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1.  Angiotensin II Reduces Cardiac AdipoR1 Expression through AT1 Receptor/ROS/ERK1/2/c-Myc Pathway 
PLoS ONE  2013;8(1):e49915.
Adiponectin, an abundant adipose tissue-derived protein, exerts protective effect against cardiovascular disease. Adiponectin receptors (AdipoR1 and AdipoR2) mediate the beneficial effects of adiponectin on the cardiovascular system. However, the alteration of AdipoRs in cardiac remodeling is not fully elucidated. Here, we investigated the effect of angiotensin II (AngII) on cardiac AdipoRs expression and explored the possible molecular mechanism. AngII infusion into rats induced cardiac hypertrophy, reduced AdipoR1 but not AdipoR2 expression, and attenuated the phosphorylations of adenosine monophosphate-activated protein kinase and acetyl coenzyme A carboxylase, and those effects were all reversed by losartan, an AngII type 1 (AT1) receptor blocker. AngII reduced expression of AdipoR1 mRNA and protein in cultured neonatal rat cardiomyocytes, which was abolished by losartan, but not by PD123319, an AT2 receptor antagonist. The antioxidants including reactive oxygen species (ROS) scavenger NAC, NADPH oxidase inhibitor apocynin, Nox2 inhibitor peptide gp91 ds-tat, and mitochondrial electron transport chain complex I inhibitor rotenone attenuated AngII-induced production of ROS and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2. AngII-reduced AdipoR1 expression was reversed by pretreatment with NAC, apocynin, gp91 ds-tat, rotenone, and an ERK1/2 inhibitor PD98059. Chromatin immunoprecipitation assay demonstrated that AngII provoked the recruitment of c-Myc onto the promoter region of AdipoR1, which was attenuated by PD98059. Moreover, AngII-induced DNA binding activity of c-Myc was inhibited by losartan, NAC, apocynin, gp91 ds-tat, rotenone, and PD98059. c-Myc small interfering RNA abolished the inhibitory effect of AngII on AdipoR1 expression. Our results suggest that AngII inhibits cardiac AdipoR1 expression in vivo and in vitro and AT1 receptor/ROS/ERK1/2/c-Myc pathway is required for the downregulation of AdipoR1 induced by AngII.
PMCID: PMC3551944  PMID: 23349663
2.  Inhibition of HIV Type 1 Replication by Human T Lymphotropic Virus Types 1 and 2 Tax Proteins in Vitro 
AIDS Research and Human Retroviruses  2013;29(7):1061-1067.
Patients with HIV-1 and human T-lymphotropic virus type 2 (HTLV-2) coinfections often exhibit a clinical course similar to that seen in HIV-1-infected individuals who are long-term nonprogressors. These findings have been attributed in part to the ability of HTLV-2 to activate production of antiviral chemokines and to downregulate the CCR5 coreceptor on lymphocytes. To further investigate these observations, we tested the ability of recombinant Tax1 and Tax2 proteins to suppress HIV-1 viral replication in vitro. R5-tropic HIV-1 (NLAD8)-infected peripheral blood mononuclear cells (PBMCs) were treated daily with recombinant Tax1 and Tax2 proteins (dosage range 1–100 pM). Culture supernatants were collected at intervals from days 1 to 22 postinfection and assayed for levels of HIV-1 p24 antigen by ELISA. Treatment of PBMCs with Tax2 protein resulted in a significant reduction in HIV-1 p24 antigen levels (p<0.05) at days 10, 14, and 18 postinfection compared to HIV-1-infected or mock-treated PBMCs. This was preceded by the detection of increased levels of CC-chemokines MIP-1α/CCL3, MIP-1β/CCL4, and RANTES/CCL5 on days 1–7 of infection. Similar, but less robust inhibition was observed in Tax1-treated PBMCs. These results support the contention that Tax1 and Tax2 play a role in generating antiviral responses against HIV-1 in vivo and in vitro.
PMCID: PMC3685691  PMID: 23464580
3.  Regulation of the SK3 channel by MicroRNA-499 - potential role in atrial fibrillation 
MicroRNAs are important regulators of gene expression, including those involving electrical remodeling in atrial fibrillation (AF). Recently, KCNN3, the gene that encodes the small conductance calcium-activated potassium channel 3 (SK3), was found to be strongly associated with AF.
This study sought to evaluate the changes in atrial myocardial microRNAs in patients with permanent AF and to determine the role of microRNA on the regulation of cardiac SK3 expression.
Atrial tissue obtained during cardiac surgery from patients (4 sinus rhythm and 4 permanent AF) was analyzed by microRNA arrays. Potential targets of microRNAs were predicted by software programs. The effects of specific microRNAs on target gene expression were evaluated in HL-1 cells from a continuously proliferating mouse hyperplastic atrial cardiomyocyte cell line. Interactions between microRNAs and targets were further evaluated by luciferase reporter assay and by Argonaute pull-down assay.
