Publications by authors named "Ashley Martinez"

23 Publications

  • Page 1 of 1

Distinct patterns of apolipoprotein C-I, C-II, and C-III isoforms are associated with markers of Alzheimer's disease.

J Lipid Res 2020 Dec 18;62:100014. Epub 2020 Dec 18.

Isoformix Inc, Phoenix, Arizona, USA. Electronic address:

Apolipoproteins C-I, C-II, and C-III interact with ApoE to regulate lipoprotein metabolism and contribute to Alzheimer's disease pathophysiology. In plasma, apoC-I and C-II exist as truncated isoforms, while apoC-III exhibits multiple glycoforms. This study aimed to 1) delineate apoC-I, C-II, and C-III isoform profiles in cerebrospinal fluid (CSF) and plasma in a cohort of nondemented older individuals (n = 61), and 2) examine the effect of APOE4 on these isoforms and their correlation with CSF Aβ42, a surrogate of brain amyloid accumulation. The isoforms of the apoCs were immunoaffinity enriched and measured with MALDI-TOF mass spectrometry, revealing a significantly higher percentage of truncated apoC-I and apoC-II in CSF compared with matched plasma, with positive correlation between CSF and plasma. A greater percentage of monosialylated and disialylated apoC-III isoforms was detected in CSF, accompanied by a lower percentage of the two nonsialylated apoC-III isoforms, with significant linear correlations between CSF and plasma. Furthermore, a greater percentage of truncated apoC-I in CSF and apoC-II in plasma and CSF was observed in individuals carrying at least one APOE Ɛ4 allele. Increased apoC-I and apoC-II truncations were associated with lower CSF Aβ42. Finally, monosialylated apoC-III was lower, and disialylated apoC-III greater in the CSF of Ɛ4 carriers. Together, these results reveal distinct patterns of the apoCs isoforms in CSF, implying CSF-specific apoCs processing. These patterns were accentuated in APOE Ɛ4 allele carriers, suggesting an association between APOE4 genotype and Alzheimer's disease pathology with apoCs processing and function in the brain.
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http://dx.doi.org/10.1194/jlr.RA120000919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859854PMC
December 2020

Distinct patterns of apolipoprotein C-I, C-II, and C-III isoforms are associated with markers of Alzheimer's disease.

J Lipid Res 2020 Dec 18;62:100014. Epub 2020 Dec 18.

Isoformix Inc, Phoenix, Arizona, USA. Electronic address:

Apolipoproteins C-I, C-II, and C-III interact with ApoE to regulate lipoprotein metabolism and contribute to Alzheimer's disease pathophysiology. In plasma, apoC-I and C-II exist as truncated isoforms, while apoC-III exhibits multiple glycoforms. This study aimed to 1) delineate apoC-I, C-II, and C-III isoform profiles in cerebrospinal fluid (CSF) and plasma in a cohort of nondemented older individuals (n = 61), and 2) examine the effect of APOE4 on these isoforms and their correlation with CSF Aβ42, a surrogate of brain amyloid accumulation. The isoforms of the apoCs were immunoaffinity enriched and measured with MALDI-TOF mass spectrometry, revealing a significantly higher percentage of truncated apoC-I and apoC-II in CSF compared with matched plasma, with positive correlation between CSF and plasma. A greater percentage of monosialylated and disialylated apoC-III isoforms was detected in CSF, accompanied by a lower percentage of the two nonsialylated apoC-III isoforms, with significant linear correlations between CSF and plasma. Furthermore, a greater percentage of truncated apoC-I in CSF and apoC-II in plasma and CSF was observed in individuals carrying at least one APOE Ɛ4 allele. Increased apoC-I and apoC-II truncations were associated with lower CSF Aβ42. Finally, monosialylated apoC-III was lower, and disialylated apoC-III greater in the CSF of Ɛ4 carriers. Together, these results reveal distinct patterns of the apoCs isoforms in CSF, implying CSF-specific apoCs processing. These patterns were accentuated in APOE Ɛ4 allele carriers, suggesting an association between APOE4 genotype and Alzheimer's disease pathology with apoCs processing and function in the brain.
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http://dx.doi.org/10.1194/jlr.RA120000919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859854PMC
December 2020

Brain delivery of supplemental docosahexaenoic acid (DHA): A randomized placebo-controlled clinical trial.

EBioMedicine 2020 Sep 17;59:102883. Epub 2020 Jul 17.

Department of Medicine, Keck School of Medicine USC, United States; Department of Neurology, Keck School of Medicine USC, United States. Electronic address:

Background: Past clinical trials of docosahexaenoic Acid (DHA) supplements for the prevention of Alzheimer's disease (AD) dementia have used lower doses and have been largely negative. We hypothesized that larger doses of DHA are needed for adequate brain bioavailability and that APOE4 is associated with reduced delivery of DHA and eicosapentaenoic acid (EPA) to the brain before the onset of cognitive impairment.

