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Enriched environment (EE), characterized by multi-sensory stimulation, represents a non-invasive alternative for alleviating epileptic seizures. However, the mechanism by which EE exerts its therapeutic impact remains incompletely understood. Here, it is elucidated that EE mitigates seizure susceptibility through the augmentation of adult neurogenesis within the entorhinal cortex (EC) circuit. A substantial upregulation of adult hippocampal neurogenesis concomitant with a notable reduction in seizure susceptibility has been found following exposure to EE. EE-enhanced adult-born dentate granule cells (abDGCs) are functionally activated during seizure events. Importantly, the selective activation of abDGCs mimics the anti-seizure effects observed with EE, while their inhibition negates these effects. Further, whole-brain c-Fos mapping demonstrates increased activity in DG-projecting EC CaMKIIα + neurons in response to EE. Crucially, EC CaMKIIα + neurons exert bidirectional modulation over the proliferation and maturation of abDGCs that can activate local GABAergic interneurons; thus, they are essential components for the anti-seizure effects mediated by EE. Collectively, this study provides compelling evidence regarding the circuit mechanisms underlying the effects of EE treatment on epileptic seizures, shedding light on the involvement of the EC-DG circuit in augmenting the functionality of abDGCs. This may help for the translational application of EE for epilepsy management., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Objective: Major negative life events, such as trauma exposure, can play a key role in igniting or exacerbating psychopathology. However, few disorders are diagnosed with respect to precipitating events, and the role of these events in the unfolding of new psychopathology is not well understood. The authors conducted a multisite transdiagnostic longitudinal study of trauma exposure and related mental health outcomes to identify neurobiological predictors of risk, resilience, and different symptom presentations., Methods: A total of 146 participants (discovery cohort: N=69; internal replication cohort: N=77) were recruited from emergency departments within 72 hours of a trauma and followed for the next 6 months with a survey, MRI, and physiological assessments., Results: Task-based functional MRI 2 weeks after a motor vehicle collision identified four clusters of individuals based on profiles of neural activity reflecting threat reactivity, reward reactivity, and inhibitory engagement. Three clusters were replicated in an independent sample with a variety of trauma types. The clusters showed different longitudinal patterns of posttrauma symptoms., Conclusions: These findings provide a novel characterization of heterogeneous stress responses shortly after trauma exposure, identifying potential neuroimaging-based biotypes of trauma resilience and psychopathology.

COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was recognised by the WHO as a pandemic in 2020. Host preparation to combat the virus is an important strategy to avoid COVID-19 severity. Thus, the relationship between eating habits, nutritional status and their effects on the immune response and further implications in viral respiratory infections is an important topic discussed in this review. Malnutrition causes the most diverse alterations in the immune system, suppressing of the immune response and increasing the susceptibility to infections such as SARS-CoV-2. On the other hand, obesity induces low-grade chronic inflammation caused by excess adiposity, which increases angiotensin-converting enzyme 2. It decreases the immune response favouring SARS-CoV-2 virulence and promoting respiratory distress syndrome. The present review highlights the importance of food choices considering their inflammatory effects, consequently increasing the viral susceptibility observed in malnutrition and obesity. Healthy eating habits, micronutrients, bioactive compounds and probiotics are strategies for COVID-19 prevention. Therefore, a diversified and balanced diet can contribute to the improvement of the immune response to viral infections such as COVID-19.