Twenty one microRNAs showed significant, greater than two-fold changes in AF. miR-499 was upregulated by 2.33 fold (P<0.01) in AF atria, whereas SK3 protein expression was down-regulated by 46% (P<0.05). Transfection of miR-499 mimic in HL-1 cells resulted in the downregulation of SK3 protein expression, while that of miR-499 inhibitor upregulated SK3 expression. Binding of miR-499 to the 3′UTR of KCNN3 was confirmed by luciferase reporter assay and by the enhanced presence of SK3 mRNA in Argonaute pulled-down microRNA-induced silencing complexes (mRISC) after transfection with miR-499.
Atrial miRNA-499 is significantly upregulated in AF, leading to SK3 downregulation and possibly contributing to the electrical remodeling in AF.
PMCID: PMC3710704  PMID: 23499625
atrial fibrillation; microRNA; SK3 channel; electrical remodeling; small-conductance calcium-activated potassium channel
4.  Postpartum Substance Use and Depressive Symptoms: A Review 
Women & health  2013;53(5):479-503.
National survey data suggest that new mothers have high prevalences of alcohol and illicit drug use. Depression correlates with substance use, and new mothers with postpartum depression (PPD) may be at high risk for substance use. Understanding postpartum substance use and its relationship to PPD can inform future research and intervention. A literature search was conducted resulting in 12 studies published from 1999–2012 examining postpartum alcohol use, drug use, or combined postpartum depression and substance use. Postpartum alcohol (prevalence range 30.1%−49%) and drug use (4.5%–8.5%) were lower than use among not pregnant, not postpartum women (41.5%–57.5%; 7.6%–10.6%, respectively) but higher than use among pregnant women (5.4%–11.6%; 3.7%–4.3%, respectively). Correlates of postpartum problem drinking were being unemployed, unmarried, and a cigarette smoker. Prevalence of drug use was highest among white new mothers, followed by Blacks and Hispanics, but Black new mothers appeared at greater risk of drug use. No identified studies examined correlates of postpartum drug use beyond race/ethnicity. Postpartum depressive symptoms were prevalent among postpartum substance users and those with a substance use history (19.7%–46%). The postpartum period is a critical time. Prevalent substance use and the scarcity of studies warrant research to identify means to reduce maternal substance use.
PMCID: PMC3742364  PMID: 23879459
alcohol; depression; drug use; postpartum
5.  A potent and selective small molecule inhibitor for the lymphoid-specific tyrosine phosphatase (LYP), a target associated with autoimmune diseases 
Journal of medicinal chemistry  2013;56(12):4990-5008.
Lymphoid-specific tyrosine phosphatase (LYP), a member of the protein tyrosine phosphatase (PTP) family of signaling enzymes, is associated with a broad spectrum of autoimmune diseases. Herein we describe our structure-based lead optimization efforts within a 6-hydroxy-benzofuran-5-carboxylic acid series culminating in the identification of compound 8b, a potent and selective inhibitor of LYP with a Ki value of 110 nM and more than 9-fold selectivity over a large panel of PTPs. The structure of LYP in complex with 8b was obtained by X-ray crystallography, providing detailed information about the molecular recognition of small-molecule ligands binding LYP. Importantly, compound 8b possesses highly efficacious cellular activity in both T- and mast cells and is capable of blocking anaphylaxis in mice. Discovery of 8b establishes a starting point for the development of clinically useful LYP inhibitors for treating a wide range of autoimmune disorders.
PMCID: PMC3711248  PMID: 23713581
6.  Langerhans cells are generated by two distinct PU.1-dependent transcriptional networks 
The Journal of Experimental Medicine  2013;210(13):2967-2980.
Langerhans cell homeostasis and differentiation depends on PU.1, the latter via regulation of TGF-β–dependent binding of PU.1 to the regulatory elements of RUNX3.
Langerhans cells (LCs) are the unique dendritic cells found in the epidermis. While a great deal of attention has focused on defining the developmental origins of LCs, reports addressing the transcriptional network ruling their differentiation remain sparse. We addressed the function of a group of key DC transcription factors—PU.1, ID2, IRF4, and IRF8—in the establishment of the LC network. We show that although steady-state LC homeostasis depends on PU.1 and ID2, the latter is dispensable for bone marrow–derived LCs. PU.1 controls LC differentiation by regulating the expression of the critical TGF-β responsive transcription factor RUNX3. PU.1 directly binds to the Runx3 regulatory elements in a TGF-β–dependent manner, whereas ectopic expression of RUNX3 rescued LC differentiation in the absence of PU.1 and promoted LC differentiation from PU.1-sufficient progenitors. These findings highlight the dual molecular network underlying LC differentiation, and show the central role of PU.1 in these processes.
PMCID: PMC3865480  PMID: 24249112
7.  Mitogenomic sequences effectively recover relationships within brush-footed butterflies (Lepidoptera: Nymphalidae) 
BMC Genomics  2014;15(1):468.