Methods: 33 individuals were provided with a vitamin B complex (1 mg vitamin B12, 100 mg of vitamin B6 and 800 mcg of folic acid per day) and randomized to 2,152 mg of DHA per day or placebo over 6 months. 26 individuals completed both lumbar punctures and MRIs, and 29 completed cognitive assessments at baseline and 6 months. The primary outcome was the change in CSF DHA. Secondary outcomes included changes in CSF EPA levels, MRI hippocampal volume and entorhinal thickness; exploratory outcomes were measures of cognition.

Findings: A 28% increase in CSF DHA and 43% increase in CSF EPA were observed in the DHA treatment arm compared to placebo (mean difference for DHA (95% CI): 0.08 µg/mL (0.05, 0.10), p<0.0001; mean difference for EPA: 0.008 µg/mL (0.004, 0.011), p<0.0001). The increase in CSF EPA in non-APOE4 carriers after supplementation was three times greater than APOE4 carriers. The change in brain volumes and cognitive scores did not differ between groups.

Interpretation: Dementia prevention trials using omega-3 supplementation doses equal or lower to 1 g per day may have reduced brain effects, particularly in APOE4 carriers.

Trial Registration: NCT02541929.

Funding: HNY was supported by R01AG055770, R01AG054434, R01AG067063 from the National Institute of Aging and NIRG-15-361854 from the Alzheimer's Association, and MGH by the L. K. Whittier Foundation. This work was also supported by P50AG05142 (HCC) from the National Institutes of Health. Funders had no role in study design, data collection, data analysis, interpretation, or writing of the report.
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http://dx.doi.org/10.1016/j.ebiom.2020.102883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502665PMC
September 2020

One-Year Evaluation of a Targeted Medication Therapy Management Intervention for Older Adults.

J Manag Care Spec Pharm 2020 Apr;26(4):520-528

Department of Pharmacy Practice and Science, College of Pharmacy, and Department of Epidemiology, College of Public Health, University of Kentucky, and Sanders-Brown Center on Aging, Lexington, Kentucky.

Background: Older adults are especially susceptible to adverse effects of inappropriate medication therapy, and anticholinergic medications are common culprits for cognitive dysfunction due to their action on the central nervous system. Medication therapy management (MTM) interventions can aid in deprescribing and reducing inappropriate medication use in older adults. However, there is sparse literature on the long-term sustainability of these interventions.

Objectives: To (a) investigate whether the deprescribing of anticholinergic medications during an 8-week randomized controlled trial (RCT) of a targeted MTM intervention is sustained at 1-year postintervention follow-up and (b) compare anticholinergic utilization trends in the study population with a large sample of similar individuals not exposed to the intervention.

Methods: Participants in the targeted MTM (tMTM) RCT had normal cognition or mild cognitive impairment and were recruited from enrollees in a longitudinal study at the University of Kentucky Alzheimer's Disease Center (ADC) and thus have pertinent medical information gathered approximately annually. In this posttrial observational follow-up, sustainability of the anticholinergic deprescribing intervention was assessed in participants in the RCT, and anticholinergic medication use trends were described from the RCT baseline (which occurred immediately following an ADC visit) to the next annual visit in all participants. Mean change in anticholinergic burden from RCT baseline to the next annual visit was estimated using analysis of covariance, and participants were compared with 2 external samples. Anticholinergic burden was measured using the Anticholinergic Drug Scale (ADS). The odds of decreasing baseline anticholinergic burden and number of total and strong anticholinergic medications at the follow-up study time point was assessed using logistic regression.

Results: Of the deprescribing changes made during the initial RCT, 50% were sustained after 1 year. Participants in the tMTM trial reported decreases in the use of anticholinergic antihistamines and bladder agents (-6.5 and -4.4%, respectively), but there was no change in the use of anticholinergic agents targeted at the central nervous system. While the anticholinergic burden of RCT participants decreased over 1 year (adjusted mean ADS change [95% CI] = -0.33 [-0.72, 0.07]), it was not different than the change observed in 2 external samples at the trial center (-0.20 [-0.42, 0.02]) and nationally (-0.33 [-0.39, -0.26]). There were no statistically significant differences between trial participants and external samples in the odds of decreasing anticholinergic burden nor in decreasing the number of total, or strongly anticholinergic, medications at the 1-year follow-up.

Conclusions: This study demonstrates that the sustainability of deprescribing is limited to the period of intervention, rather than affording lasting effects even over periods as short as 1 year, which was demonstrated not only in the small group of RCT participants but also by comparison with external groups. Future work should extend the duration of intervention and follow-up periods for MTM interventions to allow further insights regarding the sustainability of deprescribing efforts in older adults.

Disclosures: The original trial was supported by a pilot study award from the University of Kentucky Center for Clinical and Translational Sciences (UL1TR000117). Additional support for this study was provided by the National Institutes of Health/National Institute on Aging (R01 AG054130). Jicha reports contract research for Esai, Biohaven, Alltech, Suven, Novartis, and Lilly. The other authors have nothing to disclose.
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http://dx.doi.org/10.18553/jmcp.2020.26.4.520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7396972PMC
April 2020

Attitudes toward deprescribing in a middle-aged health disparities population.

Res Social Adm Pharm 2020 10 10;16(10):1502-1507. Epub 2020 Mar 10.

