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1.
Drug Alcohol Depend ; 207: 107804, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31862556

RESUMO

BACKGROUND: Individuals with opioid use disorder (OUD) exhibit high levels of economic demand for opioids, with high levels of consumption and relative insensitivity to changes in price. Because the medications used to treat OUD in medication-assisted therapy (MAT) act as antagonists or agonists at µ opioid receptors, they may alter the relationship between price and opioid intake. METHODS: This study examined demand for a commonly abused synthetic prescription opioid, fentanyl, in male rats following s.c. pre-treatment with naltrexone (0.1-1.0 mg/kg), morphine (0.3-3.0 mg/kg) or buprenorphine (0.3-3.0 mg/kg). We normalized demand curves to intake at the lowest price and estimated effects on elasticity (sensitivity to changes in price). Rats were first trained to earn fentanyl (5 µg/kg/infusion) on a fixed ratio schedule, then they underwent daily training under a threshold procedure designed to produce within-session demand curve estimates. Rats received 14 threshold sessions before undergoing a series of tests encompassing each drug, at each dose. RESULTS: Elasticity was increased by pretreatment with naltrexone, morphine or buprenorphine. Morphine also decreased initial intake, when the price for fentanyl was lowest. In contrast, initial intake was increased by naltrexone (according to an inverted-U shaped curve). The effects of naltrexone did not persist after the test session, but morphine and buprenorphine continued affecting demand elasticity 24 h or 48 h after the test, respectively. CONCLUSIONS: These results indicate that fentanyl demand is sensitive to blockade or activation of opioid receptors by the drug classes used for MAT in humans.

2.
J Clin Periodontol ; 47(4): 442-450, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31860742

RESUMO

AIM: To investigate the role of Epstein-Barr virus (EBV), cytomegalovirus (CMV), and anaerobic bacteria in the progression of periodontitis. METHODS: Eighty-one adults with generalized moderate to severe periodontitis were randomly assigned to: oral hygiene or scaling and root planning ± placebo or polyunsaturated fatty acids fish oil. Subgingival plaque samples collected from three healthy and three disease sites at weeks 0, 16, and 28 and from sites demonstrating disease progression were analysed for EBV, CMV, P. gingivalis (Pg), T. forsythia (Tf), and T. denticola (Td) DNA using quantitative polymerase chain reaction. RESULTS: Cytomegalovirus was detected in 0.3% (4/1454) sites. EBV was present in 12.2% of healthy sites (89/728) and 27.6% disease sites (201/726; p < .0001), but was in low copy number. Disease progression occurred in 28.4% of participants (23/81) and developed predominantly at sites identified as diseased (75/78; 96.2%). CMV and EBV were not associated with disease progression (p = .13) regardless of treatment. In contrast, disease sites were associated with higher levels of Pg, Td, Tf, and total bacteria, and sites that exhibited disease progression were associated with an abundance of Td and Tf (p < .04). CONCLUSION: Disease progression was associated with Gram-negative anaerobic bacteria; not EBV or CMV.

3.
Cerebrovasc Dis ; 48(3-6): 251-256, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31851968

RESUMO

INTRODUCTION: Mechanical thrombectomy has become standard of care for emergent large vessel occlusive stroke. Estimates of incidence for thrombectomy eligibility vary significantly. National Institutes of Health Stroke Scale (NIHSS) of 10 or greater is highly predictive of large vessel occlusion. Using our Kentucky Appalachian Stroke Registry (KApSR), we evaluated temporal trends in stroke admissions with NIHSS ≥10 to determine patient characteristics among that group along with effects and needs in thrombectomy utilization. METHODS: Using the KApSR database that captures patients throughout the Appalachian region in our stroke network, we evaluated patients admitted with ischemic stroke with NIHSS ≥10. We recorded demographics, comorbidities, treatment (thrombectomy, decompressive craniectomy), and county of origin. Change in NIHSS from admission to discharge was used as an indicator of inpatient outcome. RESULTS: Between 2010 and 2016, 1,510 patients were admitted with NIHSS ≥10. 87.2% had high blood pressure, 69.6% had dyslipidemia, and 41.7% used tobacco. There were significant sex differences in the types of patients presenting with NIHSS ≥10 with females being older on average and having more atrial fibrillation and obesity. There was an increase in thrombectomy utilization from 2010 to 2016, but only 7.5% of the potentially eligible patients underwent the procedure. In comparison to the period 2010-2014, the 2015-2016 period had higher rates of obesity and tobacco abuse. CONCLUSION: Among patients with significant burden of ischemic stroke, the most common coexisting medical condition was high blood pressure. Patients who underwent thrombectomy had significantly better inpatient clinical improvement. These data support the need to maximize utilization of thrombectomy along with need to devote increased resources on modifiable stroke risk factors.


