As each reading block lasted 20 sec and contained a maximum of 30 irregular words or nonwords, the presentation rate did not exceed 90 irregular words or nonwords per minute. The order of the reading tasks (i.e., irregular words vs. nonwords) was counterbalanced across the 13 blocks in such a way that seven blocks began with irregular word reading

and six blocks with DNA PK inhibitor nonword reading. The order of the blocks was also counterbalanced across participants. Figure 1 depicts the design of one block. Figure 1 Time course for one of the 13 blocks beginning with irregular word reading. During the baseline and resting periods, Inhibitors,research,lifescience,medical participants were instructed to relax and minimize Inhibitors,research,lifescience,medical their thoughts while fixating a cross presented in central position on the computer screen. Individual reading

speed and number of errors were recorded. Nonwords were judged as correctly produced if the participant applied the spelling-to-sound correspondences in the French language. If a nonword had more than one acceptable pronunciation (e.g., acho can be pronounced [aʃo] or [ako]), both pronunciations Inhibitors,research,lifescience,medical were judged as correct. The total session duration was approximately 90 min, including the setup of the helmet, sources, detectors, and electrodes. Data acquisition Data were gathered with a rate of 19.5312 Hz using a 128-channel spectrometer Imagent Tissue Oxymeter (ISS Inc., Champaign, IL)

that included 55 sources and 16 detectors, and the software package Boxy (Photon Migration Inhibitors,research,lifescience,medical Imaging Lab, Massachusetts General Hospital, MA). Two wavelengths were used: 690 nm, sensitive to HbR concentration changes, and 830 nm, sensitive to HbO concentration changes. No detector saturation occurred during the experiment. The sources and the detectors were placed on the participant’s scalp using a custom-built, rigid but comfortable helmet allowing head movements and aloud verbalization. Hair around sources and detectors was parted to avoid interference with light emission and detection. Two different helmet sizes were used (57 and 59 Inhibitors,research,lifescience,medical cm) depending on the head circumference of the participants. A standard montage was created for each helmet using the click here software Brainsight™ Frameless 39 (Rogue Research, Canada). According to the International 10–20 system (Jasper 1958), sources and detectors were placed bilaterally over cerebral regions classically involved in reading processes: Broca and Wernicke areas, the left middle and superior temporal gyri, the left parietal gyrus, the left temporo-occipital region, the left visual cortex, and their right homologous regions. The source–detector distance varied from 2 to 5 cm. Figure 2 shows the regions covered by the montage. Figure 2 Layout of the 55 sources and 16 detectors over the left and right hemispheres used for all 12 participants.

Human mutations in SOD2 are thought to play a role in numerous human disease conditions including cancer, mitochondrial disease, cardiopathy, diabetic neuropathy, and neurodegeneration (Rosenblum et al. 1996; Valenti et al. 2004; Mollsten et al. 2007). Within the human SOD2 gene six mutations have been characterized: three mutations have been identified within promoter region that presumably reduce expression (Xu et al. 1999, 2007, 2008), one mutation affects the mitochondrial targeting of the enzyme (Rosenblum et al. 1996), and Inhibitors,research,lifescience,medical two missense mutations affect coding exon 3 (Borgstahl et al. 1996; Hernandez-Saavedra and McCord 2003). SOD2Ala16Val affects the MTS

and is associated with cardiomyopathy (Rosenblum et al. 1996; Valenti et al. 2004) Inhibitors,research,lifescience,medical and diabetic nephropathy (Mollsten et al. 2007). There has been significant work performed in model systems to understand the role of SOD2. In a murine model, mice lacking SOD2 (SOD2tm1Cje) develop dilated cardiomyopathy and neonatal lethality (Li et al. 1995); this same mutation in a different genetic background exhibits inhibition or inactivation of electron transport chain and other mitochondrial

enzymes, and results in the accumulation of oxidative DNA damage (Melov et al. 1999). In Drosophila, previous studies have shown that SOD2 Inhibitors,research,lifescience,medical RNAi and null mutations are associated with reduced longevity and neural dysfunction (Kirby et al. 2002; Duttaroy et al. 2003; Belton et al. 2006; Martin et al. 2009). Here,

