Palliative Care for Pediatric Urology.

Palliative care in the field of urology has largely been limited to adult oncologic conditions. Although there is a plethora of established literature suggesting the advantageous impact of palliative care, there is limited integration of palliative care in adult urology. This underutilization is further exacerbated in pediatric urology, and palliative care in pediatric urology remains an underexplored area despite the prevalence of several life-limiting conditions in this patient population. This paper highlights the potential need for palliative care intervention in a variety of urologic conditions in the pediatric population, including congenital lower urinary tract obstruction, neurogenic bladder dysfunction, exstrophy-epispadias complex, and congenital bilateral renal agenesis. Each condition poses unique challenges that can be addressed with the inclusion of a palliative care team, including decision-making spanning prenatal-neonatal-pediatric periods, acute and chronic symptom management, family relations, body image issues, risk of recurrent hospitalizations and surgeries, and potentially fatal complications. Alongside standard urologic interventions, palliative care can serve as an additional means of addressing physical and psychosocial symptoms experienced by pediatric urology patients to enhance the quality of life of patients and their families.

Plasma and cerebrospinal fluid inflammatory markers and human aggression.

A growing body of work suggests that individuals with aggressive behavior and/or aggressive tendencies have evidence of chronic, low level, inflammation as manifested by elevated circulating levels of acute phase reactant proteins and pro-inflammatory cytokines. While animal studies report that direct application of pro-inflammatory proteins in brain increase aggressive behavior, there is no data on the relationship of central levels of these proteins and aggression in human subjects. We simultaneously measured levels of both plasma and lumbar cerebrospinal fluid (CSF) C-Reactive Protein (CRP) and IL-6, IL-8, and TNF-α in 77 medically healthy, drug-free, individuals with varying degrees of aggression including 22 individuals with DSM-5 Intermittent Explosive Disorder (IED). Aggression was assessed using the Life History of Aggression (LHA) and the Buss-Perry Aggression Questionnaire (BPAQ). Plasma and CSF levels of CRP, IL-8, and TNF-α, but not IL-6, correlated significantly with each other. Aggressive individuals with IED displayed elevated plasma, but not CSF, levels of proinflammatory markers and this relationship was specific to IED. Similarly, composite aggression scores correlated significantly with plasma, but not CSF, pro-inflammatory markers. Aggressive behavior in humans is correlated with Plasma, but not CSF, proinflammatory markers despite the observation that these two sets of markers are significantly correlated. Since the direct application of proinflammatory proteins in brains of animals increase aggressive behavior, proinflammatory proteins likely influence brain-based behavior in a manner not reflected in lumbar CSF.

Associations of agression and use of caffeine, alcohol and nicotine in healthy and aggressive individuals.

BACKGROUND: Caffeine, alcohol, and nicotine are the three most commonly used psychoactive substances in the world. Given the known propensity of these substances to influence behavior, the relationship between these substances and aggressive and impulsive behaviors, in particular is of interest. METHODS: 1062 adult individuals participated in this study including those with Intermittent Explosive Disorder (IED) and non-aggressive healthy (HC) and psychiatric (PC) controls. Data regarding current and life use of caffeine, alcohol, and nicotine were recorded as were responses on measures of aggression, anger, and impulsivity. RESULTS: Dimensional measures of aggression, anger, and impulsiveness were variably but significantly related to the consumption of these commonly used psychoactive substances. These findings were generally mirrored when using the categorical construct of IED. Finally, these findings were not due to comorbidity with other psychiatric disorders. CONCLUSIONS: These data confirm a link between these externalizing behaviors and these three legal and commonly consumed psychoactive substances in clinically relevant individuals.

Narcissistic and Borderline Personality Disorders: Relationship With Oxidative Stress.

The authors hypothesized that personality disorders characterized by interpersonal hypersensitivity would be associated with an elevated concentration of 8-hydroxy-2'-deoxyguanosine (8-OH-DG), the oxidized form of guanine, and a biomarker of oxidative stress burden. One hundred ninety-five male and female adults underwent semistructured diagnostic interviews, completed questionnaire measures of social cognition and emotional attribution, and had blood drawn for determination of plasma 8-OH-DG. A hierarchical linear regression model revealed that narcissistic and borderline personality disorders predicted 8-OH-DG level independently of the effects of age, gender, recent alcohol and cigarette use, current major depression, and posttraumatic stress disorder. In all subjects, 8-OH-DG level was also correlated with the number of borderline personality disorder symptoms present. Narcissistic and borderline personality disorders predicted oxidative stress burden independently of potentially confounding factors.

