Browsing by Subject "Cortisol"

Now showing 1 - 6 of 6
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    Application of Pharmacometrics to Rare Diseases
    (2016-10) Ahmed, Mariam
    Rare diseases affect an estimated 600–700 million people across the globe and are often chronic, progressive, degenerative, and life threatening.  In United States, there are more than 7,000 known rare diseases, of which less than 5% are treatable with approximately 550 approved orphan drugs. Drug development for rare disease possesses several layers of challenges. Pharmacometrics represents an attractive tool during orphan drug development as it provides a way to integrate knowledge about the disease and its treatment in a quantitative framework. These models can be utilized to optimize clinical trial designs for evaluation of treatments under development. X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder, most commonly affecting boys, associated with increased very long chain fatty acids (C26:0) in all tissues, causing cerebral demyelination and adrenocortical insufficiency. Certain monounsaturated long-chain fatty acids including oleic and erucic acids, known as Lorenzo's oil (LO), lower plasma C26:0 levels. We characterized the effect of LO administration on plasma C26:0 concentrations and determined whether there is an association between plasma concentrations of erucic acid or C26:0 and the likelihood of developing brain MRI abnormalities in asymptomatic boys. Non-linear mixed effects modelling was performed on 2384 samples that were collected during an open label single arm trial. The subjects (n = 104) were administered LO daily at ~2–3 mg/ kg with a mean follow-up of 4.88 ± 2.76 years. The effect of erucic acid exposure on plasma C26:0 concentrations was characterized by an inhibitory fractional Emax model. A Weibull model was used to characterize the time-to-developing MRI abnormality. The population estimate for the fractional maximum reduction of C26:0 plasma concentrations was 0.76 (bootstrap 95% CI 0.73, 0.79). Our time-to-event analyses showed that every mg/L increase in time-weighted average of erucic acid and C26:0 plasma concentrations was, respectively, associated with a 3.7% reduction and a 753% increase in the hazard of developing MRI abnormality. However, the results were not significant (P = 0.5344, 0.1509, respectively). Congenital adrenal hyperplasia (CAH) is a form of adrenal insufficiency characterized by impaired cortisol synthesis. Replacement with oral hydrocortisone (HC) does somewhat correct the resulting over-production of adrenal androgens, but significant medical problems follow these children into adulthood. To better understand dosing requirements, population pharmacokinetics of cortisol was characterized in children with CAH. Children with CAH (n=48; median [range] age and weight were: 7.1 years [1.47-18.2 years] and 29.3 kg [10.8-80.6 kg], respectively) receiving oral HC, had 12 serum samples obtained over 6 hours starting at 0800 h. Nonlinear mixed-effect modeling assuming a one-compartment model and allometric scaling was used for data analysis. The model included information on circadian rhythm from historical data to allow simulation of 24-h profiles of cortisol. Effects of disease phenotype, formulation type, pubertal stage, and sex on cortisol disposition were examined. Clearance (CL/F) and volume of distribution (V/F) were: 21.7.(WT/70)3/4 L/h and 37.6.(WT/70) L, respectively, and a resulting half-life of 0.896 hr. The bioavailability of the suspension was comparable to tablet formulation (99.6% relative to the tablet formulation). Our model-based simulations suggest many children with CAH are exposed to prolonged periods of hypocortisolemia and hyperandrogenemia over 24 hours with current hydrocortisone dosage regimens.
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    Context, cortisol, and executive functions among children experiencing homelessness.
    (2011-08) Cutuli, Joseph J.
