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Open Access Publications from the University of California

Scholarly Works (15 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2012)

Background: There were more than 170,000 documented DUs in Vietnam as of June 2012 and it was estimated that 80% of them are heroin injectors. Vietnam started its National MMT Program with a successful pilot project in 2008-2009 in Hai Phong and Ho Chi Minh City. In early 2010, the Vietnam Government approved a scale-up plan with the goal to provide MMT to 80,000 DUs by 2015. Approximately 10,000 DUs were receiving MMT in Vietnam in late 2012.

Objective: (1) To describe perceived facilitators of and barriers to MMT enrollment among opioid IDUs in Hai Phong; (2) To characterize the opioid current IDU population in Hai Phong regarding characteristics and factors that may influence MMT enrollment; (3) To identify factors associated with MMT enrollment among opioid IDUs in Hai Phong.

Methods: Study sites were 2 urban and 2 rural districts in Hai Phong, randomly selected from districts with operating MMT clinics. Qualitative study: In-depth interviews were conducted anonymously with 36 opioid IDUs (from 3 different groups). Cross-sectional survey: 600 current opioid IDUs were recruited via pharmacies and needle-and-syringe programs for anonymous ACASI interviews. Case-control study: Cases were 150 opioid IDUs who had registered for MMT, and controls were 446 current opioid IDUs who had never registered for MMT. For both cases and controls, data were collected anonymously by ACASI interviews.

Results: From qualitative interviews, facilitators and barriers are presented in 3 levels: Structural, family and individual levels. Cross-sectional data on the following areas are presented: demographic and familial characteristics, drug use and cessation history, general health and HIV-related behaviors, MMT-related beliefs, attitude, social pressure and other factors that may influence MMT enrollment. Rural and urban participants were significantly different in many aspects. Based on case-control data, positive predictors and negative predictors of MMT registration are presented.

Conclusion: Facilitators should be enhanced and barriers should be addressed by MMT program managers and policy makers in Vietnam. The cross-sectional data can be used for program planning and outreach purposes. The results on factors associated with MMT enrollment can be used to identify groups of IDUs who may need supports for MMT participation.