Effects of Intranasal Oxytocin on Stress-Induced Cigarette Craving in Daily Smokers.

BACKGROUND: Cigarette smoking is a well-known public health concern, and there is an urgent need to develop new treatments to reduce smoking or facilitate abstinence. One factor that is known to contribute to relapse is stress, making the stress response an important target for treatment. The neuropeptide oxytocin (OT) is believed to have stress-reducing effects, and in addition there is evidence that it reduces drug craving. The purpose of the present study was to examine the effects of intranasal OT on stress-induced cigarette craving in regular smokers after 12 h of abstinence. METHOD: Daily smokers (n = 48) completed a stress induction task and a nonstressful control task at two different sessions, receiving intranasal OT (40 IU) or placebo (PBO) before or after the task. Subjects were randomly assigned to one of three groups: Group PP (n = 16) received PBO before and after the stress/control tasks, Group OP (n = 16) received OT before the tasks and PBO after, and Group PO (n = 16) received PBO before the tasks and OT shortly after completing the tasks. Cigarette craving as well as subjective and physiological responses to stress was assessed. RESULTS: OT did not alter responses to stress, whether it was administered before or after the stressful task, on measures of cigarette craving, anxiety, heart rate, blood pressure, and cortisol levels. CONCLUSIONS: The current study findings do not support several previous reports that OT reduced either stress or drug craving. IMPLICATIONS: This study finds a null result of the neuropeptide oxytocin on stress-induced cigarette craving. Reporting null findings is part of the process of identifying potential treatments for addictive disorders.

Oxytocin Reduces Cigarette Consumption in Daily Smokers.

INTRODUCTION: Despite widespread knowledge of the dangers of cigarette consumption, smoking continues to be a public health concern. One compound that has shown potential for treatment in preclinical models is the neuropeptide oxytocin (OT). The purpose of the present study was to examine the effects of intranasal oxytocin on cigarette craving, behavioral economic demand for cigarettes, and cigarette consumption, in regular smokers after 18 hours of abstinence. METHOD: Otherwise healthy daily smokers (n = 35) completed two sessions where they received OT (40 IU intranasal) or placebo (PBO) and completed measures of craving and cigarette demand, and they were given six opportunities to smoke partial cigarettes in exchange for money. RESULTS: On average participants smoked few cigarettes after receiving OT than after receiving PBO, and they reported less desire for additional cigarettes during the smoking period. OT did not affect cigarette demand or standardized measures of cigarette craving. CONCLUSIONS: This study suggests that OT decreases some indices of smoking desire and consumption, providing modest support for the idea that OT might be effective for reducing cigarette smoking. IMPLICATIONS: This study provides new evidence that oxytocin might have clinical value in the treatment of addictive disorders, in this case tobacco addiction. The study adds to a growing literature suggesting that this neuropeptide, which is mainly known for its role in social bonding and attachment, may also affect mood and motivational states relevant to addiction.

Intermittent Explosive Disorder and Substance Use Disorder: Analysis of the National Comorbidity Survey Replication Sample.

OBJECTIVE: A relationship between aggression and substance use has been debated for many years. While substance use increases the risk of aggressive behavior, no studies have reported on the relationship between impulsive aggression and substance use/disorder, specifically. METHODS: We analyzed data from the community-based National Comorbidity Survey Replication (N = 9,282 subjects) in order to examine the relationship between current DSM-5 intermittent explosive disorder (IED), a disorder of impulsive aggression, and current substance use disorders (SUDs), overall, and with regard to alcohol, tobacco, and cannabis use disorders and nondisordered use. RESULTS: Occurrence of current SUD was elevated in current IED versus non-IED adult subjects, and onset of IED preceded that of SUD in 92.5% of comorbid IED + SUD cases. This relationship was not due to the presence, or absence, of current depressive or anxiety disorders. Examination of the severity of IED and of SUD revealed that the presence of IED increases SUD severity but that the presence of SUD does not increase IED severity. CONCLUSIONS: Subjects with IED are at increased risk of developing SUD, compared with those without IED. This suggests that history of recurrent, problematic, impulsive aggression is a risk factor for the later development of SUD rather than the reverse. If so, effective treatment of impulsive aggression, before the onset of substance misuse, may prevent, or delay, the development of SUD in young people.