    Homelessness represents a context of risk for child development. Yet, many homeless children show good develop outcomes, nonetheless. The processes of risk and resilience that contribute to this variability involve adaptive systems impacted by factors across levels of analysis, such as cortisol and physiology, executive functions (EF) and other aspects of psychological functioning, and parenting behavior and the family context. This study employs a resilience framework that is grounded in developmental-ecological theory and recognizes factors at multiple levels of analysis. The goal is to elucidate explanatory models of the processes of risk and resilience by incorporating relationships with cortisol, a component of physiological adaptive systems related to the stress response, self-regulation, and other functions. Families in this study were all staying in an emergency homeless shelter and contained a child entering kindergarten or first grade. Children were separated from caregivers and completed a session of cognitive tasks that assessed executive functions and other abilities, followed by a session of parent-child interaction tasks. Saliva samples were collected throughout both sessions and assayed for cortisol concentrations. Parents reported on risk factors and stressful negative life events for each child. Initial levels of child cortisol were negatively related to EF, affirming a proposed inverted-U relationship between cortisol and cognition among this sample of high-risk children. Higher rates of stressful, negative life events were not related to cortisol, nor was positive parenting behavior. However, harsh, hostile, and insensitive parenting behaviors were related to higher levels of child cortisol, but only during the session when parent and child were together. There were no differences based on variables of interested when it came to changes in cortisol over either session. Results are discussed with respect to proposed mechanisms of the interface between cortisol, parenting and EF at different levels of analysis in the context of high developmental risk.
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    The Effects of Child Maltreatment, Genetic Factors, and HPA Axis Functioning on Internalizing Symptoms in African American Children: A Moderated Mediation Model
    (2017-08) VanZomeren, Adrienne
    Child maltreatment is a potent relational pathogen that alters functioning across diverse developmental domains, and has been shown to increase risk for a host of mental health problems, including internalizing disorders. Similarities in the neuroendocrine profiles of individuals who develop internalizing symptoms and individuals who have been maltreated are striking, and suggest a role of neuroendocrine functioning, specifically the hypothalamic-pituitary-adrenal (HPA) axis, in the pathogenesis of internalizing disorders following child maltreatment. Risk and protective genetic factors, particularly relevant to HPA axis functioning, have been discovered, further highlighting involvement of the HPA axis and offering ideas about how some maltreated children may evade the biological impact of maltreatment. There has been movement in the field toward identifying mediators and moderators at multiple levels of analysis to best inform developmental mechanisms, which may ultimately aid in the treatment and prevention of deleterious outcomes following child maltreatment. Utilizing a large, ethnically homogenous sample, the current study employed exploratory and confirmatory factor analysis and structural equation modeling to examine associations among child maltreatment, risk across multiple HPA-related genes, daytime cortisol patterns, and internalizing symptoms in effort to clarify biological mechanisms. Results revealed that experiences of maltreatment prior to age 5 were most predictive of internalizing symptoms in African American youth, whereas maltreatment occurring at or after age 5 was most predictive of HPA axis dysregulation in the form of blunted diurnal decrease of cortisol. Genetic factors did not alter the relationship between maltreatment and cortisol, nor were genetic risk patterns reflected in HPA functioning. There was no mediation of the relationship between maltreatment and internalizing symptoms by HPA dysfunction. Results are interpreted through a developmental psychopathology lens, emphasizing the principle of equifinality, whereby children follow multiple pathways toward internalizing symptoms. Implications for future research, particularly the need for longitudinal studies in this area, are discussed.
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    The impacts of social support and early life stress on stress reactivity in children and adolescents
    (2013-08) Hostinar, Camelia Elena
    The goal of the present study was to investigate the impacts of social support and early life stress on individual differences in HPA axis reactivity in children (ages 9-10) and adolescents (ages 15-16). The primary aims were: 1) to experimentally manipulate the provision of social support in the laboratory and examine its effect on levels of salivary cortisol in response to the Trier Social Stress Test for Children; 2) to investigate parenting quality variables that may moderate the social buffering effect based on coding of videotaped parent-child interactions; 3) to analyze the role of early life stress (orphanage-rearing versus birth family rearing) and current social network characteristics in predicting the cortisol response; and 4) to explore age and sex differences in stress reactivity and the social buffering of stress. A sample of 162 participants was recruited, roughly equally divided between the two age groups, experimental conditions (half were exposed to a parent support condition before the stress task, whereas half received support from a stranger), early life experience (adopted or non-adopted) and by gender. Analyses of cortisol stress responses revealed that in the non-adopted group parent support provided in the laboratory significantly dampened stress reactivity in children but not in adolescents when compared to the stranger support condition. Additionally, participants reared in orphanages showed atypical patterns of HPA reactivity and of responses to social support provided before the stressor. Implications and future directions are discussed.