    Cover page: Facilitators of and Barriers to Methadone Maintenance Treatment Enrollment among Opioid Injecting Drug Users in Hai Phong, Vietnam, 2011
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2022)
    In neurodegenerative diseases including Alzheimer’s and amyotrophic lateral sclerosis, proteins that bind RNA are found in aggregated forms in autopsied brains. Evidence suggests that RNA aids nucleation of these pathological aggregates; however, the mechanism has not been investigated at the level of atomic structure. Here, we present the 3.4-Å resolution structure of fibrils of full-length recombinant tau protein in the presence of RNA, determined by electron cryomicroscopy (cryo-EM). The structure reveals the familiar in-register cross-β amyloid scaffold but with a small fibril core spanning residues Glu391 to Ala426, a region disordered in the fuzzy coat in all previously studied tau polymorphs. RNA is bound on the fibril surface to the positively charged residues Arg406 and His407 and runs parallel to the fibril axis. The fibrils dissolve when RNase is added, showing that RNA is necessary for fibril integrity. While this structure cannot exist simultaneously with the tau fibril structures extracted from patients’ brains, it could conceivably account for the nucleating effects of RNA cofactors followed by remodeling as fibrils mature.
      Cover page: Cryo-EM structure of RNA-induced tau fibrils reveals a small C-terminal core that may nucleate fibril formation
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2021)
      Amyloidosis of human islet amyloid polypeptide (hIAPP) is a pathological hallmark of type II diabetes (T2D), an epidemic afflicting nearly 10% of the worlds population. To visualize disease-relevant hIAPP fibrils, we extracted amyloid fibrils from islet cells of a T2D donor and amplified their quantity by seeding synthetic hIAPP. Cryo-EM studies revealed four fibril polymorphic atomic structures. Their resemblance to four unseeded hIAPP fibrils varies from nearly identical (TW3) to non-existent (TW2). The diverse repertoire of hIAPP polymorphs appears to arise from three distinct protofilament cores entwined in different combinations. The structural distinctiveness of TW1, TW2 and TW4 suggests they may be faithful replications of the pathogenic seeds. If so, the structures determined here provide the most direct view yet of hIAPP amyloid fibrils formed during T2D.
        Cover page: Cryo-EM structures of hIAPP fibrils seeded by patient-extracted fibrils reveal new polymorphs and conserved fibril cores.
        • Article
        • Peer Reviewed
        UC San Francisco Previously Published Works (2017)
        Understanding the extent to which vascular disease and its risk factors are associated with prodromal dementia, notably Alzheimer's disease (AD), may enhance predictive accuracy as well as guide early interventions. One promising avenue to determine this relationship consists of looking for reliable and sensitive in-vivo imaging methods capable of characterizing the subtle brain alterations before the clinical manifestations. However, little is known from the imaging perspective about how risk factors such as vascular disease influence AD progression. Here, for the first time, we apply an innovative T1 and DTI fusion analysis of 3D corpus callosum (CC) on mild cognitive impairment (MCI) populations with different levels of vascular profile, aiming to de-couple the vascular factor in the prodromal AD stage. Our new fusion method successfully increases the detection power for differentiating MCI subjects with high from low vascular risk profiles, as well as from healthy controls. MCI subjects with high and low vascular risk profiles showed differed alteration patterns in the anterior CC, which may help to elucidate the inter-wired relationship between MCI and vascular risk factors.
          Cover page: A T1 and DTI fused 3D corpus callosum analysis in MCI subjects with high and low cardiovascular risk profile
          • Article
          • Peer Reviewed
          UC Davis Previously Published Works (2020)

          Introduction

          Low- and middle-income countries have rapidly increasing numbers of people with dementia, yet little evidence on family caregiving interventions. We tested the preliminary efficacy and feasibility of a family caregiving intervention in northern Vietnam.

          Methods

          Nine clusters comprising 60 family caregivers were randomized to a culturally adapted version of a four- to six-session, multicomponent intervention delivered in-home over 2 to 3 months, or enhanced control. Eligible caregivers were ≥18 years of age and scored ≥6 on the Zarit Burden Inventory (ZBI).

          Results

          Fifty-one caregivers (85%) completed the study. Using analysis of covariance with 3-month assessment as the outcome and baseline assessment as a covariate, intervention group caregivers had an average ZBI (primary outcome) score 1.2 standard deviation (SD) lower (P = .02) and Patient Health Questionnaire-4 (psychological distress) score 0.7 SD lower (P = .03) than controls.

          Discussion

          In the first study of its kind in Vietnam, a culturally adapted, manualized, family caregiver intervention was both efficacious and feasible.
            Cover page: Advancing family dementia caregiver interventions in low‐ and middle‐income countries: A pilot cluster randomized controlled trial of Resources for Advancing Alzheimer's Caregiver Health in Vietnam (REACH VN)
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2021)

            Aims

            In mammalian ventricles, electrical gradients establish electrical heterogeneities as essential tissue mechanisms to optimize mechanical efficiency and safeguard electrical stability. Electrical gradients shape mammalian electrocardiographic patterns; disturbance of electrical gradients is proarrhythmic. The zebrafish heart is a popular surrogate model for human cardiac electrophysiology thanks to its remarkable recapitulation of human electrocardiogram and ventricular action potential features. Yet, zebrafish ventricular electrical gradients are largely unexplored. The goal of this study is to define the zebrafish ventricular electrical gradients that shape the QRS complex and T wave patterns at baseline and under oxidative stress.

