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1.
Nicotine Tob Res ; 2019 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-31096265

RESUMO

INTRODUCTION: Cigarette smoking continues to be one of the most important behavioral causes of morbidity and mortality in the world. Varenicline, an α4ß2 nicotinic acetylcholine receptor (nAChR) partial agonist, has been shown to increase smoking quit rates compared with nicotine-based products. This human laboratory, double-blind, placebo-controlled study examined varenicline and placebo effects on α4ß2-nAChRs occupancy, nicotine-induced change in [11C]raclopride binding potential (BPND) and behavioral measures of cigarette smoking, nicotine craving, and withdrawal. METHODS: Current nicotine dependent, daily smokers (N=17) were randomized to varenicline 1 mg twice daily or placebo for 13 days. Using positron emission tomography (PET), we characterized α4ß2-nAChRs occupancy using [18F]AZAN and dopamine receptor binding using [11C]raclopride as well as behavioral measures of cigarettes smoked, craving and nicotine withdrawal. RESULTS: Varenicline compared with placebo resulted in significant reductions in [18F]AZAN BPND in multiple brain regions including thalamus, midbrain, putamen and ventral striatum. Following administration of a controlled-dose nicotine cigarette, dopamine release was significantly suppressed in the ventral striatum in the varenicline-treated compared with the placebo group. There was a significant relationship between α4ß2-nAChRs BPND measured in thalamus during the [18F]AZAN scan and nicotine-induced change in raclopride BPND in the ventral striatum. CONCLUSION: This is the first human study to demonstrate a direct relationship between the extent of varenicline occupancy of α4ß2-nAChRs and the magnitude of dopamine release following nicotine use. IMPLICATIONS: It has remained unclear how nicotinic receptor blockade through partial agonist medications such as varenicline promotes smoking cessation. One hypothesized mechanism is downstream dampening of the mesolimbic reward dopamine system. For the first time in human smokers, we observed a direct relationship between the extent of varenicline blockade of α4ß2-nACh nicotinic receptors and the magnitude of dopamine release following smoking. This has mechanistic and therapeutic implications for improving smoking cessation interventions.

2.
J Vis Exp ; (140)2018 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-30417882

RESUMO

As genomes of a wider variety of animals become available, there is an increasing need for tools that can capture dynamic epigenetic changes in these animal models. The rat is one particular model animal where an epigenetic tool can complement many pharmacological and behavioral studies to provide insightful mechanistic information. To this end, we adapted the SureSelect Target Capture System (referred to as Methyl-Seq) for the rat, which can assess DNA methylation levels across the rat genome. The rat design targeted promoters, CpG islands, island shores, and GC-rich regions from all RefSeq genes. To implement the platform on a rat experiment, male Sprague Dawley rats were exposed to chronic variable stress for 3 weeks, after which blood samples were collected for genomic DNA extraction. Methyl-Seq libraries were constructed from the rat DNA samples by shearing, adapter ligation, target enrichment, bisulfite conversion, and multiplexing. Libraries were sequenced on a next-generation sequencing platform and the sequenced reads were analyzed to identify DMRs between DNA of stressed and unstressed rats. Top candidate DMRs were independently validated by bisulfite pyrosequencing to confirm the robustness of the platform. Results demonstrate that the rat Methyl-Seq platform is a useful epigenetic tool that can capture methylation changes induced by exposure to stress.

3.
Psychoneuroendocrinology ; 97: 164-173, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30036794

RESUMO

Chronic exposure to cortisol is associated with cardiovascular, metabolic, and psychiatric disorders. Although cortisol can be readily measured from peripheral sources such as blood, urine, or saliva, multiple samplings spanning several days to weeks are necessary to reliably assess chronic cortisol exposure levels (referred to as cortisol load). Although cortisol levels in hair have been proposed as a measure of cortisol load, measurement is cumbersome and many people are not candidates due to short hair length and use of hair dyes. To date, there are no blood biomarkers that capture cortisol load. To identify a blood biomarker capable of integrating one-month cortisol exposure levels, 75 healthy participants provided 30+ days of awakening and bedtime saliva cortisol and completed psychosocial measures of anxiety, depression, and stress. Mean daily awakening and bedtime cortisol levels were then compared to CpG methylation levels, gene expression, and genotypes of the stress response gene FKBP5 obtained from blood drawn on the last day of the study. We found a correlation between FKBP5 methylation levels and mean 30+day awakening and bedtime cortisol levels (|r|≥0.32, p ≤ 0.006). We also observed a sex-specific correlation between bedtime cortisol levels and FKBP5 mRNA expression in female participants (r = 0.42, p = 0.005). Dividing the 30-day sampling period into four weekly bins showed that the correlations for both methylation and expression were not being driven by cortisol levels in the week preceding the blood draw. We also identified a female-specific association between FKBP5 mRNA expression and scores on the Beck Anxiety Inventory (r = 0.37, p = 0.013) and Beck Depression Inventory-II (r = 0.32, p = 0.033). Finally, DNA was genotyped at four SNPs, and variation in rs4713902 was shown to have an effect on FKBP5 expression under a codominant model (f = 3.41, p = 0.048) for females only. Our results suggest that blood FKBP5 DNA methylation and mRNA expression levels may be a useful marker for determining general or sex-specific 30-day cortisol load and justifies genome-wide approaches that can potentially identify additional cortisol markers with broader clinical utility.

