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1.  Effects of several quinones on insulin aggregation 
Scientific Reports  2014;4:5648.
Protein misfolding and aggregation are associated with more than twenty diseases, such as neurodegenerative diseases and metabolic diseases. The amyloid oligomers and fibrils may induce cell membrane disruption and lead to cell apoptosis. A great number of studies have focused on discovery of amyloid inhibitors which may prevent or treat amyloidosis diseases. Polyphenols have been extensively studied as a class of amyloid inhibitors, with several polyphenols under clinical trials as anti-neurodegenerative drugs. As oxidative intermediates of natural polyphenols, quinones widely exist in medicinal plants or food. In this study, we used insulin as an amyloid model to test the anti-amyloid effects of four simple quinones and four natural anthraquinone derivatives from rhubarb, a traditional herbal medicine used for treating Alzheimer's disease. Our results demonstrated that all eight quinones show inhibitory effects to different extent on insulin oligomerization, especially for 1,4-benzoquinone and 1,4-naphthoquinone. Significantly attenuated oligomerization, reduced amount of amyloid fibrils and reduced hemolysis levels were found after quinones treatments, indicating quinones may inhibit insulin from forming toxic oligomeric species. The results suggest a potential action of native anthraquinone derivatives in preventing protein misfolding diseases, the quinone skeleton may thus be further explored for designing effective anti-amyloidosis compounds.
doi:10.1038/srep05648
PMCID: PMC4090620  PMID: 25008537
2.  Rapid Birth-and-Death Evolution of Imprinted snoRNAs in the Prader-Willi Syndrome Locus: Implications for Neural Development in Euarchontoglires 
PLoS ONE  2014;9(6):e100329.
Imprinted small nucleolar RNAs (snoRNAs) are only found in eutherian genomes and closely related to brain functions. A complex human neurological disease, Prader-Willi syndrome (PWS), is primarily attributed to the deletion of imprinted snoRNAs in chromosome 15q11-q13. Here we investigated the snoRNA repertoires in the PWS locus of 12 mammalian genomes and their evolution processes. A total of 613 imprinted snoRNAs were identified in the PWS homologous loci and the gene number was highly variable across lineages, with a peak in Euarchontoglires. Lineage-specific gene gain and loss events account for most extant genes of the HBII-52 (SNORD115) and the HBII-85 (SNORD116) gene family, and remarkable high gene-birth rates were observed in the primates and the rodents. Meanwhile, rapid sequence substitution occurred only in imprinted snoRNA genes, rather than their flanking sequences or the protein-coding genes located in the same imprinted locus. Strong selective constraints on the functional elements of these imprinted snoRNAs further suggest that they are subjected to birth-and-death evolution. Our data suggest that the regulatory role of HBII-52 on 5-HT2CR pre-mRNA might originate in the Euarchontoglires through adaptive process. We propose that the rapid evolution of PWS-related imprinted snoRNAs has contributed to the neural development of Euarchontoglires.
doi:10.1371/journal.pone.0100329
PMCID: PMC4063771  PMID: 24945811
3.  Cerebral Atherosclerosis is Associated with Cystic Infarcts and Microinfarcts, but not Alzheimer Pathologic Changes 
Background and Purpose
Some studies have reported associations between intracranial atherosclerosis and Alzheimer disease (AD) pathology. We aimed to correlate severity of cerebral atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy (CAA) with neurofibrillary tangles, neuritic plaques, and cerebral infarcts.
Methods
This autopsy study (n = 163) was drawn from a longitudinal study of subcortical ischemic vascular disease, AD, and normal aging. Multivariable logistic regression models were used to test associations among the 3 forms of cerebrovascular disease and the presence of ischemic and neurodegenerative brain lesions. Apolipoprotein E genotype was included as a covariate in these multivariable models.
Results
Cerebral atherosclerosis was positively associated with microinfarcts (odds ratio (OR) = 2.3; 95% confidence interval (CI) = 1.2–4.4) and cystic infarcts (OR = 2.0, 95%CI = 1.0–4.2), but not AD pathology. Arteriolosclerosis showed a positive correlation with lacunar infarcts (OR = 2.0, 95%CI = 1.0–4.2), but not AD pathology. CAA was inversely associated with lacunar infarcts (OR = 0.6, 95%CI = 0.41–1.1), but positively associated with Braak & Braak stage (OR = 1.5, 95%CI = 1.1–2.1) and CERAD plaque score (OR = 1.5, 95%CI = 1.1–2.2).
Conclusions
Microinfarcts, which have been correlated with severity of cognitive impairment, were most strongly associated with atherosclerosis. Possible pathogenetic mechanisms include artery-to-artery emboli, especially micro-emboli that may include atheroemboli or platelet-fibrin emboli. Arteriolosclerosis was positively, while CAA was negatively correlated with lacunar infarcts, which might prove helpful in clinical differentiation of arteriolosclerotic from CAA-related vascular brain injury.
doi:10.1161/STROKEAHA.113.001945
PMCID: PMC4049465  PMID: 23887837
Atherosclerosis; Alzheimer; Microinfarct; Infarct
4.  A Contig-Based Strategy for the Genome-Wide Discovery of MicroRNAs without Complete Genome Resources 
PLoS ONE  2014;9(2):e88179.
