Acute hemodynamic effects of norepinephrine inhibition in patients with severe chronic congestive heart failure

AbstractThe pathophysiologic role of high levels of circulating catecholamines in patients with congestive heart failure remains unclear. To assess the hemodynamic contribution of circulating catecholamines, metyrosine (alpha-methylp-tyrosine), an inhibitor of catecholamine synthesis, was administered to nine patients with acutely decompensated chronic congestive heart failure. Baseline left ventricular ejection fraction averaged 23.3 ± 9.9%, whereas cardiac output averaged 3.69 ± 1.03 liters/min, with a pulmonary wedge pressure of 27.4 ± 8.5 mm Hg.After 48 h of metyrosine administration, plasma norepinephrine concentration decreased from 919.4 ± 810.6 to 335.4 ± 143.1 pg/ml (p < 0.05). Plasma epinephrine concentration averaged 176.4 ± 166.0 pg/ml at baseline, and was unchanged during metyrosine administration. Despite the significant decrease in circulating norepinephrine, no significant hemodynamic changes were observed during metyrosine administration.These results suggest that high levels of circulating norepinephrine may be more a marker of severe congestive heart failure than an important contributor to the underlying pathophysiology at this advanced stage of the disease process

Adverse childhood experiences and deleterious outcomes in adulthood: A consideration of the simultaneous role of genetic and environmental influences in two independent samples from the United States

Background Adverse childhood experiences (ACEs) are a potent risk factor. Despite these findings, studies have also recognized the importance of considering additional sources of genetic and environmental influence that cluster within families. Objective To properly control for latent sources of genetic and within-family environmental influences and isolate the association between ACEs and the following outcomes in adulthood: physical health, depressive symptoms, educational attainment, income attainment, alcohol problems, and antisocial behavior. Participants and Setting Two independent samples of twins and siblings from the United States: the Midlife Development in the United States (MIDUS) study (N = 862) and the National Longitudinal Study of Adolescent to Adult Health (Add Health; N = 3112). Methods Sibling comparison models, which control for latent sources of genetic and within-family environmental influences, were estimated to examine whether differential exposure to ACEs was associated with the examined outcomes. Results Families that experienced more adversity also experienced more deleterious outcomes. However, siblings that experienced more adversity were no more likely to experience deleterious outcomes than their co-siblings. However, greater exposure to ACEs was associated with increases in depressive symptoms (Add Health). Additional models revealed that the similarity between siblings from the same family stemmed from latent sources of within-family environmental influences not captured by traditional ACEs measures. Conclusions Considering genetic influences and additional latent sources of within-family influences is crucial in isolating the effects of ACEs. Currently employed ACEs measures may not adequately capture the full range of impactful sources of family-level environmental influence

Comparison of Outcomes between Endoscopic and Transcleral Cyclophotocoagulation.

Importance: Traditionally cyclophotocoagulation has been reserved as a treatment of last resort for eyes with advanced stage glaucoma, but increasingly it is offered to eyes with less severe disease. Endoscopic approaches in particular are utilized in increasing numbers of patients despite only a small number of publications on its results. Objective: The purpose of this study was to compare the efficacy and safety of endoscopic and transcleral cyclophotocoagulation (ECP and TCP) procedures in eyes with refractory glaucomas. Design, Setting, and Participants: A chart review was performed on consecutive patients who underwent ECP and TCP at a tertiary ophthalmology care center between January 2000 and December 2010. Cases with fewer than 3 months of follow-up or that had concurrent pressure reducing procedures were excluded. The main outcome measures examined were intraocular pressure (IOP), number of glaucoma medications, best corrected visual acuity (BCVA), additional glaucoma procedure required, and complications. Main Outcomes and Measures: Forty-two eyes (42 patients) that underwent ECP and forty-four eyes (44 patients) that underwent TCP were identified. The TCP group had a statistically higher mean age (71.2 ± 16.7 vs. 58.1 ± 22.9 years, respectively), larger proportion of neovascular glaucoma (40.9% vs. 16.7%), worse initial BCVA (logMAR 2.86 vs. 1.81), and higher preoperative IOP (45.3 vs. 26.6 mmHg) than the ECP group. At 12 months follow-up, the mean IOP difference between groups was not statistically significant, although the change in IOP from baseline to 12 months was greater for the TCP group (p = 0.006). The rates of progression to no light perception (NLP) and phthisis bulbi were significantly higher amongst TCP eyes than ECP eyes (27.2% vs. 4.8%, p = 0.017, and 20.5% vs. 0%, p = 0.003, respectively). Of these eyes that progressed, a majority had neovascular glaucoma (NVG). Corneal decompensation was the most frequent complication following ECP (11.9%). Conclusions and Relevance: In patients with preoperative BCVA of 20/400 or better, overall complication rates (cystoid macular edema, exudative retinal detachment, inflammation, cornea decompensation) were higher after ECP than with TCP. In refractory glaucomas in a real world setting (not a trial), TCP was more frequently used in ischemic eyes. TCP was associated with a higher rate of progression to phthisis bulbi and loss of light perception than ECP. However, ECP was associated with a clinically significant rate of corneal decompensation. These outcomes likely were related to the severity of underlying ocular diseases found in these eyes