Assuntos
Isquemia Encefálica/terapia , Tomada de Decisão Clínica , Técnicas de Apoio para a Decisão , Avaliação da Deficiência , Seleção de Pacientes , Acidente Vascular Cerebral/terapia , Trombectomia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Região dos Apalaches/epidemiologia , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/epidemiologia , Isquemia Encefálica/fisiopatologia , Comorbidade , Estudos Transversais , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sistema de Registros , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores Sexuais , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/fisiopatologia , Trombectomia/efeitos adversos , Resultado do Tratamento
4.
FASEB J ; 33(12): 13966-13981, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31638830

RESUMO

The cause of antiseizure drug (ASD) resistance in epilepsy is poorly understood. Here, we focus on the transporter P-glycoprotein (P-gp) that is partly responsible for limited ASD brain uptake, which is thought to contribute to ASD resistance. We previously demonstrated that cyclooxygenase-2 (COX-2) and the prostaglandin E receptor, prostanoid E receptor subtype 1, are involved in seizure-mediated P-gp up-regulation. Thus, we hypothesized that inhibiting microsomal prostaglandin E2 (PGE2) synthase-1 (mPGES-1), the enzyme generating PGE2, prevents blood-brain barrier P-gp up-regulation after status epilepticus (SE). To test our hypothesis, we exposed isolated brain capillaries to glutamate ex vivo and used a combined in vivo-ex vivo approach by isolating brain capillaries from humanized mPGES-1 mice to study P-gp levels. We demonstrate that glutamate signaling through the NMDA receptor, cytosolic phospholipase A2, COX-2, and mPGES-1 increases P-gp protein expression and transport activity levels. We show that mPGES-1 is expressed in human, rat, and mouse brain capillaries. We show that BI1029539, an mPGES-1 inhibitor, prevented up-regulation of P-gp expression and transport activity in capillaries exposed to glutamate and in capillaries from humanized mPGES-1 mice after SE. Our data provide key signaling steps underlying seizure-induced P-gp up-regulation and suggest that mPGES-1 inhibitors could potentially prevent P-gp up-regulation in epilepsy.-Soldner, E. L. B., Hartz, A. M. S., Akanuma, S.-I., Pekcec, A., Doods, H., Kryscio, R. J., Hosoya, K.-I., Bauer, B. Inhibition of human microsomal PGE2 synthase-1 reduces seizure-induced increases of P-glycoprotein expression and activity at the blood-brain barrier.

5.
Commun Stat Theory Methods ; 48(23): 5733-5747, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31649416

RESUMO

Continuous-time multi-state models are commonly used to study diseases with multiple stages. Potential risk factors associated with the disease are added to the transition intensities of the model as covariates, but missing covariate measurements arise frequently in practice. We propose a likelihood-based method that deals efficiently with a missing covariate in these models. Our simulation study showed that the method performs well for both 'missing completely at random' and 'missing at random' mechanisms. We also applied our method to a real dataset, the Einstein Aging Study.

