Publications by authors named "Chao-Yin Chen"

48 Publications

Dietary management and major clinical events in patients with long-chain fatty acid oxidation disorders enrolled in a phase 2 triheptanoin study.

Clin Nutr ESPEN 2021 Feb 25;41:293-298. Epub 2020 Dec 25.

Ultragenyx Pharmaceutical Inc., 60 Leveroni Ct, Novato, CA, USA.

Background & Aims: Long-chain fatty acid oxidation disorders (LC-FAOD) are rare, life-threatening, autosomal recessive disorders that lead to energy depletion and major clinical events (MCEs), such as acute metabolic crises of hypoglycemia, cardiomyopathy, and rhabdomyolysis. The aim of this study was to report a post hoc analysis of diet diary data from the phase 2 UX007-CL201 study (NCT01886378).

Methods: In the single-arm, open-label, phase 2 UX007-CL201 study, the safety and efficacy of 78 weeks of treatment with triheptanoin, an odd-carbon, medium-chain triglyceride consisting of three 7-carbon fatty acids on a glycerol backbone, was investigated in subjects with LC-FAOD versus a retrospective 78-week period when subjects were optimally managed under published dietary guidelines. Subject dietary reports were collected to analyze the relationship between diet, triheptanoin treatment, and MCEs. Referring metabolic physicians completed a survey on patient management and clinical outcomes before and after initiation of triheptanoin. Before initiating triheptanoin, subjects received a mean daily caloric intake (DCI) of 17.4% from medium-chain triglycerides (MCT). During the study, subjects received a mean of 27.5% DCI from triheptanoin. Protein (13.7% vs 14.5% DCI), long-chain fat (13.1% vs 10.5% DCI), and carbohydrate (55.3% vs 47.1% DCI) intake were consistent between the pre-triheptanoin and triheptanoin treatment periods, respectively.

Results: Following 78 weeks of treatment, mean annualized MCE rate decreased by 48.1% (p = 0.021) and mean annualized MCE event-day rate decreased by 50.3% (p = 0.028). A weak association existed between improvement in annualized MCE rate and change in percent DCI from MCT (Spearman rank correlation: r = -0.38; 95% CI: -0.675, 0.016). However, there was large variability in the association and no specific pattern of change for larger or smaller changes in dose. Seventy-two percent of physicians reported that triheptanoin had a clinically meaningful benefit on medical management of their patients.

Conclusions: Treatment with triheptanoin at the protocol-specified dose decreased the rate of MCEs in patients with LC-FAOD independently from other dietary changes between the pre-triheptanoin and triheptanoin treatment periods.

Trial Registration: ClinicalTrials.gov identifier: NCT01886378.
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http://dx.doi.org/10.1016/j.clnesp.2020.11.018DOI Listing
February 2021

CRL5-dependent regulation of the small GTPases ARL4C and ARF6 controls hippocampal morphogenesis.

Proc Natl Acad Sci U S A 2020 09 1;117(37):23073-23084. Epub 2020 Sep 1.

Department of Cell Biology and Human Anatomy, University of California, Davis, CA 95616;

The small GTPase ARL4C participates in the regulation of cell migration, cytoskeletal rearrangements, and vesicular trafficking in epithelial cells. The ARL4C signaling cascade starts by the recruitment of the ARF-GEF cytohesins to the plasma membrane, which, in turn, bind and activate the small GTPase ARF6. However, the role of ARL4C-cytohesin-ARF6 signaling during hippocampal development remains elusive. Here, we report that the E3 ubiquitin ligase Cullin 5/RBX2 (CRL5) controls the stability of ARL4C and its signaling effectors to regulate hippocampal morphogenesis. Both RBX2 knockout and Cullin 5 knockdown cause hippocampal pyramidal neuron mislocalization and development of multiple apical dendrites. We used quantitative mass spectrometry to show that ARL4C, Cytohesin-1/3, and ARF6 accumulate in the RBX2 mutant telencephalon. Furthermore, we show that depletion of ARL4C rescues the phenotypes caused by Cullin 5 knockdown, whereas depletion of CYTH1 or ARF6 exacerbates overmigration. Finally, we show that ARL4C, CYTH1, and ARF6 are necessary for the dendritic outgrowth of pyramidal neurons to the superficial strata of the hippocampus. Overall, we identified CRL5 as a key regulator of hippocampal development and uncovered ARL4C, CYTH1, and ARF6 as CRL5-regulated signaling effectors that control pyramidal neuron migration and dendritogenesis.
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http://dx.doi.org/10.1073/pnas.2002749117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502717PMC
September 2020

Growth Curves for Children with X-linked Hypophosphatemia.

J Clin Endocrinol Metab 2020 10;105(10)

Pediatrics, University of Virginia School of Medicine, Charlottesville, Virginia.

Context: We characterized linear growth in infants and children with X-linked hypophosphatemia (XLH).

Objective: Provide linear growth curves for children with XLH from birth to early adolescence.

Design: Data from 4 prior studies of XLH were pooled to construct growth curves. UX023-CL002 was an observational, retrospective chart review. Pretreatment data were collected from 3 interventional trials: two phase 2 trials (UX023-CL201, UX023-CL205) and a phase 3 trial (UX023-CL301).

Setting: Medical centers with expertise in treating XLH.

Patients: Children with XLH, 1-14 years of age.

Intervention: None.

Main Outcome Measure: Height-for-age linear growth curves, including values for the 5th, 10th, 25th, 50th, 75th, 90th, and 95th percentiles for children with XLH compared to population norms.

Results: A total of 228 patients (132 girls, 96 boys) with 2381 height measurements were included. Nearly all subjects (> 99%) reported prior management with supplementation therapy. Compared to the Center for Disease Control and Prevention growth curves, boys at age 3 months, 6 months, 9 months, 1 year, and 2 years had median height percentiles of 46%, 37%, 26%, 18%, and 5%, respectively; for girls the median height percentiles were 52%, 37%, 25%, 18%, and 7%, respectively. Annual growth in children with XLH fell below that of healthy children near 1 year of age and progressively declined during early childhood, with all median height percentiles < 8% between 2 and 12 years old.

Conclusion: Children with XLH show decreased height gain by 1 year of age and remain below population norms thereafter. These data will help evaluate therapeutic interventions on linear growth for pediatric XLH.
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http://dx.doi.org/10.1210/clinem/dgaa495DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7448934PMC
October 2020

Device profile of the MobiusHD EVBA system for the treatment of resistant hypertension: overview of its mechanism of action, safety and efficacy.

Expert Rev Med Devices 2020 Jul 16;17(7):649-658. Epub 2020 Jun 16.

Department of Vascular Medicine, University Medical Center Utrecht, Utrecht University , Utrecht, The Netherlands.

Introduction: Early promising results of renal nerve denervation awakened interest in developing medical device alternatives for patients with resistant hypertension. The subsequent sham-controlled renal nerve denervation randomized trials were disappointing leading researchers and innovators to explore alternative device and trial designs to address this significant unmet need. We describe the innovation process leading to the first endovascular carotid baroreflex amplification device currently undergoing clinical trials in the United States and Europe.