Regulation of Reactive Oxygen Species and the Antioxidant Protein DJ-1 in Mastocytosis

Neoplastic accumulation of mast cells in systemic mastocytosis (SM) associates with activating mutations in the receptor tyrosine kinase KIT. Constitutive activation of tyrosine kinase oncogenes has been linked to imbalances in oxidant/antioxidant mechanisms in other myeloproliferative disorders. However, the impact of KIT mutations on the redox status in SM and the potential therapeutic implications are not well understood. Here, we examined the regulation of reactive oxygen species (ROS) and of the antioxidant protein DJ-1 (PARK-7), which increases with cancer progression and acts to lessen oxidative damage to malignant cells, in relationship with SM severity. ROS levels were increased in both indolent (ISM) and aggressive variants of the disease (ASM). However, while DJ-1 levels were reduced in ISM with lower mast cell burden, they rose in ISM with higher mast cell burden and were significantly elevated in patients with ASM. Studies on mast cell lines revealed that activating KIT mutations induced constant ROS production and consequent DJ-1 oxidation and degradation that could explain the reduced levels of DJ-1 in the ISM population, while IL-6, a cytokine that increases with disease severity, caused a counteracting transcriptional induction of DJ-1 which would protect malignant mast cells from oxidative damage. A mouse model of mastocytosis recapitulated the biphasic changes in DJ-1 and the escalating IL-6, ROS and DJ-1 levels as mast cells accumulate, findings which were reversed with anti-IL-6 receptor blocking antibody. Our findings provide evidence of increased ROS and a biphasic regulation of the antioxidant DJ-1 in variants of SM and implicate IL-6 in DJ-1 induction and expansion of mast cells with KIT mutations. We propose consideration of IL-6 blockade as a potential adjunctive therapy in the treatment of patients with advanced mastocytosis, as it would reduce DJ-1 levels making mutation-positive mast cells vulnerable to oxidative damage

Temporal trends in symptom experience predict the accuracy of recall PROs

Objective - Patient-reported outcome measures with reporting periods of a week or more are often used to evaluate the change of symptoms over time, but the accuracy of recall in the context of change is not well understood. This study examined whether temporal trends in symptoms that occur during the reporting period impact the accuracy of 7-day recall reports. Methods - Women with premenstrual symptoms (n = 95) completed daily reports of anger, depression, fatigue, and pain intensity for 4 weeks, as well as 7-day recall reports at the end of each week. Latent class growth analysis was used to categorize recall periods based on the direction and rate of change in the daily reports. Agreement (level differences and correlations) between 7-day recall and aggregated daily scores was compared for recall periods with different temporal trends. Results - Recall periods with positive, negative, and flat temporal trends were identified and they varied in accordance with weeks of the menstrual cycle. Replicating previous research, 7-day recall scores were consistently higher than aggregated daily scores, but this level difference was more pronounced for recall periods involving positive and negative trends compared with flat trends. Moreover, correlations between 7-day recall and aggregated daily scores were lower in the presence of positive and negative trends compared with flat trends. These findings were largely consistent for anger, depression, fatigue, and pain intensity. Conclusion - Temporal trends in symptoms can influence the accuracy of recall reports and this should be considered in research designs involving change

A Quantitative Genetic Analysis of the Associations Among Language Skills, Peer Interactions, and Behavioral Problems in Childhood: Results From a Sample of Twins

A body of empirical research has revealed that there are associations among language skills, peer interactions, and behavioral problems in childhood. At the same time, however, there has been comparatively less research devoted to exploring the mutual unfolding of these factors over the first few years of life. The current study is designed to partially address this gap in the literature by examining how language skills, negative peer interactions, and behavioral problems are interrelated in a sample of twins drawn from the Early Childhood Longitudinal Study–Birth Cohort (ECLS-B). Employing a quantitative genetic framework, the results of the current study revealed that variance in language skills, negative peer interactions, and externalizing behavioral problems were all due to a combination of genetic and environmental factors. Bivariate Cholesky models indicated that most of the covariance among language skills, negative peer interactions, and externalizing behavioral problems was due to common genetic factors. Additional analyses using a modified DeFries–Fulker approach nested within a path model revealed a bidirectional association between negative peer interactions and externalizing behavioral problems, wherein there appeared to be feedback loops between the two. Implications of the results are discussed and avenues for future research are offered