6.
J Neurosci Methods ; 327: 108391, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31408649

RESUMO

BACKGROUND: Disparate research sites using identical or near-identical magnetic resonance imaging (MRI) acquisition techniques often produce results that demonstrate significant variability regarding volumetric quantification of white matter hyperintensities (WMH) in the aging population. The sources of such variability have not previously been fully explored. NEW METHOD: 3D FLAIR sequences from a group of randomly selected aged subjects were analyzed to identify sources-of-variability in post-acquisition processing that can be problematic when comparing WMH volumetric data across disparate sites. The methods developed focused on standardizing post-acquisition protocol processing methods to develop a protocol with less than 0.5% inter-rater variance. RESULTS: A series of experiments using standard MRI acquisition sequences explored post-acquisition sources-of-variability in the quantification of WMH volumetric data. Sources-of-variability included: the choice of image center, software suite and version, thresholding selection, and manual editing procedures (when used). Controlling for the identified sources-of-variability led to a protocol with less than 0.5% variability between independent raters in post-acquisition WMH volumetric quantification. COMPARISON WITH EXISTING METHOD(S): Post-acquisition processing techniques can introduce an average variance approaching 15% in WMH volume quantification despite identical scan acquisitions. Understanding and controlling for such sources-of-variability can reduce post-acquisition quantitative image processing variance to less than 0.5%. DISCUSSION: Considerations of potential sources-of-variability in MRI volume quantification techniques and reduction in such variability is imperative to allow for reliable cross-site and cross-study comparisons.

7.
Artigo em Inglês | MEDLINE | ID: mdl-31103527

RESUMO

OBJECTIVE: To examine postoperative bleeding in patients taking antiplatelet and anticoagulant medications after invasive periodontal procedures. STUDY DESIGN: This 6-year retrospective study collected data from the electronic health records of patients who underwent invasive periodontal procedures at the College of Dentistry, University of Kentucky Lexington, from January 1, 2011 through April 1, 2017. Records were included when the medical history was current, an invasive periodontal procedure was performed, an antiplatelet or anticoagulant medication was taken, and a postoperative visit was documented. RESULTS: Four hundred and fifty-six patients (age range 22-89 years; mean age 66.1 years; 58% male) met the inclusion criteria and underwent 867 invasive periodontal procedures. Antiplatelet medications, warfarin, a direct oral anticoagulant, or a combination of these drugs were taken during 484 scaling and root planing procedures, 218 implant placements, 53 open flap debridements, 16 gingival grafts, 15 lateral windows, and 71 other. Medications were continued in 99.6% of patients during the procedure. Postoperative bleeding occurred after three procedures (0.35%) and resolved with local hemostatic measures. Medications were temporarily discontinued in four instances (range 1-5 days); none of these patients experienced postoperative bleeding. CONCLUSIONS: Postoperative bleeding was infrequent in patients who underwent an invasive periodontal procedure while taking an antiplatelet or anticoagulant drug.


Assuntos
Anticoagulantes/efeitos adversos , Inibidores da Agregação de Plaquetas/efeitos adversos , Hemorragia Pós-Operatória , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Hemorragia Pós-Operatória/induzido quimicamente , Estudos Retrospectivos , Varfarina , Adulto Jovem
8.
J Alzheimers Dis ; 68(2): 625-633, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30856115

RESUMO

Tobacco smoking was examined as a risk for dementia and neuropathological burden in 531 initially cognitively normal older adults followed longitudinally at the University of Kentucky's Alzheimer's Disease Center. The cohort was followed for an average of 11.5 years; 111 (20.9%) participants were diagnosed with dementia, while 242 (45.6%) died without dementia. At baseline, 49 (9.2%) participants reported current smoking (median pack-years = 47.3) and 231 (43.5%) former smoking (median pack-years = 24.5). The hazard ratio (HR) for dementia for former smokers versus never smokers based on the Cox model was 1.64 (95% CI: 1.09, 2.46), while the HR for current smokers versus never smokers was 1.20 (0.50, 2.87). However, the Fine-Gray model, which accounts for the competing risk of death without dementia, yielded a subdistribution hazard ratio (sHR) = 1.21 (0.81, 1.80) for former and 0.70 (0.30, 1.64) for current smokers. In contrast, current smoking increased incidence of death without dementia (sHR = 2.38; 1.52, 3.72). All analyses were adjusted for baseline age, education, sex, diabetes, head injury, hypertension, overweight, APOEɛ4, family history of dementia, and use of hormone replacement therapy. Once adjusted for the competing risk of death without dementia, smoking was not associated with incident dementia. This finding was supported by neuropathology on 302 of the participants.

