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1.  Trajectories of Behavioral Disturbance in Dementia 
Predicting the progression of dementia is a challenge for clinicians yet this information is highly valued by patients’ families. An informally observed 4-stage model of dementia can be helpful in educating caregivers and preparing them for what lies ahead. In the behavioral variant of frontotemporal dementia (bvFTD), this model describes the evolution of behavioral disturbances and is characterized by an inflection point between stage 2 (progressively severe behavioral aberration) and stage 3 (increasing apathy and remission of behavior problems). In this study we sought evidence for this model using a database of serial Neuropsychiatric Inventory (NPI) scores for 45 patients with FTD and 47 patients with Alzheimer’s disease (AD). We transformed the NPI scores into a single variable for each participant that represented the rate of change in NPI score over time (NPI slope) and used this as the dependent variable in a multivariate linear regression. Age at onset of dementia, NPI score at initial visit, and duration of illness at first NPI all contributed significantly to the regression model for NPI slope in the bvFTD group. Participants with an initial NPI acquired before 6 years of disease duration tended to have a more positive NPI slope (representing worsening behavioral disturbances) than those with an initial NPI performed after 6 years. None of the aforementioned variables were significantly associated with NPI slope in the AD group. These results support a crescendo-decrescendo trajectory of behavioral symptoms in bvFTD but do not suggest that there is a similar pattern in AD, and further longitudinal data collection is necessary.
PMCID: PMC4309273  PMID: 22531424
Alzheimer’s disease; agitation; apathy; behavioral symptoms; disease progression; frontotemporal dementia; longitudinal study; neurobehavioral manifestations
2.  Having a family doctor was associated with lower utilization of hospital-based health services 
Primary care in the United States and most countries in Asia are provided by a variety of doctors. However, effectiveness of such diversified primary care in gate-keeping secondary medical services is unknown. This study aimed to evaluate health services utilization rates of hospital emergency and admission services among people who used different primary care doctors in Hong Kong.
This study was a population-based cross-sectional telephone survey using structured questionnaire on health services utilization rates and pattern in Hong Kong in 2007 to 2008. Information on the choice of primary care doctors, utilization rates and patterns of primary care service were collected. Poisson and logistic regression analyses were used to explore any differences in service utilization rates and patterns among people using different types of primary care doctors.
Out of 3148 subjects who completed the survey, 1896 (60.2%) had regular primary care doctors, of whom 1150 (60.7%) regarded their regular doctors as their family doctors (RFD). 1157 (36.8%) of them did not use any regular doctors (NRD). Only 4.3% of the RFD group (vs 7.8% of other regular doctors (ORD) and 9.6% of NRD) visited emergency service and only 1.7% (vs 3.6% of ORD and 4.0% of NRD) were admitted to hospital for their last episode of illness. Regression analyses controlling for sociodemographics and health status confirmed that respondents having RFD were less likely to use emergency service than people who had NRD (OR 0.479) or ORD (OR 0.624) or being admitted to hospital (OR 0.458 vs NRD and 0.514 vs ORD) for their last episode of illness.
Primary care is the most effective in gate-keeping secondary care among people with regular family doctors. People without any regular primary care doctor were more likely to use emergency service as primary care. The findings supported a family doctor-led primary care model.
Trial registration number ID: NCT01422031.
Electronic supplementary material
The online version of this article (doi:10.1186/s12913-015-0705-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4312460  PMID: 25627936
Family doctor; Health utilization; Hospitalization; Emergency services; Chinese; Count data
3.  Natural Whisker-Guided Behavior by Head-Fixed Mice in Tactile Virtual Reality 
The Journal of Neuroscience  2014;34(29):9537-9550.
During many natural behaviors the relevant sensory stimuli and motor outputs are difficult to quantify. Furthermore, the high dimensionality of the space of possible stimuli and movements compounds the problem of experimental control. Head fixation facilitates stimulus control and movement tracking, and can be combined with techniques for recording and manipulating neural activity. However, head-fixed mouse behaviors are typically trained through extensive instrumental conditioning. Here we present a whisker-based, tactile virtual reality system for head-fixed mice running on a spherical treadmill. Head-fixed mice displayed natural movements, including running and rhythmic whisking at 16 Hz. Whisking was centered on a set point that changed in concert with running so that more protracted whisking was correlated with faster running. During turning, whiskers moved in an asymmetric manner, with more retracted whisker positions in the turn direction and protracted whisker movements on the other side. Under some conditions, whisker movements were phase-coupled to strides. We simulated a virtual reality tactile corridor, consisting of two moveable walls controlled in a closed-loop by running speed and direction. Mice used their whiskers to track the walls of the winding corridor without training. Whisker curvature changes, which cause forces in the sensory follicles at the base of the whiskers, were tightly coupled to distance from the walls. Our behavioral system allows for precise control of sensorimotor variables during natural tactile navigation.
