Impostorism in American medical students during early clinical training: gender differences and intercorrelating factors.

OBJECTIVES: This study examined the incidence and severity of impostorism in third-year medical students as they transitioned from the preclinical to clinical phases of training. METHODS: A cross-sectional study was conducted in third-year medical students (N=215).  Respondents completed a voluntary, anonymous, 60-item survey that included the Clance Impostor Phenomenon Scale and the Perceived Stress Scale.  Student's-t, Mann-Whitney, and Chi-Square tests and Pearson correlation were used to determine differences between subgroups of students and relationships between instruments scores and demographic parameters. RESULTS: Fifty-nine percent of students responded with N=112 (59% female) completing at least one instrument. The mean impostor score was 63.0 ± 14.6 (moderate-to-frequent impostor feelings) and was 9% higher in females (U=1181, p = .046). Perceived Stress scores for females were 17% higher than males (t(109)=2.87, p=.005).  Females had lower United States Medical Licensing Examination (USMLE) Step 1 scores (t(107)= 3.06,  p=.003).  Impostor and perceived stress scores were correlated for males (r(46)=.47, p=.002) and females (r(64)=.54,p<.0001). Impostor and USMLE Step 1 scores were negatively correlated for males (r(45) =-.32, p= .034) but not females (r(63) = -.11, p=.40). CONCLUSIONS:  These findings demonstrate the intercorrelation between impostorism and stress in male and female medical students and raise interesting questions regarding the contributions of gender and other factors involved with medical training.

Impostorism in third-year medical students: an item analysis using the Clance impostor phenomenon scale.

INTRODUCTION: Impostorism, feelings of distrust in one's abilities and accomplishments despite evidence to the contrary, is frequent in medical students and negatively affects student wellness. METHODS: The aspects of impostorism that were most prevalent in medical students during the transition from the preclinical to clinical phases of their training were assessed using an anonymous, voluntary 60-item survey that included the Clance Impostor Phenomenon Scale (CIPS) and a 2-item burnout assessment administered in October-November 2018. Ratings of individual CIPS items were compared between items for the entire sample and in subpopulations of students. The correlation of individual CIPS items with CIPS total score was also determined. RESULTS: A total of 127 of 215 (59%) surveyed students responded, with 112 completing the CIPS with mean score of 63.0 ± 14.6 (moderate-to-frequent impostor feelings). Ratings of individual CIPS items differed significantly between items. Responses also differed depending on gender and perceived burnout or depersonalization. DISCUSSION: Third-year medical students identified most strongly with items related to unfounded fear of failure, hesitance to share recognition before it is announced, remembering failures rather than successes, believing themselves less capable than others, and worrying about succeeding. In contrast, attribution of accomplishments to luck was not prominent for these students. Responses to certain items also differed depending on gender and perceived burnout or depersonalization, but not self-reported under-represented minority status. This observation may inform the development of interventions tailored to foster wellness as students negotiate the transition from the preclinical to clinical phases of their training.

The adverse effects of pramipexole on probability discounting are not reversed by acute D2 or D3 receptor antagonism.

Pramipexole (PPX) is a D2 and D3 dopamine receptor agonist approved for clinical use, which is associated with a higher risk of impulse-control disorders. Using a rat model, we recently found that low doses of the monoamine-depleting agent reserpine (RES; 1 mg/kg/day, SC) dramatically increased the untoward effects of PPX (0.3 mg/kg/day, SC) on probability discounting, a key impulsivity function. To further understand the neurobehavioral mechanisms underlying these effects, we first tested whether the combination of PPX and RES may lead to a generalized enhancement in risk taking, as tested in the suspended wire-beam paradigm. The association of RES and PPX did not augment the proclivity of rats to cross the bridge in order to obtain a reward, suggesting that the effects of RES and PPX on probability discounting do not reflect a generalized increase in impulsivity. We then studied what receptors mediate the effects of PPX in RES-treated rats. The combination of RES and PPX increased membrane expression and binding of D3, but not D2 dopamine receptors, in the nucleus accumbens. However, the behavioral effects of PPX and RES were not reduced by acute treatments with the D2/D3 receptor antagonist raclopride (0.01-0.05 mg/kg, SC), the highly selective D2 receptor antagonist L-741,626 (0.1-1 mg/kg, SC) or the D3 receptor antagonists GR 103691 (0.1-0.3 mg/kg, SC) and SB 277011A (1-10 mg/kg, SC). These findings collectively suggest that the effects of PPX in probability discounting do not reflect generalized enhancements in impulsivity or acute dopamine D2 or D3 receptor activation.