MicroRNAs (miRNAs) are important regulators of many cellular processes and exist in a wide range of eukaryotes. High-throughput sequencing is a mainstream method of miRNA identification through which it is possible to obtain the complete small RNA profile of an organism. Currently, most approaches to miRNA identification rely on a reference genome for the prediction of hairpin structures. However, many species of economic and phylogenetic importance are non-model organisms without complete genome sequences, and this limits miRNA discovery. Here, to overcome this limitation, we have developed a contig-based miRNA identification strategy. We applied this method to a triploid species of edible banana (GCTCV-119, Musa spp. AAA group) and identified 180 pre-miRNAs and 314 mature miRNAs, which is three times more than those were predicted by the available dataset-based methods (represented by EST+GSS). Based on the recently published miRNA data set of Musa acuminate, the recall rate and precision of our strategy are estimated to be 70.6% and 92.2%, respectively, significantly better than those of EST+GSS-based strategy (10.2% and 50.0%, respectively). Our novel, efficient and cost-effective strategy facilitates the study of the functional and evolutionary role of miRNAs, as well as miRNA-based molecular breeding, in non-model species of economic or evolutionary interest.
doi:10.1371/journal.pone.0088179
PMCID: PMC3917882  PMID: 24516608
5.  Importance of Hospital Entry: Walk-in STEMI and Primary Percutaneous Coronary Intervention 
Introduction
Patients with ST elevation myocardial infarction (STEMI) require rapid identification and triage to initiate reperfusion therapy. Walk-in STEMI patients have longer treatment times compared to emergency medical service (EMS) transported patients. While effective triage of large numbers of critically ill patients in the emergency department is often cited as the reason for treatment delays, additional factors have not been explored. The purpose of this study was to evaluate baseline demographic and clinical differences between walk-in and EMS-transported STEMI patients and identify factors associated with prolonged door to balloon (D2B) time in walk-in STEMI patients.
Methods
We performed a retrospective review of 136 STEMI patients presenting to an urban academic teaching center from January 2009 through December 2010. Baseline demographics, mode of hospital entry (walk-in versus EMS transport), treatment times, angiographic findings, procedures performed and in-hospital clinical events were collected. We compared walk-in and EMS-transported STEMI patients and identified independent factors of prolonged D2B time for walk-in patients using stepwise logistic regression analysis.
Results
Walk-in patients (n=51) were more likely to be Latino and presented with a higher heart rate, higher systolic blood pressure, prior history of diabetes mellitus and were more likely to have an elevated initial troponin value, compared to EMS-transported patients. EMS-transported patients (n=64) were more likely to be white and had a higher prevalence of left main coronary artery disease, compared to walk-in patients. Door to electrocardiogram (ECG), ECG to catheterization laboratory (CL) activation and D2B times were significantly longer for walk-in patients. Walk-in patients were more likely to have D2B time >90 minutes, compared to EMS- transported patients; odds ratio 3.53 (95% CI 1.03, 12.07), p=0.04. Stepwise logistic regression identified hospital entry mode as the only independent predictor for prolonged D2B time.
Conclusion
Baseline differences exist between walk-in and EMS-transported STEMI patients undergoing primary percutaneous coronary intervention (PCI). Hospital entry mode was the most important predictor for prolonged treatment times for primary PCI, independent of age, Latino ethnicity, heart rate, systolic blood pressure and initial troponin value. Prolonged door to ECG and ECG to CL activation times are modifiable factors associated with prolonged treatment times in walk-in STEMI patients. In addition to promoting the use of EMS transport, efforts are needed to rapidly identify and expedite the triage of walk-in STEMI patients.
doi:10.5811/westjem.2013.9.17855
PMCID: PMC3935790  PMID: 24578769
6.  INCREASING INTENT TO DONATE IN HISPANIC AMERICAN HIGH SCHOOL STUDENTS: RESULTS OF A PROSPECTIVE OBSERVATIONAL STUDY 
Transplantation proceedings  2013;45(1):13-19.
Background
High school students are an important target audience for organ donation education. A novel educational intervention focused on Hispanic American (HA) high school students might improve organ donation rates.
Methods
A prospective observational study was conducted in five Los Angeles High Schools with a high percentage of HA students. A ‘culturally sensitive’ educational program was administered to students in the 9th to 12th grades. Pre-intervention surveys that assessed awareness, knowledge, perception and beliefs regarding donation as well as the intent to become an organ donor were compared to post-intervention surveys.
Results
A total of 10,146 high school students participated in the study. After exclusions, 4876 pre-intervention and 3182 post-intervention surveys were analyzed. A significant increase in the overall knowledge, awareness, and beliefs regarding donation was observed after the intervention, as evidenced by a significant increase in the percentage of correct answers on the survey (41% pre- v. 44% post-, p<0.0001). When specifically examining HA students, there was a significant increase in the intent to donate organs (AOR 1.21, 95%CI: 1.09, 1.34, p=0.0003).