PMCID: PMC4099538  PMID: 25031397
4.  Pax6 Mediates β-Catenin Signaling for Self-Renewal and Neurogenesis by Neocortical Radial Glial Stem Cells 
Stem cells (Dayton, Ohio)  2014;32(1):45-58.
The Wnt/β-catenin pathway is a critical stem cell regulator and plays important roles in neuroepithelial cells during early gestation. However, the role of Wnt/β-catenin signaling in radial glia, a major neural stem cell population expanded by midgestation, remains poorly understood. This study shows that genetic ablation of β-catenin with hGFAP-Cre mice inhibits neocortical formation by disrupting radial glial development. Reduced radial glia and intermediate progenitors are found in the β-catenin-deficient neocortex during late gestation. Increased apoptosis and divergent localization of radial glia in the subventricular zone are also observed in the mutant neocortex. In vivo and in vitro proliferation and neurogenesis as well as oligodendrogenesis by cortical radial glia or by dissociated neural stem cells are significantly defective in the mutants. Neocortical layer patterning is not apparently altered, while astrogliogenesis is ectopically increased in the mutants. At the molecular level, the expression of the transcription factor Pax6 is dramatically diminished in the cortical radial glia and the sphere-forming neural stem cells of β-catenin-deficient mutants. Chromatin immunoprecipitation and luciferase assays demonstrate that β-catenin/Tcf complex binds to Pax6 promoter and induces its transcriptional activities. The forced expression of Pax6 through lentiviral transduction partially rescues the defective proliferation and neurogenesis by β-catenin-deficient neural stem cells. Thus, Pax6 is a novel downstream target of the Wnt/β-catenin pathway, and β-catenin/Pax6 signaling plays critical roles in self-renewal and neurogenesis of radial glia/neural stem cells during neocortical development.
PMCID: PMC3963407  PMID: 24115331
Neural stem cells; Radial glia; Wnt/β-catenin; Pax6; Proliferation; Neurogenesis
5.  Chinese translation and validation of a parental feeding style questionnaire for parents of Hong Kong preschoolers 
BMC Public Health  2014;14(1):1194.
Childhood obesity is a major public health issue in many countries, including China. The importance of parenting relative to the healthy development of children requires the development of instruments for assessing parental influence on child dietary pattern. This study aimed to confirm the internal reliability and validity of a self-report measure on parental feeding styles, including emotional feeding, instrumental feeding, prompting or encouragement to eat, and control over eating.
A 27-item parental feeding style questionnaire (PFSQ) was translated into Chinese and then translated back into English to verify consistency. The questionnaire was then used to conduct a cross-sectional survey on the parents of Hong Kong preschoolers. The internal reliability and validity of the questionnaire were examined by Cronbach’s alpha and exploratory factor analysis, respectively.
4,553 completed questionnaires were received. Cronbach’s alpha of subscales ranged from 0.63 to 0.81, and the overall reliability was good (alpha = 0.75). The factor structure of this questionnaire was similar to that of the original and Turkish versions. One-factor structure was identified for emotional feeding, instrumental feeding (four items), and prompting or encouragement to eat, whereas a two-factor structure was revealed for control over eating.
The Chinese version of the PFSQ has good reliability and validity in assessing parental feeding styles in Hong Kong. Researchers can use this instrument to improve their understanding on how parental feeding styles may affect the dietary patterns and ultimately the weight statuses of children among Chinese-speaking populations across different countries.
PMCID: PMC4251682  PMID: 25413727
Validation; Parental feeding style questionnaire; Childhood obesity
6.  Genetic Analysis of a Novel Tubulin Mutation That Redirects Synaptic Vesicle Targeting and Causes Neurite Degeneration in C. elegans 
PLoS Genetics  2014;10(11):e1004715.