Mitogenomic phylogenies have revealed well-supported relationships for many eukaryote groups. In the order Lepidoptera, 113 species mitogenomes had been sequenced (May 14, 2014). However, these data are restricted to ten of the forty-three recognised superfamilies, while it has been challenging to recover large numbers of mitogenomes due to the time and cost required for primer design and sequencing. Nuclear rather than mitochondrial genes have been preferred to reconstruct deep-level lepidopteran phylogenies, without seriously evaluating the potential of entire mitogenomes. Next-generation sequencing methods remove these limitations by providing efficiently massive amounts of sequence data. In the present study, we simultaneously obtained a large number of nymphalid butterfly mitogenomes to evaluate the utility of mitogenomic phylogenies by comparing reconstructions to the now quite well established phylogeny of Nymphalidae.
We newly obtained 30 nymphalid mitogenomes via pyrosequencing on the Roche 454 GS Junior system, and combined these sequences with publicly accessible data to provide a 70-taxa dataset covering 37 genes for a 15,495 bp alignment. Polymorphic sites were not homogeneously distributed across the gene. Two gene regions, nad6 and 3’ end of nad5, were most variable, whereas the cox1 and 5’ ends of rrnL were most conserved. Phylogenetic relationships inferred by two likelihood methods were congruent and strongly supported (>0.95 posterior probability; ML bootstrap >85%), across the majority of nodes for multiple partitioning strategies and substitution models. Bayes factor results showed that the most highly partitioned dataset is the preferred strategy among different partitioning schemes. The most striking phylogenetic findings were that the subfamily Danainae not Libytheinae was sister of the remaining brush-footed butterflies and that, within Limenitidini, the genus Athyma was clearly polyphyletic. None of the single-gene phylogenies recovered the highly supported topologies generated on the basis of the whole mitogenomic data.
Thirty mitogenomes were assembled with 89% completeness from the contigs of pyrosequencing-derived reads. Entire mitogenomes or higher-quality sequences could be obtained by increasing pyrosequencing read coverage or by additional Sanger sequencing. Our mitogenomic phylogenies provide robust nodal support at a range of levels, demonstrating that mitogenomes are both accurate and efficient molecular markers for inferring butterfly phylogeny.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-468) contains supplementary material, which is available to authorized users.
PMCID: PMC4070565  PMID: 24923777
Athyma; Bayes factor; DNA Barcoding; cox1 gene; Limenitidinae; Limenitidini; Mitogenomic phylogeny; Papilionoidea; Pyrosequencing
8.  A facile hydroxyindole carboxylic acid-based focused library approach for potent and selective inhibitors of Mycobacterium protein tyrosine phosphatase B** 
ChemMedChem  2013;8(6):904-908.
A facile hydroxyindole carboxylic acid-based focused amide library approach was designed to target both the PTP active site and a unique nearby pocket for enhanced affinity and selectivity. High throughput screening of the focused library let to the identification of a highly potent (Ki=50 nM) and selective (>100-fold against a large panel of PTPs) inhibitor 11a for mPTPB, an essential virulence factor for Mycobacterium tuberculosis. Importantly, 11a displayed highly efficacious cellular activity and was capable of reversing the altered immune responses induced by mPTPB in macrophages.
PMCID: PMC3755370  PMID: 23568546
Focused amide library; HydroxyIndole carboxylic acid; PTP; mPTPB inhibitor; Tuberculosis
9.  Pachytene piRNAs instruct massive mRNA elimination during late spermiogenesis 
Cell Research  2014;24(6):680-700.
Spermatogenesis in mammals is characterized by two waves of piRNA expression: one corresponds to classic piRNAs responsible for silencing retrotransponsons and the second wave is predominantly derived from nontransposon intergenic regions in pachytene spermatocytes, but the function of these pachytene piRNAs is largely unknown. Here, we report the involvement of pachytene piRNAs in instructing massive mRNA elimination in mouse elongating spermatids (ES). We demonstrate that a piRNA-induced silencing complex (pi-RISC) containing murine PIWI (MIWI) and deadenylase CAF1 is selectively assembled in ES, which is responsible for inducing mRNA deadenylation and decay via a mechanism that resembles the action of miRNAs in somatic cells. Such a highly orchestrated program appears to take full advantage of the enormous repertoire of diversified targeting capacity of pachytene piRNAs derived from nontransposon intergenic regions. These findings suggest that pachytene piRNAs are responsible for inactivating vast cellular programs in preparation for sperm production from ES.
PMCID: PMC4042167  PMID: 24787618
pachytene piRNAs; MIWI; CAF1; pi-RISC; mRNA deadenylation; ES
10.  A New Class of Multimerization Selective Inhibitors of HIV-1 Integrase 
PLoS Pathogens  2014;10(5):e1004171.