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    Interplay Between Frontolimbic Resting State Connectivity And Hypothalamic-Pituitary-Adrenal Axis Functioning In Adolescents With And Without Depression
    (2019-03) Thai, Michelle
    Depression is associated with abnormalities in HPA-axis functioning and neural circuitry that underlie the stress response. Although positive associations have been found between cortisol levels and amygdala metabolism, activation, and volume, the associations between cortisol and resting state functional connectivity (RSFC) has not been examined. RSFC captures intrinsic connections between brain regions that may set the stage for the rallying of the HPA system. The association between frontolimbic RSFC in particular and HPA axis functioning is critical since stress system functioning involves activating to and recovering from threat, processes mediated by limbic and prefrontal activity respectively. The purpose of this study was to examine the association between cortisol and frontolimbic RSFC in healthy controls and adolescents with depression. Overall, healthy controls tended to show positive correlations between frontolimbic connectivity and cortisol levels in the context of the TSST whereas patients with depression showed an inverse relationship. Positive association between neural and HPA stress systems in healthy controls may suggest coordinated upregulation and downregulation of these two stress systems in response to stress. In contrast, in patients with depression, excessive recruitment of the mPFC by the amygdala may interfere with HPA system recruitment efficiency and successful rallying of HPA axis in response to social stress. These findings provide evidence that the intrinsic quality of this frontolimbic channel is related to HPA axis functioning, and patients with MDD show different patterns of associations compared to HC, which may interfere with adaptive stress functioning.
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    The Study of Work-Related Stress among Law Enforcement Personnel
    (2022-03) Nam, Yoon-Sung
    Law enforcement has been extensively documented as one of the most stressful occupations [1]. With sudden disruptions due to the COVID-19 pandemic and the civil unrest following the murder of George Floyd in May 2020, new sources of stress (e.g., negative public interaction, risk of infection) have created unprecedented challenges for law enforcement. A large body of work has shown that the stressors experienced in law enforcement are associated with PTSD, suicidal ideation, and depression at a rate higher than the general population [2-12]. However, much of the current stress literature focuses on sworn officers and largely overlooks the growing non-sworn population. This represents a significant public health concern with more than 300,000 civilians working in a non-sworn position [13]. Despite the adverse impacts of stress being well-described among sworn officers, very little is known about the levels of stress within non-sworn personnel and how they compare to sworn officers [14, 15]. In addition to these knowledge gaps, work-related stress has largely been measured by surveys. While surveys provide valuable insight, they are subject to recall bias [16, 17]. Emerging research using cortisol has shown great promise in addressing survey limitations but remains mixed as to whether biomarkers correlate with stress. To address these knowledge gaps, this study used a mixed-methods approach to characterize work-related stress across two large urban Minnesota law enforcement departments. A total of 37 interviews explored novel stressors including barriers and facilitators to accessing mental health resources; 417 surveys quantified the prevalence of work-related stressors and PTSD among sworn and non-sworn personnel; 38 hair samples were collected to demonstrate the possibility of analyzing cortisol among a high-stressed occupation. The prevalence of PTSD symptomology was 24% among sworn and 39% among non-sworn personnel. Results indicated that mental health stigma was a perceived barrier to seeking help. Service providers familiar with law enforcement facilitated seeking help. Non-sworn respondents had lower organizational stress than sworn personnel. Responding to the civil unrest was particularly stressful for early-career non-sworn personnel. This study demonstrated the possibility of using hair samples in studies of stress within law enforcement.