Neuronal cargos are differentially targeted to either axons or dendrites, and this polarized cargo targeting critically depends on the interaction between microtubules and molecular motors. From a forward mutagenesis screen, we identified a gain-of-function mutation in the C. elegans α-tubulin gene mec-12 that triggered synaptic vesicle mistargeting, neurite swelling and neurodegeneration in the touch receptor neurons. This missense mutation replaced an absolutely conserved glycine in the H12 helix with glutamic acid, resulting in increased negative charges at the C-terminus of α-tubulin. Synaptic vesicle mistargeting in the mutant neurons was suppressed by reducing dynein function, suggesting that aberrantly high dynein activity mistargeted synaptic vesicles. We demonstrated that dynein showed preference towards binding mutant microtubules over wild-type in microtubule sedimentation assay. By contrast, neurite swelling and neurodegeneration were independent of dynein and could be ameliorated by genetic paralysis of the animal. This suggests that mutant microtubules render the neurons susceptible to recurrent mechanical stress induced by muscle activity, which is consistent with the observation that microtubule network was disorganized under electron microscopy. Our work provides insights into how microtubule-dynein interaction instructs synaptic vesicle targeting and the importance of microtubule in the maintenance of neuronal structures against constant mechanical stress.
Author Summary
Axons and dendrites are two classes of neuronal process that differ in their functions and molecular compositions. Proteins important for synaptic functions are mostly synthesized in the cell body and sorted differentially into the axon or dendrites. Microtubules in the axon and dendrite maintain their structural integrity and regulate polarized protein transport into these compartments. We identified a novel α-tubulin mutation in C. elegans that caused mistargeting of synaptic vesicles and induced progressive neurite swelling, which resulted in late-onset neurodegeneration. We showed that this tubulin mutation weakened microtubule network and abnormally increased microtubule affinity for dynein, a motor protein responsible for cargo sorting to the dendrite. This enhanced microtubule-dynein affinity is due to augmented negative charge at the carboxyl terminus of α-tubulin. Neurite swelling and neurodegeneration could be ameliorated by reduced physical activity, suggesting that recurrent mechanical strain from muscle contraction jeopardized neurite integrity in the long run. Mutations in α- and β-tubulins are found in human neurological diseases; our findings therefore contribute to understanding the pathogenic mechanism of human neurological diseases associated with tubulin mutations.
PMCID: PMC4230729  PMID: 25392990
7.  Transcriptome reconstruction and annotation of cynomolgus and African green monkey 
BMC Genomics  2014;15(1):846.
Non-human primates (NHPs) and humans share major biological mechanisms, functions, and responses due to their close evolutionary relationship and, as such, provide ideal animal models to study human diseases. RNA expression in NHPs provides specific signatures that are informative of disease mechanisms and therapeutic modes of action. Unlike the human transcriptome, the transcriptomes of major NHP animal models are yet to be comprehensively annotated.
In this manuscript, employing deep RNA sequencing of seven tissue samples, we characterize the transcriptomes of two commonly used NHP animal models: Cynomolgus macaque (Macaca fascicularis) and African green monkey (Chlorocebus aethiops). We present the Multi-Species Annotation (MSA) pipeline that leverages well-annotated primate species and annotates 99.8% of reconstructed transcripts. We elucidate tissue-specific expression profiles and report 13 experimentally validated novel transcripts in these NHP animal models.
We report comprehensively annotated transcriptomes of two non-human primates, which we have made publically available on a customized UCSC Genome Browser interface. The MSA pipeline is also freely available.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-846) contains supplementary material, which is available to authorized users.
PMCID: PMC4194418  PMID: 25277458
Cynomolgus macaque; Macaca fascicularis; African green monkey; Chlorocebus aethiops; RNA-seq; Transcriptome; Genomics; Annotation; Database
8.  Factors influencing adolescent girls’ decision in initiation for human papillomavirus vaccination: a cross-sectional study in Hong Kong 
BMC Public Health  2014;14(1):925.
Cervical cancer is one of the common cancers among women worldwide. Despite HPV vaccination being one of the effective preventive measures, it is not included in government vaccination programme in Hong Kong. This study aimed to assess the knowledge of and attitude towards cervical cancer prevention among Chinese adolescent girls in Hong Kong, and to identify factors influencing the initiation of HPV vaccination.
This was a cross-sectional study conducted in Hong Kong during the period of October 2010 to November 2010. A self-administered questionnaire was used, with 1,416 girls from 8 secondary schools completing the questionnaire. Knowledge scores were composited and initiation of HPV vaccination was staged based on stage of change. Analyses were conducted to identify the association of initiation of HPV vaccination with participant’s personal and family factors as well as their knowledge and attitude towards cervical cancer prevention.