Conclusion
This is the first study to demonstrate a significant increase in the intent to donate among HA high school students following an educational intervention.
doi:10.1016/j.transproceed.2012.08.009
PMCID: PMC3564055  PMID: 23375270
High school; Organ Donation; Education; and Hispanic Americans
7.  Ultrasound-assisted extraction of total flavonoids from Aconitum gymnandrum 
Pharmacognosy Magazine  2014;10(Suppl 1):S141-S146.
Background:
Aconitum gymnandrum is a Chinese traditional herb used as carminative and analgesic. In this study, A. gymnandrum was used as an experimental matrix.
Materials and Methods:
Optimized ultrasonic extraction technology of total flavonoids from the A. gymnandrum Maxim was studied by using the methodology of single factor and orthogonal design to study the effects of operation conditions, such as ethanol content, ultrasonic wave power, temperature, ultrasonic wave radiation time, and the ratio of sample weight to solvent volume.
Result:
Through the orthogonal experiment, the optimal extraction conditions were determined as follows: Ultrasonic power 100 W, ultrasonic temperature 45°C, 60% ethyl alcohol, extraction time 30 min, and solid–liquid ratio 1:20.
Conclusion:
Under the optimum parameters, the extraction ratio of total flavonoids from the A. gymnandrum Maxim is about 1.278%.
doi:10.4103/0973-1296.127364
PMCID: PMC4047569  PMID: 24914295
Aconitum gymnandrum; orthogonal design; total flavonoids; ultrasound-assisted extraction
8.  A Focused Educational Program after Religious Services to Improve Organ Donation in Hispanic Americans 
Clinical transplantation  2012;26(6):E634-E640.
Religion is an important determinant in Hispanic Americans (HA) becoming organ donors as HA often believe religion forbids donation. We investigated the effect of an educational program targeting HA organ donation in places of worship. A prospective observational study was conducted at four Catholic churches with a high percentage of HA. A 45 minute ‘culturally sensitive’ educational program, conducted in Spanish, was implemented. Organ donation awareness, knowledge, perception and beliefs, as well as the intent to become an organ donor, were measured before and after the intervention. Differences between before and after the intervention were analyzed. A total of 182 surveys were collected before and 159 surveys were collected after the educational program. A significant increase was observed in organ donation knowledge (54% vs. 70%, p<0.0001), perception (43% vs. 58%, p<0.0001) and beliefs (50% vs. 60%, p=0.0001). However, no significant difference was found in the willingness to discuss donation with family, intent-to-donate, or registering to donate after the intervention. This study demonstrates that a focused educational program in places of worship can significantly improve HA knowledge, perceptions, and beliefs regarding organ donation. Further work is needed to understand why intent-to-donate does not increase despite the increase in organ donation awareness.
doi:10.1111/ctr.12036
PMCID: PMC3538818  PMID: 23106648
organ donation; Hispanic; church; religion; transplantation
9.  De novo combined lamivudine and adefovir dipivoxil therapy vs entecavir monotherapy for hepatitis B virus-related decompensated cirrhosis 
AIM: To compare efficacy of combined lamivudine (LAM) and adefovir dipivoxil (ADV) therapy with that of entecavir (ETV) monotherapy for hepatitis B virus (HBV)-related decompensated liver cirrhosis.
METHODS: A total of 120 naïve patients with HBV-related decompensated cirrhosis participated in this study. Sixty patients were treated with combined LAM and ADV therapy (LAM + ADV group), while the other 60 were treated with ETV monotherapy (ETV group) for two years. Tests for liver and kidney function, alpha-fetoprotein, HBV serum markers, HBV DNA load, prothrombin time (PT), and ultrasonography or computed tomography scan of the liver were performed every 1 to 3 mo. Repeated measure ANOVA and the χ2 test were performed to compare the efficacy, side effects, and the cumulative survival rates at 48 and 96 wk.
RESULTS: Forty-five patients in each group were observed for 96 wk. No significant differences in HBV DNA negative rates and alanine aminotransferase (ALT) normalization rates at weeks 48 (χ2 = 2.12 and 2.88) and 96 (χ2 = 3.21 and 3.24) between the two groups were observed. Hepatitis B e antigen seroconversion rate in the LAM + ADV group at week 96 was significantly higher in the ETV group (43.5% vs 36.4%, χ2 = 4.09, P < 0.05). Viral breakthrough occurred in 2 cases (4.4%) by week 48 and in 3 cases (6.7%) by week 96 in the LAM + ADV group, and no viral mutation was detected. In the ETV group, viral breakthrough occurred in 1 case (2.2%) at the end of week 96. An increase in albumin (F = 18.9 and 17.3), decrease in total bilirubin and in ALT (F = 16.5, 17.1 and 23.7, 24.8), reduced PT (F = 22.7 and 24.5), and improved Child-Turcotte-Pugh and the model for end-stage liver disease scores (F = 18.5, 17.8, and 24.2, 23.8) were observed in both groups. The cumulative rates of mortality and liver transplantation were 16.7% (10/60) and 18.3% (11/60) in the LAM + ADV and ETV groups, respectively.