Addiction is a chronic brain disease that has dramatic health and socioeconomic consequences worldwide. Multiple approaches have been used for decades to clarify the neurobiological basis of this disease and to identify novel potential treatments. This review summarizes the main brain networks involved in the vulnerability to addiction and specific innovative technological approaches to investigate these neural circuits. First, the evolution of the definition of addiction across the Diagnostic and Statistical Manual of Mental Disorders (DSM) is revised. We next discuss several innovative experimental techniques that, combined with behavioral approaches, have allowed recent critical advances in understanding the neural circuits involved in addiction, including DREADDs, calcium imaging, and electrophysiology. All these techniques have been used to investigate specific neural circuits involved in vulnerability to addiction and have been extremely useful to clarify the neurobiological basis of each specific component of the addictive process. These novel tools targeting specific brain regions are of great interest to further understand the different aspects of this complex disease. This article is part of the special issue on 'Vulnerabilities to Substance Abuse.'., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background and Aims: Internet addiction (IA) is common among young students. This study aimed to examine the influence and mechanisms of IA and susceptible personality traits on the impact of suicidal ideation in adolescent students in China., Methods: This cross-sectional study (09/2012-09/2015) used stratified cluster sampling with "school type" for stratification; 136,266 students from 63 schools completed the questionnaire. Logistic regression analysis was performed to estimate the effect of IA (Young's Internet Addiction Test) and susceptible personality (Barratt impulsiveness scale, Buss & Perry Aggression Questionnaire; and Eysenck Personality Questionnaire-R Short Scale) on suicidal ideation (Scale of Suicidal Ideation)., Results: Suicidal ideation was observed in 20,218 (14.77%) of the students, and IA was detected in 28,836 (21.16%) subjects. Compared with those without IA, students with IA had a higher prevalence of suicidal ideation (P < 0.0001). No planning impulsiveness had a predictive effect on suicidal ideation in the impulsive personality trait, while in the aggressive personality trait, hostility and self-aggression had a predictive effect on suicidal ideation (all P < 0.0001). High psychoticism and neuroticism were impact factors for suicidal ideation, but extroversion was a protective factor (all P < 0.0001)., Discussion: These results highlight the importance of assessing personality traits and reducing IA as a possible means of lessening suicidal ideation. Susceptible personality (such as high psychoticism, high neuroticism, and low extroversion) play a prominent role in influencing the probability of having suicidal behavior among those recently exposed to IA., Conclusions: IA and susceptible personality traits were significantly correlated with suicidal and self-harm ideation among adolescent students.

Background: There is currently no concise systematic review or meta-analysis addressing cardio-metabolic risk factors in women experiencing infertility., Objectives: To determine whether infertile women have higher levels of cardiovascular risk factors compared with fertile women., Search Strategy: We performed a systematic literature search using PubMed, Embase and CINAHL, Scopus and additional manual and bibliographic searches for relevant articles (end search date 6 November 2019)., Selection Criteria: We selected studies that compared cardio-metabolic risk factors in fertile and infertile women of reproductive age., Data Collection and Analysis: At least two authors independently screened potentially eligible studies., Main Results: There was an increased presence of several cardio-metabolic risk factors in infertile women compared with fertile women. Infertile women had statistically significant higher body mass index (BMI), increased total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG) compared with fertile women. Fasting glucose, fasting insulin, homeostatic model assessment of insulin resistance (HOMA-IR) and mean arterial pressure were not found to be different between fertile and infertile women. A subgroup analysis revealed that TC, fasting glucose and fasting insulin were increased, and high-density lipoprotein was decreased only in women with polycystic ovarian syndrome compared with fertile women, whereas BMI, TG and LDL-C were statistically significantly increased in women with any indication of infertility compared with fertile women., Conclusions: Infertile women have a higher level of cardio-metabolic risk factors compared with fertile women. This finding has clinical implications for infertile women in general, and those attempting to conceive through medically assisted reproduction., Tweetable Abstract: Infertile women appear to have a higher level of cardio-metabolic risk factors compared with fertile women., (© 2020 Royal College of Obstetricians and Gynaecologists.)