The uptake rate of HPV vaccination was low (7%) with 58% respondents in pre-contemplation and contemplation stage. The survey identified a significant gap in knowledge on cervical cancer prevention. The main channels of information were from media and very few from schools or parents. However, 70% expressed their wishes to have more information on cancer prevention, and 78% stated that they were willing to change their lifestyles if they knew the ways of prevention. Multivariate analysis identified three independent significant factors for initiation of vaccination (action and intention): perceived cancer as terrifying disease, school should provide more information on cancer prevention, and comments from relatives and friends having received the vaccine. The cost of vaccination and socio-economic background were not found to be significant.
Public education on cervical cancer needs to be well penetrated into the community for more sharing among friends and relatives. School as setting to provide source of information would facilitate uptake rate of HPV vaccine as students have expressed their wishes that school should provide more information on prevention of cancer. School and community education on cancer prevention would help adolescents to have better understanding of the seriousness of cancer.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2458-14-925) contains supplementary material, which is available to authorized users.
PMCID: PMC4176578  PMID: 25195604
Cervical cancer; Cancer prevention; Human papillomavirus (HPV) vaccine; Chinese girls; School health education; Community health education
9.  Leukemogenesis Induced by an Activating β-catenin mutation in Osteoblasts 
Nature  2014;506(7487):240-244.
Cells of the osteoblast lineage affect homing, 1, 2 number of long term repopulating hematopoietic stem cells (HSCs) 3, 4, HSC mobilization and lineage determination and B lymphopoiesis 5-8. More recently osteoblasts were implicated in pre-leukemic conditions in mice 9, 10. Yet, it has not been shown that a single genetic event taking place in osteoblasts can induce leukemogenesis. We show here that in mice, an activating mutation of β-catenin in osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukemia (AML) with common chromosomal aberrations and cell autonomous progression. Activated β-catenin stimulates expression of the Notch ligand Jagged-1 in osteoblasts. Subsequent activation of Notch signaling in HSC progenitors induces the malignant changes. Demonstrating the pathogenetic role of the Notch pathway, genetic or pharmacological inhibition of Notch signaling ameliorates AML. Nuclear accumulation and increased β-catenin signaling in osteoblasts was also identified in 38% of patients with MDS/AML. These patients showed increased Notch signaling in hematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce AML, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeutic approach to AML.
PMCID: PMC4116754  PMID: 24429522
10.  RNA Polymerase I Stability Couples Cellular Growth to Metal Availability 
Molecular cell  2013;51(1):105-115.
Zinc is an essential cofactor of all major eukaryotic RNA polymerases. How the activity of these enzymes is coordinated or regulated according to cellular zinc levels is largely unknown. Here we show that the stability of RNA Polymerase I (RNAPI) is tightly coupled to zinc availability in vivo. In zinc deficiency, RNAPI is specifically degraded by proteolysis in the vacuole in a pathway dependent on the exportin Xpo1p and deubiquitination of the RNAPI large subunit Rpa190p by Ubp2p and Ubp4p. RNAPII is unaffected, which allows for expression of genes required in zinc deficiency. RNAPI export to the vacuole is required for survival during zinc starvation, suggesting that degradation of zinc-binding subunits might provide a last resort zinc reservoir. These results reveal a hierarchy of cellular transcriptional activities during zinc starvation, and show that degradation of the most active cellular transcriptional machinery couples cellular growth and proliferation to zinc availability.
PMCID: PMC3713077  PMID: 23747013
11.  Dynamic O-GlcNAcylation and its roles in the cellular stress response and homeostasis 
Cell Stress & Chaperones  2013;18(5):535-558.
O-linked N-acetyl-β-d-glucosamine (O-GlcNAc) is a ubiquitous and dynamic post-translational modification known to modify over 3,000 nuclear, cytoplasmic, and mitochondrial eukaryotic proteins. Addition of O-GlcNAc to proteins is catalyzed by the O-GlcNAc transferase and is removed by a neutral-N-acetyl-β-glucosaminidase (O-GlcNAcase). O-GlcNAc is thought to regulate proteins in a manner analogous to protein phosphorylation, and the cycling of this carbohydrate modification regulates many cellular functions such as the cellular stress response. Diverse forms of cellular stress and tissue injury result in enhanced O-GlcNAc modification, or O-GlcNAcylation, of numerous intracellular proteins. Stress-induced O-GlcNAcylation appears to promote cell/tissue survival by regulating a multitude of biological processes including: the phosphoinositide 3-kinase/Akt pathway, heat shock protein expression, calcium homeostasis, levels of reactive oxygen species, ER stress, protein stability, mitochondrial dynamics, and inflammation. Here, we will discuss the regulation of these processes by O-GlcNAc and the impact of such regulation on survival in models of ischemia reperfusion injury and trauma hemorrhage. We will also discuss the misregulation of O-GlcNAc in diseases commonly associated with the stress response, namely Alzheimer’s and Parkinson’s diseases. Finally, we will highlight recent advancements in the tools and technologies used to study the O-GlcNAc modification.