CONCLUSION: Both LAM + ADV combination therapy and ETV monotherapy can effectively inhibit HBV replication, improve liver function, and decrease mortality.
doi:10.3748/wjg.v19.i37.6278
PMCID: PMC3787360  PMID: 24115827
Chronic hepatitis B; Decompensated liver cirrhosis; Lamivudine; Adefovir dipivoxil; Combination therapy; Entecavir
10.  Coronary Artery Disease is Associated with Cognitive Decline Independent of MRI Changes in Cognitively Normal Elderly 
BACKGROUND/OBJECTIVES
White matter hyperintensities (WMH) and silent brain infarcts (SBI) have been associated with both vascular factors and cognitive decline. We examined among cognitively normal elderly, whether vascular factors predict cognitive decline and whether these associations are mediated by MRI measures of subclinical vascular brain injury.
DESIGN
Prospective multi-site longitudinal study of subcortical ischemic vascular diseases
SETTING
Memory and aging centers in California
PARTICIPANTS
We studied 74 participants who were cognitively normal at entry and received at least 2 neuropsychological evaluations and 2 MRI exams over an average follow-up of 6.9 years.
MEASUREMENTS
Item response theory was used to create composite scores of global, verbal memory, and executive functioning. Volumetric MRI measures included WMH, SBI, hippocampus, and cortical gray matter (CGM). We used linear mixed effects models to examine the associations between vascular factors, MRI measures, and cognitive scores.
RESULTS
History of coronary artery disease (CAD) was associated with greater declines in global, verbal memory, and executive cognition. The CAD associations remained after controlling for changes in WMH, SBI, hippocampal and CGM volumes.
CONCLUSION
History of CAD may be a surrogate marker for clinically significant atherosclerosis which also affects the brain. Structural MRI measures of WMH and SBI do not fully capture the potential adverse effects of atherosclerosis on the brain. Future longitudinal studies of cognition should incorporate direct measures of atherosclerosis in cerebral arteries, as well as more sensitive neuroimaging measures.
doi:10.1111/j.1532-5415.2011.03839.x
PMCID: PMC3302932  PMID: 22283410
cognitively normal elderly; coronary artery disease; cognitive decline; MRI
11.  crcTRP: A Translational Research Platform for Colorectal Cancer 
Colorectal cancer is a leading cause of cancer mortality in both developed and developing countries. Transforming basic research results into clinical practice is one of the key tasks of translational research, which will greatly improve the diagnosis and treatments of colorectal cancer. In this paper, a translational research platform for colorectal cancer, named crcTRP, is introduced. crcTRP serves the colorectal cancer translational research by providing various types of biomedical information related with colorectal cancer to the community. The information, including clinical data, epidemiology data, individual omics data, and public omics data, was collected through a multisource biomedical information collection solution and then integrated in a clinic-omics database, which was constructed with EAV-ER model for flexibility and efficiency. A preliminary exploration of conducting translational research on crcTRP was implemented and worked out a set of clinic-genomic relations, linking clinical data with genomic data. These relations have also been applied to crcTRP to make it more conductive for cancer translational research.
doi:10.1155/2013/930362
PMCID: PMC3575041  PMID: 23431356
12.  Bisphenol A Accelerates Toxic Amyloid Formation of Human Islet Amyloid Polypeptide: A Possible Link between Bisphenol A Exposure and Type 2 Diabetes 
PLoS ONE  2013;8(1):e54198.
Bisphenol A (BPA) is a chemical compound widely used in manufacturing plastic products. Recent epidemiological studies suggest BPA exposure is positively associated with the incidence of type 2 diabetes mellitus (T2DM), however the mechanisms underlying this link remain unclear. Human islet amyloid polypeptide (hIAPP) is a hormone synthesized and secreted by the pancreatic β-cells. Misfolding of hIAPP into toxic oligomers and mature fibrils can disrupt cell membrane and lead to β-cell death, which is regarded as one of the causative factors of T2DM. To test whether there are any connections between BPA exposure and hIAPP misfolding, we investigated the effects of BPA on hIAPP aggregation using thioflavin-T based fluorescence, transmission electronic microscopy, circular dichroism, dynamic light scattering, size-exclusion chromatography,fluorescence-dye leakage assay in an artificial micelle system and the generation of reactive oxygen species in INS-1 cells. We demonstrated that BPA not only dose-dependently promotes the aggregation of hIAPP and enhances the membrane disruption effects of hIAPP, but also promotes the extent of hIAPP aggregation related oxidative stress. Taken together, our results suggest that BPA exposure increased T2DM risk may involve the exacerbated toxic aggregation of hIAPP.
doi:10.1371/journal.pone.0054198
PMCID: PMC3553173  PMID: 23372685
13.  1-Chloro-1H-1,2,3-benzotriazole 
The title compound, C6H4ClN3, is essentially planar, with a maximum deviation of 0.007 (3) Å. In the crystal, a short contact of 2.818 (3) Å is observed between N and Cl atoms of adjacent mol­ecules.