Intranasal oxytocin dampens cue-elicited cigarette craving in daily smokers: a pilot study.

Despite moderate success with pharmacological and behavioral treatments, smoking relapse rates remain high, and many smokers report that smoking cues lead to relapse. Therefore, treatments that target cue reactivity are needed. One candidate for reducing craving is the neuropeptide oxytocin (OT). Here, we investigated the effects of intranasal OT on two types of craving for cigarettes: craving following overnight abstinence and craving elicited by smoking-related cues. In this within-subject, placebo-controlled pilot study, smokers (N=17) abstained from smoking for 12 h before attending two sessions randomized to intranasal OT or placebo (i.e. saline nasal spray). On each session, participants received two doses of OT (20 IU) or placebo at 1-h intervals, and rated craving before and after each dose. Spontaneous cigarette craving was assessed after the first spray, and cue-elicited craving was assessed following the second spray. OT did not reduce levels of spontaneous craving after the first spray, but significantly dampened cue-induced smoking craving. These results provide preliminary evidence that OT can reduce cue-induced smoking craving in smokers. These findings provide an important link between preclinical and clinical studies aimed at examining the effectiveness of OT as a novel treatment for drug craving.

Tryptophan, kynurenine, and kynurenine metabolites: Relationship to lifetime aggression and inflammatory markers in human subjects.

Inflammatory proteins are thought to be causally involved in the generation of aggression, possibly due to direct effects of cytokines in the central nervous system and/or by generation of inflammatory metabolites along the tryptophan-kynurenine (TRP/KYN) pathway, including KYN and its active metabolites kynurenic acid (KA), quinolinic acid (QA), and picolinic acid (PA). We examined plasma levels of TRP, KYN, KA, QA, and PA in 172 medication-free, medically healthy, human subjects to determine if plasma levels of these substances are altered as a function of trait aggression, and if they correlate with current plasma levels of inflammatory markers. Plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), and soluble interleukin-1 receptor-II (sIL-1RII) protein were also available in these subjects. We found normal levels of TRP but reduced plasma levels of KYN (by 48%), QA (by 6%), and a QA/KA (by 5%) ratio in subjects with Intermittent Explosive Disorder (IED) compared to healthy controls and psychiatric controls. Moreover, the metabolites were not associated with any of the inflammatory markers studied. These data do not support the hypothesis that elevated levels of KYN metabolites would be present in plasma of subjects with IED, and associated with plasma inflammation. However, our data do point to a dysregulation of the KYN pathway metabolites in these subjects. Further work will be necessary to replicate these findings and to understand their role in inflammation and aggression in these subjects.

Childhood trauma and parental style: Relationship with markers of inflammation, oxidative stress, and aggression in healthy and personality disordered subjects.

Recent studies suggest that early life trauma is associated with elevations in circulating markers of inflammation in human subjects. History of aggression as a behavior, or aggression as a personality trait, is also associated with elevations of these inflammatory markers. Since early life trauma is associated with the development and maintenance of aggression in later life we examined the relationship of early life adversity, plasma inflammation markers (IL-6 and CRP) and oxidative stress markers (8-OH-DG and 8-ISO), and aggression in adult subjects with (n=79) and without (n=55) personality disorder. We used a series of mediated and moderated path models to test whether the effects of early adversity on later aggression may be mediated through markers of inflammation. Childhood abuse and parental control were associated with basal IL-6 and CRP concentrations. Path modeling suggested that childhood abuse was associated with aggression indirectly through CRP while parental control influenced aggression indirectly through IL-6 and CRP. Furthermore, these effects were independent of the effect of current depression. The results suggest that disruption of inflammatory processes represent one pathway by which early adversity influences aggression.

Inflammatory markers and chronic exposure to fluoxetine, divalproex, and placebo in intermittent explosive disorder.