University of Kentucky College of Pharmacy, Department of Pharmacy Practice and Science, 789 South Limestone Avenue, Lexington, KY, 40536, USA; University of Kentucky College of Public Health, Department of Epidemiology, 111 Washington Avenue, Lexington, KY, 40536, USA; Sanders-Brown Center on Aging, 800 South Limestone, Lexington, KY, 40536, USA; Institute for Pharmaceutical Outcomes and Policy, 789 South Limestone Avenue, Lexington, KY, 40536, USA. Electronic address:

Background: Patients' attitudes toward deprescribing are crucial to understand before developing interventions, but no such data exists in the medically underserved, health disparities population of rural Appalachian United States.

Objective(s): Assess Appalachian women's openness to deprescribing medications and determine if polypharmacy influenced their attitudes toward deprescribing.

Methods: Before and after a cognitive behavioral therapy intervention, middle-aged Appalachian women self-reported medication use and completed the revised Patients' Attitudes Toward Deprescribing Questionnaire (rPATD). Responses were described, stratified by presence of polypharmacy.

Results: 30 women completed the rPATD pre- and post-intervention (mean [SD] age 55.8 [6.6] years; 96.7% white). Those with polypharmacy (n = 16) had higher burden and involvement scores (median 2.8 vs 2.0, p = 0.01; 4.9 vs 4.6, p = 0.06), and lower appropriateness scores (3.4 vs 3.9, p = 0.04). Burden, concerns about stopping, and involvement factor scores were similar before and after the intervention (p = 0.08, 0.86, and 0.41 respectively). ≥90% of participants were satisfied with their current medications yet would be willing to stop one or more.

Conclusions: Middle-aged women in rural Appalachian United States are open to deprescribing; polypharmacy is associated with lower belief in the appropriateness of medications. Larger studies are needed to inform future deprescribing interventions for this and other similarly disadvantaged populations.
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http://dx.doi.org/10.1016/j.sapharm.2020.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483264PMC
October 2020

INtervention for Cognitive Reserve Enhancement in delaying the onset of Alzheimer's Symptomatic Expression (INCREASE), a randomized controlled trial: rationale, study design, and protocol.

Trials 2019 Dec 30;20(1):806. Epub 2019 Dec 30.

Sanders-Brown Center on Aging, Lexington, KY, USA.

Background: The course of Alzheimer's disease (AD) includes a 10-20-year preclinical period with progressive accumulation of amyloid β (Aβ) plaques and neurofibrillary tangles in the absence of symptomatic cognitive or functional decline. The duration of this preclinical stage in part depends on the rate of pathologic progression, which is offset by compensatory mechanisms, referred to as cognitive reserve (CR). Comorbid medical conditions, psychosocial stressors, and inappropriate medication use may lower CR, hastening the onset of symptomatic AD. Here, we describe a randomized controlled trial (RCT) designed to test the efficacy of a medication therapy management (MTM) intervention to reduce inappropriate medication use, bolster cognitive reserve, and ultimately delay symptomatic AD.

Methods/design: Our study aims to enroll 90 non-demented community-dwelling adults ≥ 65 years of age. Participants will undergo positron emission tomography (PET) scans, measuring Aβ levels using standardized uptake value ratios (SUVr). Participants will be randomly assigned to MTM intervention or control, stratified by Aβ levels, and followed for 12 months via in-person and telephone visits. Outcomes of interest include: (1) medication appropriateness (measured with the Medication Appropriateness Index (MAI)); (2) scores from Trail Making Test B (TMTB), Montreal Cognitive Assessment (MoCA), and California Verbal Learning Test (CVLT); (3) perceived health status (measured with the SF-36). We will also evaluate pre- to post-intervention change in: (1) use of inappropriate medications as measured by MAI; 2) CR Change Score (CRCS), defined as the difference in scopolamine-challenged vs unchallenged cognitive scores at baseline and follow-up. Baseline Aβ SUVr will be used to examine the relative impact of preclinical AD (pAD) pathology on CRCS, as well as the interplay of amyloid burden with inappropriate medication use.

Discussion: This manuscript describes the protocol of INCREASE ("INtervention for Cognitive Reserve Enhancement in delaying the onset of Alzheimer's Symptomatic Expression"): a randomized controlled trial that investigates the impact of deprescribing inappropriate medications and optimizing medication regimens on potentially delaying the onset of symptomatic AD and AD-related dementias.

Trial Registration: ClinicalTrials.gov, NCT02849639. Registered on 29 July 2016.
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http://dx.doi.org/10.1186/s13063-019-3993-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937673PMC
December 2019

Quality Improvement: Increasing Essential Visits in a Triage Clinic.

Clin J Oncol Nurs 2019 10;23(5):475-477

MD Anderson Cancer Center.