doi:10.1107/S1600536812044820
PMCID: PMC3589014  PMID: 23476250
14.  Chinese-Language Montreal Cognitive Assessment for Cantonese or Mandarin Speakers: Age, Education, and Gender Effects 
The Montreal Cognitive Assessment Chinese-Language Los Angeles version (MoCA-ChLA) was developed and administered during an in-home interview to 1,192 participants (mean age 62.5 years, mean education 11.6 years) in a population-based Chinese American Eye Study (CHES) in Los Angeles. The MoCA-ChLA score (mean ± SD) was 23.8 ± 4.2 with little ceiling and no floor effects. The score increased with higher education, decreased with advancing age, and was not related to gender. Compared to the education 1–6 years group, the mean MoCA-ChLA score was 2.6 and 4.6 higher in the education 7–11 and 12–20 years groups, respectively. The Mandarin- (n = 612) and Cantonese- (n = 612) speaking subgroups performed comparably; Cronbach's alpha of the MoCA-ChLA score was 0.78 and 0.79 for these two groups, respectively. Item response theory analysis showed good discriminating power for executive function and memory. These properties support the MoCA-ChLA as a useful screening tool for aging and dementia studies for Mandarin or Cantonese speakers.
doi:10.1155/2012/204623
PMCID: PMC3399373  PMID: 22830073
15.  Vascular risk factors and Alzheimer's disease: are these risk factors for plaques and tangles or for concomitant vascular pathology that increases the likelihood of dementia? An evidence-based review 
Recent epidemiologic studies have noted that risk factors for atherosclerosis (for example, diabetes mellitus, hypertension, and hyperlipidemia) are associated with increased risk of incident Alzheimer's disease (AD). In this evidence-based review, we frame the proposition as a question: are vascular risk factors also risk factors for plaques and tangles or just for concomitant vascular pathology that increases the likelihood of dementia? To date, no representative, prospective studies with autopsy (evidence level A) show significant positive associations between diabetes mellitus, hypertension, or intracranial atherosclerosis and plaques or tangles. Some prospective, representative, epidemiologic studies (evidence level B) show associations between diabetes, hypertension, hyperlipidemia, and aggregated risk factors with clinically diagnosed incident AD. However, the strength of association diminishes in the following order: vascular dementia (VaD) > AD + VaD > AD. This pattern is arguably more consistent with the hypothesis that atherosclerosis promotes subclinical vascular brain injury, thereby increasing the likelihood of dementia and in some cases making symptoms present earlier. Several autopsy studies from AD brain banks (evidence level C) have observed positive associations between intracranial atherosclerosis and severity of plaques and tangles. However, these studies may reflect selection bias; these associations are not confirmed when cases are drawn from non-dementia settings. We conclude that, at the present time, there is no consistent body of evidence to show that vascular risk factors increase AD pathology.
doi:10.1186/alzrt98
PMCID: PMC3471388  PMID: 22182734
16.  Antiaging Effect of Pine Pollen in Human Diploid Fibroblasts and in a Mouse Model Induced by D-Galactose 
The present paper was designed to investigate the effect of pine pollen against aging in human diploid fibroblast 2BS cells and in an accelerated aging model, which was established by subcutaneous injections with D-galactose daily for 8 weeks in C57BL/6J mice. Pine pollen (1 mg/mL and 2 mg/mL) is proved to delay the replicative senescence of 2BS cells as evidenced by enhanced cell proliferation, decreased SA-β-Gal activity, and reversed expression of senescence-associated molecular markers, such as p53, p21Waf1, p16INK4a, PTEN, and p27Kip1 in late PD cells. Besides, pine pollen reversed D-galactose-induced aging effects in neural activity and inflammatory cytokine levels, as indicated by improved memory latency time and reduced error rate in step-down test and decreased concentrations of IL-6 and TNF-α in model mice. Similar to the role of AGEs (advanced glycation endproducts) formation inhibitor aminoguanidine (AG), pine pollen inhibited D-galactose-induced increment of AGEs levels thus reversed the aging phenotypes in model mice. Furthermore, the declined antioxidant activity was obviously reversed upon pine pollen treatment, which may account for its inhibitory effect on nonenzymatic glycation (NEG) in vivo. Our finding presents pine pollen as an attractive agent with potential to retard aging and attenuate age-related diseases in humans.
doi:10.1155/2012/750963
PMCID: PMC3345248  PMID: 22577492
17.  Cognitive Effects of Atypical Antipsychotic Medications in Patients with Alzheimer’s Disease: Outcomes from CATIE-AD 
The American Journal of Psychiatry  2011;168(8):831-839.
Objective
The impact of the atypical antipsychotics, olanzapine, quetiapine and risperidone on cognition in patients with Alzheimer’s disease is unclear. This report describes the effects of time and treatment on neuropsychological function during the Clinical Antipsychotic Trials of Intervention Effectiveness Alzheimer’s disease study (CATIE-AD).