we report a novel missense mutation affecting SOD2 in Drosophila that Inhibitors,research,lifescience,medical leads to reduced longevity, sensitivity to hyperoxia, progressive increased mitochondrial ROS accumulation, neurodegeneration, and abnormal brain morphology. Our data demonstrate aberrant axonal targeting that likely underlies the abnormal brain morphology. Importantly, in silico studies support the conclusion that this mutation does Inhibitors,research,lifescience,medical not result in a major structural change to the SOD2 protein, yet Endocrinology antagonist dramatic reductions in steady state protein levels result, suggesting a marked increase in protein turnover of this mutant mitochondrial protein. Materials and Methods enough Fly husbandry, life spans, and stress-sensitivity tests Flies were maintained on standard cornmeal, molasses food. Life spans and stress-sensitivity tests were performed at 25 and 29°C, as previously reported (Palladino et al. 2002, 2003; Celotto et al. 2006b; Fergestad et al. 2006b, 2008; Seigle et al. 2008). The SOD2 mutant reported here was initially studied in the lab of Dr. Barry Ganetzky at the University of Wisconsin Madison where it was known as “hr2” and was identified in our previous screen of conditional mutants (Palladino et al. 2002). The SOD2 deficiency line utilized is Df(2R)Exel7145 and was obtained from the Bloomington Stock Center. Western blot Four fly heads were homogenized in 60 μL ice-cold lysis buffer (50 mmol/L Tris pH 6.8, 10% glycerol, 2% SDS, 0.

Consequently, the EGCG and placebo groups were combined to determine whether there was an association between changes in psychiatric symptoms and cytokine production from week 0 to week 10. Supplementary Table

3 shows nonsignificant reductions for TNF-α, IFN-γ, IL-10, and IL-9 (5.5%, 17.8%, 23.1%, and 22.3%, respectively). Discussion This 8-week, double-blind, prospective study of daily EGCG supplementation versus placebo in patients with schizophrenia, schizoaffective disorder, or bipolar disorder did not find significant differences in the efficacy or tolerability between the two treatments. Both EGCG and placebo groups showed significant decreases in psychiatric symptoms over time. Inhibitors,research,lifescience,medical The reduction in psychiatric symptomology was accompanied by nonsignificant

decreases in the production of Th1, Th2, and Th9 cytokines. It is well known that obesity is a significant contributor Inhibitors,research,lifescience,medical to inflammation [Stienstra et al. 2012]. According to the Centers for Disease Control and Prevention, an adult who has a BMI between 25 and 29.9 is considered overweight, and an adult who has a BMI of 30 or higher is considered obese (see http://www.cdc.gov/obesity/adult/defining.html). Inhibitors,research,lifescience,medical Based on these criteria, the mean BMIs for both the placebo and EGCG groups were greater than 32, placing them in the obese category. Consequently, the degree of inflammation in our sample may have contributed to the lack of statistically significant Inhibitors,research,lifescience,medical reductions in cytokine levels from Selleck Idarubicin baseline to week 10. Although we did not find significant treatment differences between EGCG and placebo groups, both groups showed significant reductions in psychotic, depressive, and anxiety symptoms, which were associated with reduced expression of cytokines. Pharmacokinetics play a critical role in the clinical outcomes Inhibitors,research,lifescience,medical of drug therapy. Studies designed to investigate drug interactions with EGCG and its absorption show significant variability between subjects [e.g. Chow et al. 2006; reviewed in Colalto, 2010]. This variability suggests that pharmacogenetic factors may influence the pharmacokinetic mechanisms as well as the potential therapeutic effects of EGCG. Recently, a common polymorphism

in the genetic code for catechol-O-methyltransferase (COMT) was investigated to assess the impact of COMT genotype on green tea catechin absorption and metabolism in humans. The authors of reported that the COMT polymorphism [i.e. Val(158/108)Met] does not appear to have a significant influence on EGCG absorption and elimination [Miller and Schwarz, 2012]. More research studies are needed to better understand the pharmacokinetic mechanisms of EGCG. Limitations of this study included a small sample size, broad diagnostic criteria, a single dose strength of EGCG, and no standardized use of antipsychotic medications. Standardizing the antipsychotic medications would have been optimal, but we proposed that EGCG would serve as an adjunct to schizophrenia pharmacotherapy.