PMCID: PMC3745259  PMID: 23620203
O-GlcNAc; Stress; Signal transduction; O-GlcNAc transferase; O-GlcNAcase; Post-translational modification
12.  Cross-Sectional Study on Attitudes among General Practitioners towards Pneumococcal Vaccination for Middle-Aged and Elderly Population in Hong Kong 
PLoS ONE  2013;8(11):e78210.
To study the attitudes among general practitioners towards pneumococcal vaccination for middle-aged (50–64) and elderly population (over 65) in Hong Kong and the factors affecting their decision to advise pneumococcal vaccination for those age groups.
Cross-sectional study of general practitioners in private practice in Hong Kong.
Members of Hong Kong Medical Association delivering general practice services in private sector.
Measuring Tool
Self-administered questionnaire.
Main Outcome Measures
Intention to recommend pneumococcal vaccination, barriers against pneumococcal vaccination.
53.4% of the respondents would actively recommend pneumococcal vaccination to elderly patients but only 18.8% would recommend for middle-aged patients. Consultation not related to pneumococcal vaccine was the main reason for not recommending pneumococcal vaccine (43.6%). Rarity of pneumonia in their daily practice was another reason with 68.4% of respondents attending five or less patients with pneumonia each year. In multivariate analysis, factors such as respondents would get vaccination when reaching age 50 (ORm 10.1), and attending 6 pneumonia cases or more per year (ORm 2.28) were found to be associated with increasing likelihood for recommending vaccination to the middle-aged. While concerns of marketing a product (ORm 0.41), consultation not related to vaccination (ORm 0.45) and limited time (ORm 0.38) were factors that reduced the likelihood.
Public policy is needed to increase the awareness of impact of pneumococcal pneumonia and the availability of preventive measures.
PMCID: PMC3818320  PMID: 24223775
13.  Evaluation of the Sustaining Effects of Tai Chi Qigong in the Sixth Month in Promoting Psychosocial Health in COPD Patients: A Single-Blind, Randomized Controlled Trial 
The Scientific World Journal  2013;2013:425082.
Objectives. To evaluate the sustaining effects of Tai Chi Qigong (TCQ) in improving the psychosocial health in chronic obstructive pulmonary disease (COPD) patients in the sixth month. Background. COPD affects both physical and emotional aspects of life. Measures to minimize patients' suffering need to be implemented. Methods. 206 COPD patients were randomly assigned into three groups: TCQ group, exercise group, and control group. The TCQ group completed a three-month TCQ program, the exercise group practiced breathing and walking exercise, and the control group received usual care. Results. Significant group-by-time interactions in quality of life (QOL) using St. George's respiratory questionnaire (P = 0.002) and the perceived social support from friends using multidimensional scale of perceived social support (P = 0.04) were noted. Improvements were observed in the TCQ group only. Conclusions. TCQ has sustaining effects in improving psychosocial health; it is also a useful and appropriate exercise for COPD patients.
PMCID: PMC3824309  PMID: 24282383
14.  Knowledge, Attitude, Practice and Barriers on Vaccination against Human Papillomavirus Infection: A Cross-Sectional Study among Primary Care Physicians in Hong Kong 
PLoS ONE  2013;8(8):e71827.