Method
CATIE-AD included 421 Alzheimer’s disease outpatients with psychosis or agitated/aggressive behavior, randomized to masked, flexible-dose olanzapine, quetiapine, risperidone or placebo. Based on clinician’s judgment, patients could discontinue originally assigned medication and be randomized to another medication. They were followed for 36 weeks. Cognitive assessments were obtained at baseline, 12 weeks, 24 weeks and 36 weeks. Outcomes were compared among 357 patients with baseline and at least one follow-up cognitive measure obtained while on their prescribed medication or placebo for at least 2 weeks before cognitive testing.
Results
Overall, patients showed steady, significant declines over time in most cognitive areas, including Mini-mental State Examination (2.4 points over 36 weeks) and Alzheimer’s Disease Assessment Scale-cog (4.4 points). Patients on antipsychotics declined more than patients on placebo on multiple cognitive measures, including the MMSE (p=0.004), BPRS cognitive subscale (p=0.05), and a cognitive summary score summarizing change on 18 cognitive tests (p=0.004).
Conclusions
In CATIE-AD atypical antipsychotics were associated with worsening cognitive function at a magnitude consistent with one year’s deterioration compared with placebo. Further cognitive impairment is an additional risk of atypical antipsychotic treatment for Alzheimer’s disease patients that should be considered when considering treatment.
doi:10.1176/appi.ajp.2011.08121844
PMCID: PMC3310182  PMID: 21572163
18.  Rise in dermal CD11c+ dendritic cells associates with early-stage development of psoriatic lesions 
Archives of Dermatological Research  2012;304(6):443-449.
There is limited information available regarding the phenotype and function of leukocytes involved in the earliest stages of psoriatic lesion development. In this study, we examined the presence of different types of leukocytes in psoriatic point lesions collected at three 1-week interval time points from a recent and simultaneously formed group of point lesions. The cells were quantified and compared with K16 expression and epidermal thickness, both typically increased in this disease and considered as hallmarks. We found a significant correlation between K16+ cell increment and the increase in epidermal thickness in the timeframe of 14 days. The change in CD3+, CD4+, and CD8+ T-cell numbers in the dermis showed a significant association with these two features from d7 to d14, whereas in the epidermis only CD8+ T cells demonstrated a significant correlation. Remarkably, the relationship between T cells and disease progression was preceded by a significant correlation of CD11c+ dendritic cells (DCs) with K16 expression and epidermal thickness from baseline onwards. Interestingly, there was also a numeric correlation of CD11c+ DCs with the CD3+ T-cell shifts from d7 to d14. A significant correlation was also found between dermal CD14+ cells and K16 expression from d7 to d14. BDCA-2+ plasmacytoid DCs were absent in non-lesional skin, but found at low numbers in most lesions. The change in plasmacytoid DC or neutrophil numbers did not correlate with lesion development. In conclusion, our study suggests a relevant role for T cells, and in particular dermal CD11c+ DCs, in the earliest stage of psoriatic lesion development.
doi:10.1007/s00403-012-1231-7
PMCID: PMC3401310  PMID: 22438166
Psoriasis; Point lesion; Early infiltrate; T cell; Dendritic cell; CD11c
19.  Combination of blood oxygen level–dependent functional magnetic resonance imaging and visual evoked potential recordings for abnormal visual cortex in two types of amblyopia 
Molecular Vision  2012;18:909-919.
Purpose
To elucidate the different neuromechanisms of subjects with strabismic and anisometropic amblyopia compared with normal vision subjects using blood oxygen level–dependent functional magnetic resonance imaging (BOLD-fMRI) and pattern-reversal visual evoked potential (PR-VEP).
Methods
Fifty-three subjects, age range seven to 12 years, diagnosed with strabismic amblyopia (17 cases), anisometropic amblyopia (20 cases), and normal vision (16 cases), were examined using the BOLD-fMRI and PR-VEP of UTAS-E3000 techniques. Cortical activation by binocular viewing of reversal checkerboard patterns was examined in terms of the calcarine region of interest (ROI)-based and spatial frequency–dependent analysis. The correlation of cortical activation in fMRI and the P100 amplitude in VEP were analyzed using the SPSS 12.0 software package.
Results
In the BOLD-fMRI procedure, reduced areas and decreased activation levels were found in Brodmann area (BA) 17 and other extrastriate areas in subjects with amblyopia compared with the normal vision group. In general, the reduced areas mainly resided in the striate visual cortex in subjects with anisometropic amblyopia. In subjects with strabismic amblyopia, a more significant cortical impairment was found in bilateral BA 18 and BA 19 than that in subjects with anisometropic amblyopia. The activation by high-spatial-frequency stimuli was reduced in bilateral BA 18 and 19 as well as BA 17 in subjects with anisometropic amblyopia, whereas the activation was mainly reduced in BA 18 and BA 19 in subjects with strabismic amblyopia. These findings were further confirmed by the ROI-based analysis of BA 17. During spatial frequency–dependent VEP detection, subjects with anisometropic amblyopia had reduced sensitivity for high spatial frequency compared to subjects with strabismic amblyopia. The cortical activation in fMRI with the calcarine ROI-based analysis of BA 17 was significantly correlated with the P100 amplitude in VEP recording.
