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Introduction Exposure to both prenatal stress (PS) and chronic stress in later life is associated with the development of mood disorders like depression. PS has been found to be related with alterations in the fetal hypothalamo-pituitary-adrenal (HPA) axis, which, in turn, may influence the serotonergic (5-HT) system. 5-HT may also be involved in depression promoted by chronic stress in later life. Therefore, disturbances in the 5-HT system may play an important role in the pathology of depression. In the present study we examined the effects of prenatal restraint stress and/or chronic mild stress (CMS) on 5-HT and tryptophan hydroxylase 2 (TPH2) immunoreactivity within the dorsal raphe nucleus, the hippocampus and the prefrontal cortex of adult male and female Sprague-Dawley rats. Methodology Pregnant rats were individually restrained in transparent plastic cylinders whilst being exposed to bright light three times a day during the last week of pregnancy. For CMS, two random stressors, e.g. empty cage or flashing lights, each lasting for three hours, were applied for a period of three weeks. The effects of PS and/or CMS on 5-HT and TPH2 were analyzed by means of immunohistochemistry and the NIH ImageJ software. Obtained values were statistically analyzed using Two-way ANOVA and post-hoc LSD. Results The data show that PS and chronic stress in later life affect the rat 5-HT system in a region- and sex-specific way. In males, a significant interaction of PS and CMS on the density of positive 5-HT neurons in the dorsal raphe nucleus was observed. Further, a tendency towards increased hippocampal 5-HT immunoreactivity, and significantly elevated 5-HT intensity in the prefrontal cortex were found. In females, stress did not result in any alterations. Concerning TPH2, a PS and CMS interaction was observed in the hippocampus within both sexes. Conclusion PS and CMS alter the 5-HT system in males, with increased hippocampal and prefrontal cortex 5-HT immunoreactivity and reduced levels in the raphe, which might represent compensatory mechanisms. In females no alteration was found indicating a higher susceptibility in males. Regarding TPH2, both sexes were affected to a lesser extent. CMS partially normalized some effects of PS. The observed changes may represent a morphological basis of PS- and/or CMS-related emotional disturbances. [ABSTRACT FROM AUTHOR]

Type-2 diabetes raises the risk for Alzheimer's disease (AD)-type dementia and the conversion from mild cognitive impairment to dementia, yet mechanisms connecting type-2 diabetes to AD remain largely unknown. Amylin, a pancreatic β-cell hormone co-secreted with insulin, participates in the central regulation of satiation, but also forms pancreatic amyloid in persons with type-2 diabetes and synergistically interacts with brain amyloid β (Aβ) pathology, in both sporadic and familial Alzheimer's disease (AD). Growing evidence from studies of tumor growth, together with early observations in skeletal muscle, indicates amylin as a potential trigger of cellular metabolic reprogramming. Because the blood, cerebrospinal fluid, and brain parenchyma in humans with AD have increased concentrations of amylin, amylin-mediated pathological processes in the brain may involve neuronal metabolic remodeling. This review summarizes recent progress in understanding the link between prediabetic hypersecretion of amylin and risk of neuronal metabolic remodeling and AD and suggests nutritional and medical effects of food constituents that might prevent and/or ameliorate amylin-mediated neuronal metabolic remodeling., (© 2023 The Authors. Molecular Nutrition & Food Research published by Wiley‐VCH GmbH.)

