory disturbance confined to the eyes and regional facial structures. Although a poor prognosis has been mentioned in previously reported patients, the precise pathomechanism and clinical significance are still unknown. PATIENTS AND METHODS: We report four patients with ocular salt-and-pepper pain, and review the clinical course, neuroimaging and prognosis in another eight patients reported in the literature. RESULTS: In our series, they were three men and one woman, and their underlying cause was pontine hemorrhage; hypertensive hemorrhage in three and cavernous hemangioma in one patient, respectively. In these 12 salt-and-pepper patients, the identifiable etiology was exclusively brainstem stroke. Life-threatening or disable neurological deterioration ensued within 24 h after pain onset in all patients. Their ocular pain subsided rapidly after neurological deterioration occurred. A dual excitation of nociceptive quinothalamic pain fiber and disinhibition of trigeminosensory system from pontine reticular formation and cerulotrigeminospinal circuit may be responsible for this pain. CONCLUSION: In clinical practice, ocular salt-and-pepper pain in quiet eyes should be alerted for intracranial pathology and neurological deterioration until underlying cause is identified.

Comparison of acute versus convalescent stage high-sensitivity C-Reactive protein level in predicting clinical outcome after acute ischemic stroke and impact of erythropoietin.

BACKGROUND AND AIM: Currently, no data on the optimal time point after acute ischemic stroke (IS) at which high-sensitivity C-reactive protein (hs-CRP) level is most predictive of unfavorable outcome. We tested the hypothesis that hs-CRP levels during both acute (48 h after IS) and convalescent (21 days after IS) phases are equally important in predicting 90-day clinical outcome after acute IS. We further evaluated the impact of erythropoietin (EPO), an anti-inflammatory agent, on level of hs-CRP after acute IS. METHODS: Totally 160 patients were prospectively randomized to receive either EPO therapy (group 1, n = 80) (5,000 IU each time, subcutaneously) at 48 h and 72 h after acute IS, or placebo (group 2, n = 80). Serum level of hs-CRP was determined using ELISA at 48 h and on day 21 after IS and once in 60 healthy volunteers. RESULTS: Serum level of hs-CRP was substantially higher in all patients with IS than in healthy controls at 48 h and day 21 after IS (all p < 0.001). Levels of hs-CRP did not differ between group 1 and 2 at 48 h and day 21 after IS (all p > 0.5). Multivariate analysis showed that hs-CRP levels (at 48 h and day 21) were independently predictive of 90-day major adverse neurological event (MANE) (defined as recurrent stroke, NIHSS≥8, or death) (all p < 0.03), whereas EPO therapy was independently predictive of reduced 90-day MANE (all p < 0.02). CONCLUSION: EPO therapy which was independently predictive of freedom from 90-day MANE did not alter the crucial role of hs-CRP levels measured at 48 h and 21-day in predicting unfavorable clinical outcome after IS.