9.
PLoS One ; 14(2): e0212435, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30802256

RESUMO

BACKGROUND: Memory assessment is a key factor for the diagnosis of cognitive impairment. However, memory performance over time may be quite heterogeneous within diagnostic groups. METHOD: To identify latent trajectories in memory performance and their associated risk factors, we analyzed data from Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who were classified either as cognitively normal or as Mild Cognitive Impairment (MCI) at baseline and were administered the Rey Auditory Verbal Learning test (RAVLT) for up to 9 years. Group-based trajectory modeling on the 30-minute RAVLT delayed recall score was applied separately to the two baseline diagnostic groups. RESULTS: There were 219 normal subjects with mean age 75.9 (range from 59.9 to 89.6) and 52.5% male participants, and 372 MCI subjects with mean age 74.8 (range from 55.1 to 89.3) and 63.7% male participants included in the analysis. For normal subjects, six trajectories were identified. Trajectories were classified into three types, determined by the shape, each of which may comprise more than one trajectory: stable (~30% of subjects), curvilinear decline (~ 28%), and linear decline (~ 42%). Notably, none of the normal subjects assigned to the stable stratum progressed to dementia during the study period. In contrast, all trajectories identified for the MCI group tended to decline, although some participants were later re-diagnosed with normal cognition. Age, sex, and education were significantly associated with trajectory membership for both diagnostic groups, while APOE ɛ4 was only significantly associated with trajectories among MCI participants. CONCLUSION: Memory trajectory is a strong indicator of dementia risk. If likely trajectory of memory performance can be identified early, such work may allow clinicians to monitor or predict progression of individual patient cognition. This work also shows the importance of longitudinal cognitive testing and monitoring.


Assuntos
Cognição , Disfunção Cognitiva/psicologia , Memória Episódica , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/psicologia , Disfunção Cognitiva/diagnóstico , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Testes de Memória e Aprendizagem , Pessoa de Meia-Idade , Modelos Psicológicos , Modelos Estatísticos , Prognóstico , Fatores de Risco
10.
Stat Med ; 38(12): 2103-2114, 2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-30680767

RESUMO

The Nun Study, a longitudinal study to examine risk factors for the progression of dementia, consists of subjects who were already diagnosed with dementia (ie, prevalent cohort) and those who do not have dementia (ie, incident cohort) at study enrollment. When assessing the risk factors' effects on the survival time from dementia diagnosis until death, utilizing data from both cohorts supports more efficient statistical inference because the two cohorts provide valuable complementary information. A major challenge in analyzing the combined cohort data is that the prevalent cases are not representative of the target population. Moreover, the dates of dementia diagnosis are not ascertained for the prevalent cohort in the Nun Study. Hence, the survival time for the prevalent cohort is only partially observed from study enrollment until death or censoring, with the time from dementia diagnosis to study enrollment missing. In this paper, we propose an efficient estimation method that uses both incident and prevalent cohorts under the proportional mean residual life model. By assuming proportionality of the mean residual life time with covariates in the incident cohort, we can utilize the natural relationship between the mean residual life function and the hazard function of the survival time measured from enrollment until death for the prevalent cohort. We evaluate the efficiency gain from using the combined cohort data through simulations and demonstrate that the proposed method is valid and efficient.

12.
Obstet Gynecol ; 132(5): 1091-1100, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30303916

RESUMO

OBJECTIVE: To estimate the effect of ultrasound screening on stage at detection and long-term disease-specific survival of at-risk women with epithelial ovarian cancer. METHODS: Eligibility included all asymptomatic women 50 years of age or older and women 25 years of age or older with a documented family history of ovarian cancer. From 1987 to 2017, 46,101 women received annual ultrasound screening in a prospective cohort trial. Women with a persisting abnormal screen underwent tumor morphology indexing, serum biomarker analysis, and surgery. RESULTS: Seventy-one invasive epithelial ovarian cancers and 17 epithelial ovarian tumors of low malignant potential were detected. No women with a low malignant potential tumor experienced recurrent disease. Stage distribution for screen-detected invasive epithelial ovarian cancers was stage I-30 (42%), stage II-15 (21%), stage III-26 (37%), and stage IV-0 (0%). Follow-up varied from 9.2 months to 27 years (mean 7.9 years). Disease-specific survival at 5, 10, and 20 years for women with invasive epithelial ovarian cancer detected by screening was 86±4%, 68±7%, and 65±7%, respectively, vs 45±2%, 31±2%, and 19±3%, respectively, for unscreened women with clinically detected ovarian cancer from the same geographic area who were treated at the same institution by the same treatment protocols (P<.001). Twenty-seven percent of screen-detected malignancies were type I and 73% were type II. The disease-specific survival of women with type I and type II screen-detected tumors was significantly higher than that of women with clinically detected type I and type II tumors and was related directly to earlier stage at detection. CONCLUSION: Annual ultrasound screening of at-risk asymptomatic women was associated with lower stage at detection and increased 5-, 10-, and 20-year disease-specific survival of women with both type I and type II epithelial ovarian cancer. CLINICAL TRIAL REGISTRATION: OnCore Clinical Trials Management System, NCI-2013-01954.