Again the benefits are the numbers of patients who can be assessed at any time as well as the ease of gathering and verifying the data. This system will be of greater initial utility in North America where a greater number of homes are connected to the Internet. However, it is likely that Europe will catch up in a few years and a second methodology for the remote assessment of cognitive Inhibitors,research,lifescience,medical function will be available. Selected abbreviations and acronyms AD Alzheimer’s disease ADAS Alzheimer’s Disease Assessment Scale CDR Cognitive Drug Research [system] CFF critical flicker fusion CRT choice reaction time

DC disturbance of consciousness DLB dementia with Lewy bodies DSST Digit Symbol Substitution Test GABA gamma-aminobutyric acid 5-HT 5-hydroxytryptamine
Several different classes of antipsychotic medications have been reliably shown to reduce active psychotic symptoms in schizophrenia and other psychoses1; all Inhibitors,research,lifescience,medical these drugs block the D2 family of dopamine receptors. Unfortunately,

the drug action is accompanied by side effects, which have inevitably limited their use. The first antipsychotic drug, chlorpromazin, was discovered serendipitously by Delay and Deniker,2 who were testing preanesthetic agents in schizophrenia for their “calming” action. Shortly after their discovery, a mechanism of action was proposed,3 and subsequently many similar drugs were synthesized Inhibitors,research,lifescience,medical and marketed; these are called traditional or first-generation antipsychotics.

Between 1975 and 1990, almost no new drug discovery occurred in schizophrenia. Then, in the 1990s, a second generation of antipsychotic drugs was Inhibitors,research,lifescience,medical developed – drugs with at least the same, possibly greater, antipsychotic action, but with significantly reduced motor side effects.4 The loss of motor side effects has produced a generation of medications far better tolerated by psychotic patients, and thus critically improving compliance. These secondgeneration drugs still possess the ability to block the D2 family of dopamine receptors, but have broader MLN0128 receptor affinity profiles, particularly affinity at the serotonin-2 Inhibitors,research,lifescience,medical (5 -hydroxy tryptamine-2 [5-HT2]) receptors. The mechanism of the antipsychotic action of these drug families certainly involves blockade of the D2 dopamine receptor. However, the mechanism whereby the brain translates this primary antidopaminergic action into a reduction in psychosis all remains unclear. Moreover, the additional new “ingredients” of action in the secondgeneration drugs also remain obscure, although 5-HT2 receptor antagonism has been often invoked.5 Recently, new technologies have been applied to human brain research to address these important questions, and the results have been supplemented by data from new directions in animal pharmacology. This paper will review the new antipsychotic agents, and then propose an overall mechanism of antipsychotic action.

In follow-up studies to the NAA findings, it. was hypothesized

that, in addition to increasing functional neurochemical markers of neuronal viability, lithium-induced increases in bcl-2 would also lead to neuropil increases, and thus to increased brain gray matter volume in patients with bipolar disorder. In this clinical research investigation,130 brain tissue volumes were examined Inhibitors,research,lifescience,medical using high-resolution three-dimensional MRI and validated quantitative brain tissue segmentation methodology to identify and quantify the various components by volume, including total brain white and gray matter content. Measurements were made at baseline (medicationfree, after a. minimum 14-day washout) and then repeated after 4 weeks of lithium at therapeutic doses. This study revealed Inhibitors,research,lifescience,medical that, chronic lithium significantly increases total gray matter content in the human brain of patients with bipolar disorder (Figure 2).130 No significant changes were observed in brain white matter volume or in quantitative

measures of regional cerebral water content, thereby providing strong evidence that the observed increases in gray matter content, are likely due to neurotrophic effects as opposed to any possible cell swelling and/or osmotic effects associated with lithium treatment. A finer-grained subregional analysis Inhibitors,research,lifescience,medical of this brain imaging data is ongoing, and suggests that, lithium produces a regionally selective increase

in gray matter, with prominent, effects being observed in hippocampus and caudate (unpublished observations). Figure 2. Brain matter is increased following 4 weeks of lithium administration at therapeutic levels in bipolar disorder patients. À Inhibitors,research,lifescience,medical slice of brain tissue volumes using high-resolution three-dimensional magnetic resonance imaging (MRI) (124 images, 1.5-mm … Concluding remarks: implications for development of new medications As discussed, there is a. considerable Inhibitors,research,lifescience,medical body of evidence both conceptually and experimentally in support of the regulation of signaling cascades regulating GSK2606414 molecular weight synaptic plasticity and cellular resilience in the treatment (and potentially pathophysiology) of mood disorders. Regulation of signal transduction within critical regions of the brain affects the intracellular signal generated click here by multiple neurotransmitter systems; these effects thus represent, attractive putative mediators of the pathophysiology of mood disorders and the therapeutic actions of antidepressants and mood stabilizers. It is also becoming increasingly clear that, for many refractory mood disorder patients, new drugs that simply mimic many “traditional” drugs, which directly or indirectly alter neurotransmitter levels, and those which bind to cell surface receptors may be of limited benefit.