This study explored the knowledge, attitude, practice and barriers to prescribe human papillomavirus (HPV) vaccines among private primary care physicians in Hong Kong. A self-administered questionnaire survey was conducted by sending letters to doctors who had joined a vaccination program for school girls. From 720 surveys sent, 444 (61.7%) completed questionnaires were returned and analyzed. For knowledge, few responded to questions accurately on the prevalence of cervical HPV (27.9%) and genital wart infection (13.1%) among sexually active young women in Hong Kong, and only 44.4% correctly answered the percentage of cervical cancers caused by HPV. For attitude, most agreed that HPV vaccination should be fully paid by the Government (68.3%) as an important public health strategy. Vaccination against HPV was perceived as more important than those for genital herpes (52.2%) and Chlamydia (50.1%) for adolescent health, and the majority selected adolescents aged 12–14 years as the ideal group for vaccination. Gardasil® (30.9%) and Cervarix® (28.0%) were almost equally preferred. For practice, the factors influencing the choice of vaccine included strength of vaccine protection (61.1%), long-lasting immunity (56.8%) and good antibody response (55.6%). The most significant barriers to prescribe HPV vaccines consisted of parental refusal due to safety concerns (48.2%), and their practice of advising vaccination was mostly affected by local Governmental recommendations (78.7%). A substantial proportion of physicians had recommended HPV vaccines for their female clients/patients aged 18–26 years for protection of cervical cancer (83.8%) or both cervical cancer and genital warts (85.5%). The knowledge on HPV infection was low among physicians in Hong Kong. Prescription of HPV vaccine was hindered by the perceived parental concerns and was mostly relied on Governmental recommendations. Educational initiatives should be targeted towards both physicians and parents, and the Government should consider full subsidy to enhance vaccine uptake rate.
PMCID: PMC3749199  PMID: 23990994
15.  Correction: Chlamydia trachomatis Co-opts GBF1 and CERT to Acquire Host Sphingomyelin for Distinct Roles during Intracellular Development 
PLoS Pathogens  2013;9(8):10.1371/annotation/f8e7c7e3-c347-4243-9146-db77900cb90c.
PMCID: PMC3752017
16.  Human Vocal Attractiveness as Signaled by Body Size Projection 
PLoS ONE  2013;8(4):e62397.
Voice, as a secondary sexual characteristic, is known to affect the perceived attractiveness of human individuals. But the underlying mechanism of vocal attractiveness has remained unclear. Here, we presented human listeners with acoustically altered natural sentences and fully synthetic sentences with systematically manipulated pitch, formants and voice quality based on a principle of body size projection reported for animal calls and emotional human vocal expressions. The results show that male listeners preferred a female voice that signals a small body size, with relatively high pitch, wide formant dispersion and breathy voice, while female listeners preferred a male voice that signals a large body size with low pitch and narrow formant dispersion. Interestingly, however, male vocal attractiveness was also enhanced by breathiness, which presumably softened the aggressiveness associated with a large body size. These results, together with the additional finding that the same vocal dimensions also affect emotion judgment, indicate that humans still employ a vocal interaction strategy used in animal calls despite the development of complex language.
PMCID: PMC3634748  PMID: 23638065
17.  Nonamnestic Presentations of Early-Onset Alzheimer’s Disease 
Early-onset Alzheimer’s disease (EOAD) beginning before the age of 65 may differ from late-onset AD (LOAD) in clinical course and frequency of nonamnestic presentations. In a 10-year retrospective review, 125 patients with EOAD, diagnosed clinically and verified by functional neuroimaging, were compared with 56 patients with LOAD and further classified depending on predominant cognitive difficulty on presentation. Eighty (64%) of the patients with EOAD had a nonamnestic presentation, compared with only 7 (12.5%) of the patients with LOAD. Compared with LOAD, the patients with EOAD had a shorter duration with lower Mini-Mental State Examination scores. The neuroimaging reports among the patients with EOAD showed more hippocampal atrophy with an amnestic presentation, more left parietal changes with impaired language presentations, and more right parietal and occipital changes with impaired visuospatial presentations. These findings indicate that EOAD differs from LOAD in a more aggressive course and in having predominantly nonamnestic presentations that vary in neuropathological location.
PMCID: PMC3625669  PMID: 22871906
Alzheimer’s disease; early-onset; aphasia; posterior cortical atrophy; apraxia
18.  Development of Peptide Nucleic Acid Probes for Detection of the HER2 Oncogene 
PLoS ONE  2013;8(4):e58870.
Peptide nucleic acids (PNAs) have gained much interest as molecular recognition tools in biology, medicine and chemistry. This is due to high hybridization efficiency to complimentary oligonucleotides and stability of the duplexes with RNA or DNA. We have synthesized 15/16-mer PNA probes to detect the HER2 mRNA. The performance of these probes to detect the HER2 target was evaluated by fluorescence imaging and fluorescence bead assays. The PNA probes have sufficiently discriminated between the wild type HER2 target and the mutant target with single base mismatches. Furthermore, the probes exhibited excellent linear concentration dependence between 0.4 to 400 fmol for the target gene. The results demonstrate potential application of PNAs as diagnostic probes with high specificity for quantitative measurements of amplifications or over-expressions of oncogenes.