Areas Covered: We provide a brief overview of carotid baroreceptor physiology and then couple this knowledge with the fundamental principles of strain pattern changes that led to the proposed innovation. The mechanism of blood pressure reduction via enhancing innate physiologic carotid sinus baroreceptor signaling through changes in pulsatile focal carotid bulb strain is described alongside preclinical testing and early clinical results.

Expert Opinion: The collective data to date suggest endovascular carotid baroreflex amplification may be an innovative alternative for resistant hypertension patients. However, well-controlled studies will be needed to assess efficacy, safety, durability, and risk: benefit of this permanent intravascular carotid implant.

Subject Codes: high blood pressure, hypertension, treatment, physiology.
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http://dx.doi.org/10.1080/17434440.2020.1779054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7453969PMC
July 2020

Cardiopulmonary Health Effects of Airborne Particulate Matter: Correlating Animal Toxicology to Human Epidemiology.

Toxicol Pathol 2019 12 23;47(8):954-961. Epub 2019 Oct 23.

Center for Health and the Environment, University of California, Davis, USA.

The effects of particulate matter (PM) on cardiopulmonary health have been studied extensively over the past three decades. Particulate matter is the primary criteria air pollutant most commonly associated with adverse health effects on the cardiovascular and respiratory systems. The mechanisms by which PM exerts its effects are thought to be due to a variety of factors which may include, but are not limited to, concentration, duration of exposure, and age of exposed persons. Adverse effects of PM are strongly driven by their physicochemical properties, sites of deposition, and interactions with cells of the respiratory and cardiovascular systems. The direct translocation of particles, as well as neural and local inflammatory events, are primary drivers for the observed cardiopulmonary health effects. In this review, toxicological studies in animals, and clinical and epidemiological studies in humans are examined to demonstrate the importance of using all three approaches to better define potential mechanisms driving health outcomes upon exposure to airborne PM of diverse physicochemical compositions.
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http://dx.doi.org/10.1177/0192623319879091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911013PMC
December 2019

Individual heat map assessments demonstrate vestronidase alfa treatment response in a highly heterogeneous mucopolysaccharidosis VII study population.

JIMD Rep 2019 Sep 26;49(1):53-62. Epub 2019 Jun 26.

Pediatric Clinical Research Center UCSF Benioff Children's Hospital Oakland Oakland California.

Mucopolysaccharidosis (MPS) VII is an ultra-rare, progressively debilitating, life-threatening lysosomal disease caused by deficiency of the enzyme, β-glucuronidase. Vestronidase alfa is an approved enzyme replacement therapy for MPS VII. UX003-CL301 was a phase 3, randomized, placebo-controlled, blind-start study examining the efficacy and safety of vestronidase alfa 4 mg/kg intravenously administered every 2 weeks to 12 patients with MPS VII. Due to the rarity of disease, broad eligibility criteria resulted in a highly heterogeneous population with variable symptoms. For an integrated view of the diverse data, the changes from baseline (or randomization for the placebo period) in clinical endpoints were grouped into three functional domains (mobility, fatigue, and fine motor + self-care) and analyzed post-hoc as subject-level heat maps. Mobility assessments included the 6-minute walk test, 3-minute stair climb test, Bruininks-Oseretsky test (BOT-2) gross motor function subtests, and patient-reported outcome assessments (PROs) related to movement, pain, and ambulation. Fatigue assessments included the Pediatric Quality of Life Multidimensional Fatigue Scale and other fatigue-related PROs. Fine motor + self-care assessments included BOT-2 fine motor function subtests and PROs for eating, dressing, hygiene, and caregiver assistance. Most subjects showed improvement in at least one domain. Two subjects improved in two or more domains and two subjects did not show clear improvement in any domain. Both severely and mildly affected subjects improved with vestronidase alfa in clinical assessments, PRO results, or both. Heat map analysis demonstrates how subjects responded to treatment across multiple domains, providing a useful visual tool for studying rare diseases with variable symptoms.
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http://dx.doi.org/10.1002/jmd2.12043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718107PMC
September 2019

The Use of Percent Change in RR Interval for Data Exclusion in Analyzing 24-h Time Domain Heart Rate Variability in Rodents.

Front Physiol 2019 6;10:693. Epub 2019 Jun 6.

Department of Pharmacology, School of Medicine, University of California, Davis, Davis, CA, United States.

While epidemiological data support the link between reduced heart rate variability (HRV) and a multitude of pathologies, the mechanisms underlying changes in HRV and disease progression are poorly understood. Even though we have numerous rodent models of disease for mechanistic studies, not being able to reliably measure HRV in conscious, freely moving rodents has hindered our ability to extrapolate the role of HRV in the progression from normal physiology to pathology. The sheer number of heart beats per day (>800,000 in mice) makes data exclusion both time consuming and daunting. We sought to evaluate an RR interval exclusion method based on percent (%) change of adjacent RR intervals. Two approaches were evaluated: % change from "either" and "both" adjacent RR intervals. The data exclusion method based on standard deviation (SD) was also evaluated for comparison. Receiver operating characteristic (ROC) curves were generated to determine the performance of each method. Results showed that exclusion based on % change from "either" adjacent RR intervals was the most accurate method in identifying normal and abnormal RR intervals, with an overall accuracy of 0.92-0.99. As the exclusion value increased (% change or SD), the sensitivity (correctly including normal RR intervals) increased exponentially while the specificity (correctly rejecting abnormal RR intervals) decreased linearly. Compared to the SD method, the "either" approach had a steeper rise in sensitivity and a more gradual decrease in specificity. The intersection of sensitivity and specificity where the exclusion criterion had the same accuracy in identifying normal and abnormal RR intervals was 10-20% change for the "either" approach and ∼ 1 SD for the SD-based exclusion method. Graphically (tachogram and Lorenz plot), 20% change from either adjacent RR interval resembled the data after manual exclusion. Finally, overall (SDNN) and short-term (rMSSD) indices of HRV generated using 20% change from "either" adjacent RR intervals as the exclusion criterion were closer to the manual exclusion method with lower subject-to-subject variability than those generated using the 2 SD exclusion criterion. Thus, 20% change from "either" adjacent RR intervals is a good criterion for data exclusion for reliable 24-h time domain HRV analysis in rodents.
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http://dx.doi.org/10.3389/fphys.2019.00693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562196PMC
June 2019

Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial.

Lancet 2019 06 16;393(10189):2416-2427. Epub 2019 May 16.

Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.

Background: X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia.

Methods: In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705.

Findings: Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8-1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved.

Interpretation: Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy.

Funding: Ultragenyx Pharmaceutical and Kyowa Kirin International.
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http://dx.doi.org/10.1016/S0140-6736(19)30654-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179969PMC
June 2019

Rickets severity predicts clinical outcomes in children with X-linked hypophosphatemia: Utility of the radiographic Rickets Severity Score.

Bone 2019 05 14;122:76-81. Epub 2019 Feb 14.

Yale University School of Medicine, New Haven, CT, USA.