Patients with cancer should report symptoms related to treatment, but many patients not actively being treated for disease present to oncology clinics for care that could be managed in other settings. These nonessential visits may lead to lessened appointment availability for patients with essential issues related to disease and treatment. In an outpatient breast cancer clinic, a quality improvement initiative was implemented to decrease the number of nonessential patient encounters and to increase the number of essential encounters. This intervention involved creating and implementing a triage protocol used by nursing staff to designate appropriate levels of care. Findings suggest that doing so can optimize workflow and improve patient access to essential disease- and treatment- related care.
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http://dx.doi.org/10.1188/19.CJON.475-477DOI Listing
October 2019

Internet-Based Cognitive Behavioral Therapy for Insomnia in Appalachian Women: A Pilot Study.

Behav Sleep Med 2020 Sep-Oct;18(5):680-689. Epub 2019 Aug 30.

Department of Pharmacy Practice and Science, University of Kentucky , Lexington.

Objective/background: Appalachian women are disproportionately affected by insufficient sleep but live in a healthcare shortage area with prevalent prescription drug abuse. A self-administered, non-pharmacologic intervention such as Internet-based cognitive behavioral therapy for insomnia (CBT-I) may be ideal in this population, but psycho-social characteristics (e.g., high depression rates) and cultural norms (e.g., suspicion of technology) necessitate a pilot study. We evaluated the effectiveness of Sleep Healthy Using the Internet (SHUTi) on insomnia severity, sleep quality, perceived stress, depression symptoms, and sleep aid use in Appalachian women ages 45 +.

Participants: Forty-six women enrolled; 38 completed the six-week intervention in 2018 (mean age 55 years).

Methods: We employed a single group, pre/post-test, mixed-methods design. Participants completed an online survey and a qualitative interview pre- and post-intervention. Quantitative data were analyzed using one-way repeated measures ANOVA or generalized estimating equations. Interviews were qualitatively analyzed using a multi-stage coding process.

Results: Positive and statistically significant ( < .01) improvements were observed on mean scores for the Insomnia Severity Index (15.1 to 6.5), the Pittsburgh Sleep Quality Index (12.1 to 8.5), the Perceived Stress Scale (20 to 14.6), and the Center for Epidemiologic Studies Depression Scale Revised (9.8 to 5.2). The odds of reporting sleep medication use post-intervention were significantly lower than pre-intervention (OR 0.28 [95% CI 0.11-0.74]). Interviews highlighted most and least helpful intervention components and suggested that participants benefitted from SHUTi.

Conclusions: Internet-based CBT-I may be a useful, non-pharmacologic treatment that reduces insomnia severity, perceived stress, depression symptoms, and sleep aid use in middle-aged Appalachian women.
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http://dx.doi.org/10.1080/15402002.2019.1661249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048659PMC
September 2020

Statin Use and Gastrointestinal Hemorrhage: A Large Retrospective Cohort Study.

Am J Cardiovasc Drugs 2019 Feb;19(1):65-74

College of Pharmacy, University of Kentucky, Lexington, KY, USA.

Background: Nearly 70% of Americans with cardiovascular disease use statins, which have documented bleeding effects independent of their cholesterol-lowering activities. However, the literature is conflicting regarding the association between statin use and gastrointestinal hemorrhage.

Objectives: The aim of this study was to investigate the risk of gastrointestinal hemorrhage in statin users.

Methods: In this retrospective cohort study, data from the Truven Health MarketScan Research Database (2009-2015) were used to investigate the risk of gastrointestinal hemorrhage amongst statin users aged 30-65 years at the initial prescription claim. Statin users and a group of negative controls (i.e. other chronic medication users) were followed until first gastrointestinal hemorrhage event (both inpatient and outpatient, as well as restricted to inpatient), and were censored at treatment discontinuation, disenrollment from coverage, or the end of the study period.

Results: Statin users had an elevated risk of gastrointestinal hemorrhage, which was especially apparent in the first year of treatment (1-year adjusted hazard ratio 1.19; 95% confidence interval (CI) 1.15-1.23). The risk of gastrointestinal hemorrhage leading to hospitalization was even higher (1-year adjusted hazard ratio 1.38; 95% CI 1.30-1.69). High-intensity statin users had a greater rate of gastrointestinal hemorrhage than moderate-intensity users (incidence rates per 1000 subject-years 22.2 (95% CI 21.9-22.8) vs. 21.5 (95% CI 21.3-21.8), respectively).

Conclusions: In a population of commercially insured subjects aged 30-65 years, statin users had a higher risk for gastrointestinal hemorrhage than other chronic medication users. These findings are important when treating patients at a high risk for bleeding events.
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http://dx.doi.org/10.1007/s40256-018-0301-4DOI Listing
February 2019

Treatment of immune thrombocytopenic purpura associated with cytomegalovirus infection in a child with pre-B cell acute lymphoblastic leukaemia after central nervous system relapse.

BMJ Case Rep 2017 Sep 25;2017. Epub 2017 Sep 25.

Department of Pediatric Hematology-Oncology, University of California, San Diego, California, USA.