Repeated panic attacks are the core symptom of panic disorder and severely stressful for patients. Additional to the psychological response, the physiological symptoms are an important aspect of the experienced panic. However, data on the extent of hypothalamic-pituitary-adrenal (HPA)-axis activation during panic attacks is inconsistent. Therefore, in the present study, we aimed at investigating the stress-axis activity in more detail by including Copeptin (CoP) as a stable surrogate parameter for the vasopressinergic hypothalamic activity during experimentally induced panic attacks in healthy adults (N = 21). During a placebo-controlled panic challenge with 35% CO 2 compared to normal air inhalation, we measured CoP and the peripheral effector hormones Adrenocorticotropic Releasing Hormone (ACTH) and cortisol in plasma along with the psychological response to panic anxiety. We analyzed hormonal secretion patterns, their correlations and individual panic ratings over time and explored differences between female and male participants. We found a significant CO 2 -induced increase of CoP plasma levels and psychological panic symptoms after CO 2 -administration, while no positive correlations of CoP levels with the peripheral HPA-axis hormones and with panic symptoms were present. No differences between female and male participants concerning their psychological response nor their baseline CoP levels, the release of CoP or its increase during the experiment were found. CoP could be a sensitive indicator for an organism's physiologic acute hypothalamic response during stress and panic attacks., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Islet amyloid polypeptide (amylin) secreted from the pancreas crosses from the blood to the brain parenchyma and forms cerebral mixed amylin-β amyloid (Aβ) plaques in persons with Alzheimer's disease (AD). Cerebral amylin-Aβ plaques are found in both sporadic and early-onset familial AD; however, the role of amylin-Aβ co-aggregation in potential mechanisms underlying this association remains unknown, in part due to lack of assays for detection of these complexes. Here, we report the development of an ELISA to detect amylin-Aβ hetero-oligomers in brain tissue and blood. The amylin-Aβ ELISA relies on a monoclonal anti-Aβ mid-domain antibody (detection) and a polyclonal anti-amylin antibody (capture) designed to recognize an epitope that is distinct from the high affinity amylin-Aβ binding sites. The utility of this assay is supported by the analysis of molecular amylin-Aβ codeposition in postmortem brain tissue obtained from persons with and without AD pathology. By using transgenic AD-model rats, we show that this new assay can detect circulating amylin-Aβ hetero-oligomers in the blood and is sensitive to their dissociation to monomers. This is important because therapeutic strategies to block amylin-Aβ co-aggregation could reduce or delay the development and progression of AD., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Impairment of vascular pathways of cerebral β-amyloid (Aβ) elimination contributes to Alzheimer disease (AD). Vascular damage is commonly associated with diabetes. Here we show in human tissues and AD-model rats that bloodborne islet amyloid polypeptide (amylin) secreted from the pancreas perturbs cerebral Aβ clearance. Blood amylin concentrations are higher in AD than in cognitively unaffected persons. Amyloid-forming amylin accumulates in circulating monocytes and co-deposits with Aβ within the brain microvasculature, possibly involving inflammation. In rats, pancreatic expression of amyloid-forming human amylin indeed induces cerebrovascular inflammation and amylin-Aβ co-deposits. LRP1-mediated Aβ transport across the blood-brain barrier and Aβ clearance through interstitial fluid drainage along vascular walls are impaired, as indicated by Aβ deposition in perivascular spaces. At the molecular level, cerebrovascular amylin deposits alter immune and hypoxia-related brain gene expression. These converging data from humans and laboratory animals suggest that altering bloodborne amylin could potentially reduce cerebrovascular amylin deposits and Aβ pathology., (© 2023. The Author(s).)

Inborn errors of metabolism (IEMs) are characterized by deficits in metabolic enzymes as a result of an inherited disease, leading to the accumulation or decreased excretion of proteins, carbohydrates and lipids. Although IEMs are often diagnosed during childhood, adolescent and adult onset variants may be accompanied by less somatic and more psychiatric manifestations, which often hampers recognition by psychiatrists of the distinction between a primary and secondary psychiatric disorder. To help clinicians in the diagnostic process, we aimed to provide an overview of psychiatric manifestations in IEMs. Our literature search yielded 4380 records in total, of which 88 studies were included in the qualitative synthesis. Reported psychiatric disorders in adolescent and adult IEMs included depression, anxiety disorder, psychosis, attention deficit hyperactivity disorder, autism spectrum disorder, bipolar disorder and obsessive-compulsive disorder as assessed by semi-structured diagnostic interviews and validated questionnaires. A diagnostic screener and multidisciplinary IEM clinics are proposed to help clinicians during the diagnostic process, to prevent diagnostic delay and to raise awareness of the psychiatric manifestations among IEMs., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Culturally responsive teaching is a vital skill for nurse educators. A diverse nursing workforce is needed in the US to represent the population's demographics. Recruiting, retaining, and engaging a diverse student body is critical to addressing issues of disparities and cultural sensitivity in health care. In a project to promote success among diverse nursing students, nurse educators collaborated to create and present faculty development programs to build culturally responsive teaching skills. This article includes examples of culturally responsive teaching and describes the project and the faculty development curriculum and teaching materials produced., (© Copyright 2022 Creative Health Care Management.)