The quinoline-based allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are promising candidates for clinically useful antiviral agents. Studies using these compounds have highlighted the role of IN in both early and late stages of virus replication. However, dissecting the exact mechanism of action of the quinoline-based ALLINIs has been complicated by the multifunctional nature of these inhibitors because they both inhibit IN binding with its cofactor LEDGF/p75 and promote aberrant IN multimerization with similar potencies in vitro. Here we report design of small molecules that allowed us to probe the role of HIV-1 IN multimerization independently from IN-LEDGF/p75 interactions in infected cells. We altered the rigid quinoline moiety in ALLINIs and designed pyridine-based molecules with a rotatable single bond to allow these compounds to bridge between interacting IN subunits optimally and promote oligomerization. The most potent pyridine-based inhibitor, KF116, potently (EC50 of 0.024 µM) blocked HIV-1 replication by inducing aberrant IN multimerization in virus particles, whereas it was not effective when added to target cells. Furthermore, KF116 inhibited the HIV-1 IN variant with the A128T substitution, which confers resistance to the majority of quinoline-based ALLINIs. A genome-wide HIV-1 integration site analysis demonstrated that addition of KF116 to target or producer cells did not affect LEDGF/p75-dependent HIV-1 integration in host chromosomes, indicating that this compound is not detectably inhibiting IN-LEDGF/p75 binding. These findings delineate the significance of correctly ordered IN structure for HIV-1 particle morphogenesis and demonstrate feasibility of exploiting IN multimerization as a therapeutic target. Furthermore, pyridine-based compounds present a novel class of multimerization selective IN inhibitors as investigational probes for HIV-1 molecular biology.
Author Summary
The administration of highly active-antiretroviral therapy (HAART) has changed what was once a terminal disease into a manageable chronic infection. The success of HAART is manifested by reduced mortality and morbidity of HIV-1 infected patients. However, evolution of HIV-1 strains resistant to current therapies is a major clinical problem in the fight against AIDS. Therefore, new inhibitors with novel mechanisms of action are needed. One such mechanism is to target multimerization of HIV-1 integrase. In the present study, we report the design of pyridine-based small molecules that contain a rotatable single bond to allow optimal bridging between interacting integrase subunits. As a result, pyridine-based compounds stabilized interacting IN subunits and promoted aberrant, higher order integrase multimerization. The most potent compound, KF116, potently inhibited HIV-1 replication by interfering with proper maturation of HIV-1 particles, whereas KF116 at therapeutically relevant (submicromolar) concentrations had no detectable effects on LEDGF/p75 mediated HIV-1 integration. Our findings highlight HIV-1 integrase multimerization as a plausible therapeutic target and offer a path for designing improved inhibitors for potential clinical use.
PMCID: PMC4038613  PMID: 24874515
11.  Complications of Treating Terrible Triad Injury of the Elbow: A Systematic Review 
PLoS ONE  2014;9(5):e97476.
Terrible triad injury of the elbow (TTIE), comprising elbow dislocation with radial head and coronoid process fracture, is notoriously challenging to treat and has typically been associated with complications and poor outcomes. The objective of this systematic review was to summarize the most recent available evidence regarding functional outcomes and complications following surgical management of TTIE.
Medline, EMBASE, Cochrane Library, and Google Scholar were searched to identify relevant studies, which were included if they were retrospective or prospective in design, involved participants who had TTIE, and were published in English. Outcomes of interest were functional outcomes and complications.
Sixteen studies, involving 312 patients, were included in the systematic review. Mean follow up after surgery was typically 25 to 30 months. Mean Mayo elbow performance scores ranged from 78 to 95. Mean Broberg-Morrey scores ranged from 76 to 90. Mean DASH scores ranged from 9 to 31. The proportion of patients who required reoperation due to complications ranged from 0 to 54.5% (overall  = 70/312 [22.4%]). Most of these complications were related to hardware fixation problems, joint stiffness, joint instability, and ulnar neuropathy. The most common complications that did not require reoperation were heterotopic ossification (39/312 [12.5%] patients) and arthrosis (35/312 [11.2%] patients).
The results of this systematic review indicate that functional outcomes after surgery for TTIE are generally satisfactory and that complications are common. Further research is warranted to determine which surgical techniques optimize functional outcomes and reduce the risk of complications.
PMCID: PMC4022574  PMID: 24832627
12.  Different angiotensin receptor blockers and incidence of diabetes: a nationwide population-based cohort study 
Angiotensin receptor blockers (ARBs) have been shown to exert various peroxisome proliferator-activated receptor gamma (PPARγ) binding activities and insulin-sensitizing effects. The objective of this study was to investigate the association of different ARBs with new-onset diabetes mellitus.
In the respective cohort, a total of 492,530 subjects who initiated ARB treatment between January 2004 and December 2009 were identified from Taiwan National Health Insurance Database. The primary outcome was newly diagnosed diabetes, defined as at least one hospital admission or two or more outpatient visits within a year with an ICD-9-CM code 250. Cox proportional regression was used to estimate the risk of diabetes associated with each ARB, using losartan as the reference.