Post-exam feedback with question rationales improves re-test performance of medical students on a multiple-choice exam.

This study compared the effects of two types of delayed feedback (correct response or correct response + rationale) provided to students by a computer-based testing system following an exam. The preclinical medical curriculum at the University of Kansas Medical Center uses a two-exam system for summative assessments in which students test, revisit material, and then re-test (same content, different questions), with the higher score used to determine the students' grades. Using a quasi-experimental design and data collected during the normal course of instruction, test and re-test scores from midterm multiple choice examinations were compared between academic year (AY) 2015-2016, which provided delayed feedback with the correct answer only, and AY 2016-2017, where delayed feedback consisted of the correct answer plus a rationale. The average increase in score on the re-test was 2.29 ± 6.83% (n = 192) with correct answer only and 3.92 ± 7.12% (n = 197) with rationales (p < 0.05). The effect of the rationales was not different in students of differing academic abilities based on entering composite MCAT scores or Year 1 GPA. Thus, delayed feedback with exam question rationales resulted in a greater increase in exam score between the test and re-test than feedback with correct response only. This finding suggests that delayed elaborative feedback on a summative exam produced a small, but significant, improvement in learning, in medical students.

Regional differences in dopamine release in the R6/2 mouse caudate putamen.

Huntington's disease (HD) is a fatal neurodegenerative disorder that is characterized by degeneration of the striatum. Here, fast-scan cyclic voltammetry at carbon-fiber microelectrodes was used to uncover regional differences in dopamine (DA) release in the caudate putamen of R6/2 and wild-type control mice. We found a decreasing ventral-to-dorsal gradient in DA release, evoked by a single electrical stimulus pulse, in aged R6/2 mice. Moreover, under more intense stimulation conditions (120 pulses), DA release was significantly attenuated in the dorsal, but not in the ventral caudate. Autoradiography measurements using [3H]WIN 35,428 revealed that the overall density of DA transporter (DAT) protein molecules was significantly less in R6/2 mice compared to WT control mice; however, quadrants of the caudate putamen were not differentially altered in the R6/2 mice. These data collectively suggest that DA release in the dorsal caudate region is more vulnerable with age progression compared to the ventral region.

N-3 (Omega-3) Fatty Acids: Effects on Brain Dopamine Systems and Potential Role in the Etiology and Treatment of Neuropsychiatric Disorders.

BACKGROUND & OBJECTIVE: A number of neuropsychiatric disorders, including Parkinson's disease, schizophrenia, attention deficit hyperactivity disorder, and, to some extent, depression, involve dysregulation of the brain dopamine systems. The etiology of these diseases is multifactorial, involving genetic and environmental factors. Evidence suggests that inadequate levels of n-3 (omega- 3) polyunsaturated fatty acids (PUFA) in the brain may represent a risk factor for these disorders. These fatty acids, which are derived from the diet, are a major component of neuronal membranes and are of particular importance in brain development and function. Low levels of n-3 PUFAs in the brain affect the brain dopamine systems and, when combined with appropriate genetic and other factors, increase the risk of developing these disorders and/or the severity of the disease. This article reviews the neurobiology of n-3 PUFAs and their effects on dopaminergic function. CONCLUSION: Clinical studies supporting their role in the etiologies of diseases involving the brain dopamine systems and the potential of n-3 PUFAs in the treatment of these disorders are discussed.

Lipids in psychiatric disorders and preventive medicine.