The Rickets Severity Score (RSS) was used to evaluate X-linked hypophosphatemic rickets (XLH), a genetic disorder mediated by increased circulating FGF23. The reliability of the RSS was assessed using data from a randomized, phase 2 clinical trial that evaluated the effects of burosumab, a fully human anti-FGF23 monoclonal antibody, in 52 children with XLH ages 5 to 12 years. Bilateral knee and wrist radiographs were obtained at baseline, week 40, and week 64. We evaluated the relationships of the RSS to the Radiographic Global Impression of Change (RGI-C), serum alkaline phosphatase (ALP), height Z-score, 6-minute walk test (6MWT) percent predicted, and the Pediatric Orthopedic Society of North America Pediatric Outcomes Data Collection Instrument (POSNA-PODCI). The RSS showed moderate-to-substantial inter-rater reliability (weighted kappa, 0.45-0.65; Pearson correlation coefficient (r), 0.83-0.89) and substantial intra-rater reliability (weighted Kappa, 0.66; r = 0.91). Baseline RSS correlated with serum ALP (r = 0.47). Baseline RSS identified two subgroups (higher [RSS ≥1.5] and lower RSS [RSS <1.5]) that discriminated between subjects with greater and lesser rachitic disease. Higher RSS was associated with more severe clinical features, including impaired growth (Z-score, -2.12 vs -1.44) and walking ability (6MWT percent predicted, 77% vs 86%), more severe self-reported pain (29.9 [more severe] vs 45.3 [less severe]) and less physical function (29.6 [more severe] vs 40.9 [less severe]). During burosumab treatment, greater reductions in RSS corresponded to higher RGI-C global scores (r = -0.65). Improvements in RSS correlated with decreased serum ALP (r = 0.47). These results show the reliability of the RSS in XLH, and demonstrate that higher RSS values are associated with greater biochemical, clinical, and functional impairments in children with XLH.
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http://dx.doi.org/10.1016/j.bone.2019.02.010DOI Listing
May 2019

Results from a 78-week, single-arm, open-label phase 2 study to evaluate UX007 in pediatric and adult patients with severe long-chain fatty acid oxidation disorders (LC-FAOD).

J Inherit Metab Dis 2019 01;42(1):169-177

Ultragenyx Pharmaceutical Inc., Novato, California, USA.

Long-chain fatty acid oxidation disorders (LC-FAOD) are rare disorders characterized by acute crises of energy metabolism and severe energy deficiency that may present with cardiomyopathy, hypoglycemia, and/or rhabdomyolysis, which can lead to frequent hospitalizations and early death. An open-label Phase 2 study evaluated the efficacy of UX007, an investigational odd-carbon medium-chain triglyceride, in 29 subjects with severe LC-FAOD. UX007 was administered over 78 weeks at a target dose of 25-35% total daily caloric intake (mean 27.5%). The frequency and duration of major clinical events (hospitalizations, emergency room visits, and emergency home interventions due to rhabdomyolysis, hypoglycemia, and cardiomyopathy) occurring during 78 weeks of UX007 treatment was compared with the frequency and duration of events captured retrospectively from medical records for 78 weeks before UX007 initiation. The mean annualized event rates decreased from 1.69 to 0.88 events/year following UX007 initiation (p = 0.021; 48.1% reduction). The mean annualized duration rate decreased from 5.96 to 2.96 days/year (p = 0.028; 50.3% reduction). Hospitalizations due to rhabdomyolysis, the most common event, decreased from 1.03 to 0.63 events/year (p = 0.104; 38.7% reduction). Initiation of UX007 eliminated hypoglycemia events leading to hospitalization (from 11 pre-UX007 hospitalizations, 0.30 events/year vs. 0; p = 0.067) and intensive care unit (ICU) care (from 2 pre-UX007 ICU admissions, 0.05 events/year vs. 0; p = 0.161) and reduced cardiomyopathy events (3 events vs. 1 event; 0.07 to 0.02 events/year; 69.7% decrease). The majority of treatment-related adverse events (AEs) were mild to moderate gastrointestinal symptoms, including diarrhea, vomiting, and abdominal or gastrointestinal pain, which can be managed with smaller, frequent doses mixed with food.
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http://dx.doi.org/10.1002/jimd.12038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348052PMC
January 2019

Exposure to Secondhand Smoke and Arrhythmogenic Cardiac Alternans in a Mouse Model.

Environ Health Perspect 2018 12;126(12):127001

Department of Pharmacology, University of California, Davis, Davis, California, USA.

Background: Epidemiological evidence suggests that a majority of deaths attributed to secondhand smoke (SHS) exposure are cardiovascular related. However, to our knowledge, the impact of SHS on cardiac electrophysiology, [Formula: see text] handling, and arrhythmia risk has not been studied.

Objectives: The purpose of this study was to investigate the impact of an environmentally relevant concentration of SHS on cardiac electrophysiology and indicators of arrhythmia.

Methods: Male C57BL/6 mice were exposed to SHS [total suspended particles (THS): [Formula: see text], nicotine: [Formula: see text], carbon monoxide: [Formula: see text], or filtered air (FA) for 4, 8, or 12 wk ([Formula: see text]]. Hearts were excised and Langendorff perfused for dual optical mapping with voltage- and [Formula: see text]-sensitive dyes.

Results: At slow pacing rates, SHS exposure did not alter baseline electrophysiological parameters. With increasing pacing frequency, action potential duration (APD), and intracellular [Formula: see text] alternans magnitude progressively increased in all groups. At 4 and 8 wk, there were no statistical differences in APD or [Formula: see text] alternans magnitude between SHS and FA groups. At 12 wk, both APD and [Formula: see text] alternans magnitude were significantly increased in the SHS compared to FA group ([Formula: see text]). SHS exposure did not impact the time constant of [Formula: see text] transient decay ([Formula: see text]) at any exposure time point. At 12 wk exposure, the recovery of [Formula: see text] transient amplitude with premature stimuli was slightly (but nonsignificantly) delayed in SHS compared to FA hearts, suggesting that [Formula: see text] release via ryanodine receptors may be impaired.

Conclusions: In male mice, chronic exposure to SHS at levels relevant to social situations in humans increased their susceptibility to cardiac alternans, a known precursor to ventricular arrhythmia. https://doi.org/10.1289/EHP3664.
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http://dx.doi.org/10.1289/EHP3664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6371715PMC
December 2018

Qualitative Research to Explore the Patient Experience of X-Linked Hypophosphatemia and Evaluate the Suitability of the BPI-SF and WOMAC® as Clinical Trial End Points.

Value Health 2018 08 6;21(8):973-983. Epub 2018 Jun 6.

Ultragenyx Pharmaceutical, Novato, CA, USA.

Background: X-linked hypophosphatemia (XLH) is a rare genetic disorder characterized by renal phosphate wasting and defective bone mineralization. Symptoms include bone pain, joint pain, stiffness, and fatigue. Published evidence regarding the patient experience of XLH is sparse and no XLH-specific outcome measures have been validated.

Objectives: To understand the symptoms, impacts, and patient experience of XLH and to evaluate the face and content validity of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC®) and the Brief Pain Inventory Short Form (BPI-SF) for use as end points in XLH clinical trials.