A total of 65,358 incident diabetes cases were identified out of 1,771,173 person-years. Olmesartan initiators had a small but significantly increased risk of developing diabetes after adjusting for baseline characteristics and mean daily dose (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.03-1.12). After excluding those followed for less than one year, the increase in diabetes risk are more pronounced (HR, 1.09; 95% CI, 1.05-1.14). This association was consistent across all subgroup analyses. Similar results were observed when a more strict definition of diabetes combining both diabetes diagnosis and anti-diabetic treatment was used. On the other hand, there was no difference in diabetes risk between telmisartan and losartan.
Among all ARBs, olmesartan might be associated with a slightly increased risk of diabetes mellitus. Our data suggest differential diabetes risks associated with ARBs beyond a class effect.
PMCID: PMC4039330  PMID: 24886542
Angiotensin receptor antagonists; Diabetes mellitus; Cohort studies
13.  Food, Class, and Health: The Role of the Perceived Body in the Social Reproduction of Health 
Health communication  2012;28(4):341-350.
The association between social class and cardiovascular health is complex, involving a constant interplay of factors as individuals integrate external information from the media, health care providers, and people they know with personal experience to produce health behaviors. This ethnographic study took place from February 2008 to February 2009 to assess how cardiovascular health information circulating in Kansas City influenced a sample of 55 women in the area. Participants were primarily Caucasian (n=41) but diverse in terms of age, income, and education. Themes identified in transcripts showed women shared the same idea of an ideal body: young and thin, and associated this perception with ideas about good health, intelligence, and morality. Transcript themes corresponded to those found at health events and in the media that emphasized individual control over determinants of disease. Women’s physical appearance and health behaviors corresponded to class indicators. Four categories were identified to represent women’s shared beliefs and practices in relation to class, cardiovascular disease, and obesity. Findings were placed within an existing body of social theory to better understand how cardiovascular health information and women’s associated beliefs relate to health inequality.
PMCID: PMC3527688  PMID: 22746270
14.  Substance Use among Adolescent Mothers: A Review 
Maternal substance abuse is a critical problem, and adolescent mothers appear to be at high risk for such behaviors. We review studies on postpartum adolescent substance use to explore the extent of this problem and avenues for new research. Authors screened 1,300 studies, identifying 12 articles on substance use among postpartum adolescent mothers for this review. Adolescent mothers reported greater substance use before pregnancy compared to other adolescent females. Although some adolescents continued substance use during pregnancy, most stopped using only to resume within six months after birth. Comparisons of use to national samples of nulliparous adolescent females showed a higher prevalence of substance use in this population. Substances used often varied by race/ethnicity, with white mothers more likely to smoke cigarettes and use marijuana, and Black mothers more likely than whites to drink and use drugs. Of all identified studies, only one focused on Hispanics. Beliefs about drug use grew less negative as girls transitioned from pregnancy to parenthood. As they transitioned to adulthood, substance use remained prevalent and stable. Psychological distress and low self-esteem appeared to influence continued use. Friends’ cigarette smoking predicted early initiation of and persistent smoking, while increased education predicted quitting. Early initiation of substances often predicted problem behaviors. Adolescent mothers are a vulnerable population, implicating use of problem behavior theory or the self-medication hypothesis in future research. Multiple avenues for new studies are needed to help identify effective treatment and intervention for this understudied population.
PMCID: PMC3638998  PMID: 23641120
Adolescent; drug use; postpartum; postnatal; substance use; substance abuse
15.  Screening instruments for substance use and brief interventions targeting adolescents in primary care: A literature review 
Addictive behaviors  2013;38(5):2146-2153.
A review of the literature was conducted to examine substance use screening instruments commonly used with adolescents in medical settings, their comparative usefulness, and SBIRT (Screening, Brief Intervention, and Referral to Treatment).
We screened two databases (Ovid MEDLINE and PsycINFO) targeting journal articles dealing with screening for alcohol and drug use in adolescence as well as adolescent SBIRT.
Adolescents preferred paper forms and computerized questionnaires over interviews with physicians or nurses. The CRAFFT was the best studied instrument for screening for alcohol/drug use and related problems, and is the only tool with data to support its use in medical settings. Other screening instruments require more testing/evaluation in more representative samples of adolescents in primary care settings. Long term follow-up data to establish the efficacy of SBIRT in adolescence are not available. Innovative computerized approaches to screening for substance use in this population have recently been proposed. Although promising, they require further evaluation.
The CRAFFT has the most consistent data to support its use in primary care settings. The effects of SBIRT in adolescence have not been adequately evaluated. Adolescents’ opinions and preferences for SBIRT should be studied to improve their acceptance.
PMCID: PMC3623552  PMID: 23454877
adolescents; screening; alcohol screening; drug screening; SBIRT; brief interventions; substance use; substance abuse
16.  Using electronic health records data to assess comorbidities of substance use and psychiatric diagnoses and treatment settings among adults 
Journal of psychiatric research  2013;47(4):555-563.
To examine prevalences of substance use disorders (SUD) and comprehensive patterns of comorbidities among psychiatric patients ages 18–64 years (N=40,099) in an electronic health records (EHR) database.