Psychiatric disorders like mood disorders, schizophrenia, or drug addiction affect a sizeable proportion of the human population and severely compromise quality of life. Therefore, measures to prevent the manifestation, and treatments to ameliorate the symptoms, of these disorders are in high demand. Brain lipids determine the localization and function of proteins in the cell membrane of neurons. Lipids may also act as neurotransmitters or other signalling molecules. The lipid composition of the brain can be influenced by nutrition, environmental factors, and by behavioural activity. Thus, lipids represent a target for preventive medicine of psychiatric disorders. Here we review how brain lipids contribute to normal behaviour and to major psychiatric disorders with the focus on phospholipids/fatty acids, sphingolipids, and endocannabinoids. Accumulating evidence suggests a crucial role for membrane forming and signalling lipids in the brain in the etiopathologies of depression, bipolar disorders, schizophrenia, and drug addiction. Lipids also represent potential preventive interventions for these psychiatric disorders by either targeted dietary supplementation or pharmacological manipulation of lipid regulating enzymes.

Pramipexole enhances disadvantageous decision-making: Lack of relation to changes in phasic dopamine release.

Pramipexole (PPX) is a high-affinity D2-like dopamine receptor agonist, used in the treatment of Parkinson's disease (PD) and restless leg syndrome. Recent evidence indicates that PPX increases the risk of problem gambling and impulse-control disorders in vulnerable patients. Although the molecular bases of these complications remain unclear, several authors have theorized that PPX may increase risk propensity by activating presynaptic dopamine receptors in the mesolimbic system, resulting in the reduction of dopamine release in the nucleus accumbens (NAcc). To test this possibility, we subjected rats to a probability-discounting task specifically designed to capture the response to disadvantageous options. PPX enhanced disadvantageous decision-making at a dose (0.3 mg/kg/day, SC) that reduced phasic dopamine release in the NAcc. To test whether these modifications in dopamine efflux were responsible for the observed neuroeconomic deficits, PPX was administered in combination with the monoamine-depleting agent reserpine (RES), at a low dose (1 mg/kg/day, SC) that did not affect baseline locomotor and operant responses. Contrary to our predictions, RES surprisingly exacerbated the effects of PPX on disadvantageous decision-making, even though it failed to augment PPX-induced decreases in phasic dopamine release. These results collectively suggest that PPX impairs the discounting of probabilistic losses and that the enhancement in risk-taking behaviors secondary to this drug may be dissociated from dynamic changes in mesolimbic dopamine release.

Pramipexole derivatives as potent and selective dopamine D(3) receptor agonists with improved human microsomal stability.

Herein we report the synthesis and evaluation of a series of new pramipexole derivatives as highly potent and selective agonists of the dopamine-3 (D3 ) receptor. A number of these new compounds bind to the D3 receptor with sub-nanomolar affinity and show excellent selectivity (>10,000) for the D3 receptor over the D1 and D2 receptors. For example, compound 23 (N-(cis-3-(2-(((S)-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazol-6-yl)(propyl)amino)ethyl)-3-hydroxycyclobutyl)-3-(5-methyl-1,2,4-oxadiazol-3-yl)benzamide) binds to the D3 receptor with a Ki value of 0.53 nM and shows a selectivity of >20,000 over the D2 and D1 receptors in the binding assays using a rat brain preparation. It has excellent stability in human liver microsomes. Moreover, in vitro functional assays showed it to be a full agonist for the human D3 receptor.

Differential effects of intrastriatal 6-hydroxydopamine on cell number and morphology in midbrain dopaminergic subregions of the rat.

The midbrain dopaminergic perikarya are differentially affected in Parkinson׳s disease (PD). This study compared the effects of a partial unilateral intrastriatal 6-hydroxydopamine (6-OHDA) lesion model of PD on the number, morphology, and nucleolar volume of dopaminergic cells in the substantia nigra pars compacta (SNpc), ventral tegmental area (VTA), and retrorubral field (RRF). Adult, male rats (n=10) underwent unilateral intrastriatal infusion of 6-OHDA (12.5µg). Lesions were verified by amphetamine-stimulated rotation 7 days post-infusion. Rats were euthanized 14 days after treatment with 6-OHDA and brains were stained with a tyrosine hydroxylase-silver nucleolar (TH-AgNOR) stain. Dopaminergic cell number and morphology in the lesioned and intact hemispheres were quantified using stereological methods. The magnitude of decrease in planimetric volume, neuronal number, cell density, and neuronal volume resulting from 6-OHDA lesion differed between regions, with the SNpc exhibiting the greatest loss of neurons (46%), but the smallest decrease in neuronal volume (13%). The lesion also resulted in a decrease in nucleolar volume that was similar in all three regions (22-26%). These findings indicate that intrastriatal 6-OHDA lesion differentially affects dopaminergic neurons in the SNpc, VTA, and RRF; however, the resulting changes in nucleolar morphology suggest a similar cellular response to the toxin in all three cell populations.