4.
Clin Epigenetics ; 10: 82, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29951131

RESUMO

Background: Subclinical hypercortisolism and hypothalamic-pituitary-adrenal (HPA) axis dysfunction are associated with type 2 diabetes (T2DM), cardiovascular disease, and metabolic dysfunction. Intronic methylation of FKBP5 has been implicated as a potential indicator of chronic cortisol exposure. Our overall objective in this study was to determine the association of chronic cortisol exposure, measured via percent methylation of FKBP5 at intron 2, with percent glycosylated hemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-cholesterol), waist circumference (WC), and body mass index (BMI), in a clinic-based sample of 43 individuals with T2DM. Results: Greater percent methylation of the FKBP5 intron 2 at one CpG-dinucleotide region was significantly associated with higher HbA1c (ß = 0.535, p = 0.003) and LDL cholesterol (ß = 0.344, p = 0.037) and a second CpG-dinucleotide region was significantly associated with higher BMI and WC (ß = 0.516, p = 0.001; ß = 0.403, p = 0.006, respectively). Conclusions: FKBP5 methylation may be a marker of higher metabolic risk in T2DM, possibly secondary to higher exposure to cortisol. Further work should aim to assess the longitudinal association of FKBP5 with cardiovascular disease and glycemic outcomes in T2DM as a first step in understanding potential preventive and treatment-related interventions targeting the HPA axis.

5.
Psychoneuroendocrinology ; 94: 72-82, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29763783

RESUMO

Women and men differ in their risk for developing stress-related conditions such as alcohol use and anxiety disorders and there are gender differences in the typical sequence in which these disorders co-occur. However, the neural systems underlying these gender-biased psychopathologies and clinical course modifiers in humans are poorly understood and may involve both central and peripheral mechanisms regulating the limbic-hypothalamic-pituitary-adrenal axis. In the present randomized, double blind, placebo-controlled, triple-dummy crossover study, we juxtaposed a centrally-acting, citalopram (2 mg/unit BMI) neuroendocrine stimulation test with a peripherally-acting, dexamethasone (Dex) (1.5 mg)/corticotropin-releasing factor (CRF) (1 µg/kg) test in euthymic women (N = 38) and men (N = 44) with (54%) and without histories of alcohol dependence to determine whether sex, alcohol dependence or both influenced the adrenocorticotropic hormone (ACTH) and cortisol responses to the pharmacological challenges and to identify the loci of these effects. We found that central serotonergic mechanisms, along with differences in pituitary and adrenal sensitivity, mediated sexually-diergic ACTH and cortisol responses in a stressor-specific manner regardless of a personal history of alcohol dependence. Specifically, women exhibited a greater response to the Dex/CRF test than they did the citalopram test while men exhibited the opposite pattern of results. Women also had more robust ACTH, cortisol and body temperature responses to Dex/CRF than men, and exhibited a shift in their adrenal glands' sensitivity to ACTH as measured by the cortisol/log (ACTH) ratio during that session in contrast to the other test days. Our findings indicate that central serotonergic and peripheral mechanisms both play roles in mediating sexually dimorphic, stressor-specific endocrine responses in humans regardless of alcohol dependence history.