DSM-IV diagnoses among psychiatric patients in a large university system were systematically captured: SUD, anxiety (AD), mood (MD), personality (PD), adjustment, childhood-onset, cognitive/dementia, dissociative, eating, factitious, impulse-control, psychotic (schizophrenic), sexual/gender identity, sleep, and somatoform diagnoses. Comorbidities and treatment types among patients with a SUD were examined.
Among all patients, 24.9% (n=9,984) had a SUD, with blacks (35.2%) and Hispanics (32.9%) showing the highest prevalence. Among patients with a SUD, MD was prevalent across all age groups (50.2–56.6%). Patients aged 18–24 years had elevated odds of comorbid PD, adjustment, childhood-onset, impulse-control, psychotic, and eating diagnoses. Females had more PD, AD, MD, eating, and somatoform diagnoses, while males had more childhood-onset, impulse-control, and psychotic diagnoses. Blacks had greater odds than whites of psychotic and cognitive/dementia diagnoses, while whites exhibited elevated odds of PA, AD, MD, childhood-onset, eating, somatoform, and sleep diagnoses. Women, blacks, and Native American/multiple-race adults had elevated odds of using inpatient treatment; men, blacks, and Hispanics had increased odds of using psychiatric emergency care. Comorbid MD, PD, adjustment, somatoform, psychotic, or cognitive/dementia diagnoses increased inpatient treatment.
Patients with a SUD, especially minority members, use more inpatient or psychiatric emergency care than those without. Findings provide evidence for research on understudied diagnoses and underserved populations in the real-world clinical settings.
PMCID: PMC3581730  PMID: 23337131
anxiety disorders; comorbidity; comparative effectiveness research; electronic health records; mood disorders; personality disorders; substance-related disorders
17.  Anticandidal Activity and Biocompatibility of a Rechargeable Antifungal Denture Material 
Oral diseases  2012;19(3):287-295.
Candida-associated denture stomatitis is a recurrent and debilitating oral mucosal disease. Development of anticandidal denture materials represents a promising strategy to manage this condition. We have previously shown that miconazole incorporated in methacrylic acid (MAA) copolymerized diurethane dimethacrylate (UDMA) denture materials has long-term anticandidal activity. In this study, we examined the ability of culture medium conditioned with drug-free- or miconazole-MAA-UDMA discs to prevent Candida infection in an in vitro oral epithelial cell/Candida albicans co-culture system.
Material and Methods
Candida albicans (C. albicans) induced OKF6/TERT-2 cell damage was quantified by the release of lactate dehydrogenase from epithelial cells, cytokine production was quantified using protein cytokine arrays, and the expression of C. albicans genes was measured by RT-qPCR.
C. albicans had limited growth with altered expression levels of secreted aspartyl proteinase-2 and -5 in culture medium conditioned by miconazole-MAA-UDMA discs. Significantly, the ability of C. albicans to induce oral epithelial cell damage and trigger epithelial proinflammatory cytokine production was also inhibited by miconazole disc conditioned media.
Miconazole released from MAA-UDMA denture materials effectively prevents the development of candidal infection in an in vitro oral epithelial system. Further characterization of this drug-rechargeable denture material is warranted.
PMCID: PMC3654054  PMID: 22957799
Anticandidal; Rechargeable; Denture Material; Denture Stomatitis; Candida albicans; Epithelial cells
18.  Sleep apnea and risk of pneumonia: a nationwide population-based study 
Evidence evaluating the risk of pneumonia in patients with obstructive sleep apnea is limited and mostly focuses on patients who receive continuous positive airway pressure (CPAP) therapy or on pediatric patients. We aimed to explore the risk of incident pneumonia among adults with sleep apnea, either with or without the need of CPAP therapy.
From Jan. 1, 2000, we identified adult patients with sleep apnea from the Taiwan National Health Insurance Research Database. A control cohort without sleep apnea, matched for age, sex and comorbidities, was selected for comparison. The 2 cohorts were followed until Dec. 31, 2010, and observed for occurrence of pneumonia.
Of the 34 100 patients (6816 study patients and 27 284 matched controls), 2757 (8.09%) had pneumonia during a mean follow-up period of 4.50 years, including 638 (9.36%) study patients and 2119 (7.77%) controls. Kaplan–Meier analysis showed a higher incidence of pneumonia among patients with sleep apnea (log rank test, p < 0.001). After multivariate adjustment, patients with sleep apnea experienced a 1.20-fold (95% confidence interval 1.10–1.31) increase in incident pneumonia. The risk was even higher among patients who received CPAP therapy.
Sleep apnea appeared to confer a higher risk for future pneumonia, possibly in a severity-dependent manner.
PMCID: PMC3971026  PMID: 24591276
19.  The Closely Related CD103+ Dendritic Cells (DCs) and Lymphoid-Resident CD8+ DCs Differ in Their Inflammatory Functions 
PLoS ONE  2014;9(3):e91126.