Because patients with SPD are vulnerable to decompensation during times of stress and may

experience transient episodes of psychosis, they may also benefit, from techniques to facilitate stress reduction (eg, relaxation techniques, exercise, yoga, and meditation). Fortunately, there is evidence that at least some individuals with schizotypal features are likely to seek treatment in times of stress.30 Inhibitors,research,lifescience,medical In the short, term, brief courses of antipsychotic treatment may be useful if symptoms of psychosis appear. Because cognitive problems are also frequently amenable to concrete, goal-oriented approaches to treatment, SPD patients benefit, from an understanding Inhibitors,research,lifescience,medical of their cognitive strengths and weaknesses, to help them confront,

and cope with long-standing difficulties in their lives. For example, problems in attention, verbal memory, or organizational skills contribute to failures in educational, occupational, and social endeavors, while reinforcing negative selfimages and increasing performance anxiety. Knowledge of circumscribed cognitive problems allows patients to reframe their difficulties in a more positive Cilengitide manner, and facilitate selection of more realistic personal, educational, and occupational goals. Moreover, specific cognitive deficits are often subject, to at Inhibitors,research,lifescience,medical least, partial remediation. For example, standard procedures are available to attenuate deficits in the acquisition, organization, and retrieval of new information (eg, writing information down in a notebook, using appointment, books or planners, and rehearsing new information). Distractibility can be reduced by focusing on one Inhibitors,research,lifescience,medical task at a time, in contrast, to switching back and forth between activities.

The Inhibitors,research,lifescience,medical value of specific treatments for psychiatric symptoms, however, is less clear, owing to a dearth of outcome studies involving psychotherapy, psychosocial, or psych opharmacological treatments for SPD. Published studies show methodological limitations (eg, small samples, subjects with mixed diagnoses, inadequate controls, and problems with internal validity), or provide outcome data on only limited aspects of the disorder. Nevertheless, it. is clear that few treatment gains are evident from Rutecarpine recent studies, which serves to reaffirm both the chronicity and the complexity of the disorder. This is particularly true of studies that utilized psych odynamically oriented therapy, either alone or in combination with other treatments (eg, group therapy or art therapy) as the primary treatment modality. For example, McGlashan31 studied former inpatients approximately 15 years after treatment, who were given retrospective DSM-III diagnoses. The study followed up former patients with a. variety of diagnoses, including, among others, one third with pure SPD (n=10). Multiple outcome measures were employed.

Previous research has demonstrated DNA methylation changes in

a number of genes following early life stress. Epigenetic mechanisms may play a key role in the translation of environmental factors into phenotype. The epigenome is particularly susceptible to external disruption during a number of key developmental periods, and is thought most vulnerable to the effect of environmental factors during early development (Dolinoy et al. 2007). In this way, it is possible that epigenetic adaptations in Inhibitors,research,lifescience,medical response to early life adversity may play an important role in developmental plasticity, mediating phenotypic variability later in life (Bateson et al. 2004). Our study found that a CpG site in an intergenic region near the Avp gene was hypermethylated in MS males in hippocampal tissue. A recent paper by Murgatroyd et al. (2009) found hypomethylation of multiple Inhibitors,research,lifescience,medical CpG sites in the same region, but only in tissue from the para-ventricular nucleus. These CpG sites, especially site 10, were associated with Avp expression differences, suggesting an important regulatory role for this region. We did not observe DNA methylation differences in any of the same sites as the Murgatroyd et al. (2009) study, although the discrepancies between the two studies may result from our use of a different brain tissue, and Enzastaurin because the CpG sites Inhibitors,research,lifescience,medical interrogated in our assay did not overlap completely with those of Murgatroyd et al. (2009). For example, CpG Unit 2 in our assay,