Inborn errors of metabolism (IEMs) are a group of rare genetic disorders which, when emerging later in life, are often characterized by neuropsychiatric manifestations including psychosis. This study aimed to determine whether it would be useful to screen patients presenting with a psychotic disorder for IEMs by a single blood sample using Next Generation Sequencing (NGS), in order to detect rare, treatable causes of psychotic disorders. Blood was drawn from 60 patients with a psychotic disorder, with a duration of illness of less than 5 years. Blood samples were screened for 67 genes using NGS (Illumina® MiSeq sequencing technique). The results were compared to the human reference genome (GoNL, n = 498). The identified variants were classified according to the ACMG classification. For the psychotic patients, 6 variants of a likely pathogenic (class 4, n = 2) or pathogenic (class 5, n = 4) origin were found. As all variants were heterozygous, no patients were considered to be affected by an IEM. For the GoNL control group, 73 variants of a likely pathogenic (class 4, n = 31) or pathogenic (class 5, n = 42) origin were found. All of these found variants were heterozygous. Therefore, these individuals from the control group were considered to be a carrier only. Thus, no patients were identified to have an IEM as an underlying disease using this approach. However, NGS may be useful to detect variants of genes associated with IEMs in an enriched subgroup of psychotic patients., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

A polymorphism in the gene encoding the serotonin (5-HT) transporter (5-HTT) has been shown to moderate the response to CO 2 inhalation, an experimental model for panic attacks (PAs). Recurrent, unpredictable PAs represent, together with anticipatory anxiety of recurring attacks, the core feature of panic disorder (PD) and significantly interfere with patients' daily life. In addition to genetic components, accumulating evidence suggests that epigenetic mechanisms, which regulate gene expression by modifying chromatin structure, also play a fundamental role in the etiology of mental disorders. However, in PD, epigenetic mechanisms have barely been examined to date. In the present study, we investigated the relationship between methylation at the regulatory region of the gene encoding the 5-HTT and the reactivity to a 35% CO 2 inhalation in PD patients. We focused on four specific CpG sites and found a significant association between the methylation level of one of these CpG sites and the fear response. This suggests that the emotional response to CO 2 inhalation might be moderated by an epigenetic mechanism, and underlines the implication of the 5-HT system in PAs. Future studies are needed to further investigate epigenetic alterations in PD and their functional consequences. These insights can increase our understanding of the underlying pathophysiology and support the development of new treatment strategies., (Copyright © 2020. Published by Elsevier B.V.)

Background: Childhood maltreatment is a transdiagnostic risk factor for later psychopathology and has been associated with altered brain circuitry involved in the processing of threat and safety. Examining threat generalization mechanisms in young adults with childhood maltreatment and psychiatric symptoms may elucidate a pathway linking early-life adversities to the presence of subclinical psychopathology., Methods: We recruited youth aged 16–25 years with subclinical psychiatric symptomatology and healthy controls. They were dichotomized into 2 groups: 1 with a high level of childhood maltreatment (n = 58) and 1 with no or a low level of childhood maltreatment (n = 55). Participants underwent a functional MRI threat generalization paradigm, measuring self-reported fear, expectancy of an unconditioned stimulus (US) and neural responses., Results: We observed interactions between childhood maltreatment and threat generalization indices on subclinical symptom load. In individuals reporting high levels of childhood maltreatment, enhanced generalization in self-reported fear and US expectancy was related to higher levels of psychopathology. Imaging results revealed that in the group with high levels of childhood maltreatment, lower activation in the left hippocampus during threat generalization was associated with a higher symptom load. Associations between threat generalization and psychopathology were nonsignificant overall in the group with no or low levels of childhood maltreatment., Limitations: The data were acquired in a cross-sectional manner, precluding definitive insight into the causality of childhood maltreatment, threat generalization and psychopathology., Conclusion: Our results suggest that threat generalization mechanisms may moderate the link between childhood maltreatment and subclinical psychopathology during emerging adulthood. Threat generalization could represent a vulnerability factor for developing later psychopathology in individuals being exposed to childhood maltreatment., Competing Interests: R. van Winkel reports personal fees from Johnson & Johnson, outside the submitted work. No other authors declared competing interests., (© 2018 Joule Inc. or its licensors)