Methods: Face-to-face, qualitative, semistructured interviews were conducted with 18 adults with XLH in the United States using concept elicitation and cognitive debriefing techniques. Open-ended questioning elicited spontaneous concepts focusing on XLH-associated symptoms and functional limitations. Cognitive debriefing of the WOMAC® and BPI-SF assessed the relevance and patient understanding of item wording, recall period, and response options.

Results: Various distinct symptom concepts were elicited including pain symptoms, dental symptoms, sensory symptoms, tiredness/fatigue symptoms, and musculoskeletal symptoms. Participants reported experiencing significant bone and joint pain, stiffness, mobility limitations, and an impact on their ability to work. Cognitive interviewing found both instruments to be relevant and well understood by most patients.

Conclusions: The interviews generated rich, qualitative insights into the patient experience of XLH. Cognitive debriefing of the BPI-SF and WOMAC® supported their value as XLH clinical trial end points. Future research will assess the psychometric properties of these instruments for use in the XLH population.
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http://dx.doi.org/10.1016/j.jval.2018.01.013DOI Listing
August 2018

Aberrant Calcium Signaling in Astrocytes Inhibits Neuronal Excitability in a Human Down Syndrome Stem Cell Model.

Cell Rep 2018 07;24(2):355-365

Department of Biochemistry and Molecular Medicine, Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA, USA. Electronic address:

Down syndrome (DS) is a genetic disorder that causes cognitive impairment. The staggering effects associated with an extra copy of human chromosome 21 (HSA21) complicates mechanistic understanding of DS pathophysiology. We examined the neuron-astrocyte interplay in a fully recapitulated HSA21 trisomy cellular model differentiated from DS-patient-derived induced pluripotent stem cells (iPSCs). By combining calcium imaging with genetic approaches, we discovered the functional defects of DS astroglia and their effects on neuronal excitability. Compared with control isogenic astroglia, DS astroglia exhibited more-frequent spontaneous calcium fluctuations, which reduced the excitability of co-cultured neurons. Furthermore, suppressed neuronal activity could be rescued by abolishing astrocytic spontaneous calcium activity either chemically by blocking adenosine-mediated signaling or genetically by knockdown of inositol triphosphate (IP) receptors or S100B, a calcium binding protein coded on HSA21. Our results suggest a mechanism by which DS alters the function of astrocytes, which subsequently disturbs neuronal excitability.
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http://dx.doi.org/10.1016/j.celrep.2018.06.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6631348PMC
July 2018

A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial Evaluating the Efficacy of Burosumab, an Anti-FGF23 Antibody, in Adults With X-Linked Hypophosphatemia: Week 24 Primary Analysis.

J Bone Miner Res 2018 08 26;33(8):1383-1393. Epub 2018 Jun 26.

Yale School of Medicine, New Haven, CT, USA.

In X-linked hypophosphatemia (XLH), inherited loss-of-function mutations in the PHEX gene cause excess circulating levels of fibroblast growth factor 23 (FGF23), leading to lifelong renal phosphate wasting and hypophosphatemia. Adults with XLH present with chronic musculoskeletal pain and stiffness, short stature, lower limb deformities, fractures, and pseudofractures due to osteomalacia, accelerated osteoarthritis, dental abscesses, and enthesopathy. Burosumab, a fully human monoclonal antibody, binds and inhibits FGF23 to correct hypophosphatemia. This report summarizes results from a double-blind, placebo-controlled, phase 3 trial of burosumab in symptomatic adults with XLH. Participants with hypophosphatemia and pain were assigned 1:1 to burosumab 1 mg/kg (n = 68) or placebo (n = 66) subcutaneously every 4 weeks (Q4W) and were comparable at baseline. Across midpoints of dosing intervals, 94.1% of burosumab-treated participants attained mean serum phosphate concentration above the lower limit of normal compared with 7.6% of those receiving placebo (p < 0.001). Burosumab significantly reduced the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC) stiffness subscale compared with placebo (least squares [LS] mean ± standard error [SE] difference, -8.1 ± 3.24; p = 0.012). Reductions in WOMAC physical function subscale (-4.9 ± 2.48; p = 0.048) and Brief Pain Inventory worst pain (-0.5 ± 0.28; p = 0.092) did not achieve statistical significance after Hochberg multiplicity adjustment. At week 24, 43.1% (burosumab) and 7.7% (placebo) of baseline active fractures were fully healed; the odds of healed fracture in the burosumab group was 16.8-fold greater than that in the placebo group (p < 0.001). Biochemical markers of bone formation and resorption increased significantly from baseline with burosumab treatment compared with placebo. The safety profile of burosumab was similar to placebo. There were no treatment-related serious adverse events or meaningful changes from baseline in serum or urine calcium, intact parathyroid hormone, or nephrocalcinosis. These data support the conclusion that burosumab is a novel therapeutic addressing an important medical need in adults with XLH.© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jbmr.3475DOI Listing
August 2018

Burosumab Therapy in Children with X-Linked Hypophosphatemia.

N Engl J Med 2018 05;378(21):1987-1998

From Yale University School of Medicine, New Haven, CT (T.O.C.); Shriners Hospital for Children and Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine, St. Louis (M.P.W.); Indiana University School of Medicine, Indianapolis (E.A.I.); University of Groningen, Groningen, the Netherlands (A.M.B.); Birmingham Children's Hospital, Birmingham (W. Högler), Royal Manchester Children's Hospital, Manchester (R.P.), and Great Ormond Street Hospital, London (W. van't Hoff) - all in the United Kingdom; Assistance Publique-Hôpitaux de Paris Hôpital Bicêtre, Paris (A.L.); and Ultragenyx Pharmaceutical, Novato (M.M., C.-Y.C., A.S., E.K., J.S.M.), and University of California at San Francisco, San Francisco (A.A.P.) - both in California.

Background: X-linked hypophosphatemia is characterized by increased secretion of fibroblast growth factor 23 (FGF-23), which leads to hypophosphatemia and consequently rickets, osteomalacia, and skeletal deformities. We investigated burosumab, a monoclonal antibody that targets FGF-23, in patients with X-linked hypophosphatemia.

Methods: In an open-label, phase 2 trial, we randomly assigned 52 children with X-linked hypophosphatemia, in a 1:1 ratio, to receive subcutaneous burosumab either every 2 weeks or every 4 weeks; the dose was adjusted to achieve a serum phosphorus level at the low end of the normal range. The primary end point was the change from baseline to weeks 40 and 64 in the Thacher rickets severity total score (ranging from 0 to 10, with higher scores indicating greater disease severity). In addition, the Radiographic Global Impression of Change was used to evaluate rachitic changes from baseline to week 40 and to week 64. Additional end points were changes in pharmacodynamic markers, linear growth, physical ability, and patient-reported outcomes and the incidence of adverse events.