6.
Addict Biol ; 23(2): 836-845, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28419649

RESUMO

Although epidemiological research has shown an increase in drinking following stressors and trauma, limited paradigms have been validated to study the relationship between stress and drinking in the human laboratory. The current study developed a progressive ratio (PR) operant procedure to examine the effects of psychosocial stress on alcohol craving and several alcohol-motivated behaviors in persons with alcohol use disorder. Current heavy, nontreatment-seeking drinkers (N = 30) were media-recruited and completed a comprehensive assessment of recent drinking, mood and health. Participants were admitted to the clinical research unit and underwent 4-day, physician-monitored alcohol abstinence. On days 4 and 5, participants underwent the Trier Social Stress Test or a neutral session in random order followed by the alcohol-motivated response (AMR) procedure in which subjects worked for money or alcohol under a PR operant procedure. Subjects received earned money vouchers or alcohol at the conclusion of the session. The Trier Social Stress Test increased alcohol craving and rate of responding and decreased the number of changeovers between alcohol versus money reinforcers on the PR schedule. There was a positive relationship between alcohol craving and drinks earned during the stress session. This novel paradigm provides an experimental platform to examine motivation to drink without confounding by actual alcohol ingestion during the work session, thereby setting the stage for future studies of alcohol interventions.

7.
Alcohol Clin Exp Res ; 42(2): 230-237, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29286543

RESUMO

There is increasing awareness of the potential negative impacts of participant deception on research, including possibly undermining reliability and reproducibility of study findings. These deceptive individuals set their personal interests above the rules of study participation, thereby jeopardizing data quality as well as placing themselves and others at risk. The costs of participant deception are numerous. Overall, it reduces statistical power and may even result in false conclusions about efficacy and safety. To date, most studies have not utilized sufficient methods to detect rule-breaking subjects. The purpose of this article is to bring to the attention of alcohol and other drug researchers issues involving deceptive participants. The review will suggest alcohol-specific as well as more general strategies to identify and thereby minimize enrollment of these deceptive participants. Specifically, we will identify strategies that are employed in different phases of human alcohol research and advance approaches that may be helpful to the field in reducing these contaminants. As a field, we need to be more proactive in identifying the deceptive participant even at the cost of more burdensome study enrollment. In light of the systemic nature and multipronged damage that this emerging pattern of deception inflicts on clinical research, it is imperative that we each assume greater responsibility for our role in mitigating this source of research contamination.

8.
Alcohol Res ; 39(2): 147-159, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-31198654

RESUMO

During the critical developmental periods of childhood when neural plasticity is high, exposure to early life stress (ELS) or trauma may lead to enduring changes in physiological stress systems and enhanced vulnerability for psychopathological conditions such as post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) in adulthood. Clinical and preclinical studies have sought to understand the possible mechanisms linking ELS, PTSD, and AUD. Preclinical studies have employed animal models of stress to recapitulate PTSD-like behavioral deficits and alcohol dependence, providing a basic framework for identifying common physiological mechanisms that may underlie these disorders. Clinical studies have documented ELS-related endocrine dysregulation and genetic variations associated with PTSD and AUD, as well as disruption in crucial neural circuitry throughout the corticomesolimbic region. Despite limitations and challenges, both types of studies have implicated three interrelated mechanisms: hypothalamic pituitary adrenal (HPA) axis and glucocorticoid signaling dysregulation, genetics, and epigenetics. ELS exposure leads to disruption of HPA axis function and glucocorticoid signaling, both of which affect homeostatic cortisol levels. However, individual response to ELS depends on genetic variations at specific genes that moderate HPA axis and brain function, thus influencing susceptibility or resilience to psychopathologies. Epigenetic-influenced pathways also are emerging as a powerful force in helping to create the PTSD and AUD phenotypes. Dysregulation of the HPA axis has an epigenetic effect on genes that regulate the HPA axis itself, as well as on brain-specific processes such as neurodevelopment and neurotransmitter regulation. These studies are only beginning to elucidate the underpinnings of ELS, PTSD, and AUD. Larger human cohorts, identification of additional genetic determinants, and better animal models capable of recapitulating the symptoms of PTSD and AUD are needed.


Assuntos
Experiências Adversas da Infância , Alcoolismo , Comorbidade , Sistema Hipotálamo-Hipofisário , Sistema Hipófise-Suprarrenal , Transtornos de Estresse Pós-Traumáticos , Estresse Psicológico , Experiências Adversas da Infância/estatística & dados numéricos , Alcoolismo/epidemiologia , Alcoolismo/etiologia , Alcoolismo/metabolismo , Alcoolismo/fisiopatologia , Animais , Criança , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Estresse Pós-Traumáticos/etiologia , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Estresse Psicológico/complicações , Estresse Psicológico/epidemiologia , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia
9.
JACC Heart Fail ; 5(9): 642-651, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28822744