Fear generalization is a prominent feature of anxiety disorders and post-traumatic stress disorder (PTSD). It is defined as enhanced fear responding to a stimulus that bears similarities, but is not identical to a threatening stimulus. Pattern separation, a hippocampal-dependent process, is critical for stimulus discrimination; it transforms similar experiences or events into non-overlapping representations. This study is the first in humans to investigate the extent to which fear generalization relies on behavioral pattern separation abilities. Participants (N = 46) completed a behavioral task taxing pattern separation, and a neuroimaging fear conditioning and generalization paradigm. Results show an association between lower behavioral pattern separation performance and increased generalization in shock expectancy scores, but not in fear ratings. Furthermore, lower behavioral pattern separation was associated with diminished recruitment of the subcallosal cortex during presentation of generalization stimuli. This region showed functional connectivity with the orbitofrontal cortex and ventromedial prefrontal cortex. Together, the data provide novel experimental evidence that pattern separation is related to generalization of threat expectancies, and reduced fear inhibition processes in frontal regions. Deficient pattern separation may be critical in overgeneralization and therefore may contribute to the pathophysiology of anxiety disorders and PTSD., (© The Author (2017). Published by Oxford University Press.)

Incivility in nursing is a pervasive and evasive problem that many nurses do not easily recognize or may simply shrug off as "normal." However, incivility produces a hostile work environment and can jeopardize safety. A study was conducted to (a) determine nurses' ability to recognize incivility in nursing after an online educational intervention on incivility, (b) ascertain the effectiveness of online education toward assisting nurses with understanding how to ward off this behavior, and (c) determine the types and effects of incivility participants experienced. Findings suggest that education on incivility may assist nurses with identifying uncivil behaviors exhibited by nurse peers and help them understand strategies to combat it. The types of incivility reported by participants were similar to findings of other studies; effects included unsafe behaviors and somatic consequences.

The use of virtual simulations in nursing is an innovative strategy that is increasing in application. There are several terms related to virtual simulation; although some are used interchangeably, the meanings are not the same. This article presents examples of virtual simulation, virtual worlds, and virtual patients in continuing education, staff development, and academic nursing education. Virtual simulations in nursing use technology to provide safe, as realistic as possible clinical practice for nurses and nursing students. Virtual simulations are useful for learning new skills; practicing a skill that puts content, high-order thinking, and psychomotor elements together; skill competency learning; and assessment for low-volume, high-risk skills. The purpose of this article is to describe the related terms, examples, uses, theoretical frameworks, challenges, and evidence related to virtual simulations in nursing.

Recent neuro-imaging studies have implicated the cerebellum in several higher-order functions. Its role in human fear conditioning has, however, received limited attention. The current meta-analysis examines the loci of cerebellar contributions to fear conditioning in healthy subjects, thus mapping, for the first time, the neural response to conditioned aversive stimuli onto the cerebellum. By using the activation likelihood estimation (ALE) technique for analyses, we identified several distinct regions in the cerebellum that activate in response to the presentation of the conditioned stimulus: the cerebellar tonsils, lobules HIV-VI, and the culmen. These regions have separately been implicated in fear acquisition, consolidation of fear memories and expression of conditioned fear responses. Their specific role in these processes may be attributed to the general contribution of cerebellar cortical networks to timing and prediction. Our meta-analysis highlights the potential role of the cerebellum in human cognition and emotion in general, and addresses the possibility how deficits in associative cerebellar learning may play a role in the pathogenesis of anxiety disorders. Future studies are needed to further clarify the mechanistic role of the cerebellum in higher order functions and neuropsychiatric disorders., (Copyright © 2015. Published by Elsevier Ltd.)