            Methods and results

            We performed in vivo electrocardiography and ex vivo voltage-sensitive fluorescent epicardial and transmural optical mapping of adult zebrafish hearts at baseline and during acute H2O2 exposure. At baseline, apicobasal activation and basoapical repolarization gradients accounted for the polarity concordance between the QRS complex and T wave. During H2O2 exposure, differential regional impairment of activation and repolarization at the apex and base disrupted prior to baseline electrical gradients, resulting in either reversal or loss of polarity concordance between the QRS complex and T wave. KN-93, a specific calcium/calmodulin-dependent protein kinase II inhibitor (CaMKII), protected zebrafish hearts from H2O2 disruption of electrical gradients. The protection was complete if administered prior to oxidative stress exposure.

            Conclusions

            Despite remarkable apparent similarities, zebrafish and human ventricular electrocardiographic patterns are mirror images supported by opposite electrical gradients. Like mammalian ventricles, zebrafish ventricles are also susceptible to H2O2 proarrhythmic perturbation via CaMKII activation. Our findings suggest that the adult zebrafish heart may constitute a clinically relevant model to investigate ventricular arrhythmias induced by oxidative stress. However, the fundamental ventricular activation and repolarization differences between the two species that we demonstrated in this study highlight the potential limitations when extrapolating results from zebrafish experiments to human cardiac electrophysiology, arrhythmias, and drug toxicities.
              Cover page: Adult zebrafish ventricular electrical gradients as tissue mechanisms of ECG patterns under baseline vs. oxidative stress.
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2019)
              The tetrameric protein transthyretin is a transporter of retinol and thyroxine in blood, cerebrospinal fluid, and the eye, and is secreted by the liver, choroid plexus, and retinal epithelium, respectively. Systemic amyloid deposition of aggregated transthyretin causes hereditary and sporadic amyloidoses. A common treatment of patients with hereditary transthyretin amyloidosis is liver transplantation. However, this procedure, which replaces the patient's variant transthyretin with the WT protein, can fail to stop subsequent cardiac deposition, ultimately requiring heart transplantation. We recently showed that preformed amyloid fibrils present in the heart at the time of surgery can template or seed further amyloid aggregation of native transthyretin. Here we assess possible interventions to halt this seeding, using biochemical and EM assays. We found that chemical or mutational stabilization of the transthyretin tetramer does not hinder amyloid seeding. In contrast, binding of the peptide inhibitor TabFH2 to ex vivo fibrils efficiently inhibits amyloid seeding by impeding self-association of the amyloid-driving strands F and H in a tissue-independent manner. Our findings point to inhibition of amyloid seeding by peptide inhibitors as a potential therapeutic approach.
                Cover page: A pair of peptides inhibits seeding of the hormone transporter transthyretin into amyloid fibrils
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2016)

                Background

                Exposure to the commonly used dithiocarbamate (DTC) pesticides is associated with an increased risk of developing Parkinson disease (PD), although the mechanisms by which they exert their toxicity are not completely understood.

                Objective

                We studied the mechanisms of ziram's (a DTC fungicide) neurotoxicity in vivo.

                Methods

                Zebrafish (ZF) embryos were utilized to determine ziram's effects on behavior, neuronal toxicity, and the role of synuclein in its toxicity.

                Results

                Nanomolar-range concentrations of ziram caused selective loss of dopaminergic (DA) neurons and impaired swimming behavior. Because ziram increases α-synuclein (α-syn) concentrations in rat primary neuronal cultures, we investigated the effect of ziram on ZF γ-synuclein 1 (γ1). ZF express 3 synuclein isoforms, and ZF γ1 appears to be the closest functional homologue to α-syn. We found that recombinant ZF γ1 formed fibrils in vitro, and overexpression of ZF γ1 in ZF embryos led to the formation of neuronal aggregates and neurotoxicity in a manner similar to that of α-syn. Importantly, knockdown of ZF γ1 with morpholinos and disruption of oligomers with the molecular tweezer CLR01 prevented ziram's DA toxicity.

