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Open Access Publications from the University of California

UC Irvine Institute for Clinical and Translational Science (ICTS) provides a clinical research home to speed up the often slow process that guides scientific discovery to clinical application. We provide a variety of forms of support to researchers along the translational spectrum from basic research to community-based dissemination research and everything in between. Support for clinical trials can include direct funding for pilot studies, processing and storage of biological samples, nursing services, biostatistical and research design consultations, and expert consults in the areas of imaging, community-based research and informatics. We also support education and training in translational research at all levels, from high school students through to post-doctoral students and medical residents.

The interactive effects of maternal stress and diet in pregnancy on markers of inflammation

(2018)

Introduction:

Excess inflammation during pregnancy may exert adverse effects on fetal development and birth outcomes, including prematurity, intrauterine growth restriction, and preeclampsia. Maternal nutrition and stress are two of the most frequently but independently studied factors for their influence on prenatal inflammatory status, but their interaction in the context of pregnancy has been significantly understudied.

The Dietary Inflammatory Index (DII) is a validated method to characterize and quantify the cumulative inflammatory potential of an individual diet,1 and has been previously used in prenatal populations.2,3 Ecological Momentary Assessment (EMA) methods are an effective way to assess psychosocial states in real-time, ambulatory, naturalistic settings, reducing the potential for recall and saliency bias associated with traditional retrospective questionnaires.4 

Objective: The aim of this study is to investigate the combined effects of perceived stress (PSS) and dietary inflammatory index (DII) across pregnancy on markers of maternal inflammation.

Financial Support: NIH grants R01 HD-060628, HD-065825 & MH-091351; European Commission FP7 289346 Project Early Nutrition

Poster presented at the ICTS Translational Science Day at University of California Irvine on May 4, 2018

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Cover page of Association between supraclavicular brown adipose tissue composition at birth and adiposity gain from birth to 6 months of age.

Association between supraclavicular brown adipose tissue composition at birth and adiposity gain from birth to 6 months of age.

(2017)

BackgroundBrown adipose tissue (BAT) is associated with higher energy expenditure and lower adiposity in adults. However, the relationship between BAT composition and adiposity in early life is unknown. The objective of this study was to test the hypothesis that brown fat composition at birth is prospectively associated with adiposity gain during the first 6 months of postnatal life.MethodsN=35 healthy infants were followed up prospectively from intrauterine life and birth through 6 months of age. Dixon magnetic resonance imaging (MRI) scans were conducted during the neonatal period to characterize supraclavicular BAT composition. Dual-energy X-ray absorptiometry to assess total body composition was performed within the first and sixth months of life.ResultsAfter adjusting for potential confounding factors, a more brown-like composition (smaller fat fraction) of the supraclavicular BAT depot was associated with a smaller increase in percent body fat over the first 6 months of postnatal life.ConclusionsA more brown-like BAT composition at birth appears to be protective against excess adiposity gain in early life. Newborn BAT tissue may constitute a target for prevention strategies against the subsequent development of obesity.

Cover page of Phase IIa trial of fingolimod for amyotrophic lateral sclerosis demonstrates acceptable acute safety and tolerability.

Phase IIa trial of fingolimod for amyotrophic lateral sclerosis demonstrates acceptable acute safety and tolerability.

(2017)

Immune activation has been implicated in progression of amytrophic lateral sclerosis (ALS). Oral fingolimod reduces circulating lymphocytes. The objective of this phase IIa, randomized, controlled trial was to test the short-term safety, tolerability, and target engagement of fingolimod in ALS.

Randomization was 2:1 (fingolimod:placebo). Treatment duration was 4 weeks. Primary outcomes were safety and tolerability. Secondary outcomes included circulating lymphocytes and whole-blood gene expression.

Thirty participants were randomized; 28 were administered a drug (fingolimod 18, placebo 10). No serious adverse events occurred. Adverse events were similar by treatment arm, as was study discontinuation (2 fingolimod vs. 0 placebo, with no statistical difference). Forced expiratory volume in 1 second (FEV1) and FEV1/slow vital capacity changes were similar in the fingolimod and placebo arms. Circulating lymphocytes decreased significantly in the fingolimod arm (P < 0.001). Nine immune-related genes were significantly downregulated in the fingolimod arm, including forkhead box P3 (P < 0.001) and CD40 ligand (P = 0.003).

Fingolimod is safe and well-tolerated and can reduce circulating lymphocytes in ALS patients. Muscle Nerve 56: 1077-1084, 2017.

Cover page of Developmental Emergence of Phenotypes in the Auditory Brainstem Nuclei ofFmr1Knockout Mice.

Developmental Emergence of Phenotypes in the Auditory Brainstem Nuclei ofFmr1Knockout Mice.