Inhibitors,research,lifescience,medical which corresponds to site 10 in the Murgatroyd study, was unable to be assessed and therefore we are unable to determine if there are DNA methylation differences between groups for that site. However, some sites were assessed in both studies and this provides interesting directions to explore in future research. CpG Unit 1 in our study, which shows a significant hypermethylation in maternally separated animals, is shown to decrease in DNA methylation over time (from 6 week mice to 1 year mice) in the Inhibitors,research,lifescience,medical Murgatroyd et al. (2009)

study, regardless of environment. This suggests that this site may be an area for variable DNA methylation, and in the case of the maternally separated animals a dysregulation of the decrease in DNA methylation over time could be a maladaptive response to early life stress. We find modest hypermethylation across a number of sites in the promoter region of the glucocorticoid receptor following MS, specifically in DBA/2J mice. More marked hypermethylation in this region of the glucocorticoid receptor promoter following a stressful event have been reported crotamiton by a number of groups (Weaver et al. 2004; Oberlander et al. 2008; Mcgowan et al. 2009), although these are not consistently found (Daniels et al. 2009). Weaver et al. (2004) observed that rat pups raised by mothers displaying reduced nursing behaviors (licking, grooming, and arched back nursing) demonstrate marked hypermethylation across a number of CpG sites, including a region containing an NGFI-a binding site (Weaver et al. 2004).

We will separate two notions generally confounded in the literature: anatomical and functional connectivity. The rationale for this is that we suppose the latter to be related to the common pathophysiological pathway leading to the clinical expression of the disease. The anatomical aspect is assumed to be one of the possible causes for the dysfunction. We will also discuss two levels of connectivity:

a local level, mainly concerning the direct surroundings of the neurons in the gray matter, and a longrange level, mainly concerning the white fiber tracts Inhibitors,research,lifescience,medical connecting AZD0530 solubility dmso distant parts of the brain. A third anomaly of connectivity could be related to neurons connecting with erroneous targets. Gray matter connectivity Gray matter hypotrophy and atrophy have both been described in schizophrenic patients. Hypotrophy refers Inhibitors,research,lifescience,medical to a congenital reduction in the quantity of gray matter. It has been shown that such a reduction exists in patients as early as the first episode, with

the most robust evidence in the external temporal lobe, but with Inhibitors,research,lifescience,medical reductions also in the hippocampus and frontal and parietal lobes/’ However, it might be that part of the reduction is already related to an earlier origin of the disorder. Indeed, the average duration of untreated psychosis is 2.4 years, and some markers can even be traced back to the disease process long before that.7 However, the presence of similar, although lesser, gray matter reduction in relatives of patients also speaks for a congenital problem. Atrophy refers

to an acquired reduction in gray matter. The acceleration of gray matter decrease seems to occur mainly during the first year(s) of the disease process. Inhibitors,research,lifescience,medical Later on, the slope of the decrement is less striking. This gray matter reduction does not seem to be related to neuronal loss occurring after the second trimester. Indeed, Inhibitors,research,lifescience,medical only a few studies have found evidence for gliosis, a reputedly robust marker of neuronal necrosis, in the brains of patients with schizophrenia.8,9 It might be possible that some neurons are lost by apoptosis not necessarily accompanied by gliosis, but the general consensus is that most gray matter atrophy represents a reduction in from neuronal volume.10 As a matter of fact, cortical neurons are generally described as being smaller with higher density in pathological studies. Many authors have pointed out that the compartment showing the larger reduction could be the volume of axons and dendrites. In other words, there should be a reduction in the connecting parts of the neurons. In line with these arguments, synaptic spines and synaptic markers are reduced,11 as well as synaptic gene expression.12 In short, there is evidence of a reduction in local connectivity in some cortical areas in schizophrenia.