Intermittent Explosive Disorder (IED) is a disorder of impulsive aggression affecting 4-7% of the U.S. population during some period of life. In addition to other biological correlates, elevations of plasma inflammatory markers have been reported in IED, compared with control, subjects. In this study we sought to explore if treatment exposure to anti-aggressive agents, compared with placebo, would be associated with a reduction in circulating levels of inflammatory markers. Thirty IED subjects, from a 12-week, double-blind, randomized, placebo-controlled trial of fluoxetine and divalproex, in which both pre- and post-treatment levels of C-Reactive Protein (CRP), interleukin (IL)-1ß, IL-2, IL-6, IL-8, IL-10 and tumor necrosis factor (TNF)-α were obtained. Efficacy measures included the Overt Aggression Scale-Modified (OAS-M) score for Aggression and for Irritability, rate of Clinical Global Impression of Improvement (CGI-I), and rate of IED Remitters at study completion. As compared to placebo, neither fluoxetine nor divalproex reduced any of the measures of aggression. In addition, levels of CRP and pro- and anti-inflammatory cytokines showed no changes from pre- to post-treatment for any treatment condition. Correlations between pre- and post- treatment plasma CRP/cytokines were substantial (mean r=0.71, r(2)=0.50, p<0.001). Overall, circulating markers of inflammation markers were unaffected by treatment with fluoxetine or divalproex, consistent with the absence of change in measures of impulsive aggression.

Cerebrospinal fluid inflammatory cytokines and aggression in personality disordered subjects.

BACKGROUND: Neurochemical studies have pointed to a modulatory role in human aggression for a variety of central neurotransmitters and neuromodulators such as cytokines. While animal studies of cytokines suggest an aggression-facilitating role for central cytokines, especially for interleukin-1ß and other cytokines, no cerebrospinal fluid studies of cytokines have yet been reported in regard to human aggression. METHODS: Basal lumbar cerebrospinal fluid samples were obtained from 38 physically healthy subjects with DSM-5 Personality Disorder and assayed for cerebrospinal fluid interleukin-6 (log IL-6) and cerebrospinal fluid soluble IL-1 Receptor II protein in the context of their relationship with measures of aggression. RESULTS: Cerebrospinal fluid soluble interleukin-1 Receptor II (r=.35, r(2) = .12, P= .03), but not log interleukin-6 (r = -.05, r(2) = .00, P= .76), levels were positively correlated with a composite measure of aggression. Adding relevant covariates, including cerebrospinal fluid levels of serotonin and dopamine metabolites, to the statistical model doubled the strength of this relationship (partial r = .54, r(2) = .29, P= .002). No relationship was seen with history of suicidal behavior or with any measure of impulsivity, negative affectivity, or of general dimensions of personality. CONCLUSION: These data suggest a positive relationship between at least one inflammatory cytokine in the central nervous system and aggression in human subjects. This finding adds to the complex picture of the central neurochemistry of impulsive aggression in human subjects.

Elevated plasma inflammatory markers in individuals with intermittent explosive disorder and correlation with aggression in humans.

IMPORTANCE: Neurochemical studies in human aggression point to a modulatory role for a variety of central neurotransmitters. Some of these neurotransmitters play an inhibitory role, while others play a facilitatory role modulating aggression. Preclinical studies suggest a facilitatory role for inflammatory markers in aggression. Despite this, to our knowledge, no studies of aggression and inflammatory markers have been reported in psychiatric patients or in individuals with recurrent, problematic, impulsive aggressive behavior. OBJECTIVE: To test the hypothesis that plasma inflammatory markers will correlate directly with aggression and will be elevated in individuals with recurrent, problematic, impulsive aggressive behavior. DESIGN, SETTING, AND PARTICIPANTS Case-control study in a clinical research program in impulsive aggressive behavior at an academic medical center. Participants were physically healthy individuals with intermittent explosive disorder (n = 69), nonaggressive individuals with Axis I and/or II disorders (n = 61), and nonaggressive individuals without history of an Axis I or II disorder (n = 67). MAIN OUTCOMES AND MEASURES: Plasma levels of C-reactive protein and interleukin 6 were examined in the context of measures of aggression and impulsivity and as a function of intermittent explosive disorder. RESULTS: Both plasma C-reactive protein and interleukin 6 levels were significantly higher in participants with intermittent explosive disorder compared with psychiatric or normal controls. In addition, both inflammatory markers were directly correlated with a composite measure of aggression and, more specifically, with measures reflecting history of actual aggressive behavior in all participants. CONCLUSIONS AND RELEVANCE: These data suggest a direct relationship between plasma inflammatory processes and aggression in humans. This finding adds to the complex picture of the central neuromodulatory role of aggression in humans.