Psychometric characteristics of daily diaries for the Patient-Reported Outcomes Measurement Information System (PROMIS®): a preliminary investigation

Purpose - The Patient-Reported Outcomes (PRO) Measurement Information System (PROMIS®) has developed assessment tools for numerous PROs, most using a 7-day recall format. We examined whether modifying the recall period for use in daily diary research would affect the psychometric characteristics of several PROMIS measures. Methods - Daily versions of short-forms for three PROMIS domains (pain interference, fatigue, depression) were administered to a general population sample (n = 100) for 28 days. Analyses used multilevel item response theory (IRT) models. We examined differential item functioning (DIF) across recall periods by comparing the IRT parameters from the daily data with the PROMIS 7-day recall IRT parameters. Additionally, we examined whether the IRT parameters for day-to-day within-person changes are invariant to those for between-person (cross-sectional) differences in PROs. Results - Dimensionality analyses of the daily data suggested a single dimension for each PRO domain, consistent with PROMIS instruments. One-third of the daily items showed uniform DIF when compared with PROMIS 7-day recall, but the impact of DIF on the scale level was minor. IRT parameters for within-person changes differed from between-person parameters for 3 depression items, which were more sensitive for measuring change than between-person differences, but not for pain interference and fatigue items. Notably, mean scores from daily diaries were significantly lower than the PROMIS 7-day recall norms. Conclusions - The results provide initial evidence supporting the adaptation of PROMIS measures for daily diary research. However, scores from daily diaries cannot be directly interpreted on PROMIS norms established for 7-day recall

Proposing a Pedigree Risk Measurement Strategy: Capturing the Intergenerational Transmission of Antisocial Behavior in a Nationally Representative Sample of Adults

An impressive literature has revealed that variation in virtually every measurable phenotype is the result of a combination of genetic and environmental influences. Based on these findings, studies that fail to use genetically informed modeling strategies risk model misspecification and biased parameter estimates. Twin- and adoption-based research designs have frequently been used to overcome this limitation. Despite the many advantages of such approaches, many available datasets do not contain samples of twins, siblings or adoptees, making it impossible to utilize these modeling strategies. The current study proposes a measurement strategy for estimating the intergenerational transmission of antisocial behavior (ASB) within a nationally representative sample of singletons using an extended pedigree risk approach that relies on information from first- and second-degree relatives. An evaluation of this approach revealed a pattern of findings that directly aligned with studies examining ASB using more traditional twin- and adoption-based research designs. While the proposed pedigree risk approach is not capable of effectively isolating genetic and environmental influences, this overall alignment in results provides tentative evidence suggesting that the proposed pedigree risk measure effectively captures genetic influences. Future replication studies are necessary as this observation remains preliminary. Whenever possible, more traditional quantitative genetic methodologies should be favored, but the presented strategy remains a viable alternative for more limited samples

Long-term Outcomes of Enhanced Depression Treatment in Patients with Acute Coronary Syndromes

Background: The Coronary Psychosocial Evaluation Studies trial demonstrated promising results for enhanced depression treatment to reduce cardiovascular risk of patients with acute coronary syndrome and comorbid depression, but the long-term effectiveness of this intervention is unclear. Methods: A total of 157 participants with persistent depression after hospitalization for acute coronary syndromes were enrolled in the Coronary Psychosocial Evaluation Studies trial. A total of 80 participants were allocated to 6 months of enhanced depression treatment, and 77 participants were allocated to usual care. We report on an additional 12 months of observational follow-up for the composite outcome of death or first hospitalization for myocardial infarction or unstable angina. Results: Although the intervention was previously shown to have favorable cardiovascular effects during the treatment period, we observed a significant time-by-treatment group interaction during extended follow-up (P = .008). Specifically, during the 6-month treatment period, death or hospitalization for myocardial infarction/unstable angina occurred in 3 participants (4%) in the treatment group compared with 11 participants (14%) in the usual care group (hazard ratio, 0.25; 95% confidence interval, 0.07-0.90; P = .03). In contrast, during 12 months of additional observational follow-up, 11 participants (14%) in the treatment group experienced the composite outcome of death or hospitalization for myocardial infarction/unstable angina compared with 3 participants (4%) in the usual care group (hazard ratio, 2.91; 95% confidence interval, 0.80-10.56; P = .10). Conclusions: Enhanced depression treatment was associated with a reduced risk of death or hospitalization for myocardial infarction/unstable angina during active treatment, but this effect did not persist after treatment ceased. Future research is needed to confirm our findings and to determine the optimal duration of depression treatment in patients with depression after acute coronary syndromes