A 13-year-old male patient with a history of pre-B cell acute lymphoblastic leukaemia (ALL) with isolated central nervous system relapse on maintenance chemotherapy presented with severe thrombocytopenia refractory to platelet transfusions. The patient showed only modest responses to two courses of intravenous immunoglobulin and steroids. He was found to be positive for cytomegalovirus (CMV) with modest viral load. His thrombocytopenia normalised with rituximab therapy and CMV treatment supporting the diagnosis of CMV-associated immune thrombocytopenic purpura (ITP). Following treatment, the patient continued to have a stable platelet count well above the threshold for transfusions. He continued to be intermittently treated for CMV when viral loads became detectable. This report discusses the unique management considerations of ITP in a patient undergoing therapy for ALL with a review of previously reported cases and discusses the possibility of CMV viraemia as a modulating factor.
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http://dx.doi.org/10.1136/bcr-2017-221947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5747758PMC
September 2017

Student-Led Training Day Increases Student Confidence in Women's Primary Care Skills.

Fam Med 2016 Jul;48(7):551-5

Emory University School of Medicine.

Background And Objectives: Medical students are often apprehensive in approaching basic women's health concepts, including wellness exams, reproductive health concerns, and patient counseling. This study evaluates a novel student-developed and student-run Women's Health Training Day (WHTD) as a means of cultivating medical student confidence in women's primary care early in medical training.

Methods: Sixty-six first-year medical students participated in WHTD, a voluntary 6-hour weekend day of interactive workshops. Students were divided into groups of six to eight students that rotated together through five workshops focused on the breast exam, pelvic exam, microscopy, family planning, and patient interviews. Before participating in WHTD, students completed surveys indicating their confidence in performing skills related to women's health on a 5-point Likert scale. Students completed an identical survey after participating in all of the WHTD workshops. Changes in pre- and post-training day confidence scores were assessed.

Results: Students reported increased confidence in all of the composite sessions that were assessed. The specific skillsets demonstrating the greatest increases in student confidence were speculum handling during pelvic examinations, detecting abnormal breast masses, and recognizing the clinical presentations of common sexually transmitted infections. All but one of the evaluated skills, using a microscope, demonstrated a significant increase in student confidence.

Conclusions: These results indicate that the student-implemented and student-run Women's Health Training Day increases student confidence in women's primary care skills. Further studies are needed to determine whether this perceived increase in confidence is associated with increased objective knowledge pertaining to primary care and women's health.
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July 2016

Moving away from a cultural deficit to a holistic perspective: Traditional gender role values, academic attitudes, and educational goals for Mexican descent adolescents.

J Couns Psychol 2016 Apr 14;63(3):307-318. Epub 2015 Dec 14.

School of Social Work, University of Texas-Arlington.

Latina/o youth lag behind Asian American and non-Latina/o White youth in many academic areas. Previous research has taken a deficit approach to understand the factors that affect academic outcomes for Latina/o youth often neglecting to highlight both the potential positive and negative contributions of gender role values. The present study took a holistic perspective to understand the affect of traditional Latina/o gender role values (i.e., marianismo, machismo, and caballerismo) on the academic attitudes and educational goals of Mexican descent youth. Structural equation models were tested to examine the associations of "positive" and "negative" gender role values on educational goals using 524 Mexican descent adolescents from a mid-sized city in southern Texas. We hypothesized that positive aspects of traditional Latina/o gender role values (i.e., "positive marianismo" and caballerismo) would be associated with more positive attitudes toward academics and higher educational goals. We further expected negative gender role values (i.e., "negative marianismo" and machismo) to have the opposite effect. Additionally, based on the theory of planned behavior and gender schema theory, academic attitudes were hypothesized to mediate the relation between gender role values and educational goals. An alternative model was tested in which educational goals mediated the relation between gender roles and academic attitudes. Results indicated that both models fit the data well, and recommendations are made for future longitudinal research aimed at disentangling the directionality of the relations in the model. Implications for research and practice are discussed.
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http://dx.doi.org/10.1037/cou0000133DOI Listing
April 2016

Gremlin 1 identifies a skeletal stem cell with bone, cartilage, and reticular stromal potential.

Cell 2015 Jan;160(1-2):269-84

Department of Medicine and Irving Cancer Research Center, Columbia University, New York, NY 10032, USA. Electronic address:

The stem cells that maintain and repair the postnatal skeleton remain undefined. One model suggests that perisinusoidal mesenchymal stem cells (MSCs) give rise to osteoblasts, chondrocytes, marrow stromal cells, and adipocytes, although the existence of these cells has not been proven through fate-mapping experiments. We demonstrate here that expression of the bone morphogenetic protein (BMP) antagonist gremlin 1 defines a population of osteochondroreticular (OCR) stem cells in the bone marrow. OCR stem cells self-renew and generate osteoblasts, chondrocytes, and reticular marrow stromal cells, but not adipocytes. OCR stem cells are concentrated within the metaphysis of long bones not in the perisinusoidal space and are needed for bone development, bone remodeling, and fracture repair. Grem1 expression also identifies intestinal reticular stem cells (iRSCs) that are cells of origin for the periepithelial intestinal mesenchymal sheath. Grem1 expression identifies distinct connective tissue stem cells in both the bone (OCR stem cells) and the intestine (iRSCs).
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http://dx.doi.org/10.1016/j.cell.2014.11.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4436082PMC
January 2015

Postpartum transabdominal laparoscopic adrenalectomy for pheochromocytoma presenting with abruption and hypertensive emergency.