Results: The mean Thacher rickets severity total score decreased from 1.9 at baseline to 0.8 at week 40 with every-2-week dosing and from 1.7 at baseline to 1.1 at week 40 with every-4-week dosing (P<0.001 for both comparisons); these improvements persisted at week 64. The mean serum phosphorus level increased after the first dose in both groups, and more than half the patients in both groups had levels within the normal range (3.2 to 6.1 mg per deciliter [1.0 to 2.0 mmol per liter]) by week 6. Stable serum phosphorus levels were maintained through week 64 with every-2-week dosing. Renal tubular phosphate reabsorption increased from baseline in both groups, with an overall mean increase of 0.98 mg per deciliter (0.32 mmol per liter). The mean dose of burosumab at week 40 was 0.98 mg per kilogram of body weight with every-2-week dosing and 1.50 mg per kilogram with every-4-week dosing. Across both groups, the mean serum alkaline phosphatase level decreased from 459 U per liter at baseline to 369 U per liter at week 64. The mean standing-height z score increased in both groups, with greater improvement seen at all time points with every-2-week dosing (an increase from baseline of 0.19 at week 64) than with every-4-week dosing (an increase from baseline of 0.12 at week 64). Physical ability improved and pain decreased. Nearly all the adverse events were mild or moderate in severity.

Conclusions: In children with X-linked hypophosphatemia, treatment with burosumab improved renal tubular phosphate reabsorption, serum phosphorus levels, linear growth, and physical function and reduced pain and the severity of rickets. (Funded by Ultragenyx Pharmaceutical and Kyowa Hakko Kirin; ClinicalTrials.gov number, NCT02163577 ; EudraCT number, 2014-000406-35 ).
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http://dx.doi.org/10.1056/NEJMoa1714641DOI Listing
May 2018

Ca/calmodulin binding to PSD-95 mediates homeostatic synaptic scaling down.

EMBO J 2018 01 8;37(1):122-138. Epub 2017 Nov 8.

Department of Pharmacology, University of California, Davis, CA, USA

Postsynaptic density protein-95 (PSD-95) localizes AMPA-type glutamate receptors (AMPARs) to postsynaptic sites of glutamatergic synapses. Its postsynaptic displacement is necessary for loss of AMPARs during homeostatic scaling down of synapses. Here, we demonstrate that upon Ca influx, Ca/calmodulin (Ca/CaM) binding to the N-terminus of PSD-95 mediates postsynaptic loss of PSD-95 and AMPARs during homeostatic scaling down. Our NMR structural analysis identified E17 within the PSD-95 N-terminus as important for binding to Ca/CaM by interacting with R126 on CaM. Mutating E17 to R prevented homeostatic scaling down in primary hippocampal neurons, which is rescued via charge inversion by ectopic expression of CaM, as determined by analysis of miniature excitatory postsynaptic currents. Accordingly, increased binding of Ca/CaM to PSD-95 induced by a chronic increase in Ca influx is a critical molecular event in homeostatic downscaling of glutamatergic synaptic transmission.
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http://dx.doi.org/10.15252/embj.201695829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5753037PMC
January 2018

Defective GABAergic neurotransmission in the nucleus tractus solitarius in Mecp2-null mice, a model of Rett syndrome.

Neurobiol Dis 2018 Jan 18;109(Pt A):25-32. Epub 2017 Sep 18.

Department of Pathology and Laboratory Medicine, University of California Davis, One Shields Avenue, Davis, CA 95616, United States; M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute, University of California Davis, One Shields Avenue, Davis, CA 95616, United States. Electronic address:

Rett syndrome (RTT) is a devastating neurodevelopmental disorder caused by loss-of-function mutations in the X-linked methyl-CpG binding protein 2 (Mecp2) gene. GABAergic dysfunction has been implicated contributing to the respiratory dysfunction, one major clinical feature of RTT. The nucleus tractus solitarius (NTS) is the first central site integrating respiratory sensory information that can change the nature of the reflex output. We hypothesized that deficiency in Mecp2 gene reduces GABAergic neurotransmission in the NTS. Using whole-cell patch-clamp recordings in NTS slices, we measured spontaneous inhibitory postsynaptic currents (sIPSCs), miniature IPSCs (mIPSCs), NTS-evoked IPSCs (eIPSCs), and GABA receptor (GABA-R) agonist-induced responses. Compared to those from wild-type mice, NTS neurons from Mecp2-null mice had significantly (p<0.05) reduced sIPSC amplitude, sIPSC frequency, and mIPSC amplitude but not mIPSC frequency. Mecp2-null mice also had decreased eIPSC amplitude with no change in paired-pulse ratio. The data suggest reduced synaptic receptor-mediated phasic GABA transmission in Mecp2-null mice. In contrast, muscimol (GABA-R agonist, 0.3-100μM) and THIP (selective extrasynaptic GABA-R agonist, 5μM) induced significantly greater current response in Mecp2-null mice, suggesting increased extrasynaptic receptors. Using qPCR, we found a 2.5 fold increase in the delta subunit of the GABA-Rs in the NTS in Mecp2-null mice, consistent with increased extrasynaptic receptors. As the NTS was recently found required for respiratory pathology in RTT, our results provide a mechanism for NTS dysfunction which involves shifting the balance of synaptic/extrasynaptic receptors in favor of extrasynaptic site, providing a target for boosting GABAergic inhibition in RTT.
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http://dx.doi.org/10.1016/j.nbd.2017.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696074PMC
January 2018

Efficacy and safety of the glycine transporter type-1 inhibitor AMG 747 for the treatment of negative symptoms associated with schizophrenia.

Schizophr Res 2017 04 24;182:90-97. Epub 2016 Oct 24.

Semel Institute for Neuroscience at UCLA, Los Angeles, CA, United States; VA Desert Pacific Mental Illness Research, Education, and Clinical Center, Los Angeles, CA, United States.

Objective: To determine the safety and efficacy of AMG 747, an oral inhibitor of glycine transporter type-1 (GlyT1), as an add-on to antipsychotic therapy in clinically stable people with schizophrenia with enduring negative symptoms.

Method: Analysis of pooled data from two phase 2 studies. Adults diagnosed with schizophrenia stabilized on antipsychotic medication randomized (2:2:2:3) to orally receive daily AMG 747 (5mg, 15mg, or 40mg) or placebo. Primary endpoint was Negative Symptom Assessment (NSA)-16 total score change from baseline to week 12.

Results: Studies were terminated early after a report of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN) in one participant (40-mg AMG 747). At termination, 232 participants had enrolled and 153 completed 12weeks of treatment. At week 12, change from baseline NSA-16 total score showed no differences between groups. Mean decrease in Positive and Negative Syndrome Scale (PANSS) Negative Symptom Factor Score (NSFS) and NSA-16 global score were greater with 15-mg AMG 747 than placebo (p<0.05). Changes in PANSS-Positive Symptom Factor Scale were not significantly different for any group. Changes in patient-reported outcomes (Sheehan Disability Scale and Quality of Life Enjoyment and Satisfaction Questionnaire) showed trends consistent with greater efficacy of 15-mg AMG 747 compared with placebo (p≤0.1). Adverse event rates were similar among all groups, with no clear differences observed.