PMCID: PMC3622650  PMID: 23593123
19.  The Impact of Leadership Programme on Self-Esteem and Self-Efficacy in School: A Randomized Controlled Trial 
PLoS ONE  2012;7(12):e52023.
Leadership training programs by experiential learning among adolescents are very popular worldwide and in particular developed countries, but there exists few studies which formally assessed their impact on the psychological well-being of program participants. This study evaluated the effectiveness of leadership training programs on self-esteem and self-efficacy among adolescents.
Methodology/Principal Findings
a total of 180 students of the same grade of one secondary school were randomized into an intervention (n = 50) and a control group (n = 130). The students in the intervention group participated in a 6-month program of leadership training and service learning, while the control group did not participate in any training. Their self-esteem and self-efficacy were assessed by Rosenberg Self-Esteem questionnaire and Chinese Adaptation of the General Self-Efficacy Scale, respectively, before and after the program. Both scales have been recognized internationally as valid and reliable survey instruments to measure these psychological attributes. The scores were compared by Student’s tests according to gender. A total of 180 students were enrolled during the study period October, 2009 to May, 2010. Their mean age was 15.18 years (0.62) and 56.7% were male. Students allocated to the intervention and control group had statistically similar demographic characteristics except gender (male 36.0% vs. 64.6%, p = 0.001). Overall, the self-esteem scores increased by 1.28 and decreased by 0.30 (p = 0.161) while the self-efficacy scores increased by 0.26 and decreased by 0.76 (p = 0.429) in the intervention and control group, respectively. Among female students, the intervention group showed significant improvements in both self-esteem (2.38 vs. −0.24, p<0.001) and self-efficacy (1.32 vs. –0.04, p = 0.043).
Leadership training program were not found to be effective to enhance self-esteem and self-efficacy in adolescents, except girls who showed modest increase in these outcomes. Future research should assess the reasons why these programs are effective among female.
PMCID: PMC3525562  PMID: 23272199
20.  Synthesis of novel cyclic NGR/RGD peptide analogs via on resin click chemistry 
Targeted drug deliveries as well as high resolution imaging of cancerous tissues and organs via specific cancer cell markers have become important in chemotherapeutic interventions of cancer treatment. Short peptides such as RGD and NGR are showing promising results for targeted drug delivery and in vivo imaging. We have applied on resin Huisgen's 1,3-dipolar cycloaddition to synthesize new cyclic RGD and NGR peptide analogs. Preliminary binding assays of these new analogs by fluorescence polarization indicates specific binding to purified CD13 (Aminopeptidase N) and cell lysates from MCF-7 and SKOV-3 cancer cell lines.
PMCID: PMC3472425  PMID: 21050757
21.  Comparison of clinical characteristics between familial and non-familial early onset Alzheimer’s disease 
Journal of neurology  2012;259(10):2182-2188.
Although familial Alzheimer’s disease (FAD) is an early onset AD (EAD), most patients with EAD do not have a familial disorder. Recent guidelines recommend testing for genes causing FAD only in those EAD patients with two first-degree relatives. However, some patients with FAD may lack a known family history or other indications for suspecting FAD but might nonetheless be carriers of FAD mutations. The study was aimed to identify clinical features that distinguish FAD from non-familial EAD (NF-EAD). A retrospective review of a university-based cohort of 32 FAD patients with PSEN1-related AD and 81 with NF-EAD was conducted. The PSEN1 patients, compared to the NF-EAD patients, had an earlier age of disease onset (41.8 ± 5.2 vs. 55.9 ± 4.8 years) and, at initial assessment, a longer disease duration (5.1 ± 3.4 vs. 3.3 ± 2.6 years) and lower MMSE scores (10.74 ± 8.0 vs. 20.95 ± 5.8). Patients with NF-EAD were more likely to present with non-memory deficits, particularly visuospatial symptoms, than were FAD patients. When age, disease duration, and MMSE scores were controlled in a logistical regression model, FAD patients were more likely to have significant headaches, myoclonus, gait abnormality, and pseudobulbar affect than those with NF-EAD. In addition to a much younger age of onset, FAD patients with PSEN1 mutations differed from those with NF-EAD by a history of headaches and pseudobulbar affect, as well as myoclonus and gait abnormality on examination. These may represent differences in pathophysiology between FAD and NF-EAD and in some contexts such findings should lead to genetic counseling and appropriate recommendations for genetic testing for FAD.