RESUMO

OBJECTIVES: This study examined the association of aldosterone and plasma renin activity (PRA) with incident cardiovascular disease (CVD), using a composite endpoint of coronary heart disease, stroke, and/or heart failure and mortality among African Americans in the Jackson Heart Study. BACKGROUND: There is a paucity of data for the association of aldosterone and PRA with incident CVD or all-cause mortality among community-dwelling African Americans. METHODS: A total of 4,985 African American adults, 21 to 94 years of age, were followed for 12 years. Aldosterone, PRA, and cardiovascular risk factors were collected at baseline (from 2000 to 2004). Incident events included coronary heart disease and stroke (assessed from 2000 to 2011) and heart failure (assessed from 2005 to 2011). Cox models were used to estimate hazard ratios (HRs) for incident CVD and mortality, adjusting for age, sex, education, occupation, current smoking, physical activity, dietary intake, and body mass index. RESULTS: Among 4,160 participants without prevalent CVD over a median follow-up of 7 years, there were 322 incident CVD cases. In adjusted analyses, each 1-U SD increase in log-aldosterone and log-PRA were associated with HR of 1.26 (95% confidence intervals [CI]: 1.14 to 1.40) and 1.16 (95% CI: 1.02 to 1.33) for incident CVD, respectively. Over a median of 8 years, 513 deaths occurred among 4,985 participants. In adjusted analyses, each 1-U SD increase in log-aldosterone and log-PRA were associated with HRs of 1.13 (95% CI: 1.04 to 1.23) and 1.12 (95% CI: 1.01 to 1.24) for mortality, respectively. CONCLUSIONS: Elevated aldosterone and PRA may play a significant role in the development of CVD and all-cause mortality among African Americans.


Assuntos
Aldosterona/fisiologia , Doenças Cardiovasculares/mortalidade , Renina/fisiologia , Adulto , Afro-Americanos/etnologia , Idoso , Idoso de 80 Anos ou mais , Aldosterona/metabolismo , Índice de Massa Corporal , Doenças Cardiovasculares/etnologia , Causas de Morte , Doença das Coronárias/etnologia , Doença das Coronárias/mortalidade , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etnologia , Infarto do Miocárdio/mortalidade , Estudos Prospectivos , Renina/metabolismo , Fatores de Risco , Acidente Vascular Cerebral/etnologia , Acidente Vascular Cerebral/mortalidade , Estados Unidos/epidemiologia , Adulto Jovem
10.
Drug Alcohol Depend ; 178: 380-385, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28704766

RESUMO

OBJECTIVE: To examine the association between perceived stress and subsequent alcohol use in women living with HIV. METHODS: Women (n=338) receiving HIV care between April 2006 and July 2010 who enrolled in either a brief intervention for hazardous drinking or a cohort of non-hazardous drinkers completed a 90-day drinking and drug use history, and completed stress, depression and anxiety measures at 0, 6, and 12 months. We examined the association between perceived stress at months 0 or 6 and measures of quantity and frequency of alcohol use in months 3-6 and 9-12, respectively. RESULTS: The association between perceived stress and subsequent alcohol use depended on whether women were heavy or moderate drinkers at index visit. Among women reporting ≥7 drinks/week at index visit, high levels of perceived stress were associated with subsequent increased alcohol intake. However, among women reporting >0 but <7 drinks/week at index visit, high levels of perceived stress were associated with a subsequent reduction in drinking. CONCLUSIONS: Baseline drinking status moderates the relationship between perceived stress and subsequent alcohol use. Perceived stress is an important therapeutic target in women who are heavy drinkers.


Assuntos
Consumo de Bebidas Alcoólicas , Ansiedade/psicologia , Infecções por HIV/complicações , Consumo de Bebidas Alcoólicas/terapia , Estudos de Coortes , Depressão , Feminino , Humanos , Percepção
11.
Alcohol Clin Exp Res ; 41(6): 1093-1104, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28376280

RESUMO

BACKGROUND: The current study examined independent and interactive effects of polymorphisms of the mu opioid receptor gene (OPRM1, A118G) and variable number tandem repeats of the dopamine transporter gene (DAT1, SLC6A3) on alcohol consumption and subjective responses to alcohol in 127 young, healthy, social drinkers. METHODS: Participants completed an in-person assessment, which included self-reported alcohol drinking patterns and blood sampling for DNA, and in a second visit, a cumulative alcohol dosing procedure with subjective ratings across multiple time points and breath alcohol contents (0.03 to 0.1%). DNA was analyzed for OPRM1 AA versus AG/GG (*G) genotypes, DAT1 10-repeat allele (A10) versus 9 or lesser alleles (A9), and ancestral informative markers. RESULTS: There were significant epistatic interactions between OPRM1 and DAT1 genotypes. Subjective High Assessment Scale scores after alcohol consumption were highest in *G and A9 carriers, and lowest in *G and A10 carriers. Negative subjective effects were also highest in *G and A9 carriers. Effects were similar in a sensitivity analysis limited to Caucasian subjects. There were independent and epistatic interactions on drinking. The OPRM1 *G allele was independently associated with fewer heavy drinking days. The A9 allele was associated with a greater number of drinking days, which was attenuated in carriers of the *G allele. CONCLUSIONS: These findings highlight the biological importance of interactions between these 2 genes and interactions between brain opioid and dopamine systems.