                Conclusions

                These data show that ziram is selectively toxic to DA neurons in vivo, and this toxicity is synuclein-dependent. These findings have important implications for understanding the mechanisms by which pesticides may cause PD. Citation: Lulla A, Barnhill L, Bitan G, Ivanova MI, Nguyen B, O'Donnell K, Stahl MC, Yamashiro C, Klärner FG, Schrader T, Sagasti A, Bronstein JM. 2016. Neurotoxicity of the Parkinson disease-associated pesticide ziram is synuclein-dependent in zebrafish embryos. Environ Health Perspect 124:1766-1775; http://dx.doi.org/10.1289/EHP141.
                  Cover page: Neurotoxicity of the Parkinson Disease-Associated Pesticide Ziram Is Synuclein-Dependent in Zebrafish Embryos
                  • Article
                  • Peer Reviewed
                  UC San Francisco Previously Published Works (2020)
                  The Hoarding Rating Scale, Self Report (HRS-SR) is a 5-item assessment developed to ascertain the presence and severity of hoarding symptoms. This study aimed to evaluate the validity of an online adaptation of the HRS-SR in a remote, unsupervised internet sample of 23,214 members of the Brain Health Registry (BHR), an online research registry that evaluates and longitudinally monitors cognition, medical and psychiatric health status. Convergent validity was assessed among a sub-sample of 1,183 participants who completed additional, remote measures of self-reported hoarding behaviors. Structured clinical interviews conducted in-clinic and via video conferencing tools were conducted among 230 BHR participants; ROC curves were plotted to assess the diagnostic performance of the internet-based HRS-SR using best estimate hoarding disorder (HD) diagnoses as the gold standard. The area under the curve indicated near-perfect model accuracy, and was confirmed with 10-fold cross validation. Sensitivity and specificity for distinguishing clinically relevant hoarding were optimized using an HRS-SR total score cut-off of 5. Longitudinal analyses indicated stability of HRS-SR scores over time. Findings indicate that the internet-based HRS-SR is a useful and valid assessment of hoarding symptoms, though additional research using samples with more diverse hoarding behavior is needed to validate optimal cut-off values.
                    Cover page: Internet-based hoarding assessment: The reliability and predictive validity of the internet-based Hoarding Rating Scale, Self-Report.
                    • Article
                    • Peer Reviewed
                    UC San Francisco Previously Published Works (2022)
                    BACKGROUND: The relationships between hoarding disorder (HD) and other neurological and psychiatric disorders remain largely unknown. Although psychiatric burden in those with HD is high, less is known about neurological disorders. Furthermore, which disorders are primarily associated with HD vs which can be better explained via a relationship with another disorder has not been determined. To address these questions, we examined comorbidity patterns of psychiatric and neurological disorders in a large online registry of adults using network analyses. METHODS: We first examined psychiatric comorbidity among 252 participants completing clinician administered psychiatric assessments. Using the Brain Health Registry (BHR) (N = 15,978), we next analyzed prevalence of self-reported neurological and psychiatric disorders among participants with no/minimal hoarding, subclinical hoarding, and clinically significant hoarding and used network analyses to identify direct and indirect relationships between HD and the assessed psychiatric and neurological disorders. RESULTS: The most prevalent comorbidity in clinically assessed participants with HD was major depressive disorder (MDD, 62%), followed by generalized anxiety disorder (GAD, 32%). Network analyses in the BHR indicated that the strongest direct relationships with HD were attention-deficit hyperactivity disorder (ADHD), major depressive disorder (MDD), and obsessive-compulsive disorder (OCD). The relationships between HD and neurological disorders, including mild cognitive impairment, were weak or non-existent after controlling for other disorders. CONCLUSIONS: ADHD, MDD, and OCD form a triad of psychiatric disorders directly associated with HD. Despite their high comorbidity rates, the associations among anxiety disorders and HD were weak or indirect.
                      Cover page: Identifying psychiatric and neurological comorbidities associated with hoarding disorder through network analysis.
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