Tranylcypromine substituted cis-hydroxycyclobutylnaphthamides as potent and selective dopamine D3 receptor antagonists.

We report a class of potent and selective dopamine D3 receptor antagonists based upon tranylcypromine. Although tranylcypromine has a low affinity for the rat D3 receptor (K(i) = 12.8 µM), our efforts have yielded (1R,2S)-11 (CJ-1882), which has K(i) values of 2.7 and 2.8 nM at the rat and human dopamine D3 receptors, respectively, and displays respective selectivities of >10000-fold and 223-fold over the rat and human D2 receptors. Evaluation in a ß-arrestin functional assay showed that (1R,2S)-11 is a potent and competitive antagonist at the human D3 receptor.

Streptozotocin-induced diabetes partially attenuates the effects of a high-fat diet on liver and brain fatty acid composition in mice.

The current study addresses the effects of a high-fat diet on liver and brain fatty acid compositions and the interaction of that diet with diabetes in a type 1 mouse model. Adult, male, normal and streptozotocin-induced diabetic C57BL/6 mice were fed standard (14 % kcal from fat) or high-fat (54 % kcal from fat, hydrogenated vegetable shortening and corn oil) diets for 8 weeks. Liver and whole brain total phospholipid fatty acid compositions were then determined by TLC/GC. In the liver of non-diabetic mice, the high-fat diet increased the percentages of 18:1n-9, 20:4n-6, and 22:5n-6 and decreased 18:2n-6 and 22:6n-3. Diabetes increased 16:0 in liver, and decreased 18:1n-7 and 20:4n-6. The effects of the high-fat diet on liver phospholipids in diabetic mice were similar to those in non-diabetic mice, or were of smaller magnitude. In the brain, the high-fat diet increased 18:0 and 20:4n-6 of non-diabetic, but not diabetic mice. Brain 22:5n-6 acid was increased by the high-fat diet in both non-diabetic and diabetic mice, but this increase was smaller in diabetic mice. Diabetes alone did not alter the percentage of any individual fatty acid in brain. This indicates that the effects of a high-fat diet on liver and brain phospholipid fatty acid compositions are partially attenuated by concomitant hyperglycemia with hypoinsulinemia.

Low brain DHA content worsens sensorimotor outcomes after TBI and decreases TBI-induced Timp1 expression in juvenile rats.

The effects of dietary modulation of brain DHA content on outcomes after TBI were examined in a juvenile rat model. Long-Evans rats with normal or diet-induced decreases in brain DHA were subjected to a controlled cortical impact or sham surgery on postnatal day 17. Rats with the greatest decreases in brain DHA had the poorest sensorimotor outcomes after TBI. Ccl2, Gfap, and Mmp 9 mRNA levels, and MMP-2 and -9 enzymatic activities were increased after TBI regardless of brain DHA level. Lesion volume was not affected by brain DHA level. In contrast, TBI-induced Timp1 expression was lower in rats on the Deficient diet and correlated with brain DHA level. These data suggest that decreased brain DHA content contributes to poorer sensorimotor outcomes after TBI through a mechanism involving modulation of Timp1 expression.

Altered nucleolar morphology in substantia nigra dopamine neurons following 6-hydroxydopamine lesion in rats.