Conclusions
This study suggested that different types of amblyopia had different cortical responses and combinations of spatial frequency–dependent BOLD-fMRI with PR-VEP could differentiate among various kinds of amblyopia according to the different cortical responses. This study can supply new methods for amblyopia neurology study.
PMCID: PMC3335782  PMID: 22539870
20.  Successful bortezomib treatment in combination with dexamethasone and thalidomide for previously untreated epidural plasmacytoma 
Oncology Letters  2011;3(3):557-559.
Epidural plasmacytoma is a rare clinical entity of plasma cell neoplasms. The optimal management of extra medullary plasmacytoma remains unclear, particularly for bulky masses. In this study, we report the case of a 35-year-old male who presented with the inability to walk, urinary incontinence and superficial and deep sensory disturbance. Spinal magnetic resonance imaging revealed a large epidural mass compressing the spinal cord at the level of T2–T4. The patient underwent surgical T2–T4 vertebral canal decompression. Histopathological examination and other findings confirmed the diagnosis of extramedullary plasmacytoma. The patient was treated with bortezomib in combination with dexamethasone and thalidomide. Following 4 cycles of chemotherapy, the patient achieved an excellent clinical response. Over 1 year following the initial diagnosis, the patient was in complete remission with no evidence of local relapse or evolution to multiple myeloma. This is the first case of a previously untreated epidural plasmacytoma, which was successfully treated with bortezomib-containing chemotherapy.
doi:10.3892/ol.2011.539
PMCID: PMC3464085  PMID: 22740951
bortezomib; epidural; plasmacytoma
21.  A set of miRNAs that involve in the pathways of drug resistance and leukemic stem-cell differentiation is associated with the risk of relapse and glucocorticoid response in childhood ALL 
Human Molecular Genetics  2011;20(24):4903-4915.
Relapse is a major challenge in the successful treatment of childhood acute lymphoblastic leukemia (ALL). Despite intensive research efforts, the mechanisms of ALL relapse are still not fully understood. An understanding of the molecular mechanisms underlying treatment outcome, therapy response and the biology of relapse is required. In this study, we carried out a genome-wide microRNA (miRNA) microarray analysis to determine the miRNA expression profiles and relapse-associated miRNA patterns in a panel of matched diagnosis–relapse or diagnosis–complete remission (CR) childhood ALL samples. A set of miRNAs differentially expressed either in relapsed patients or at diagnosis compared with CR was further validated by quantitative real-time polymerase chain reaction in an independent sample set. Analysis of the predicted functions of target genes based on gene ontology ‘biological process’ categories revealed that the abnormally expressed miRNAs are associated with oncogenesis, classical multidrug resistance pathways and leukemic stem cell self-renewal and differentiation pathways. Several targets of the miRNAs associated with ALL relapse were experimentally validated, including FOXO3, BMI1 and E2F1. We further investigated the association of these dysregulated miRNAs with clinical outcome and confirmed significant associations for miR-708, miR-223 and miR-27a with individual relapse-free survival. Notably, miR-708 was also found to be associated with the in vivo glucocorticoid therapy response and with disease risk stratification. These miRNAs and their targets might be used to optimize anti-leukemic therapy, and serve as novel targets for development of new countermeasures of leukemia. This fundamental study may also contribute to establish the mechanisms of relapse in other cancers.
doi:10.1093/hmg/ddr428
PMCID: PMC3221537  PMID: 21926415
22.  Curcumin Inhibits Neuronal and Vascular Degeneration in Retina after Ischemia and Reperfusion Injury 
PLoS ONE  2011;6(8):e23194.
Background
Neuron loss, glial activation and vascular degeneration are common sequelae of ischemia-reperfusion (I/R) injury in ocular diseases. The present study was conducted to explore the ability of curcumin to inhibit retinal I/R injury, and to investigate underlying mechanisms of the drug effects.
Methodology/Principal Findings
Different dosages of curcumin were administered. I/R injury was induced by elevating the intraocular pressure for 60 min followed by reperfusion. Cell bodies, brn3a stained cells and TUNEL positive apoptotic cells in the ganglion cell layer (GCL) were quantitated, and the number of degenerate capillaries was assessed. The activation of glial cells was measured by the expression level of GFAP. Signaling pathways including IKK-IκBα, JAK-STAT1/3, ERK/MAPK and the expression levels of β-tubulin III and MCP-1 were measured by western blot analysis. Pre-treatment using 0.01%–0.25% curcumin in diets significantly inhibited I/R-induced cell loss in GCL. 0.05% curcumin pre-treatment inhibited I/R-induced degeneration of retinal capillaries, TUNEL-positive apoptotic cell death in the GCL, brn3a stained cell loss, the I/R-induced up-regulation of MCP-1, IKKα, p-IκBα and p-STAT3 (Tyr), and down-regulation of β-tubulin III. This dose showed no effect on injury-induced GFAP overexpression. Moreover, 0.05% curcumin administered 2 days after the injury also showed a vaso-protective effect.