Shoulder surgery is a primary intervention for shoulder pain, yet many individuals experience persistent postoperative pain. Previously, we found individuals categorized as having a high-risk phenotype (comprised of COMT variation and pain catastrophizing) had approximately double the chance of not reaching a 12-month pain recovery criterion. As a means to better understand the development of persistent postoperative shoulder pain, this study advanced our previous work by examining temporal ordering of postoperative shoulder recovery based on potential mediating factors, and expansion of outcomes to include movement-evoked pain and shoulder active range of motion. Before surgery, individuals were categorized as either high-risk (high pain catastrophizing, COMT-genotype linked to low enzyme activity [n = 41]) or low-risk (low pain catastrophizing, COMT-genotype linked to normal enzyme activity [n = 107]). We then compared potential mediating variables at 3, 6, and 12 months postoperatively 1) endogenous pain modulation defined by a conditioned pain modulation paradigm; and 2) and emotion factors such as anxiety, fear of movement, and depressive symptoms. At 3 months, the high-risk subgroup had higher fear and movement-evoked pain, and causal mediation analysis confirmed the direct effect of risk subgroup on 12-month movement evoked pain. However, baseline to 12-month change in depressive symptoms were found to mediate 53% of the total effect of risk subgroup on 12-month movement-evoked pain. This study introduces potential temporal components and relationships to the development of persistent postoperative shoulder pain, which future studies will confirm and assess for potential therapeutic targets. PERSPECTIVE: This study expands upon postoperative shoulder recovery measures to include movement-evoked pain and depressive symptoms, and provides preliminary indication of temporal ordering to postoperative shoulder recovery for a preidentified high-risk subgroup. Future studies will distinguish temporal components of shoulder surgery that may optimize treatment targets of postoperative recovery., (Copyright © 2019 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Previous findings suggested deficits in pleasure experience in schizophrenia, but little is known in psychosis risk prodrome, especially in adolescence. Aim of this study was (1) to assess anhedonia in distinct help-seeking subgroups of adolescents identified through the ultra-high risk (UHR) criteria, (2) to explore any association of anhedonia with other psychopathological aspects in the UHR group, and (3) to monitor longitudinally the stability of anhedonia in UHR individuals across 1-year follow-up period. 123 participants (13-18 years) completed the Comprehensive Assessment of At-Risk Mental States (CAARMS), the Beck Depression Inventory-II, the Schizotypal Personality Questionnaire-Brief version, the Brief-O-LIFE questionnaire (BOL), and the Brief version of the World Health Organization Quality of Life scale (WHOQOL-BREF). Two different indexes of anhedonia were used: CAARMS "Anhedonia" item 4.3 and BOL "Introvertive Anhedonia" subscale scores. No difference in anhedonia levels between UHR and First Episode Psychosis (FEP) groups was found. UHR adolescents showed higher CAARMS and BOL anhedonia scores than non-UHR/FEP. After 1-year follow-up period, UHR adolescents had a significant decrease in severity only in CAARMS anhedonia subscores. In UHR subgroup, CAARMS anhedonia measures showed significant correlations with impaired role functioning and negative symptoms, while BOL anhedonia was significantly correlated with specific schizotypal personality traits concerning interpersonal deficits. Anhedonia is prominent in the psychosis prodrome, also in adolescence. Its severity is not statistically different from that of FEP adolescents and is related to more severe functioning impairment and a worse quality of life.

Social cognition refers to the mental operations governing social interactions. Recent research has highlighted the importance of social cognition in determining functional outcome in patients with schizophrenia and in psychosis risk populations. The aim of this review is to investigate the neural correlates of social cognition in different psychosis risk populations, potentially representing different levels of risk i.e. high schizotypy (SR), familial risk (FR) and clinical high risk (CHR). PsychINFO, Web of Science and PubMed were systematically searched, and 39 papers were included in the final review. Results in FR samples were highly inconclusive. In SR samples, findings showed a tendency towards increased task related activity in frontal cortex regions. The most consistent results come from CHR samples, where findings suggest increased task related activity in frontal and cingulate cortices. Interestingly, all studies of CHR populations also report increased activity in temporal cortex and abnormal response to neutral stimuli during emotional processing tasks. These findings are discussed in relation to dopamine models of psychosis due to temporal cortex abnormality., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