Conclusions: Significant treatment effects of 15-mg AMG 747, but not higher or lower doses, were observed on secondary endpoints but not on the primary outcome. These results replicate previous reports of an inverted-U dose response curve and suggest further evaluation of GlyT1 inhibitors in schizophrenia negative symptoms is warranted.

Trial Registration: Clinicaltrials.govNCT01568216 (https://clinicaltrials.gov/ct2/show/NCT01568216) and NCT01568229 (https://clinicaltrials.gov/ct2/show/NCT01568229?term=NCT01568229&rank=1); EudraCT number 2011-004844-23 and 2011-004845-42.
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http://dx.doi.org/10.1016/j.schres.2016.10.027DOI Listing
April 2017

Perampanel inhibition of AMPA receptor currents in cultured hippocampal neurons.

PLoS One 2014 17;9(9):e108021. Epub 2014 Sep 17.

Department of Neurology, School of Medicine and Center for Neuroscience, University of California Davis, Sacramento, California, United States of America.

Perampanel is an aryl substituted 2-pyridone AMPA receptor antagonist that was recently approved as a treatment for epilepsy. The drug potently inhibits AMPA receptor responses but the mode of block has not been characterized. Here the action of perampanel on AMPA receptors was investigated by whole-cell voltage-clamp recording in cultured rat hippocampal neurons. Perampanel caused a slow (τ∼1 s at 3 µM), concentration-dependent inhibition of AMPA receptor currents evoked by AMPA and kainate. The rates of block and unblock of AMPA receptor currents were 1.5×105 M-1 s-1 and 0.58 s-1, respectively. Perampanel did not affect NMDA receptor currents. The extent of block of non-desensitizing kainate-evoked currents (IC50, 0.56 µM) was similar at all kainate concentrations (3-100 µM), demonstrating a noncompetitive blocking action. Parampanel did not alter the trajectory of AMPA evoked currents indicating that it does not influence AMPA receptor desensitization. Perampanel is a selective negative allosteric AMPA receptor antagonist of high-affinity and slow blocking kinetics.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0108021PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4168215PMC
December 2015

Restrictive symptomatic inclusion criteria create barriers to clinical research in schizophrenia negative symptoms: an analysis of the CATIE dataset.

Eur Neuropsychopharmacol 2014 Oct 17;24(10):1615-21. Epub 2014 Aug 17.

Bar Ilan University, Ramat Gan, 22 Akiva Street, 43263 Raanana, Israel.

Background: Persistent negative symptoms are an important area of clinical research. However, there is limited consensus on how to define positive and negative symptom severity thresholds for inclusion in clinical trials. From the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) dataset we evaluated the performance of varying baseline negative and positive symptom thresholds on baseline symptom severity, change from baseline, and negative symptom variance attributable to positive symptom change.

Methods: In CATIE, we first identified the group of subjects lacking an exacerbation prior to study enrollment. Six subsets with varying baseline positive and negative symptom thresholds were then identified. Baseline characteristics were summarized; negative and positive symptom change from baseline through month 3 was calculated both as crude change and change adjusted for corresponding baseline scores. Sensitivity analyses and correlations were calculated to assess the extent to which negative symptom variance was attributable to positive symptom change.

Results: More restrictive baseline symptom severity thresholds yielded a considerably smaller sample size and higher negative and lower positive symptoms at baseline. Unadjusted negative symptom change was greater with more restrictive criteria; when adjusted for baseline severity the magnitude of change was comparable across subsets. The amount of variance in negative symptom change attributed to positive symptom change was also comparable across subsets.

Conclusions: The use of restrictive positive and negative symptom thresholds yields a marked decrease in eligible sample size with no clear improvement in adjusted negative symptom change or amount of variance associated with positive symptom change.
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http://dx.doi.org/10.1016/j.euroneuro.2014.08.004DOI Listing
October 2014

Balance control in elderly people with osteoporosis.

J Formos Med Assoc 2014 Jun 18;113(6):334-9. Epub 2014 Mar 18.

Department of Orthopedic Surgery, National Taiwan University & Hospital, Taipei, Taiwan. Electronic address:

Osteoporosis is a prevalent health concern among older adults and is associated with an increased risk of falls that incur fracture, injury, or mortality. Identifying the risk factors of falls within this population is essential for the development of effective regimes for fall prevention. Studies have shown that muscle quality and good posture alignments are critical for balance control in elderly individuals. People with osteoporosis often have muscle weakness and increased spine kyphosis leading to vertebral fractures and poor balance control, or even falls. Therefore, improving muscle quality, strengthening weak muscles, and correcting postural alignment are essential elements for the prevention of falls and fractures in older adults with osteoporosis. This review reports the necessary information regarding the critical factors of balance control in older adults with osteoporosis, as well as testing the clinical innovations of exercise training to improve the long-term prognosis of osteoporosis in this vulnerable population.
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http://dx.doi.org/10.1016/j.jfma.2014.02.006DOI Listing
June 2014

AKAP150 contributes to enhanced vascular tone by facilitating large-conductance Ca2+-activated K+ channel remodeling in hyperglycemia and diabetes mellitus.

Circ Res 2014 Feb 9;114(4):607-15. Epub 2013 Dec 9.

From the Department of Pharmacology, University of California, Davis (M.A.N., M.N.-C., C.B.N., C.-Y.C., J.L.P., L.T.I., D.M.B., M.F.N.); Department of Pharmacology, University of Colorado, Denver (M.L.D.); Department of Pharmacology, Howard Hughes Medical Institute, University of Washington, Seattle, WA (P.J.N., S.A.H., J.D.S.); and Department of Physiology and Biophysics, University of Washington, Seattle (L.F.S.).

Rationale: Increased contractility of arterial myocytes and enhanced vascular tone during hyperglycemia and diabetes mellitus may arise from impaired large-conductance Ca(2+)-activated K(+) (BKCa) channel function. The scaffolding protein A-kinase anchoring protein 150 (AKAP150) is a key regulator of calcineurin (CaN), a phosphatase known to modulate the expression of the regulatory BKCa β1 subunit. Whether AKAP150 mediates BKCa channel suppression during hyperglycemia and diabetes mellitus is unknown.

Objective: To test the hypothesis that AKAP150-dependent CaN signaling mediates BKCa β1 downregulation and impaired vascular BKCa channel function during hyperglycemia and diabetes mellitus.

Methods And Results: We found that AKAP150 is an important determinant of BKCa channel remodeling, CaN/nuclear factor of activated T-cells c3 (NFATc3) activation, and resistance artery constriction in hyperglycemic animals on high-fat diet. Genetic ablation of AKAP150 protected against these alterations, including augmented vasoconstriction. d-glucose-dependent suppression of BKCa channel β1 subunits required Ca(2+) influx via voltage-gated L-type Ca(2+) channels and mobilization of a CaN/NFATc3 signaling pathway. Remarkably, high-fat diet mice expressing a mutant AKAP150 unable to anchor CaN resisted activation of NFATc3 and downregulation of BKCa β1 subunits and attenuated high-fat diet-induced elevation in arterial blood pressure.