This study was intended to assess the extent to which the low-expression allele of the serotonin transporter gene promoter predicts better response to exposure-based behavior therapy in patients with panic disorder with agoraphobia (PDA). Ninety-nine patients with PDA underwent a 1-week in vivo exposure-based behavior therapy program and provided saliva samples to extract genomic DNA and classify individuals according to four allelic forms (SA, SG, LA, LG) of the 5-HTT-linked polymorphic region (5-HTTLPR). We determined whether the 5-HTTLPR genotype predicted change in avoidance behavior in PDA following treatment. After controlling for pre-treatment avoidance behavior, the 5-HTTLPR low-expression genotypes showed a more favorable response to exposure therapy two weeks following treatment, compared to the other patients. This study suggests a genetic contribution to treatment outcome following behavior therapy and implicates the serotonergic system in response to exposure-based treatments in PDA., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

Background: The biological basis of uncued panic attacks is not yet understood. An important theory concerning the nature and cause of panic disorder is the 'suffocation false alarm theory'. This alarm is supposed to be over-sensitive in panic disorder patients and can be triggered by CO2. No neurobiological substrate has been identified for such an alarm. The present study investigates differences in brain activation in panic patients, healthy individuals and experienced divers in response to CO2, representing three groups with descending sensitivity to CO2., Method: Brain activation was measured with functional magnetic resonance imaging. Subjects breathed through a mouthpiece delivering a continuous flow of 100% oxygen for two minutes, followed by a hypercapnic gas mixture (7% CO2) for the next two minutes. Statistical analysis was performed using SPM8., Results: There was a significant main effect of group in response to the CO2. Patients show increased brainstem activation in response to hypercapnia compared to controls and divers. Subjective feelings of breathing discomfort were positively correlated with brain activation in the anterior insula in all groups., Conclusion: This is the first study showing that the behavioural response to CO2 that characterises panic disorder patients is likely due to increased neural sensitivity to CO2 at brainstem level.

Exposure to prenatal stress (PS) can predispose individuals to the development of psychopathology later in life. We examined the effects of unpredictable chronic mild stress (CMS) exposure during adolescence on a background of PS in male and female Sprague-Dawley rats. PS induced more anxiety-like behavior in the elevated zero maze in both sexes, an effect that was normalized by subsequent exposure to CMS. Moreover, PS was associated with increased depression-like behavior in the forced swim test in males only. Conversely, sucrose intake was increased in PS males, whilst being decreased in females when consecutively exposed to PS and CMS. Hypothalamo-pituitary-adrenal (HPA) axis reactivity was affected in males only, with higher stress-induced plasma corticosterone levels after PS. Markedly, CMS normalized the effects of PS on elevated zero maze behavior as well as basal and stress-induced plasma corticosterone secretion. At the neurochemical level, both PS and CMS induced various sex-specific alterations in serotonin (5-HT) and tryptophan hydroxylase 2 (TPH2) immunoreactivity in the dorsal raphe nucleus, hippocampus and prefrontal cortex with, in line with the behavioral observations, more profound effects in male offspring. In conclusion, these findings show that prenatal maternal stress in Sprague-Dawley rats induces various anxiety- and depression-related behavioral and neuroendocrine changes, as well as alterations in central 5-HT and TPH2 function, predominantly in male offspring. Moreover, CMS exposure partially normalized the effects of previous PS experience, suggesting that the outcome of developmental stress exposure largely depends on the environmental conditions later in life and vice versa., (© 2013 Elsevier B.V. and ECNP. All rights reserved.)

Background: A strong movement is underway in the United States to increase the percentage of baccalaureate-prepared registered nurses (RNs). However, the percentage of associate's-prepared RNs who go on to pursue baccalaureate education remains low. The authors sought to determine facilitators and barriers that associate's-prepared RNs experience in progressing toward baccalaureate nursing education., Method: A convenience sample (n = 81) of associate's-prepared RNs was used to collect data on perceived facilitators and barriers to progression toward baccalaureate nursing education., Results: Facilitators included a desire for personal growth, professional and career enhancement, programmatic and articulation friendliness, and encouragement by others. Barriers included family and job constraints, financial concerns, and lack of differential treatment between associate's-prepared RNs and baccalaureate-prepared RNs., Conclusion: Although at first glance the identification of four facilitators and three barriers may appear to indicate an advance toward progression to baccalaureate education, the magnitude of the barriers may outweigh that of the facilitators. Therefore, the magnitude of both facilitators and barriers is worthy of future study., (Copyright 2014, SLACK Incorporated.)