It is increasingly suggested that personality traits are critical to understanding patterns of cardiovascular stress adaptation. However, studies have focused on higher-order traits with no research having examined underlying facet effects to repeated stress. The examination of facets provides a more granular examination, which has the potential to identify specific personality components that are relevant within the context of psychophysiological stress adaptation. This study objective was to determine if the underlying facets which encapsulate the dimension of emotional stability, are associated with cardiovascular adaptation to recurring stress. Continuous cardiovascular monitoring and psychometric measures were collated from 79 healthy young male and female adults, across a protocol of recurring active stress tasks. Multiple regression analysis revealed that the facet of vulnerability was associated with systolic and diastolic blood pressure adaptation across the protocol. More specifically, vulnerability was negatively associated with adaptation to recurring stress, such that those highest in vulnerability displayed a sensitization to the recurring stressor. No significant effects emerged for any other facet. Importantly, this research adds to the existing literature examining stress adaptation and has implications for future research on the relevance of examining facet effects. This study is the first to implicate the personality facet of vulnerability which encapsulates an individual's tendency to feel unable to cope with stress and becoming hopeless when faced with emergency situations, in the context of cardiovascular stress adaptation. Taken together, this study suggests that the facet of vulnerability is a critical component to consider in the context of cardiovascular stress adaptation., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Some argue that physiological and psychological stress sensitivities contribute causally to schizophrenia. Indeed, evidence shows that those with or at risk for schizophrenia have highly sensitive stress responses. However, it is unclear how psychological stress sensitivity develops. Our aim was to test whether psychological stress sensitization develops longitudinally in association with major life events and components of schizophrenia liability. We expected schizophrenia liability to predict higher psychological stress sensitivity; life events to predict subsequent increases in psychological stress sensitivity; and schizophrenia liability to moderate this relationship., Methods: In a prospective study, undergraduates (n = 184) completed a measure of schizophrenia liability at baseline. Then at 2-month intervals over 6 months, they reported on the occurrence of major life events and completed measures of psychological stress sensitivity., Results: Latent variable growth modelling showed that stress sensitivity increased following incident life events when controlling for baseline life events. Higher cognitive-perceptual and interpersonal scores predicted higher baseline sensitivity. Higher cognitive-perceptual features predicted larger increases in psychological stress sensitivity following life events whereas greater disorganization reduced growth., Conclusions: This evidence is consistent with the idea that psychological sensitization is involved in the development of schizophrenia and suggests an important link between positive features of schizophrenia liability and the magnification of psychological stress sensitivity., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The nucleus accumbens (NAc) plays critical roles in motivated behaviors, including food seeking and feeding. Differences in NAc function contribute to overeating that drives obesity, but the underlying mechanisms are poorly understood. In addition, there is a fair degree of variation in individual susceptibility versus resistance to obesity that is due in part to differences in NAc function. For example, using selectively bred obesity-prone and obesity-resistant rats, we have found that excitability of medium spiny neurons (MSNs) within the NAc core is enhanced in obesity-prone versus -resistant populations, before any diet manipulation. However, it is unknown whether consumption of sugary, fatty "junk food" alters MSN excitability. Here whole cell patch-clamp recordings were conducted to examine MSN intrinsic excitability in adult male obesity-prone and obesity-resistant rats with and without exposure to a sugary, fatty junk food diet. We replicated our initial finding that basal excitability is enhanced in obesity-prone versus obesity-resistant rats and determined that this is due to a lower fast transient potassium current ( I A ) in prone versus resistant groups. In addition, the junk food diet had opposite effects on excitability in obesity-prone versus obesity-resistant rats. Specifically, junk food enhanced excitability in MSNs of obesity-resistant rats; this was mediated by a reduction in I A . In contrast, junk food reduced excitability in MSNs from obesity-prone rats; this was mediated by an increase in inward-rectifying potassium current. Thus individual differences in obesity susceptibility influence both basal excitability and how MSN excitability adapts to junk food consumption. NEW & NOTEWORTHY Medium spiny neurons (MSNs) in the nucleus accumbens of obesity-prone rats are hyperexcitable compared with MSNs from obesity-resistant rats. We found that 10 days of "junk food" exposure reduces MSN excitability in obesity-prone rats by increasing inward-rectifying potassium current and increases MSN excitability in obesity-resistant rats by decreasing fast transient potassium current. These data show that there are basal and junk food diet-induced differences in MSN excitability in obesity-prone and obesity-resistant individuals; this may contribute to previously observed differences in incentive motivation.

Background: Recent studies suggest that people with diabetes or who are at risk of developing diabetes, i.e. prediabetic (preDM), are potentially susceptible to air pollution, but the underlying mechanisms remain unclear because the existing epidemiological studies did not include healthy control groups and only focused on limited health outcomes. We hypothesized that acute exposure to ambient fine particles (PM 2.5 ) will lead to enhanced pulmonary and cardiometabolic changes in preDM than healthy individuals., Methods: We recruited 60 preDM and 60 healthy individuals from a community of 22,343 adults in Beijing China, and arranged each subject to complete up to seven repeated clinical visits with measures of 6 cardiopulmonary biomarkers, 6 cytokines, 4 blood pressure and endothelial function outcomes and 4 glucose metabolism biomarkers.. Moving averaged daily ambient PM 2.5 in preceding 1-14 days was matched to each subject and the PM 2.5 associated effect on multiple biomarkers was estimated and compared between PreDM and healthy subjects based on linear mixed effect model., Results: All the subjects exhibited significant acute elevation of exhaled nitric oxide, white blood cells, neutrophils, interleukin-1α, and glycated haemoglobin with increased exposure to PM 2.5 . PreDM subjects had significant stronger adverse changes compared to healthy subjects in 6 cardiometabolic biomarkers, namely, interleukin-2, interleukin-8, systolic and diastolic blood pressure, augmentation pressure, and glucose. The maximum elevation of these 6 biomarkers in PreDM subjects were 8.6% [CI: 4.1-13.3%], 10.0% [CI: 3.9-16.4%], 1.9% [CI: 0.2-3.6%], 1.2% [CI: - 0.1-2.4%], 5.7% [CI: - 0.1-11.8%], 2.4% [CI: 0.7-4.2%], respectively, per an interquartile increase of ambient PM 2.5 (61.4 μg m - 3 ) throughout the exposure window of the preceding 1-14 days. No significant difference was observed for the changes in pulmonary biomarkers between the two groups., Conclusions: PreDM individuals are more susceptible to the acute cardiometabolic effect of air pollution than the healthy individuals. A considerable public health burden can be inferred, given the high prevalence of prediabetes and the ubiquity of air pollution in China and worldwide.