Conclusions: Our results support a model whereby subcellular anchoring of CaN by AKAP150 is a key molecular determinant of vascular BKCa channel remodeling, which contributes to vasoconstriction during diabetes mellitus.
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http://dx.doi.org/10.1161/CIRCRESAHA.114.302168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954117PMC
February 2014

Protection of signal processing at low temperature in baroreceptive neurons in the nucleus tractus solitarius of Syrian hamsters, a hibernating species.

Am J Physiol Regul Integr Comp Physiol 2013 Nov 25;305(10):R1153-62. Epub 2013 Sep 25.

Department of Pharmacology, University of California, Davis, California;

We previously described synaptic currents between baroreceptor fibers and second-order neurons in the nucleus tractus solitarius (NTS) that were larger in Syrian hamsters than in rats. This suggested that although electrical activity throughout the hamster brain decreased as brain temperature declined, the greater synaptic input to its NTS would support continued operation of cardiorespiratory reflexes at low body temperatures. Here, we focused on properties that would protect these neurons against potential damage from the larger synaptic inputs, testing the hypotheses that hamster NTS neurons exhibit: 1) intrinsic N-methyl-D-aspartate receptor (NMDAR) properties that limit Ca(2+) influx to a greater degree than do rat NTS neurons and 2) properties that reduce gating signals to NMDARs to a greater degree than in rat NTS neurons. Whole cell patch-clamp recordings on anatomically identified second-order NTS baroreceptive neurons showed that NMDAR-mediated synaptic currents between sensory fibers and second-order NTS neurons were larger in hamsters than in rats at 33°C and 15°C, with no difference in their permeability to Ca(2+). However, at 15°C, but not at 33°C, non-NMDAR currents evoked by glutamate released from baroreceptor fibers had significantly shorter durations in hamsters than in rats. Thus, hamster NMDARs did not exhibit lower Ca(2+) influx than did rats (negating hypothesis 1), but they did exhibit significant differences in non-NMDAR neuronal properties at low temperature (consistent with hypothesis 2). The latter (shorter duration of non-NMDAR currents) would likely limit NMDAR coincidence gating and may help protect hamster NTS neurons, enabling them to contribute to signal processing at low body temperatures.
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http://dx.doi.org/10.1152/ajpregu.00165.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841799PMC
November 2013

Temporal relationships of blood pressure, heart rate, baroreflex function, and body temperature change over a hibernation bout in Syrian hamsters.

Am J Physiol Regul Integr Comp Physiol 2013 Oct 31;305(7):R759-68. Epub 2013 Jul 31.

Department of Neurobiology, Physiology, & Behavior, University of California, Davis, Davis, California;

Hibernating mammals undergo torpor during which blood pressure (BP), heart rate (HR), metabolic rate, and core temperature (TC) dramatically decrease, conserving energy. While the cardiovascular system remains functional, temporal changes in BP, HR, and baroreceptor-HR reflex sensitivity (BRS) over complete hibernation bouts and their relation to TC are unknown. We implanted BP/temperature telemetry transmitters into Syrian hamsters to test three hypotheses: H-1) BP, HR, and BRS decrease concurrently during entry into hibernation and increase concurrently during arousal; H-2) these changes occur before changes in TC; and H-3) the pattern of changes is consistent over successive bouts. We found: 1) upon hibernation entry, BP and HR declined before TC and BRS, suggesting baroreflex control of HR continues to regulate BP as the BP set point decreases; 2) during the later phase of entry, BRS decreased rapidly whereas BP and TC fell gradually, suggesting the importance of TC in further BP declines; 3) during torpor, BP slowly increased (but remained relatively low) without changes in HR or BRS or increased TC, suggesting minimal baroreflex or temperature influence; 4) during arousal, increased TC and BRS significantly lagged increases in BP and HR, consistent with establishment of tissue perfusion before increased TC/metabolism; and 5) the temporal pattern of these changes was similar over successive bouts in all hamsters. These results negate H-1, support H-2 with respect to BP and HR, support H-3, and indicate that the baroreflex contributes to cardiovascular regulation over a hibernation bout, albeit operating in a fundamentally different manner during entry vs. arousal.
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http://dx.doi.org/10.1152/ajpregu.00450.2012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3798792PMC
October 2013

Hemoglobin stability in patients with anemia, CKD, and type 2 diabetes: an analysis of the TREAT (Trial to Reduce Cardiovascular Events With Aranesp Therapy) placebo arm.

Am J Kidney Dis 2013 Feb 16;61(2):238-46. Epub 2012 Nov 16.

Department of Medicine, Harvard Medical School, Brigham and Women's Hospital, Boston, MA 02115, USA.

Background: Sparse data are available about the natural history of hemoglobin (Hb) level trends in contemporary patients with anemia, chronic kidney disease (CKD), and type 2 diabetes mellitus. We intended to describe Hb level trends over time with no or minimal administration of erythropoiesis-stimulating agents.

Study Design: Prospective clinical trial cohort.

Setting & Participants: 2,019 individuals with type 2 diabetes, moderate anemia, and CKD from the placebo arm of the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) followed up for 2.3 years with an average of 32 monthly Hb level determinations per patient. Darbepoetin alfa was administered only if Hb level decreased to <9 g/dL.

Outcomes & Measurements: Number of protocol-directed doses of darbepoetin alfa received due to an Hb level decrease to <9 g/dL.

Results: 1,106 (55%) placebo patients consistently maintained an Hb level ≥9 g/dL and received no protocol-directed darbepoetin alfa. The other patients received 1 (16%), 2-4 (16%), or 5 or more (13%) doses of darbepoetin alfa. Those who received no darbepoetin alfa doses had higher baseline Hb levels, higher estimated glomerular filtration rates (eGFRs), less proteinuria, and lower ferritin and transferrin saturation values. On average, Hb levels were stable or increased in all groups. Compared with individuals who received no darbepoetin alfa, those who received 5 or more doses were more likely to receive intravenous iron therapy and blood transfusions and progress to renal replacement therapy, but were not at higher risk of death. The strongest predictors of requiring 5 or more doses of darbepoetin alfa were lower baseline Hb level, lower eGFR, and higher proteinuria level.

Limitations: Post hoc analysis of a clinical trial of a specific population with diabetes, anemia, and non-dialysis-dependent CKD.

Conclusions: In the TREAT placebo arm, Hb levels were stable with no or minimal protocol-directed darbepoetin alfa during 2.3 years of follow-up. Most patients with moderate anemia, non-dialysis-dependent CKD, and type 2 diabetes are able to maintain a stable Hb level without implementing long-term erythropoiesis-stimulating agent therapy.
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http://dx.doi.org/10.1053/j.ajkd.2012.08.043DOI Listing
February 2013

Lower extremity kinematics in children with and without flexible flatfoot: a comparative study.

BMC Musculoskelet Disord 2012 Mar 2;13:31. Epub 2012 Mar 2.

Department of Physical Therapy and Assistive Technology, National Yang-Ming University, 155 LiNong Street Section 2, Pei-Tou District, Taipei, Taiwan 112.