PMCID: PMC3442121  PMID: 22460587
Dementia; Early onset Alzheimer’s disease; Familial Alzheimer’s disease; PSEN1 gene
22.  Communication between Corneal Epithelial Cells and Trigeminal Neurons Is Facilitated by Purinergic (P2) and Glutamatergic Receptors 
PLoS ONE  2012;7(9):e44574.
Previously, we demonstrated that nucleotides released upon mechanical injury to corneal epithelium activate purinergic (P2) receptors resulting in mobilization of a Ca2+ wave. However, the tissue is extensively innervated and communication between epithelium and neurons is critical and not well understood. Therefore, we developed a co-culture of primary trigeminal neurons and human corneal limbal epithelial cells. We demonstrated that trigeminal neurons expressed a repertoire of P2Yand P2X receptor transcripts and responded to P2 agonists in a concentration-dependent manner. Mechanical injuries to epithelia in the co-cultures elicited a Ca2+ wave that mobilized to neurons and was attenuated by Apyrase, an ectonucleotidase. To elucidate the role of factors released from each cell type, epithelial and neuronal cells were cultured, injured, and the wound media from one cell type was collected and added to the other cell type. Epithelial wound media generated a rapid Ca2+ mobilization in neuronal cells that was abrogated in the presence of Apyrase, while neuronal wound media elicited a complex response in epithelial cells. The rapid Ca2+ mobilization was detected, which was abrogated with Apyrase, but it was followed by Ca2+ waves that occurred in cell clusters. When neuronal wound media was preincubated with a cocktail of N-methyl-D-aspartate (NMDA) receptor inhibitors, the secondary response in epithelia was diminished. Glutamate was detected in the neuronal wound media and epithelial expression of NMDA receptor subunit transcripts was demonstrated. Our results indicate that corneal epithelia and neurons communicate via purinergic and NMDA receptors that mediate the wound response in a highly orchestrated manner.
PMCID: PMC3436752  PMID: 22970252
23.  Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia 
Brain  2011;134(9):2456-2477.
Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, ‘possible’ behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). ‘Probable’ behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia ‘with definite frontotemporal lobar degeneration’ requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer’s disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met ‘possible’ criteria, and 104 (76%) met criteria for ‘probable’ behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with ‘possible’ and ‘probable’ criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines.
PMCID: PMC3170532  PMID: 21810890
behavioural variant frontotemporal dementia; diagnostic criteria; frontotemporal lobar degeneration; FTD; pathology
24.  Intracellular recording in behaving animals 
Electrophysiological recordings from behaving animals provide an unparalleled view into the functional role of individual neurons. Intracellular approaches can be especially revealing as they provide information about a neuron’s inputs and intrinsic cellular properties, which together determine its spiking output. Recent technical developments have made intracellular recording possible during an ever-increasing range of behaviors in both head-fixed and freely moving animals. These recordings have yielded fundamental insights into the cellular and circuit mechanisms underlying neural activity during natural behaviors in such areas as sensory perception, motor sequence generation, and spatial navigation, forging a direct link between cellular and systems neuroscience.
PMCID: PMC3408887  PMID: 22054814
25.  Intracellular determinants of hippocampal CA1 place and silent cell activity in a novel environment 
Neuron  2011;70(1):109-120.
For each environment a rodent has explored, its hippocampus contains a map consisting of a unique subset of neurons, called place cells, that have spatially-tuned spiking there, with the remaining neurons being essentially silent. Using whole-cell recording in freely moving rats exploring a novel maze, we observed differences in intrinsic cellular properties and input-based subthreshold membrane potential levels underlying this division into place and silent cells. Compared to silent cells, place cells had lower spike thresholds and peaked versus flat subthreshold membrane potentials as a function of animal location. Both differences were evident from the beginning of exploration. Additionally, future place cells exhibited higher burst propensity before exploration. Thus, internal settings appear to predetermine which cells will represent the next novel environment encountered. Furthermore, place cells fired spatially-tuned bursts with large, putatively calcium-mediated depolarizations that could trigger plasticity and stabilize the new map for long-term storage. Our results provide new insight into hippocampal memory formation.
PMCID: PMC3221010  PMID: 21482360

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