Assuntos
Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/psicologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Epistasia Genética/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores Opioides mu/genética , Adulto , Testes Respiratórios/métodos , Feminino , Humanos , Masculino , Método Simples-Cego , Adulto Jovem
12.
Alcohol Clin Exp Res ; 41(4): 836-845, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28281290

RESUMO

BACKGROUND: Stress and anxiety are widely considered to be causally related to alcohol craving and consumption, as well as development and maintenance of alcohol use disorder (AUD). However, numerous preclinical and human studies examining effects of stress or anxiety on alcohol use and alcohol-related problems have been equivocal. This study examined relationships between scores on self-report anxiety, anxiety sensitivity, and stress measures and frequency and intensity of recent drinking, alcohol craving during early withdrawal, as well as laboratory measures of alcohol craving and stress reactivity among heavy drinkers with AUD. METHODS: Media-recruited, heavy drinkers with AUD (N = 87) were assessed for recent alcohol consumption. Anxiety and stress levels were characterized using paper-and-pencil measures, including the Beck Anxiety Inventory (BAI), the Anxiety Sensitivity Index-3 (ASI-3), and the Perceived Stress Scale (PSS). Eligible subjects (N = 30) underwent alcohol abstinence on the Clinical Research Unit; twice daily measures of alcohol craving were collected. On day 4, subjects participated in the Trier Social Stress Test; measures of cortisol and alcohol craving were collected. RESULTS: In multivariate analyses, higher BAI scores were associated with lower drinking frequency and reduced drinks/drinking day; in contrast, higher ASI-3 scores were associated with higher drinking frequency. BAI anxiety symptom and ASI-3 scores also were positively related to Alcohol Use Disorders Identification Test total scores and AUD symptom and problem subscale measures. Higher BAI and ASI-3 scores but not PSS scores were related to greater self-reported alcohol craving during early alcohol abstinence. Finally, BAI scores were positively related to laboratory stress-induced cortisol and alcohol craving. In contrast, the PSS showed no relationship with most measures of alcohol craving or stress reactivity. CONCLUSIONS: Overall, clinically oriented measures of anxiety compared with perceived stress were more strongly associated with a variety of alcohol-related measures in current heavy drinkers with AUD.


Assuntos
Consumo de Bebidas Alcoólicas/psicologia , Transtornos Induzidos por Álcool/psicologia , Ansiedade/psicologia , Relações Interpessoais , Percepção , Estresse Psicológico/psicologia , Adulto , Consumo de Bebidas Alcoólicas/epidemiologia , Transtornos Induzidos por Álcool/diagnóstico , Transtornos Induzidos por Álcool/epidemiologia , Ansiedade/diagnóstico , Ansiedade/epidemiologia , Fissura , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Psicológico/diagnóstico , Estresse Psicológico/epidemiologia , Adulto Jovem
13.
World Neurosurg ; 97: 317-325, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27742515

RESUMO

OBJECTIVE: The transition from microscopic to fully endoscopic transsphenoidal surgery requires a surgeon to assess how the change in technique will affect the extent of tumor resection (EOR), outcomes, and complications. We compared a single surgeon's experience transitioning from one technique to the other and examined the operative outcomes and EOR between microscopic versus endoscopic transsphenoidal surgery. METHODS: Retrospective data analysis of adult patients who were treated surgically for a pituitary adenoma between August 2005 and May 2015 by a single neurosurgeon, who was originally trained and practiced in the microscopic transsphenoidal approach. Patient demographics, perioperative conditions, tumor characteristics, operative times, volumetric EOR, postoperative outcome, and the endoscopic learning curve were evaluated. RESULTS: One hundred and nine patients underwent microscopic transsphenoidal surgery and 275 patients underwent a fully endoscopic approach. The patient characteristics were similar in the 2 groups. Operative room time was significantly shorter in the endoscopic group than in the microscopic group (180.2 vs. 215.6 minutes; P < 0.001). The endoscopic and microscopic groups had similar volumetric EOR (85.1% vs. 82.8%; P = 0.371) as well as residual tumor volume (1.06 cm3 vs. 1.15 cm3; P = 0.765). The mean length of hospital stay was 2.4 days in the endoscopic group and 3.2 days in the microscopic group (P = 0.03). CONCLUSIONS: During the transition from the microscopic to the endoscopic approach, similar surgical outcomes and EOR were achieved in the 2 cohorts. In our experience, the endoscopic approach offers the advantage of shorter operative times and lengths of hospital stays after the surgeon has developed more experience with the technique.