Assuntos
Carcinoma Epitelial do Ovário/diagnóstico por imagem , Carcinoma Epitelial do Ovário/secundário , Detecção Precoce de Câncer/estatística & dados numéricos , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica , Doenças Assintomáticas , Antígeno Ca-125/sangue , Carcinoma Epitelial do Ovário/genética , Carcinoma Epitelial do Ovário/terapia , Análise Custo-Benefício , Procedimentos Cirúrgicos de Citorredução , Detecção Precoce de Câncer/economia , Reações Falso-Negativas , Reações Falso-Positivas , Feminino , Humanos , Proteínas de Membrana/sangue , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/terapia , Estudos Prospectivos , Taxa de Sobrevida , Ultrassonografia
13.
PLoS One ; 13(9): e0202191, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30212453

RESUMO

BACKGROUND: We previously reported increased unstimulated blood levels of interferon-gamma in persons with latent tuberculosis infection (LTBI) in the United States, suggesting enhanced immune activation in LTBI. To investigate this further in a TB-endemic setting, we assessed interferon-gamma levels in persons with and without LTBI in Peru. METHODS: We analyzed data from patients with and without a recent type 1 (spontaneous) acute myocardial infarction (AMI) who were enrolled from two public hospital networks in Lima, Peru, and underwent LTBI testing using the QuantiFERON® TB Gold In-tube (QFT) assay. Participants with a positive QFT test were defined as having LTBI, whereas participants with a negative QFT test were defined as non-LTBI. Unstimulated interferon-gamma was quantified via enzyme-linked immunosorbent assay in the QFT nil-tube, which does not contain antigens. We compared unstimulated interferon-gamma levels between LTBI and non-LTBI groups using the Wilcoxon rank sum test. We used proportional odds modeling for multivariable analysis. RESULTS: Data from 214 participants were included in this analysis. Of those, 120 (56%) had LTBI. There were no significant differences in age, sex and comorbidities between LTBI and non-LTBI participants, except for recent AMI that was more frequent in LTBI. LTBI participants had higher unstimulated interferon-gamma levels compared to non-LTBI participants (median, interquartile range; 14 pg/mL, 6.5-52.8 vs. 6.5 pg/mL, 4.5-15; P<0.01). LTBI remained associated with higher unstimulated interferon-gamma levels after controlling for age, sex, recent AMI, history of hypertension, diabetes mellitus, dyslipidemia, end stage renal disease, malignancy, obesity, and tobacco use (adjusted odds ratio, 2.93; 95% confidence interval, 1.8-4.9). In a sensitivity analysis that excluded participants with AMI, the association between unstimulated interferon-gamma and LTBI remained present (adjusted odds ratio; 3.93; 95% confidence interval, 1.9-8.2). CONCLUSIONS: LTBI was associated with higher unstimulated interferon-gamma levels. These data suggest ongoing immune activation in LTBI.