Am Surg 2015 Jan;81(1):E34-5

Department of Surgery, University of South Carolina, Columbia, South Carolina, USA.

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January 2015

The relationship between glucose metabolism, resting-state fMRI BOLD signal, and GABAA-binding potential: a preliminary study in healthy subjects and those with temporal lobe epilepsy.

J Cereb Blood Flow Metab 2015 Mar 31;35(4):583-91. Epub 2015 Mar 31.

Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.

Glucose metabolism has been associated with magnitude of blood oxygen level-dependent (BOLD) signal and connectivity across subjects within the default mode and dorsal attention networks. Similar correlations within subjects across the entire brain remain unexplored. [(18)F]-fluorodeoxyglucose positron emission tomography ([(18)F]-FDG PET), [(11)C]-flumazenil PET, and resting-state functional magnetic resonance imaging (fMRI) scans were acquired in eight healthy individuals and nine with temporal lobe epilepsy (TLE). Regional metabolic rate of glucose (rMRGlu) was correlated with amplitude of low frequency fluctuations (ALFFs) in the fMRI signal, global fMRI connectivity (GC), regional homogeneity (ReHo), and gamma-aminobutyric acid A-binding potential (GABAA BP(ND)) across the brain. Partial correlations for ALFFs, GC, and ReHo with GABAA BP(ND) were calculated, controlling for rMRGlu. In healthy subjects, significant positive correlations were observed across the brain between rMRGlu and ALFF, ReHo and GABAA BP(ND), and between ALFFs and GABAA BP(ND), controlling for rMRGlu. Brain-wide correlations between rMRGlu and ALFFs were significantly lower in TLE patients, and correlations between rMRGlu and GC were significantly greater in TLE than healthy subjects. These results indicate that the glutamatergic and GABAergic systems are coupled across the healthy human brain, and that ALFF is related to glutamate use throughout the healthy human brain. TLE may be a disorder of altered long-range connectivity in association with glutamate function.
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http://dx.doi.org/10.1038/jcbfm.2014.228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420874PMC
March 2015

Communal nesting exerts epigenetic influences on affective and social behaviors in rats selectively bred for an infantile trait.

Physiol Behav 2015 Feb 13;139:97-103. Epub 2014 Nov 13.

Department of Psychology and Program in Neuroscience, Williams College, Williamstown, MA 01267, USA. Electronic address:

Communal nesting (CN) is a mouse model of early social enrichment during pregnancy and lactation. In this study, a rat model of CN was developed to determine if CN exerts an epigenetic effect in rats selectively bred for an infantile affective trait (high and low rates of ultrasonic distress calls). High and Low offspring from CN groups were compared to standard reared (SN) offspring on five measures of social and affective behavior at three critical ages. A differential effect of the CN paradigm on High and Low lines was seen in measures of anxiety and arousal, but not in measures of depression or social behavior. Neonatal CN subjects emitted fewer distress calls than SN subjects when separated from their dams, and the High line subjects were more affected by the CN procedure. As juveniles, CN subjects showed increased social behaviors in tests of juvenile parenting and play compared to SN subjects. In adulthood, CN differentially increased the activity of Low line subjects. All CN subjects displayed less anxiety behavior in an open field compared to SN subjects; High line subjects were more anxious than Lows. CN reduced immobility and increased attempts to escape on the Porsolt forced swim task relative to SN subjects. These results extend the usefulness of this early enrichment paradigm from mice to rats, and found some rodent species differences in outcomes dependent on the behavioral test. They also emphasize the importance of social contact during pregnancy and lactation on offspring's optimal development across behaviors and ages.
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http://dx.doi.org/10.1016/j.physbeh.2014.11.007DOI Listing
February 2015

The 5-HT1A receptor and 5-HT transporter in temporal lobe epilepsy.

Neurology 2013 Apr 20;80(16):1465-71. Epub 2013 Mar 20.

Clinical Epilepsy Section, National Institutes of Neurological Disorders and Stroke, NIH, Bethesda, MD, USA.

Objective: To study 5-HT transport and 5-HT1A receptors in temporal lobe epilepsy (TLE) and depression.

Methods: Thirteen patients had PET with [(11)C]DASB for 5-HTT and [(18)F]FCWAY for 5-HT1A receptor binding, MRI, and psychiatric assessment. Sixteen healthy volunteers had [(11)C]DASB, 19 had [(18)F]FCWAY, and 6 had both PET studies. We used a reference tissue model to estimate [(11)C]DASB binding. [(18)F]FCWAY volume of distribution was corrected for plasma-free fraction. Images were normalized to common space. The main outcome was the regional asymmetry index. Positive asymmetry indicates relative reduced binding (reflecting transporter activity) ipsilateral to epileptic foci.

Results: Mean regional [(11)C]DASB binding and asymmetry did not differ between patients and controls. [(18)F]FCWAY asymmetry was significantly greater for patients than controls in hippocampus, amygdala, and fusiform gyrus. On analysis of variance with region as a repeated measure, depression diagnosis had a significant effect on [(11)C]DASB asymmetry, with significantly higher [(11)C]DASB asymmetry in insular cortex (trend for fusiform gyrus). In insular cortex, patients had a significant correlation between [(18)F]FCWAY asymmetry and [(11)C]DASB asymmetry.