63-65 In light of the evidence for structural brain changes in prefrontal cortex,the following sections will consider the evidence for changes in functional brain activity in bipolar disorder. Imaging studies of mania Data from neurocognitive studies indicate

widespread impairments in executive, attentional, and emotional function during the manic phase Inhibitors,research,lifescience,medical of bipolar disorder. Functional imaging studies that scanned manic patients at, rest, have indicated changes in blood flow and metabolism, particularly in the orbitofrontal cortex.62,66-67 The disadvantage of these resting state studies is that it is not, possible to control for thought content during scanning, and increased activity may relate to aspects of the manic state like flights of ideas. Consequently, recent work has scanned patients while they perform a neuropsychological task, in order to investigate task-related Inhibitors,research,lifescience,medical neural activity. For example, Rubinsztein et al68 scanned a small number of manic patients with positron emission tomography while they performed a variant, of the Cambridge Gamble Task in the scanner (Figure 1). Blocks of a decision-making task were contrasted AC220 concentration against blocks of a control task that was matched for

visual and motor demands, but, without the requirement, for risk assessment, and decision-making. Compared with demographicallymatched healthy controls, the manic cases showed Inhibitors,research,lifescience,medical a dysregulation of medial and ventral prefrontal circuitry during risky decision-making. Figure 1. Brain responses during risky decision-making in patients with mania, patients with depression, and healthy controls. A: Screen display for the Risk Task. Subjects are instructed that a token has been hidden at random under one of Inhibitors,research,lifescience,medical the six boxes. They must … Using fMRI, Altshuler et al, scanned manic patients during performance of a Go-No Go task that required the suppression of impulsive responses. Compared

with matched healthy controls, the manic patients showed blunted activation of the right, lateral orbitofrontal cortex,69 a region that is thought, to be critical Inhibitors,research,lifescience,medical for inhibitory control. The affective variant of the Go-No Go task used by Murphy et al29 has also been adapted for fMRI by Elliott et al.70 In a comparison of manic patients and healthy controls, the manic group showed reduced activity in ventrolateral prefrontal cortex TCL during blocks of affective Go-No Go against, a nonemotional control condition. Manic patients also showed evidence of increased activity in the medial orbitofrontal cortex during blocks when positive stimuli were distractors (ie, to be ignored, (Figure 2). Thus, the available evidence clearly indicates pathophysiology in the ventral, orbital sectors of the prefrontal cortex. This pathophysiology is perhaps better described as a dysregulation, rather than a more simplistic “lesion” account, underlying the changes in emotional processing in the manic state. Figure 2.

Partially for this reason, Martin and colleagues more recently developed the Humor Styles Questionnaire (HSQ), which breaks humor into four broad categories, two of which are hypothesized to be psychologically

beneficial (so-called affiliative and self-enhancing humor) and two detrimental (aggressive and self-defeating humor).79 Numerous studies have supported the view that humor and laughter are therapeutic for relieving tension and anxiety,77,80–82 although the results are at times controversial and may show gender-specific Inhibitors,research,lifescience,medical differences.83–85 Nezu et al.86 reported that a sense of humor reduced stress associated with depressive symptoms, but did not significantly affect anxiety. Moran Inhibitors,research,lifescience,medical and colleagues85,87 also looked into this

question and found that while humorous stimuli caused only modest elevations in mood, an important learn more buffering effect was noted when those who viewed sad stimuli were able to use Inhibitors,research,lifescience,medical humor to prevent negative affect. A proposed mechanism for this cognitive effect has been described as a cognitive-affective shift created by humor in a threatening situation to decrease the feeling of intimidation and release emotion.80 Abel88 explores this shift as a part of the larger model for stress proposed by Lazarus and Folkman89 in which stress is dependent on the situation plus a person’s appraisal of the environment and ability to cope, which thus incorporates various personality Inhibitors,research,lifescience,medical variables. Kuiper et al.90 investigated sense of humor as a personality variable in relation to coping with stressful life events and found that those with a greater sense of humor had more positive perceptions of difficult events and were able to distance themselves emotionally

from problems. Additionally, Kuiper et al.91 and Lefcourt et al.84 found that humor appreciation and the coping technique of “distancing”92 Inhibitors,research,lifescience,medical were positively correlated. Later work showed evidence for humor- and emotion-focused coping strategies such as “minimization” and “reversal.”81 Abel found that there were indeed significant correlations between those with high trait sense of humor (measured TCL with MSHS) and their perceived level of stress, though there were no differences in the number of “everyday problems” between groups. In addition, those students with a greater sense of humor were more likely to use “positive coping strategies” (assessed with the Ways of Coping Scale92) such as distancing oneself from the stressor or solving the problems causing the stress.88 While trait levels of humor appear to be important, positive coping results are not solely dependent upon having a “good sense of humor.” Yovetich et al.