The nucleolus, the site of ribosomal ribonucleic acid (rRNA) transcription and assembly, is an important player in the cellular response to stress. Altered nucleolar function and morphology, including decreased nucleolar volume, has been observed in Parkinson's disease; thus the nucleolus represents a potential indicator of neurodegeneration in the disease. This study determined the effects of a partial unilateral intrastriatal 6-hydroxydopamine (6-OHDA) lesion, which models the dopaminergic loss found in Parkinson's disease, on the nucleoli of dopaminergic cells in the substantia nigra pars compacta (SNpc). Adult male Long-Evans rats underwent unilateral intrastriatal infusion of 6-OHDA (12.5µg). Lesions were verified by amphetamine-stimulated rotation 7 days later, and rats were euthanized 14 days after infusion. Coronal sections (50µm) were stained for tyrosine hydroxylase-silver nucleolar (TH-AgNOR) stain using MultiBrain Technology (NeuroScience Associates), which resulted in clearly defined nucleoli and neuronal outlines. Stereological methods were used to compare dopaminergic morphology between lesioned and intact hemispheres in each rat. In cells exhibiting a definable nucleolus, nucleolar volume was decreased by 16% on the ipsilateral side. The ipsilateral SNpc also exhibited an 18% decrease in SNpc planimetric volume, a 46% decrease in total TH-positive neuron number, and an 11% decrease in neuronal body volume (all P<0.05 by paired t-test). These findings suggest that the 6-OHDA lesion alters nucleolar morphology and that these changes are similar to those occurring in Parkinson's disease.

N-3 (omega-3) polyunsaturated Fatty acids in the pathophysiology and treatment of depression: pre-clinical evidence.

A growing literature suggests the association of low tissue levels and/or dietary intake of n-polyunsaturated fatty acids (PUFA) with depressive illnesses. Animal studies show that low tissue and/or dietary n-3 PUFAs can lead to behaviors and neurobiological effects associated with depression and can potentiate the consequences of stress, whereas higher levels have the opposite effect. These data support the involvement of n-3 PUFAs levels in the disease processes underlying depression. In addition, these pre-clinical findings indicate neurobiological mechanisms whereby n-3 PUFAs may contribute to the disease including control of serotonergic and dopaminergic function, modulation of brain-derived neurotrophic factor (BDNF) in the hippocampus, regulation of the hypothalamic-pituitary-adrenal axis, and effects on neuroinflammation. This evidence for a role for n-3 PUFA in the pathophysiology and treatment of depressive illness are reviewed. The implications of these finding for future pre-clinical research and clinical application are discussed.

High-affinity and selective dopamine D3 receptor full agonists.

We have designed, synthesized and evaluated a series of new compounds with the goal to identify potent and selective D(3) ligands. The two most potent and selective new D(3) ligands are compounds 38 and 52, which bind to the D(3) receptors with a K(i) value of 10,000 times over the D(1) receptors. Both 38 and 52 are full agonists with high potency at the D(3) receptor in a D(3) functional assay.

A novel use of combined tyrosine hydroxylase and silver nucleolar staining to determine the effects of a unilateral intrastriatal 6-hydroxydopamine lesion in the substantia nigra: a stereological study.

Neurotoxic lesions of the nigrostriatal pathway model the deficits found in Parkinson's disease. This study used stereology and a novel staining method to examine the effects of a partial unilateral striatal 6-hydroxydopamine (6-OHDA) lesion on substantia nigra pars compacta (SNpc) dopamine neuron number and morphology in rats. Adult male Long-Evans rats were subjected to unilateral lesion of the SNpc by intrastriatal microinjection of 6-OHDA (12.5 µg). Lesions were verified by d-amphetamine-stimulated rotation (2.5 mg/kg, sc) by force-plate rotometry 7 days post-surgery. Seven days after rotation testing, rats were euthanized, and brains were prepared for either histology (n=12) or determination of striatal dopamine content by HPLC-EC (n=20). Brains prepared for histology were stained for tyrosine hydroxylase (TH) combined with a silver nucleolar (AgNOR) stain using a modified protocol developed for stereological assessment. The AgNOR counterstain allowed for precise definition of the nucleolus of the cells, facilitating both counting and qualitative morphometry of TH-positive neurons. Stereological quantitation determined a 54% decrease in TH-positive neuron number (P<0.01), and a 14% decrease in neuron volume (P<0.05) on the lesioned side. Striatal dopamine concentration was decreased by 92% (P<0.01), suggesting that striatal dopamine analysis may overestimate the numbers of SNpc neurons lost. These findings demonstrate that combined use of TH and AgNOR staining provides improved characterization of 6-OHDA-induced pathology. Furthermore, the data suggest that decreased neuronal volume as well as number contributes to the functional deficits observed after unilateral intrastriatal 6-OHDA lesion.