Migratory CD103+ and lymphoid-resident CD8+ dendritic cells (DCs) share many attributes, such as dependence on the same transcription factors, cross-presenting ability and expression of certain surface molecules, such that it has been proposed they belong to a common sub-lineage. The functional diversity of the two DC types is nevertheless incompletely understood. Here we reveal that upon skin infection with herpes simplex virus, migratory CD103+ DCs from draining lymph nodes were more potent at inducing Th17 cytokine production by CD4+ T cells than CD8+ DCs. This superior capacity to drive Th17 responses was also evident in CD103+ DCs from uninfected mice. Their differential potency to induce Th17 differentiation was reflected by higher production of IL-1β and IL-6 by CD103+ DCs compared with CD8+ DCs upon stimulation. The two types of DCs from isolated lymph nodes also differ in expression of certain pattern recognition receptors. Furthermore, elevated levels of GM-CSF, typical of those found in inflammation, substantially increased the pool size of CD103+ DCs in lymph nodes and skin. We argue that varied levels of GM-CSF may explain the contrasting reports regarding the positive role of GM-CSF in regulating development of CD103+ DCs. Together, we find that these two developmentally closely-related DC subsets display functional differences and that GM-CSF has differential effect on the two types of DCs.
PMCID: PMC3956455  PMID: 24637385
20.  The molecule of DC-SIGN captures enterovirus 71 and confers dendritic cell-mediated viral trans-infection 
Virology Journal  2014;11:47.
Enterovirus 71 (EV71) is the main causative agent of hand, foot and mouth disease that occurs in young children. Neither antiviral agents nor vaccines are available for efficiently combating viral infection. Study of EV71–host interplay is important for understanding viral infection and developing strategies for prevention and therapy. Here the interactions of EV71 with human dendritic cells were analyzed.
EV71 capture, endocytosis, infection, and degradation in monocyte-derived dendritic cells (MDDCs) were detected by Flow cytometry or real-time (RT-) PCR, and MDDCs-mediated EV71 trans-infection of RD cells was determined via coculture system. Cell morphology or viability was monitored with microscopy or flow cytometry. SiRNA interference was used to knock down gene expression.
MDDCs can bind EV71, but these loaded-EV71 particles in MDDCs underwent a rapid degradation in the absence of efficient replication; once the captured EV71 encountered susceptible cells, MDDCs efficiently transferred surface-bound viruses to target cells. The molecule of DC-SIGN (DC-specific intercellular adhesion molecule-3 grabbing nonintegrin) mediated viral binding and transfer, because interference of DC-SIGN expression with specific siRNAs reduced EV71 binding and impaired MDDC-mediated viral trans-infection, and exogenous expression of DC-SIGN molecule on Raji cell initiated viral binding and subsequent transmission.
MDDCs could bind efficiently EV71 viruses through viral binding to DC-SIGN molecule, and these captured-viruses could be transferred to susceptible cells for robust infection. The novel finding of DC-mediated EV71 dissemination might facilitate elucidation of EV71 primary infection and benefit searching for new clues for preventing viruses from initial infection.
PMCID: PMC3995660  PMID: 24620896
Enterovirus 71; Dendritic cells; Viral trans-infection
21.  Organocatalytic Multicomponent Reaction for the Acquisition of a Selective Inhibitor of mPTPB, a Virulence Factor of Tuberculosis 
Mycobacterium protein tyrosine phosphatase B (mPTPB) is essential for the survival and persistence of Mycobacterium in the host. Thus small molecule inhibitors of mPTPB are potential anti-TB agents. We developed an efficient organocatalytic multicomponent reaction (MCR) between pyrrole, formaldehyde and aniline, affording a potent and selective mPTPB inhibitor with IC50 at 1.5 µM and >50-fold specificity. Our studies provide a successful example of using organocatalysis as a discovery tool for the acquisition of PTP inhibitors.
PMCID: PMC3586706  PMID: 23380872
22.  Identification of 23-(S)-2-Amino-3-Phenylpropanoyl-Silybin as an Antiviral Agent for Influenza A Virus Infection In Vitro and In Vivo 
It has been reported that autophagy is involved in the replication of many viruses. In this study, we screened 89 medicinal plants, using an assay based on the inhibition of the formation of the Atg12-Atg5/Atg16 heterotrimer, an important regulator of autophagy, and selected Silybum marianum L. for further study. An antiviral assay indicated that silybin (S0), the major active compound of S. marianum L., can inhibit influenza A virus (IAV) infection. We later synthesized 5 silybin derivatives (S1 through S5) and found that 23-(S)-2-amino-3-phenylpropanoyl-silybin (S3) had the best activity. When we compared the polarities of the substituent groups, we found that the hydrophobicity of the substituent groups was positively correlated with their activities. We further studied the mechanisms of action of these compounds and determined that S0 and S3 also inhibited both the formation of the Atg12-Atg5/Atg16 heterotrimer and the elevated autophagy induced by IAV infection. In addition, we found that S0 and S3 could inhibit several components induced by IAV infection, including oxidative stress, the activation of extracellular signal-regulated kinase (ERK)/p38 mitogen-activated protein kinase (MAPK) and IκB kinase (IKK) pathways, and the expression of autophagic genes, especially Atg7 and Atg3. All of these components have been reported to be related to the formation of the Atg12-Atg5/Atg16 heterotrimer, which might validate our screening strategy. Finally, we demonstrated that S3 can significantly reduce influenza virus replication and the associated mortality in infected mice. In conclusion, we identified 23-(S)-2-amino-3-phenylpropanoyl-silybin as a promising inhibitor of IAV infection.