Conclusions: Our study showed increased [(11)C]DASB asymmetry in insula and fusiform gyrus, and relatively reduced transporter activity, in subjects with both TLE and depression, as compared to subjects with TLE alone, implying reduced reuptake and thus increased synaptic 5-HT availability. This finding may represent a compensatory mechanism for 5-HT1A receptor loss. Altered serotonergic mechanisms have an important role in TLE and concomitant depression.
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http://dx.doi.org/10.1212/WNL.0b013e31828cf809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3662359PMC
April 2013

PET of serotonin 1A receptors and cerebral glucose metabolism for temporal lobectomy.

J Nucl Med 2012 Sep 10;53(9):1375-82. Epub 2012 Jul 10.

Clinical Epilepsy Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA.

Unlabelled: The objective of this study was to compare 5-hydroxytryptamine receptor 1A (5-HT(1A)) PET with cerebral metabolic rate of glucose (CMRglc) PET for temporal lobectomy planning.

Methods: We estimated 5-HT(1A) receptor binding preoperatively with (18)F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl) piperazin-1-yl]ethyl-N-(2-pyridyl) cyclohexane carboxamide ((18)F-FCWAY) PET and CMRglc measurement with (18)F-FDG in regions drawn on coregistered MRI after partial-volume correction in 41 patients who had anterior temporal lobectomy with at least a 1-y follow-up. Surgery was tailored to individual preresection evaluations and intraoperative electrocorticography. Mean regional asymmetry values and the number of regions with asymmetry exceeding 2 SDs in 16 healthy volunteers were compared between seizure-free and non-seizure-free patients. (18)F-FCWAY but not (18)F-FDG and MRI data were masked for surgical decisions and outcome assessment.

Results: Twenty-six of 41 (63%) patients seizure-free since surgery had significantly different mesial temporal asymmetries, compared with 15 non-seizure-free patients for both (18)F-FCWAY (F(1,39) = 5.87; P = 0.02) and (18)F-FDG PET (F(1,38) = 5.79; P = 0.021). The probability of being seizure-free was explained by both (18)F-FDG and (18)F-FCWAY PET, but not MRI, with a significant additional (18)F-FCWAY effect (chi(2)(2) = 9.8796; P = 0.0072) after the probability of being seizure-free was explained by (18)F-FDG. Although MRI alone was not predictive, any combination of 2 lateralizing imaging studies was highly predictive of seizure freedom.

Conclusion: Our study provides class III evidence that both 5-HT(1A) receptor PET and CMRglc PET can contribute to temporal lobectomy planning. Additional studies should explore the potential for temporal lobectomy based on interictal electroencephalography and minimally invasive imaging studies.
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http://dx.doi.org/10.2967/jnumed.112.103093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3856554PMC
September 2012

Cerebral blood flow and fMRI BOLD auditory language activation in temporal lobe epilepsy.

Epilepsia 2012 Apr 14;53(4):631-8. Epub 2012 Feb 14.

Clinical Epilepsy Section, NINDS NIH, Bethesda, Maryland 20892, USA.

Purpose: Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI), an important research and clinical tool, depends on relatively greater transient increases in (regional cerebral blood flow) rCBF than cerebral metabolic rate for oxygen during neural activity. We investigated whether reduced resting rCBF in patients with temporal lobe epilepsy affects BOLD signal during fMRI language mapping.

Methods: We used [(15)O] water positron emission tomography (PET) to measure rCBF, and 3 Tesla echo planar imaging (EPI) BOLD fMRI with an auditory description decision task in 33 patients with temporal lobe epilepsy (16 men; mean age 33.6 ± standard deviation [SD] 10.6 years; epilepsy onset 14.8 ± 10.6 years; mean duration 18.8 ± 13.2 years; 23 left focus, 10 right focus). Anatomic regions drawn on structural MRI, based on the Wake Forest Pick Atlas, included Wernicke's area (WA), inferior frontal gyrus (IFG), middle frontal gyrus (MFG), and hippocampus (HC). Laterality indices (LIs), and asymmetry indices (AIs), were calculated on coregistered fMRI and PET.

Key Findings: Twelve patients had mesial temporal sclerosis (seven on the left), two patients had a tumor or malformation of cortical development (both left), one patient a right temporal cyst, and 18 patients had normal MRI (14 left). Decreasing relative left WA CBF correlated with decreased left IFG voxel activation and decreasing left IFG LI. However, CBF WA AI was not related to left WA voxel activation itself or WA LI. There was a weak positive correlation between absolute CBF and fMRI activation in left IFG, right IFG, and left WA. Patients with normal and abnormal MRI did not differ in fMRI activation or rCBF AIs.

Significance: Reduced WA rCBF is associated with reduced fMRI activation in IFG but not WA itself, suggesting distributed network effects, but not impairment of underlying BOLD response. Hypoperfusion in TLE does not affect fMRI clinical value.
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http://dx.doi.org/10.1111/j.1528-1167.2012.03403.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319237PMC
April 2012

Searching for interference effects in learning new face-name associations.