Assuntos
Interferon gama/sangue , Tuberculose Latente/sangue , Fatores Etários , Idoso , Feminino , Humanos , Tuberculose Latente/epidemiologia , Masculino , Pessoa de Meia-Idade , Peru/epidemiologia , Fatores de Risco
14.
J Neurosci ; 38(18): 4301-4315, 2018 05 02.
Artigo em Inglês | MEDLINE | ID: mdl-29632167

RESUMO

The blood-brain barrier is dysfunctional in epilepsy, thereby contributing to seizure genesis and resistance to antiseizure drugs. Previously, several groups reported that seizures increase brain glutamate levels, which leads to barrier dysfunction. One critical component of barrier dysfunction is brain capillary leakage. Based on our preliminary data, we hypothesized that glutamate released during seizures mediates an increase in matrix-metalloproteinase (MMP) expression and activity levels, thereby contributing to barrier leakage. To test this hypothesis, we exposed isolated brain capillaries from male Sprague Dawley rats to glutamate ex vivo and used an in vivo/ex vivo approach of isolated brain capillaries from female Wistar rats that experienced status epilepticus as an acute seizure model. We found that exposing isolated rat brain capillaries to glutamate increased MMP-2 and MMP-9 protein and activity levels, and decreased tight junction protein levels, which resulted in barrier leakage. We confirmed these findings in vivo in rats after status epilepticus and in brain capillaries from male mice lacking cytosolic phospholipase A2 Together, our data support the hypothesis that glutamate released during seizures signals an increase in MMP-2 and MMP-9 protein expression and activity levels, resulting in blood-brain barrier leakage.SIGNIFICANCE STATEMENT The mechanism leading to seizure-mediated blood-brain barrier dysfunction in epilepsy is poorly understood. In the present study, we focused on defining this mechanism in the brain capillary endothelium. We demonstrate that seizures trigger a pathway that involves glutamate signaling through cytosolic phospholipase A2, which increases MMP levels and decreases tight junction protein expression levels, resulting in barrier leakage. These findings may provide potential therapeutic avenues within the blood-brain barrier to limit barrier dysfunction in epilepsy and decrease seizure burden.


Assuntos
Barreira Hematoencefálica/patologia , Epilepsia/patologia , Metaloproteinases da Matriz/metabolismo , Animais , Capilares/efeitos dos fármacos , Feminino , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Convulsões/patologia , Estado Epiléptico/metabolismo , Estado Epiléptico/patologia , Proteínas de Junções Íntimas/metabolismo
15.
J Neuropathol Exp Neurol ; 77(1): 2-20, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29186501

RESUMO

Over the course of most common neurodegenerative diseases the amygdala accumulates pathologically misfolded proteins. Misfolding of 1 protein in aged brains often is accompanied by the misfolding of other proteins, suggesting synergistic mechanisms. The multiplicity of pathogenic processes in human amygdalae has potentially important implications for the pathogenesis of Alzheimer disease, Lewy body diseases, chronic traumatic encephalopathy, primary age-related tauopathy, and hippocampal sclerosis, and for the biomarkers used to diagnose those diseases. Converging data indicate that the amygdala may represent a preferential locus for a pivotal transition from a relatively benign clinical condition to a more aggressive disease wherein multiple protein species are misfolded. Thus, understanding of amygdalar pathobiology may yield insights relevant to diagnoses and therapies; it is, however, a complex and imperfectly defined brain region. Here, we review aspects of amygdalar anatomy, connectivity, vasculature, and pathologic involvement in neurodegenerative diseases with supporting data from the University of Kentucky Alzheimer's Disease Center autopsy cohort. Immunohistochemical staining of amygdalae for Aß, Tau, α-synuclein, and TDP-43 highlight the often-coexisting pathologies. We suggest that the amygdala may represent an "incubator" for misfolded proteins and that it is possible that misfolded amygdalar protein species are yet to be discovered.


Assuntos
Tonsila do Cerebelo/patologia , Peptídeos beta-Amiloides/metabolismo , Proteínas de Ligação a DNA/metabolismo , Doenças Neurodegenerativas/patologia , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo , Tonsila do Cerebelo/metabolismo , Humanos , Doenças Neurodegenerativas/metabolismo , Dobramento de Proteína
16.
Clin Infect Dis ; 66(6): 886-892, 2018 03 05.
Artigo em Inglês | MEDLINE | ID: mdl-29069328