CJ-1639: A Potent and Highly Selective Dopamine D3 Receptor Full Agonist.

We have identified several ligands with high binding affinities to the dopamine D3 receptor and excellent selectivity over the D2 and D1 receptors. CJ-1639 (17) binds to the D3 receptor with a K(i) value of 0.50 nM and displays a selectivity of >5,000 times over D2 and D1 receptors in binding assays using dopamine receptors expressed in the native rat brain tissues. CJ-1639 binds to human D3 receptor with a K(i) value of 3.61 nM and displays over >1000-fold selectivity over human D1 and D2 receptors. CJ-1639 is active at 0.01 mg/kg at the dopamine D3 receptor in the rat and only starts to show a modest D2 activity at doses as high as 10 mg/kg. CJ-1639 is the most potent and selective D3 full agonist reported to date.

Sensorimotor behavioral tests for use in a juvenile rat model of traumatic brain injury: assessment of sex differences.

Modeling juvenile traumatic brain injury (TBI) in rodents presents several unique challenges compared to adult TBI, one of which is selecting appropriate sensorimotor behavioral tasks that enable the assessment of the extent of injury and recovery over time in developing animals. To address this challenge, we performed a comparison of common sensorimotor tests in Long-Evans rats of various sizes and developmental stages (postnatal days 16-45, 35-190 g). Tests were compared and selected for their developmental appropriateness, scalability for growth, pre-training requirements, and throughput capability. Sex differences in response to TBI were also assessed. Grid walk, automated gait analysis, rotarod, beam walk, spontaneous forelimb elevation test, and measurement of motor activity using the force-plate actometer were evaluated. Grid walk, gait analysis, and rotarod failed to meet one or more of the evaluation criteria. Beam walk, spontaneous forelimb elevation test, and measurement of motor activity using the force-plate actometer satisfied all criteria and were capable of detecting motor abnormalities in rats subjected to controlled cortical impact on postnatal day 17. No sex differences were detected in the acute effects of TBI or functional recovery during the 28 days after injury using these tests. This demonstrates the utility of these tests for the evaluation of sensorimotor function in studies using rat models of pediatric TBI, and suggests that pre-pubertal males and females respond similarly to TBI with respect to sensorimotor outcomes.

Lipopolysaccharide induces H1 receptor expression and enhances histamine responsiveness in human coronary artery endothelial cells.

Summary Histamine is a well-recognized modulator of vascular inflammation. We have shown that histamine, acting via H1 receptors (H1R), synergizes lipopolysaccharide (LPS)-induced production of prostaglandin I(2) (PGI(2)), PGE(2) and interleukin-6 (IL-6) by endothelial cells. The synergy between histamine and LPS was partly attributed to histamine -induced expression of Toll-like receptor 4 (TLR4). In this study, we examined whether LPS stimulates the H1R expression in human coronary artery endothelial cells (HCAEC) with resultant enhancement of histamine responsiveness. Incubation of HCAEC with LPS (10-1000 ng/ml) resulted in two-fold to fourfold increases in H1R mRNA expression in a time-dependent and concentration-dependent fashion. In contrast, LPS treatment did not affect H2R mRNA expression. The LPS-induced H1R mRNA expression peaked by 4 hr after LPS treatment and remained elevated above the basal level for 20-24 hr. Flow cytometric and Western blot analyses revealed increased expression of H1R protein in LPS-treated cells. The specific binding of [(3)H]pyrilamine to H1R in membrane proteins from LPS-treated HCAEC was threefold higher than the untreated cells. The LPS-induced H1R expression was mediated through TLR4 as gene silencing by TLR4-siRNA and treatment with a TLR4 antagonist inhibited the LPS effect. When HCAEC were pre-treated with LPS for 24 hr, washed and challenged with histamine, 17-, 10- and 15-fold increases in PGI(2), PGE(2) and IL-6 production, respectively, were noted. Histamine-induced enhancement of the synthesis of PGI(2), PGE(2) and IL-6 by LPS-primed HCAEC was completely blocked by an H1R antagonist. The results demonstrate that LPS, through TLR4 activation, up-regulates the expression and function of H1R and amplifies histamine-induced inflammatory responses in HCAEC.