Memory 2012 31;20(2):155-66. Epub 2012 Jan 31.

Department of Psychology, University of Colorado, Colorado Springs, CO 80918, USA.

In three experiments we attempted to increase interference using experimental manipulations in a face-name learning paradigm. All experiments included young and older adult participants because ageing is associated with increases in both susceptibility to interference and difficulty in learning face-name associations. None of the experiments produced interference for either age group: The inclusion of confusable (i.e., ambiguous) names and occupations, having to learn an additional piece of information in association with each face, and requiring participants to guess when uncertain all failed to negatively impact name learning. Interference does not appear to be the critical mechanism underlying the difficulty of learning proper names, and it cannot account for older adults' disproportionate decline in name-learning ability.
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http://dx.doi.org/10.1080/09658211.2011.649290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319713PMC
June 2012

Serotonin 1A receptors, depression, and memory in temporal lobe epilepsy.

Epilepsia 2012 Jan 2;53(1):129-33. Epub 2011 Nov 2.

Clinical Epilepsy Section, NINDS NIH, Bethesda, Maryland 20892, USA.

Purpose: Memory deficits and depression are common in patients with temporal lobe epilepsy (TLE). Previous positron emission tomography (PET) studies have shown reduced mesial temporal 5HT1A-receptor binding in these patients. We examined the relationships among verbal memory performance, depression, and 5HT1A-receptor binding measured with 18F-trans-4-fluoro-N-2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl-N-(2-pyridyl) cyclohexane carboxamide (18FCWAY) PET in a cross-sectional study.

Methods: We studied 40 patients (24 male; mean age 34.5 ± 10.7 years) with TLE. Seizure diagnosis and focus localization were based on ictal video-electroencephalography (EEG) recording. Patients had neuropsychological testing with Wechsler Adult Intelligence Score III (WAIS III) and Wechsler Memory Score III (WMS III) on stable antiepileptic drug (AED) regimens at least 24 h since the last seizure. Beck Depression Inventory (BDI) scores were obtained. We performed interictal PET with 18FCWAY, a fluorinated derivative of WAY 100635, a highly specific 5HT1A ligand, and structural magnetic resonance imaging (MRI) scans to estimate partial volume and plasma free fraction corrected 18FCWAY volume of distribution (V/f1).

Key Findings: Hippocampal V/f1 was significantly lower in area ipsilateral than contralateral to the epileptic focus (73.7 ± 27.3 vs. 95.4 ± 28.4; p < 0.001). We found a significant relation between both left hippocampal 18FCWAY V/f1 (r = 0.41; p < 0.02) and left hippocampal volume (r = 0.36; p < 0.03) and delayed auditory memory score. On multiple regression, there was a significant effect of the interaction of left hippocampal 18FCWAY V/f1 and left hippocampal volume on delayed auditory memory, but not of either alone. High collinearity was present. In an analysis of variance including the side of the seizure focus, the effect of left hippocampal 18FCWAY V/f1 but not focus laterality retained significance. Mean BDI was 8.3 ± 7.0. There was a significant inverse relation between BDI and 18FCWAY V/f1 ipsilateral to the patient's epileptic focus (r = 0.38 p < 0.02). There was no difference between patients with a right or left temporal focus. There was no relation between BDI and immediate or delayed auditory memory.

Significance: Our study suggests that reduced left hippocampal 5HT1A-receptor binding may play a role in memory impairment in patients with TLE.
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http://dx.doi.org/10.1111/j.1528-1167.2011.03309.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3253243PMC
January 2012

Effects of gestational allopregnanolone administration in rats bred for high affective behavior.

Physiol Behav 2010 Feb 31;99(2):212-7. Epub 2009 May 31.

Department of Psychology, Williams College, Williamstown, MA 01267, USA.

The anxiolytic neurosteroid allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one or 3alpha,5alpha-THP) has been proposed to play a developmental role in emergent neural regulation of affective behavior. This experiment examined whether allopregnanolone administered during the last week of gestation in rats would alter neonatal and adult offspring behaviors in the selectively-bred High vocalizing line, who have low levels of allopregnanolone and high levels of anxious/depressive behaviors. Dams were injected twice a day with the neurosteroid or vehicle, or handled as controls, and were tested on the elevated plus maze just before parturition. Maternal behavior was assessed throughout the first week of life, and affective behavior in the offspring was tested at one week of age (ultrasonic vocalizations test) and as adults (plus maze and forced swim tests). Offspring prenatally exposed to allopregnanolone were less anxious as neonates and less depressed as adults compared to both control groups. Only male adult offspring, however, revealed less anxious behavior on the plus maze. Neither the dams' anxiety behavior measured in late gestation nor their postnatal maternal behavior was altered compared to controls, suggesting a direct, long-lasting effect of gestational allopregnanolone on the developing fetal brain independent of mediating maternal factors. These results are discussed in light of new evidence about the developmental role of the GABA-A receptor prenatally.
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http://dx.doi.org/10.1016/j.physbeh.2009.05.014DOI Listing
February 2010