(2017)

Fragile X syndrome (FXS), the most common monogenic cause of autism, is often associated with hypersensitivity to sound. Several studies have shown abnormalities in the auditory brainstem in FXS; however, the emergence of these auditory phenotypes during development has not been described. Here, we investigated the development of phenotypes in FXS model [Fmr1knockout (KO)] mice in the ventral cochlear nucleus (VCN), medial nucleus of the trapezoid body (MNTB), and lateral superior olive (LSO). We studied features of the brainstem known to be altered in FXS orFmr1KO mice, including cell size and expression of markers for excitatory (VGLUT) and inhibitory (VGAT) synapses. We found that cell size was reduced in the nuclei with different time courses. VCN cell size is normal until after hearing onset, while MNTB and LSO show decreases earlier. VGAT expression was elevated relative to VGLUT in theFmr1KO mouse MNTB by P6, before hearing onset. Because glial cells influence development and are altered in FXS, we investigated their emergence in the developingFmr1KO brainstem. The number of microglia developed normally in all three nuclei inFmr1KO mice, but we found elevated numbers of astrocytes inFmr1KO in VCN and LSO at P14. The results indicate that some phenotypes are evident before spontaneous or auditory activity, while others emerge later, and suggest that Fmr1 acts at multiple sites and time points in auditory system development.

Cover page of Intermittent Ca<sup>2+</sup>signals mediated by Orai1 regulate basal T cell motility.

Intermittent Ca2+signals mediated by Orai1 regulate basal T cell motility.

(2017)

Ca2+influx through Orai1 channels is crucial for several T cell functions, but a role in regulating basal cellular motility has not been described. Here, we show that inhibition of Orai1 channel activity increases average cell velocities by reducing the frequency of pauses in human T cells migrating through confined spaces, even in the absence of extrinsic cell contacts or antigen recognition. Utilizing a novel ratiometric genetically encoded cytosolic Ca2+indicator, Salsa6f, which permits real-time monitoring of cytosolic Ca2+along with cell motility, we show that spontaneous pauses during T cell motility in vitro and in vivo coincide with episodes of cytosolic Ca2+signaling. Furthermore, lymph node T cells exhibited two types of spontaneous Ca2+transients: short-duration 'sparkles' and longer duration global signals. Our results demonstrate that spontaneous and self-peptide MHC-dependent activation of Orai1 ensures random walk behavior in T cells to optimize immune surveillance.

Cover page of Usages of Computers and Smartphones to Develop Dementia Care Education Program for Asian American Family Caregivers.

Usages of Computers and Smartphones to Develop Dementia Care Education Program for Asian American Family Caregivers.

(2017)

Families of ethnic minority persons with dementia often seek help at later stages of the disease. Little is known about the effectiveness of various methods in supporting ethnic minority dementia patients' caregivers. The objective of the study was to identify smartphone and computer usage among family caregivers of dementia patients (i.e., Korean and Vietnamese Americans) to develop dementia-care education programs for them.

Participants were asked various questions related to their computer or smartphone usage in conjunction with needs-assessment interviews. Flyers were distributed at two ethnic minority community centers in Southern California. Snowball recruitment was also utilized to reach out to the families of dementia patients dwelling in the community.

Thirty-five family caregivers, including 20 Vietnamese and 15 Korean individuals, participated in this survey. Thirty participants (30 of 35, 85.7%) were computer users. Among those, 76.7% (23 of 30) reported daily usage and 53% (16 of 30) claimed to use social media. A majority of the participants (31 of 35, 88.6%) reported that they owned smartphones. More than half of smartphone users (18 of 29, 62%) claimed to use social media applications. Many participants claimed that they could not attend in-class education due to caregiving and/or transportation issues.

Most family caregivers of dementia patients use smartphones more often than computers, and more than half of those caregivers communicate with others through social media apps. A smartphone-app-based caregiver intervention may serve as a more effective approach compared to the conventional in-class method. Multiple modalities for the development of caregiver interventions should be considered.

Cover page of Activation of PKCα and PI3K Kinases in Hypertrophic and Nodular Port Wine Stain Lesions.

Activation of PKCα and PI3K Kinases in Hypertrophic and Nodular Port Wine Stain Lesions.