Assuntos
Adenoma/cirurgia , Tempo de Internação/estatística & dados numéricos , Microcirurgia/estatística & dados numéricos , Neuroendoscopia/estatística & dados numéricos , Duração da Cirurgia , Neoplasias Hipofisárias/cirurgia , Adenoma/diagnóstico , Adenoma/epidemiologia , Competência Clínica/estatística & dados numéricos , Feminino , Humanos , Curva de Aprendizado , Masculino , Maryland/epidemiologia , Pessoa de Meia-Idade , Neurocirurgiões , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/epidemiologia , Prevalência , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
14.
Addict Biol ; 22(1): 218-228, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26416591

RESUMO

The aim of this study was to examine the relationship between family history of alcohol use disorder and striatal dopamine using positron emission tomography imaging. Participants were 84 healthy, 18- to 30-year-old, social drinkers recruited via fliers and newspaper advertisements. At assessment, participants completed measures of lifetime personal and family substance use and psychiatric symptoms. Participants underwent two consecutive positron emission tomography scans using the D2 /D3 dopamine receptor radioligand [11 C]raclopride. Scans were preceded by intravenous saline and amphetamine 0.3 mg/kg, providing measures of baseline [11 C]raclopride binding potential (BPND ) and change in [11 C]raclopride (ΔBPND ). Subjective ratings of stimulant drug effects were collected during scans. Subjects were classified as family history positive (FHP) if they reported any first-degree relative with alcohol use disorder (AUD) and family history negative (FHN) if no first-degree relatives had history of AUD. Participants were predominantly White (69.0 percent) and male (62.1 percent). Baseline [11 C]raclopride BPND was generally higher in FHP compared with FHN subjects across striatal subdivisions. There were no differences in ΔBPND across regions. Negative subjective drug effects were more pronounced in FHP than in FHN subjects. While FHN subjects evidenced the expected positive relationship between ΔBPND and positive subjective drug effects, this relationship was disrupted in FHP subjects. There are key differences in dopamine status and subjective stimulant drug experiences as a function of family AUD history. These findings have important implications for understanding risk for AUD development in FHP offspring.


Assuntos
Alcoolismo/metabolismo , Saúde da Família/estatística & dados numéricos , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismo , Resiliência Psicológica , Adolescente , Adulto , Encéfalo/metabolismo , Feminino , Humanos , Masculino , Tomografia por Emissão de Pósitrons , Risco , Adulto Jovem
15.
Psychosomatics ; 58(1): 28-37, 2017 Jan - Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27692654

RESUMO

OBJECTIVE: To estimate the crude prevalence of minor depressive disorder (MinD) in a clinic-based population of adults with type 2 diabetes. METHODS: We screened a clinical sample of 702 adults with type 2 diabetes for depressive symptoms using the Patient Health Questionnaire-2 and performed a structured diagnostic psychiatric interview on 52 screen-positive and a convenience sample of 51 screen-negative individuals. Depressive disorder diagnoses were made using Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) Text Revised criteria and categorized as MinD, major depressive disorder (MDD), or no depressive disorder. We estimated prevalence of MinD and MDD and derived 95% CIs. RESULTS: The crude prevalence of current, past, and current or past MinD was 4.3% (95% CI: 0.9-9.2%), 9.6% (95% CI: 3.9-15.9%), and 13.9% (95% CI: 7.7-21.2%), respectively. The crude prevalence of current, past, and current or past MDD was slightly higher-5.0% (95% CI: 1.9-9.4%), 12.0% (95% CI: 6.1-19.5%), and 17.0% (95% CI: 10.1-24.8%), respectively. There was a high prevalence of coexisting anxiety disorders in individuals with MinD (42.2%) and MDD (8.1%). Hemoglobin A1c levels were not significantly different in individuals with MinD or MDD compared to those without a depressive disorder. CONCLUSIONS: MinD is comparably prevalent to MDD in patients with type 2 diabetes; both disorders are associated with concomitant anxiety disorders. MinD is not included in the DSM-5; however, our data support continuing to examine patients with chronic medical conditions for MinD.