RESUMO

Background: Tuberculosis has been associated with an increased risk of cardiovascular disease (CVD), including acute myocardial infarction (AMI). We investigated whether latent tuberculosis infection (LTBI) is associated with AMI. Methods: We conducted a case-control study in 2 large national public hospital networks in Lima, Peru, between July 2015 and March 2017. Case patients were patients with a first time diagnosis of type 1 (spontaneous) AMI. Controls were patients without a history of AMI. We excluded patients with known human immunodeficiency virus infection, tuberculosis disease, or prior LTBI treatment. We used the QuantiFERON-TB Gold In-Tube assay to identify LTBI. We used logistic regression modeling to estimate the odds ratio (OR) of LTBI in AMI case patients versus non-AMI controls. Results: We enrolled 105 AMI case patients and 110 non-AMI controls during the study period. Overall, the median age was 62 years (interquartile range, 56-70 years); 69% of patients were male; 64% had hypertension, 40% dyslipidemia, and 39% diabetes mellitus; 30% used tobacco; and 24% were obese. AMI case patients were more likely than controls to be male (80% vs 59%; P < .01) and tobacco users (41% vs 20%; P < .01). LTBI was more frequent in AMI case patients than in controls (64% vs 49% [P = .03]; OR, 1.86; 95% confidence interval [CI], 1.08-3.22). After adjustment for age, sex, hypertension, dyslipidemia, diabetes mellitus, tobacco use, obesity, and family history of coronary artery disease, LTBI remained independently associated with AMI (adjusted OR, 1.90; 95% CI, 1.05-3.45). Conclusions: LTBI was independently associated with AMI. Our results suggest a potentially important role of LTBI in CVD.


Assuntos
Tuberculose Latente/complicações , Infarto do Miocárdio/complicações , Idoso , Estudos de Casos e Controles , Feminino , Humanos , Tuberculose Latente/diagnóstico , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Peru , Fatores de Risco
17.
J Addict ; 2017: 6748948, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28458942

RESUMO

It is unknown whether first-generation electronic cigarettes reduce smoking urges and withdrawal symptoms following a 24 h deprivation period. This study tested whether a first-generation electronic cigarette reduces smoking urges and withdrawal symptoms in cigarette smokers. Following 24 h of tobacco deprivation, using a within-subjects design, eight nontreatment seeking tobacco cigarette smokers (3 females) administered 10 puffs from a conventional cigarette or a first-generation electronic cigarette containing liquid with 0, 8 or 16 mg/ml nicotine. Conventional cigarettes ameliorated smoking urges and electronic cigarettes did not, regardless of nicotine concentration. First-generation electronic cigarettes may not effectively substitute for conventional cigarettes in reducing smoking urges, regardless of nicotine concentration.

18.
BMC Ophthalmol ; 17(1): 78, 2017 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-28532424

RESUMO

BACKGROUND: The purpose of this study is to evaluate the number of eyedrops available per bottle of a variety of commonly prescribed glaucoma medications. METHODS: Six bottles of each glaucoma medication were tested: three each in the vertical and horizontal orientations. Bottles were housed in a customized force gauge apparatus designed to mimic ballpoint fingertip contact with a bottle. At a standard rate, all drops were expressed from each bottle and counted with an automated drop counter. Simultaneously, bottle volume was measured and drop size and number were also estimated. The main outcome measures were: total number of drops, volume per bottle and drops per milliliter (mL) of glaucoma medication. RESULTS: A total of 192 bottles from 32 bottle designs and manufacturers were tested. Twenty-two of the 32 bottle designs had a significantly different mean number of drops in the vertical and horizontal positions, with 10 designs have more drops dispensed in the horizontal orientation and 12 in the vertical orientation. Six of the 32 bottle designs had a significantly different mean total bottle volume in the vertical and horizontal positions, with all designs having greater volume in the vertical position. An adjusted ratio of mean number of drops/mean bottle volume demonstrated a range from 20.9 drops/mL to 40.8 drops/mL. CONCLUSIONS: There is significant variability in drops and volume available per bottle of glaucoma medication depending on both the bottle position and manufacturer. These data point to the need for circumspection in prescribing glaucoma medications and caution in evaluating therapeutic outcomes.