Although depressive disorders are among the most common disorders in youth, highly efficacious treatments for childhood affective disorders are lacking. There is significant need to better understand the factors that contribute to the development and maintenance of depression in youth so that treatments can be targeted at optimal mechanisms. The aim of the current paper was to synthesize research on cognitive and neurobiological factors associated with youth depression, guided by De Raedt and Koster's model (2010) for vulnerability to depression in adults. Consistent with model predictions, there is evidence that attentional impairments are greatest in the context of negative information, relative to positive or neutral information, and some evidence that attentional deficits are associated with rumination in depressed youth. However, we found little evidence for the model's assumption that attentional bias is an etiological and maintenance factor for depression. There are several other model predictions that require additional study as current data are lacking. Overall, De Raedt and Koster's (2010) integrative cognitive and biological framework has tremendous potential to move the field forward in understanding the development of depression in youth. Additional longitudinal studies incorporating measures across biological and cognitive levels of analysis are needed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Neuroticism, a dispositional trait of heightened negative emotionality, is a vulnerability factor for psychopathology. Given neuroticism's strong association with rumination, a repetitive thought pattern that intensifies and prolongs emotions, some question whether these constructs capture the same or unique information about vulnerability for psychopathology. The present study examined whether neuroticism is genetically and environmentally distinct from two clinically relevant ruminative subtypes-anger and depressive rumination-and whether genetic and environmental influences specific to rumination versus shared with neuroticism overlap with internalizing and externalizing psychopathology. These analyses were conducted on 439 same-sex twin pairs in the Colorado Longitudinal Twin study. Rumination and neuroticism latent variables were created from multiple rumination questionnaires administered at age 23 and shortened Eysenck Personality Questionnaires administered at ages 17 and 21, respectively. Lifetime psychopathology symptoms, assessed by two structured clinical interviews, were used to create ordinal composite variables. Multivariate Cholesky decompositions indicated that neuroticism, anger rumination, and depressive rumination have common genetic and nonshared environmental influences but are differentiated by nonshared environmental influences specific to each ruminative subtype. Genetic influences common to rumination and neuroticism explained considerable variance in internalizing psychopathology, suggesting possible genetic mediation or common genetic causes. Genetic and environmental influences on externalizing psychopathology did not substantially overlap with those on neuroticism and rumination. These findings suggest that rumination and neuroticism share most genetic influences yet are influenced by distinct environmental influences. Furthermore, our results indicate that a comprehensive understanding of transdiagnostic risk factors must include an examination of both genetic and environmental influences. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The Forkhead Box G1 (FOXG1) gene encodes a transcription factor with an essential role in mammalian telencephalon development. FOXG1-related disorders, caused by deletions, intragenic mutations or duplications, are usually associated with severe intellectual disability, autistic features, and, in 87% of subjects, epileptiform manifestations. In a subset of patients with FoxG1 mutations, seizures remain intractable, prompting the need for novel therapeutic options. To address this issue, we took advantage of a haploinsufficient animal model, the FoxG1 +/- mouse. In vivo electrophysiological analyses of FoxG1 +/- mice detected hippocampal hyperexcitability, which turned into overt seizures upon delivery of the proconvulsant kainic acid, as confirmed by behavioral observations. These alterations were associated with decreased expression of the chloride transporter KCC2. Next, we tested whether a triheptanoin-based anaplerotic diet could have an impact on the pathological phenotype of FoxG1 +/- mice. This manipulation abated altered neural activity and normalized enhanced susceptibility to proconvulsant-induced seizures, in addition to rescuing altered expression of KCC2 and increasing the levels of the GABA transporter vGAT. In conclusion, our data show that FoxG1 haploinsufficiency causes dysfunction of hippocampal circuits and increases the susceptibility to a proconvulsant insult, and that these alterations are rescued by triheptanoin dietary treatment., (Copyright © 2019. Published by Elsevier Ltd.)