Assuntos
Transtorno Depressivo/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/psicologia , Baltimore/epidemiologia , Comorbidade , Transtorno Depressivo/psicologia , Diabetes Mellitus Tipo 2/psicologia , Feminino , Humanos , Entrevista Psicológica , Masculino , Pessoa de Meia-Idade , Prevalência , Índice de Gravidade de Doença , Inquéritos e Questionários
17.
Endocr Pract ; 22(9): 1057-61, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27214296

RESUMO

OBJECTIVE: Because magnetic resonance imaging (MRI) fails to detect many adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas, inferior petrosal sinus sampling (IPSS) is considered the gold standard to differentiate Cushing disease (CD) from ectopic ACTH secretion syndrome (EAS). Some authors have suggested internal jugular vein sampling (IJVS) as an alternative to IPSS. METHODS: We simultaneously compared IJVS to IPSS in 30 consecutive patients referred for ACTH-dependent Cushing syndrome and equivocal MRI exams. Five sites were simultaneously sampled in each patient (right and left IPS, right and left IJV, and femoral vein) before and after the administration of corticotrophin-releasing hormone or desmopressin. The test was considered consistent with CD when the IPS to peripheral ratio was >2 at baseline or >3 after stimulus and the IJV to peripheral ratio was >1.7 at baseline or >2 after stimulus. RESULTS: In 27 of 30 patients, IPSS results were consistent with a central source of ACTH. Two of the other 3 patients had EAS (one lung carcinoid and one occult), and 1 patient had pathology-proven CD. The sensitivity of IPSS was 96.4%. Only 64.2% of these patients had results meeting criteria for a central source of ACTH by IJVS criteria. Twenty patients with centralizing IPPS have undergone pituitary surgery. Of these, the central origin of excessive ACTH was confirmed with certainty in 16 patients. Among these 16 patients, the IPSS sensitivity was 93.8%, whereas 5 patients had false-negative IJVS (68.7% sensitivity). CONCLUSION: These results do not support the routine use of IJVS in establishing if the pituitary is the source of excessive ACTH. ABBREVIATIONS: ACTH = adrenocorticotropic hormone CD = Cushing disease CRH = corticotrophin-releasing hormone CS = Cushing syndrome DDAVP = desmopressin EAS = ectopic ACTH secretion IJVS = internal jugular vein sampling IPSS = inferior petrosal sinus sampling JVS = jugular venous sampling MRI = magnetic resonance imaging.


Assuntos
Adenoma Hipofisário Secretor de ACT/diagnóstico , Adenoma/diagnóstico , Hormônio Adrenocorticotrópico/sangue , Veias Jugulares/química , Amostragem do Seio Petroso/métodos , Hipersecreção Hipofisária de ACTH/diagnóstico , Síndrome de ACTH Ectópico/sangue , Síndrome de ACTH Ectópico/diagnóstico , Adenoma Hipofisário Secretor de ACT/sangue , Adenoma Hipofisário Secretor de ACT/metabolismo , Adenoma/sangue , Adenoma/metabolismo , Adolescente , Hormônio Adrenocorticotrópico/análise , Adulto , Idoso , Síndrome de Cushing/sangue , Síndrome de Cushing/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Hipersecreção Hipofisária de ACTH/sangue , Valor Preditivo dos Testes , Estudos Retrospectivos , Adulto Jovem
18.
Endocrine ; 53(1): 227-39, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26895003

RESUMO

Cross-sectional association has been shown between type 2 diabetes and hypothalamic-pituitary-adrenal (HPA) axis dysregulation; however, the temporality of this association is unknown. Our aim was to determine if type 2 diabetes is associated with longitudinal change in daily cortisol curve features. We hypothesized that the presence of type 2 diabetes may lead to a more blunted and abnormal HPA axis profile over time, suggestive of increased HPA axis dysregulation. This was a longitudinal cohort study, including 580 community-dwelling individuals (mean age 63.7 ± 9.1 years; 52.8 % women) with (n = 90) and without (n = 490) type 2 diabetes who attended two MultiEthnic Study of Atherosclerosis Stress ancillary study exams separated by 6 years. Outcome measures that were collected were wake-up and bedtime cortisol, cortisol awakening response (CAR), total area under the curve (AUC), and early, late, and overall decline slopes. In univariate analyses, wake-up and AUC increased over 6 years more in persons with as compared to those without type 2 diabetes (11 vs. 7 % increase for wake-up and 17 vs. 11 % for AUC). The early decline slope became flatter over time with a greater flattening observed in diabetic compared to non-diabetic individuals (23 vs. 9 % flatter); however, the change was only statistically significant for wake-up cortisol (p-value: 0.03). Over time, while CAR was reduced more, late decline and overall decline became flatter, and bedtime cortisol increased less in those with as compared to those without type 2 diabetes, none of these changes were statistically significant in adjusted models. We did not identify any statistically significant change in cortisol curve features over 6 years by type 2 diabetes status.