Assuntos
Anti-Hipertensivos/administração & dosagem , Embalagem de Medicamentos , Pressão Intraocular/efeitos dos fármacos , Glaucoma/tratamento farmacológico , Glaucoma/fisiopatologia , Humanos , Soluções Oftálmicas
19.
JAMA Neurol ; 74(5): 567-573, 2017 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-28319243

RESUMO

Importance: Oxidative stress is an established dementia pathway, but it is unknown if the use of antioxidant supplements can prevent dementia. Objective: To determine if antioxidant supplements (vitamin E or selenium) used alone or in combination can prevent dementia in asymptomatic older men. Design, Setting, and Participants: The Prevention of Alzheimer's Disease by Vitamin E and Selenium (PREADViSE) trial began as a double-blind randomized clinical trial in May 2002, which transformed into a cohort study from September 2009 to May 2015. The PREADViSE trial was ancillary to the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a randomized clinical trial of the same antioxidant supplements for preventing prostate cancer, which closed in 2009 owing to findings from a futility analysis. The PREADViSE trial recruited 7540 men, of whom 3786 continued into the cohort study. Participants were at least 60 years old at study entry and were enrolled at 130 SELECT sites, and Cox proportional hazards models were used in a modified intent-to-treat analysis to compare hazard rates among the study arms. Interventions: Participants were randomized to vitamin E, selenium, vitamin E and selenium, or placebo. While taking study supplements, enrolled men visited their SELECT site and were evaluated for dementia using a 2-stage screen. During the cohort study, men were contacted by telephone and assessed using an enhanced 2-stage cognitive screen. In both phases, men were encouraged to visit their physician if the screen results indicated possible cognitive impairment. Main Outcomes and Measures: Dementia case ascertainment relied on a consensus review of the cognitive screens and medical records for men with suspected dementia who visited their physician for an evaluation or by review of all available information, including a functional assessment screen. Results: The mean (SD) baseline age of the 7540 participants was 67.5 (5.3) years, with 3936 (52.2%) reporting a college education or better, 754 (10.0%) reporting black race, and 505 (6.7%) reporting Hispanic ethnicity. Dementia incidence (325 of 7338 men [4.4%]) was not different among the 4 study arms. A Cox model, which adjusted incidence for participant demographic information and baseline self-reported comorbidities, yielded hazard ratios of 0.88 (95% CI, 0.64-1.20) for vitamin E, 0.83 (0.60-1.13) for selenium, and 1.00 (0.75-1.35) for the combination compared with placebo. Conclusions and Relevance: Neither supplement prevented dementia. To our knowledge, this is the first study to investigate the long-term association of antioxidant supplement use and dementia incidence among asymptomatic men.


Assuntos
Antioxidantes/farmacologia , Demência/prevenção & controle , Selênio/farmacologia , Vitamina E/farmacologia , Idoso , Doença de Alzheimer/prevenção & controle , Antioxidantes/administração & dosagem , Suplementos Nutricionais , Método Duplo-Cego , Quimioterapia Combinada , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Selênio/administração & dosagem , Vitamina E/administração & dosagem
20.
Diagnostics (Basel) ; 7(1)2017 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-28335512

RESUMO

To examine how frequently and confidently healthy women report symptoms during surveillance for ovarian cancer. A symptoms questionnaire was administered to 24,526 women over multiple visits accounting for 70,734 reports. A query of reported confidence was included as a confidence score (CS). Chi square, McNemars test, ANOVA and multivariate analyses were performed. 17,623 women completed the symptoms questionnaire more than one time and >9500 women completed it more than one four times for >43,000 serially completed questionnaires. Reporting ovarian cancer symptoms was ~245 higher than ovarian cancer incidence. The positive predictive value (0.073%) for identifying ovarian cancer based on symptoms alone would predict one malignancy for 1368 cases taken to surgery due to reported symptoms. Confidence on the first questionnaire (83.3%) decreased to 74% when more than five questionnaires were completed. Age-related decreases in confidence were significant (p < 0.0001). Women reporting at least one symptom expressed more confidence (41,984/52,379 = 80.2%) than women reporting no symptoms (11,882/18,355 = 64.7%), p < 0.0001. Confidence was unrelated to history of hormone replacement therapy or abnormal ultrasound findings (p = 0.30 and 0.89). The frequency of symptoms relevant to ovarian cancer was much higher than the occurrence of ovarian cancer. Approximately 80.1% of women expressed confidence in what they reported.

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