Chronic obstructive pulmonary disease, a disease of increasing incidence, is related mainly to smoking. Although symptoms only appear at adulthood, the disease can develop from early life events. For example, bronchopulmonary dysplasia, which occurs in preterm infants, is characterized by airspace enlargement and could lead to late lung consequences. Once the lesions are established, no curative treatment is available. Stimulating lung regeneration from endogenous stem cells is therefore an exciting research domain, particularly through the activation of the mesenchymal contingent located in the lung stem cell niche., (Copyright © 2019. Published by Elsevier Masson SAS.)

Cellular parabiosis is tissue-based phenotypic suppression of cellular dysfunction by intercellular molecular traffic keeping initiated age-related diseases and conditions in long latency. Interruption of cellular parabiosis (e.g. by chronic inflammation) promotes the onset of initiated pathologies. The stability of initiated latent cancers and other age-related diseases (ARD) hints to phenotypically silent genome alterations. I propose that latency in the onset of ageing and ARD is largely due to phenotypic suppression of cellular dysfunctions via molecular traffic among neighbouring cells. Intercellular trafficking ranges from the transfer of ions and metabolites (via gap junctions) to entire organelles (via tunnelling nanotubes). Any mechanism of cell-to-cell communication resulting in functional cross-complementation among the cells is called cellular parabiosis. Such 'cellular solidarity' creates tissue homeostasis by buffering defects and averaging cellular functions within the tissues. Chronic inflammation is known to (i) interrupt cellular parabiosis by the activity of extracellular proteases, (ii) activate dormant pathologies and (iii) shorten disease latency, as in tumour promotion and inflammaging. Variation in cellular parabiosis and protein oxidation can account for interspecies correlations between body mass, ARD latency and longevity. Now, prevention of ARD onset by phenotypic suppression, and healing by phenotypic reversion, become conceivable.

Ageing is considered as a snowballing phenotype of the accumulation of damaged dysfunctional or toxic proteins and silent mutations (polymorphisms) that sensitize relevant proteins to oxidative damage as inborn predispositions to age-related diseases. Ageing is not a disease, but it causes (or shares common cause with) age-related diseases as suggested by similar slopes of age-related increase in the incidence of diseases and death. Studies of robust and more standard species revealed that dysfunctional oxidatively damaged proteins are the root cause of radiation-induced morbidity and mortality. Oxidized proteins accumulate with age and cause reversible ageing-like phenotypes with some irreversible consequences (e.g. mutations). Here, we observe in yeast that aggregation rate of damaged proteins follows the Gompertz law of mortality and review arguments for a causal relationship between oxidative protein damage, ageing and disease. Aerobes evolved proteomes remarkably resistant to oxidative damage, but imperfectly folded proteins become sensitive to oxidation. We show that α-synuclein mutations that predispose to early-onset Parkinson's disease bestow an increased intrinsic sensitivity of α-synuclein to in vitro oxidation. Considering how initially silent protein polymorphism becomes phenotypic while causing age-related diseases and how protein damage leads to genome alterations inspires a vision of predictive diagnostic, prognostic, prevention and treatment of degenerative diseases.