Background: A high percentage of young children present with flatfeet. Although the percentage of those with flatfeet declines with age, about 15% of the population maintains a flat arch. A reduction in longitudinal arch height usually combines with excessive subtalar joint pronation and may be related to other musculoskeletal problems of the lower extremity kinetic chain. The purpose of this study is to describe and compare the lower extremity kinematics between children with normal arches and those with flexible flatfeet, with the intent of providing practical information for decision making when treating children with flexible flatfeet.

Methods: Twenty children with flexible flatfeet (years age mean (SD), 9.7 (0.9) years) and 10 children with normal arches (yeas age mean (SD), 9.6 (1.2) years) were included. Kinematic data (maximum and minimum angles, and movement range, velocity, and excursion) of the hip, knee and rearfoot were collected during walking using Liberty Electromagnetic Tracking System. Kinematic variables were compared between the normal arches and flexible flatfeet groups using repeated measures mixed effects ANOVA.

Results: Movement patterns at the hip, knee and ankle joints were similar between children with flexible flatfeet and with normal arches. The results of ANOVA showed no significant main effect or interaction in any of the kinematic variables (P ≥ 0.05).

Conclusions: This study identified no kinematic adaptation during walking in children with flexible flatfoot. We suggested that future research should take the influence of the mid-foot and forefoot into consideration when examining lower extremity kinematics in children with flexible flatfoot.
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http://dx.doi.org/10.1186/1471-2474-13-31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3359242PMC
March 2012

Realignment of signal processing within a sensory brainstem nucleus as brain temperature declines in the Syrian hamster, a hibernating species.

J Comp Physiol A Neuroethol Sens Neural Behav Physiol 2012 Apr 20;198(4):267-82. Epub 2012 Jan 20.

Department of Pharmacology, University of California Davis, GBSF 3617, 451 Health Sciences Drive, Davis, CA 95616, USA.

Crucial for survival, the central nervous system must reliably process sensory information over all stages of a hibernation bout to ensure homeostatic regulation is maintained and well-matched to dramatically altered behavioral states. Comparing neural responses in the nucleus tractus solitarius of rats and euthermic Syrian hamsters, we tested the hypothesis that hamster neurons have adaptations sustaining signal processing while conserving energy. Using patch-clamp techniques, we classified second-order neurons in the nucleus as rapid-onset or delayed-onset spiking phenotypes based on their spiking onset to a depolarizing pulse (following a -80 mV prepulse). As temperature decreased from 33 to 15°C, the excitability of all neurons decreased. However, hamster rapid-onset spiking neurons had the highest spiking response and shortest action potential width at every temperature, while hamster delayed-onset spiking neurons had the most negative resting membrane potential. The frequency of spontaneous excitatory postsynaptic currents in both phenotypes decreased as temperature decreased, yet the amplitudes of tractus solitarius stimulation-evoked currents were greater in hamsters than in rats regardless of phenotype and temperature. Changes were significant (P < 0.05), supporting our hypothesis by showing that, as temperature falls, rapid-onset neurons contribute more to signal processing but less to energy conservation than do delayed-onset neurons.
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http://dx.doi.org/10.1007/s00359-011-0706-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4016980PMC
April 2012

Retrograde release of endocannabinoids inhibits presynaptic GABA release to second-order baroreceptive neurons in NTS.

Auton Neurosci 2010 Dec 1;158(1-2):44-50. Epub 2010 Jul 1.

Department of Pharmacology, University of California, Davis, CA 95616, USA.

In prior studies, we found that activation of cannabinoid-1 receptors in the nucleus tractus solitarii (NTS) prolonged baroreflex-induced sympathoinhibition in rats. In many regions of the central nervous system, activation of cannabinoid-1 receptors presynaptically inhibits γ-aminobutyric acid (GABA) release, disinhibiting postsynaptic neurons. To determine if cannabinoid-1 receptor-mediated presynaptic inhibition of GABA release occurs in the NTS, we recorded miniature inhibitory postsynaptic currents in anatomically identified second-order baroreceptive NTS neurons in the presence of ionotropic glutamate receptor antagonists and tetrodotoxin. The cannabinoid-1 receptor agonists, WIN 55212-2 (0.3-30 μM) and methanandamide (3 μM) decreased the frequency of miniature inhibitory postsynaptic currents in a concentration-dependent manner, an effect that was blocked by the cannabinoid-1 receptor antagonist, N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (AM 251, 5 μM). Importantly, depolarization of second-order baroreceptive neurons decreased the frequency of miniature inhibitory postsynaptic currents; an effect which was blocked by the cannabinoid-1 receptor antagonist. The data indicate that depolarization of second-order baroreceptive NTS neurons induces endocannabinoid release from the neurons, leading to activation of presynaptic cannabinoid-1 receptors, inhibition of GABA release and subsequent enhanced baroreflex signaling in the NTS. The data suggest that endocannabinoid signaling in the NTS regulates short-term synaptic plasticity and provide a mechanism for endocannabinoid modulation of central baroreflex control.
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http://dx.doi.org/10.1016/j.autneu.2010.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2976795PMC
December 2010

Postexercise hypotension: central mechanisms.

Exerc Sport Sci Rev 2010 Jul;38(3):122-7

Department of Pharmacology, University of California, Davis, CA 95616, USA.

A single bout of exercise can lead to a postexercise decrease in blood pressure in hypertensive individuals, called postexercise hypotension. Compelling evidence suggests that the central baroreflex pathway plays a crucial role in the development of postexercise hypotension. This review focuses on the exercise-induced changes in brainstem nuclei involved in blood pressure regulation.
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http://dx.doi.org/10.1097/JES.0b013e3181e372b5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2936915PMC
July 2010

Issues and challenges of non-tenure-track research faculty: the UC Davis School of Medicine experience.

Acad Med 2010 Jun;85(6):1041-7

University of California, Davis, School of Medicine, Sacramento, CA, USA.

Nationally, medical schools are appointing growing numbers of research faculty into non-tenure-track positions, paralleling a similar trend in universities. The American Association of University Professors (AAUP) issued a statement expressing concern that the marked growth in non-tenure-track faculty can undermine educational quality, academic freedom, and collegiality. Like other medical schools, the UC Davis School of Medicine has had a rise in non-tenure-track faculty in order to enhance its research mission, in particular in the Salaried Adjunct faculty track (SalAdj). SalAdj faculty have more difficulty in achieving promotion, report inequitable treatment and less quality of life, have less opportunity to participate in governance, and feel second-class and insecure. These issues reflect those described by the AAUP. The authors describe the efforts at UC Davis to investigate and address these issues, implementation of a plan for improvement based on task force recommendations, and the lessons learned. Supporting transfer to faculty tracks in the academic senate, enhancing financial support, ensuring eligibility for internal grants, and equitable space assignments have contributed to an improved career path and more satisfaction among SalAdj faculty. Challenges in addressing these issues include limited availability of tenure-track positions, financial resources, adequate communication regarding change, and compliance with existing faculty search policies.
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http://dx.doi.org/10.1097/ACM.0b013e3181dbfbf3DOI Listing
June 2010