PMCID: PMC3754338  PMID: 23836164
23.  Family-based association study of ZNF533, DOCK4 and IMMP2L gene polymorphisms linked to autism in a northeastern Chinese Han population*  
Objective: A study in a Caucasian population has identified two single-nucleotide polymorphisms (SNPs) in ZNF533, one in DOCK4, and two in IMMP2L, which were all significantly associated with autism. They are located in AUTS1 and AUTS5, which have been identified as autism susceptibility loci in several genome-wide screens. The present study aimed to investigate whether ZNF533, DOCK4, and IMMP2L genes are also associated with autism in a northeastern Chinese Han population. Methods: We performed a similar association study using families with three individuals (one autistic child and two unaffected parents). A family-based transmission disequilibrium test (TDT) was used to analyze the results. Results: There were significant associations between autism and the two SNPs of ZNF533 gene (rs11885327: χ 2=4.5200, P=0.0335; rs1964081: χ 2=4.2610, P=0.0390) and the SNP of DOCK4 gene (rs2217262: χ 2=5.3430, P=0.0208). Conclusions: Our data suggest that ZNF533 and DOCK4 genes are linked to a predisposition to autism in the northeastern Chinese Han population.
PMCID: PMC3955913  PMID: 24599690
Autism; ZNF533; DOCK4; IMMP2L; Northeastern Chinese Han population; Single-nucleotide polymorphism
24.  The Prevalence and Molecular Spectrum of α- and β-Globin Gene Mutations in 14,332 Families of Guangdong Province, China 
PLoS ONE  2014;9(2):e89855.
To reveal the familial prevalence and molecular variation of α- and β-globin gene mutations in Guangdong Province.
A total of 40,808 blood samples from 14,332 families were obtained and analyzed for both hematological and molecular parameters.
A high prevalence of α- and β-globin gene mutations was found. Overall, 17.70% of pregnant women, 15.94% of their husbands, 16.03% of neonates, and 16.83% of couples (pregnant women and their husbands) were heterozygous carriers of α- or β-thalassemia. The regions with the highest prevalence were the mountainous and western regions, followed by the Pearl River Delta; the region with the lowest prevalence was Chaoshan. The total familial carrier rate (both spouses were α- or β-thalassemia carriers) was 1.87%, and the individual carrier rates of α- and β-thalassemia were 1.68% and 0.20%, respectively. The total rate of moderate-to-severe fetal thalassemia was 12.78% among couples in which both parents were carriers.
There was a high prevalence of α- and β-thalassemia in Guangdong Province. This study will contribute to the development of thalassemia prevention and control strategies in Guangdong Province.
PMCID: PMC3937408  PMID: 24587075
25.  Oocytes with a Dark Zona Pellucida Demonstrate Lower Fertilization, Implantation and Clinical Pregnancy Rates in IVF/ICSI Cycles 
PLoS ONE  2014;9(2):e89409.
The morphological assessment of oocytes is important for embryologists to identify and select MII oocytes in IVF/ICSI cycles. Dysmorphism of oocytes decreases viability and the developmental potential of oocytes as well as the clinical pregnancy rate. Several reports have suggested that oocytes with a dark zona pellucida (DZP) correlate with the outcome of IVF treatment. However, the effect of DZP on oocyte quality, fertilization, implantation, and pregnancy outcome were not investigated in detail. In this study, a retrospective analysis was performed in 268 infertile patients with fallopian tube obstruction and/or male factor infertility. In 204 of these patients, all oocytes were surrounded by a normal zona pellucida (NZP, control group), whereas 46 patients were found to have part of their retrieved oocytes enclosed by NZP and the other by DZP (Group A). In addition, all oocytes enclosed by DZP were retrieved from 18 patients (Group B). No differences were detected between the control and group A. Compared to the control group, the rates of fertilization, good quality embryos, implantation and clinical pregnancy were significantly decreased in group B. Furthermore, mitochondria in oocytes with a DZP in both of the two study groups (A and B) were severely damaged with several ultrastructural alterations, which were associated with an increased density of the zona pellucida and vacuolization. Briefly, oocytes with a DZP affected the clinical outcome in IVF/ICSI cycles and appeared to contain more ultrastructural alterations. Thus, DZP could be used as a potential selective marker for embryologists during daily laboratory work.
PMCID: PMC3933533  PMID: 24586757

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