Since the circadian system seems to modulate stress responses, this study aimed to evaluate if the combination of circadian strain and stress amplifies changes expected from each factor alone. Control Balb/c mice (12:12-NS) kept in standard 12:12 light:dark cycles (LD) and submitted to no stress procedures (NS) were compared to groups submitted to shortened LD (10:10-NS), chronic mild stress (CMS) but no circadian strain (12:12-CMS), or shortened LD followed by CMS (10:10-CMS). Rest-activity/temperature rhythms and body weight were assessed throughout the experiments. In Experiment 1 mice were submitted to 3 weeks of CMS; in Experiment 2 sucrose preference and light-dark tests were performed. Also, blood samples were collected at the end of Experiment 2 to assess metabolic parameters. Relative amplitude of temperature after CMS was increased only in the 10:10-CMS group, while body weight change was reduced during CMS regardless of LD intervention. During the CMS, the relative amplitude of temperature was negatively correlated with body weight gain. No differences in behavior and metabolic parameters were seen among groups. Identifying suitable research designs to investigate our hypothesis that circadian disturbances may increase vulnerability to stress-induced depression and anxiety is warranted., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Reduced reward responsiveness (RR) may contribute to depression vulnerability. At the neurophysiological level, RR is reliably and validly assessed using the reward positivity (RewP) event-related potential component. We previously identified a blunted RewP in 9-year-old children at high risk for depression due to maternal depression, but the role of RR in pathways from parental history to the development of depressive symptoms has not been examined., Methods: At age 9, never-depressed children (N = 369) completed a task in which RewP was measured in response to monetary reward and loss feedback. Parental history of depression was assessed using semistructured interviews, and children reported on their depressive symptoms. At age 12, youth depressive symptoms were reassessed, along with a self-report measure of RR. We tested RR as a moderator of the effects of parental depression on depressive symptoms at age 12, using both neurophysiological and self-report measures and controlling for age 9 symptoms., Results: Main effects of RR and interactions with maternal depression were significant. Maternal depression predicted greater depressive symptoms in youth with blunted and average RewP but was not a significant predictor in youth with an enhanced RewP. A similar pattern was observed for self-reported RR. The two measures of RR were not correlated with each other and accounted for unique variance in symptoms. Interactions between RR and paternal depression were not significant., Conclusions: Reduced RR, as measured by neurophysiology and self-report, moderates the effects of maternal depression on depressive symptoms in offspring. Assessment of RR along with risk factors such as parental depression may aid in identifying children at greatest risk and enhancing RR could be a potential target for prevention. Results highlight the utility of multimethod approaches for advancing understanding of depression risk., (© 2018 Association for Child and Adolescent Mental Health.)

Non-communicable diseases (NCDs) are a major problem as they are the leading cause of death and represent a substantial economic cost. The 'Developmental Origins of Health and Disease Hypothesis' proposes that adverse stimuli at different life stages can increase the predisposition to these diseases. In fact, adverse in utero programming is a major origin of these diseases due to the high malleability of embryonic development. This review provides a comprehensive analysis of the scientific literature on in utero programming and NCDs highlighting potential medical strategies to prevent these diseases based upon this programming. We fully address the concept and mechanisms involved in this programming (anatomical disruptions, epigenetic modifications and microbiota alterations). We also examine the negative role of in utero programming on the increased predisposition of NCDs in the offspring, which introduces the passive medical approach that consists of avoiding adverse stimuli including an unhealthy diet and environmental chemicals. Finally, we extensively discuss active medical approaches that target the causes of NCDs and have the potential to significantly and rapidly reduce the incidence of NCDs. These approaches can be classified as direct in utero programming modifications and personalized lifestyle pregnancy programs; they could potentially provide transgenerational NCDs protection. Active strategies against NCDs constitute a promising tool for the reduction in NCDs.

Background and Objectives: Trigger warnings notify people of the distress that written, audiovisual, or other material may evoke, and were initially used to provide for the needs of those with posttraumatic stress disorder (PTSD). Since their inception, trigger warnings have become more widely applied throughout contemporary culture, sparking intense controversy in academia and beyond. Some argue that they empower vulnerable individuals by allowing them to psychologically prepare for or avoid disturbing content, whereas others argue that such warnings undermine resilience to stress and increase vulnerability to psychopathology while constraining academic freedom. The objective of our experiment was to investigate the psychological effects of issuing trigger warnings., Methods: We randomly assigned online participants to receive (n = 133) or not receive (n = 137) trigger warnings prior to reading literary passages that varied in potentially disturbing content., Results: Participants in the trigger warning group believed themselves and people in general to be more emotionally vulnerable if they were to experience trauma. Participants receiving warnings reported greater anxiety in response to reading potentially distressing passages, but only if they believed that words can cause harm. Warnings did not affect participants' implicit self-identification as vulnerable, or subsequent anxiety response to less distressing content., Limitations: The sample included only non-traumatized participants; the observed effects may differ for a traumatized population., Conclusions: Trigger warnings may inadvertently undermine some aspects of emotional resilience. Further research is needed on the generalizability of our findings, especially to collegiate populations and to those with trauma histories., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose of Review: This review offers a perspective of the utility of rodent models of stress for identifying sources of individual vulnerability to depression and cardiovascular disease comorbidity., Recent Findings: Differential stress susceptibility is found in rodents exposed to repeated social defeat as a function of their coping style. Specifically, passive coping rodents show an increase in inflammatory processes within the brain that favour the development of depressive-like symptoms and cardiovascular abnormalities. Similarly, only a sub-group of rats develops depressive-like symptoms following chronic mild stress exposure. Cardiovascular changes differ depending on individual stress susceptibility and may be related to an imbalance in the autonomic regulation of cardiac function in stress vulnerable subjects. Rodent models of stress that take into account individual phenotypic variations are useful for a better understanding of the role of neuroinflammatory and autonomic processes in the development of comorbid depression and cardiovascular disease under stressful conditions.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections and causes up to 200,000 infant deaths a year worldwide. The average rate of hospitalization for severe RSV infection is 5 per 1000 children, and the rate is three-times higher in those with congenital heart disease (CHD). Palivizumab, a monoclonal antibody, reduces hospitalization rates and intensive care admissions. It is used prophylactically and is administered as monthly doses during the RSV season. Hemodynamically unstable CHD is the most susceptible CHD to a severe episode of RSV infection. This review explores current evidence surrounding therapies, patterns of infection and identifies groups which may still be vulnerable to severe RSV infection.