Conclusions/Significance
Curcumin protects retinal neurons and microvessels against I/R injury. The beneficial effects of curcumin on neurovascular degeneration may occur through its inhibitory effects on injury-induced activation of NF-κB and STAT3, and on over-expression of MCP-1. Curcumin may therefore serve as a promising candidate for retinal ischemic diseases.
doi:10.1371/journal.pone.0023194
PMCID: PMC3153496  PMID: 21858029
23.  Abnormal Mitochondrial Dynamics and Neurodegenerative Diseases 
Biochimica et biophysica acta  2009;1802(1):135-142.
Mitochondrial dysfunction is a prominent feature of various neurodegenerative diseases. A deeper understanding of the remarkably dynamic nature of mitochondria, characterized by a delicate balance of fission and fusion, has helped to fertilize a recent wave of new studies demonstrating abnormal mitochondrial dynamics in neurodegenerative diseases. This review highlights mitochondrial dysfunction and abnormal mitochondrial dynamics in Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, and Huntington disease and discusses how these abnormal mitochondrial dynamics may contribute to mitochondrial and neuronal dysfunction. We propose that abnormal mitochondrial dynamics represents a key common pathway that mediates or amplifies mitochondrial dysfunction and neuronal dysfunction during the course of neurodegeneration.
doi:10.1016/j.bbadis.2009.09.013
PMCID: PMC2790543  PMID: 19799998
Mitochondrial Dynamics; Mitochondrial Dysfunction; Mitochondrial Distribution; Synaptic Dysfunction; DLP1; Alzheimer Disease; Parkinson's disease
24.  Diesel exhaust exposure induces angiogenesis 
Toxicology letters  2009;191(1):57-68.
Our aim was to test the hypothesis that exposure to whole diesel exhaust (WDE) would enhance angiogenesis/vasculogenesis. Male apolipoprotein E-deficient mice, with either scaffold implantation subcutaneously or hindlimb ischemia, were exposed to either WDE (containing diesel exhaust particle [DEP] at a concentration of about 1 mg/m3) or filtered air 6 hours/day, 5 days/week in a whole body exposure chamber for 2, 5, or 8 weeks, respectively. WDE exposure significantly increased total cell counts in the scaffolds, aortic, and perivascular fat tissues. Macrophage infiltration was enhanced and CD31 expression increased in the scaffolds, which was coupled by increased α-smooth muscle actin (α-SMA) expression. WDE exposure led to increased CD31 expression, while decreasing endothelial nitric oxide synthase in the aortic wall. The vessel volume measured by micro-CT was increased in ischemic and non-ischemic hindlimbs in response to WDE exposure. DEP exposure induced capillary-like tube formation in endothelial cells in vitro, and caused capillary sprouting from aortic rings ex vivo. In addition, WDE exposure significantly increased mRNA expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor (HIF)-1α, while decreasing prolylhydroxylase (PHD) 2 expression. WDE exposure increases inflammatory cell infiltration, enhances the vessel volume/flow, and increases capillary tube formation and sprouting, thereby inducing angiogenesis and vasculogenesis. The angiogenic effects may occur through increasing HIF-1α and VEGF while decreasing PHD2 expression.
doi:10.1016/j.toxlet.2009.08.006
PMCID: PMC2784267  PMID: 19683567
particulate matter; diesel exhaust; hypoxia-inducible factor 1; prolylhydroxylase 2
25.  Regulation of Colonic Epithelial Repair in Mice by Toll-like Receptors and Hyaluronic Acid 
Gastroenterology  2009;137(6):2041-2051.
Background and Aims
The protective component of the host response to dextran sodium sulfate colitis in the mouse is mediated through the activation of TLR4, the induction of COX-2 and PGE2 production. TLR4 ligands include bacterial lipolysaccharide and hyaluronic acid a, component of the extracellular matrix. Our hypothesis is that hyaluronic acid, through TLRs, plays a protective role in the host response to dextran sodium sulfate colitis.
Methods
Dextran sodium sulfate (2.5%) was administered for seven days in wild type and MyD88−/− mice. The mice also received intraperitoneal hyaluronic acid. The expression of hyaluronic acid, COX-2, and MIP2 were evaluated by immunohistochemistry.
Results
Dextran sodium sulfate induced a marked increase in hyaluronic acid in the lamina propria of wild type but not MyD88−/− mice. Treatment with DSS also induced the MyD88-dependent expression of hyaluronic acid synthases 2 and 3, enzymes involved in hyaluronic acid synthesis, in lamina propria macrophages. Exogenous hyaluronic acid induced the expression of TNFα, MIP-2 and COX-2 in the colon in a MyD88-dependent manner. In wild type, but not MyD88−/−, TLR4−/−, COX-2−/− mice, hyaluronic acid was protective against dextran sodium sulfate colitis. In wild type mice hyaluronic acid was therapeutic in established DSS colitis.
Conclusion
Endogenous hyaluronic acid expression is markedly increased in dextran sodium sulfate colitis and preserves the epithelium through TLR activation and COX-2 expression. Furthermore exogenous hyaluronic acid, through the activation of TLRs and the production of PGE2 through COX-2 has protective effects in dextran sodium sulfate colitis.
doi:10.1053/j.gastro.2009.08.055
PMCID: PMC2789856  PMID: 19732774

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