Assuntos
Ritmo Circadiano/fisiologia , Diabetes Mellitus Tipo 2/fisiopatologia , Hidrocortisona/análise , Saliva/química , Idoso , Estudos Transversais , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/fisiopatologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Sistema Hipófise-Suprarrenal/fisiopatologia
19.
J Clin Endocrinol Metab ; 101(4): 1770-8, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26908112

RESUMO

CONTEXT: Previous research has suggested that activation of the renin-angiotensin-aldosterone system may promote insulin resistance and ß-cell dysfunction, but the association with incident diabetes in African Americans is unknown. OBJECTIVE: We examined the association of aldosterone and renin with insulin resistance, ß-cell function, and incident diabetes in a large African American cohort. DESIGN: The Jackson Heart Study is a prospective study of the development and progression of cardiovascular disease in African Americans. SETTING: Participants were recruited from the tricounty area of metropolitan Jackson, Mississippi. PARTICIPANTS: A total of 5301 African American adults, aged 21­94 years, were assessed at baseline and through 12 years of follow-up. Data on aldosterone, renin, and risk factors were collected at baseline (2000­2004). Diabetes (fasting glucose ≥ 126 mg/dL, physician diagnosis, use of diabetes drugs, or glycated hemoglobin ≥ 6.5%) was assessed at baseline and through 12 years of follow-up. Participants were excluded for missing data on baseline covariates or diabetes follow-up. Cox regression was used to estimate hazard ratios (HR) for incident diabetes using sequential modeling adjusting for age, sex, education, occupation, systolic blood pressure, current smoking, physical activity, dietary intake, and body mass index. EXPOSURES: Aldosterone, renin, and diabetes risk factors were measured. OUTCOME: Outcomes included the homeostatic model assessment of insulin resistance (HOMA-IR) and incident diabetes. RESULTS: Among 3234 participants over a median of 8.0 years of follow-up, there were 554 cases of incident diabetes. Every 1% increase in log-transformed aldosterone was associated with a 0.18% higher log-transformed HOMA-IR in cross-sectional analyses of nondiabetic participants (P < .001). Log-transformed aldosterone and renin levels in the fifth vs first quintile were associated with a 78% (HR 1.78, 95% confidence interval 1.35­2.34) and 35% (HR 1.35, 95% confidence interval 1.06­1.72) increase in diabetes risk, respectively, in fully adjusted models. CONCLUSIONS: Activation of the renin-angiotensin-aldosterone system may play a significant role in the development of insulin resistance and diabetes in African Americans.


Assuntos
Aldosterona/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Resistência à Insulina/fisiologia , Células Secretoras de Insulina/fisiologia , Sistema Renina-Angiotensina/fisiologia , Renina/sangue , Adulto , Afro-Americanos , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea/fisiologia , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Hemoglobina A Glicada/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto Jovem
20.
Am J Epidemiol ; 183(5): 497-506, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26905339

RESUMO

Evidence of the link between job strain and cortisol levels has been inconsistent. This could be due to failure to account for cortisol variability leading to underestimated standard errors. Our objective was to model the relationship between job strain and the whole cortisol curve, accounting for sources of cortisol variability. Our functional mixed-model approach incorporated all available data-18 samples over 3 days-and uncertainty in estimated relationships. We used employed participants from the Multi-Ethnic Study of Atherosclerosis Stress I Study and data collected between 2002 and 2006. We used propensity score matching on an extensive set of variables to control for sources of confounding. We found that job strain was associated with lower salivary cortisol levels and lower total area under the curve. We found no relationship between job strain and the cortisol awakening response. Our findings differed from those of several previous studies. It is plausible that our results were unique to middle- to older-aged racially, ethnically, and occupationally diverse adults and were therefore not inconsistent with previous research among younger, mostly white samples. However, it is also plausible that previous findings were influenced by residual confounding and failure to propagate uncertainty (i.e., account for the multiple sources of variability) in estimating cortisol features.


Assuntos
Ritmo Circadiano/fisiologia , Hidrocortisona/metabolismo , Doenças Profissionais/metabolismo , Estresse Psicológico/metabolismo , Carga de Trabalho/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Grupos Étnicos/psicologia , Grupos Étnicos/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Profissionais/psicologia , Pontuação de Propensão , Saliva/metabolismo , Estresse Psicológico/etiologia , Vigília/fisiologia
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