(2017)

Port wine stain (PWS) is a congenital, progressive vascular malformation. Many patients with PWS develop hypertrophy and discrete nodularity during their adult life, but the mechanism(s) remain incompletely understood. In this study, we attempted to investigate activation status of PKCα, PI3K, PDPK1 and PLC-γ and protein levels of PP2A and DAG to explore their potential roles in the formation of hypertrophic and nodular PWS lesions. We found phosphorylated levels of PKCα, PI3K, PDPK1, and PLC-γ and protein levels of PP2A and DAG showed moderate increases in the endothelial cells of hypertrophic PWS as compared to the adjacent normal skin. These increases extended throughout the entire stroma of blood vessels in PWS nodules. Many proliferating cells, such as fibroblasts, also showed strong activation of PKCα, PI3K, PDPK1 and PLC-γ and upregulations of PP2A and DAG in nodular PWS lesions. Our data showed that there is aberrant activation of PKCα, PI3K, PDPK1 and PLC-γ and upregulation of PP2A and DAG mainly in endothelial cells in hypertrophic PWS areas, but presenting in the entire vasculatures and surrounding fibroblasts in PWS nodules. Our data suggest that both PKCα and PI3K signaling pathways contribute to the development of hypertrophy and nodularity in adult PWS.

Cover page of Systemic Neutrophil Depletion Modulates the Migration and Fate of Transplanted Human Neural Stem Cells to Rescue Functional Repair.

Systemic Neutrophil Depletion Modulates the Migration and Fate of Transplanted Human Neural Stem Cells to Rescue Functional Repair.

(2017)

The interaction of transplanted stem cells with local cellular and molecular cues in the host CNS microenvironment may affect the potential for repair by therapeutic cell populations. In this regard, spinal cord injury (SCI), Alzheimer's disease, and other neurological injuries and diseases all exhibit dramatic and dynamic changes to the host microenvironment over time. Previously, we reported that delayed transplantation of human CNS-derived neural stem cells (hCNS-SCns) at 9 or 30 d post-SCI (dpi) resulted in extensive donor cell migration, predominantly neuronal and oligodendrocytic donor cell differentiation, and functional locomotor improvements. Here, we report that acute transplantation of hCNS-SCns at 0 dpi resulted in localized astroglial differentiation of donor cells near the lesion epicenter and failure to produce functional improvement in an all-female immunodeficient mouse model. Critically, specific immunodepletion of neutrophils (polymorphonuclear leukocytes) blocked hCNS-SCns astroglial differentiation near the lesion epicenter and rescued the capacity of these cells to restore function. These data represent novel evidence that a host immune cell population can block the potential for functional repair derived from a therapeutic donor cell population, and support targeting the inflammatory microenvironment in combination with cell transplantation after SCI.SIGNIFICANCE STATEMENTThe interaction of transplanted cells with local cellular and molecular cues in the host microenvironment is a key variable that may shape the translation of neurotransplantation research to the clinical spinal cord injury (SCI) human population, and few studies have investigated these events. We show that the specific immunodepletion of polymorphonuclear leukocyte neutrophils using anti-Ly6G inhibits donor cell astrogliosis and rescues the capacity of a donor cell population to promote locomotor improvement after SCI. Critically, our data demonstrate novel evidence that a specific host immune cell population can block the potential for functional repair derived from a therapeutic donor cell population.

Cover page of Refractive outcomes of intraoperative wavefront aberrometry versus optical biometry alone for intraocular lens power calculation.

Refractive outcomes of intraoperative wavefront aberrometry versus optical biometry alone for intraocular lens power calculation.

(2017)

To compare the outcomes of intraoperative wavefront aberrometry versus optical biometry alone for intraocular lens (IOL) power calculation in eyes undergoing cataract surgery with monofocal IOL implantation.

Preoperative data were obtained with the IOLMaster. Intraoperative aphakic measurements and IOL power calculations were obtained in some patients with the optiwave refractive analysis (ORA) system. Analysis was performed to determine the accuracy of monofocal IOL power prediction and postoperative manifest refraction at 1 month of the ORA versus IOLMaster.

Two hundred and ninety-five eyes reviewed, 61 had only preoperative IOLMaster measurements and 234 had both IOLMaster and ORA measurements. Of these 234 eyes, 6 were excluded, 107 had the same recommended IOL power by ORA and IOLMaster. Sixty-four percent of these eyes were within ±0.5D. 95 eyes had IOL power implantation based on ORA instead of IOLMaster. Seventy percent of these eyes were within ±0.5D of target refraction. 26 eyes had IOL power chosen based on IOLMaster predictions instead of ORA. Sixty-five percent were within ±0.5D. In the group with IOLMaster without ORA measurements, 80% of eyes were within ±0.5D of target refraction. The absolute error was statistically smaller in those eyes where the ORA and IOLMaster recommended the same IOL power based on preoperative target refraction compared to instances in which IOL selection was based on ORA or IOLMaster alone. Neither prediction errors were statistically different between the ORA and IOLMaster alone.

Intraoperative wavefront aberrometry with the ORA system provides postoperative refractive results comparable to conventional biometry with the IOLMaster for monofocal IOL selection.