Background: Rheumatoid arthritis (RA) patients may suffer cardiovascular (CV) events much more than the general population, and CV disease is the leading cause of death in patients with RA. Our hypothesis was that impaired function of endothelial progenitor cells may contribute to endothelial dysfunction and the clinical CV events of patients with RA., Methods: About 27 RA patients (9 males and 18 females) with an active disease and 13 healthy subjects who served as the control group (nine males and four females) were enrolled to this prospective study. The ability to grow in culture colony-forming units of endothelial progenitor cells (CFU-EPCs) was measured, as well as their endothelial function using high-resolution ultrasonography of the brachial artery, and levels of C reactive protein (CRP) in the serum. For statistical analysis, we used the Student's t-test., Results: As a group, patients with RA were older (P < 0.0001), had severe endothelial dysfunction (P<0.0001), with impaired ability to grow CFU-EPCs (P<0.0001), and a higher inflammatory state (P = 0001). No difference was observed in BMI. All RA patients had an active disease (DAS28 3.9 ± 0.9) for 9.2 ± 6.5 years. The same differences were observed in both genders., Conclusions: Patients with RA had an impaired ability to grow EPCs and severe endothelial dysfunction. Inability to grow colonies of EPCs reflects the impaired regenerative capacity of patients with RA and may explain the endothelial dysfunction and the high CV event rate among patients with RA., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Association of Physicians. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Pneumonia is a complex pulmonary disease in need of new clinical approaches. Although triggered by a pathogen, pneumonia often results from dysregulations of host defense that likely precede infection. The coordinated activities of immune resistance and tissue resilience then dictate whether and how pneumonia progresses or resolves. Inadequate or inappropriate host responses lead to more severe outcomes such as acute respiratory distress syndrome and to organ dysfunction beyond the lungs and over extended time frames after pathogen clearance, some of which increase the risk for subsequent pneumonia. Improved understanding of such host responses will guide the development of novel approaches for preventing and curing pneumonia and for mitigating the subsequent pulmonary and extrapulmonary complications of pneumonia. The NHLBI assembled a working group of extramural investigators to prioritize avenues of host-directed pneumonia research that should yield novel approaches for interrupting the cycle of unhealthy decline caused by pneumonia. This report summarizes the working group's specific recommendations in the areas of pneumonia susceptibility, host response, and consequences. Overarching goals include the development of more host-focused clinical approaches for preventing and treating pneumonia, the generation of predictive tools (for pneumonia occurrence, severity, and outcome), and the elucidation of mechanisms mediating immune resistance and tissue resilience in the lung. Specific areas of research are highlighted as especially promising for making advances against pneumonia.

Background: Acute high level carbon monoxide (CO) exposure can cause immediate cardio-respiratory arrest in anyone, but the effects of lower level exposures in susceptible persons are less well known. The percentage of CO-bound hemoglobin in blood (carboxyhemoglobin; COHb) is a marker of exposure and potential health outcomes. Indoor air quality guidelines developed by the World Health Organization and Health Canada, among others, are set so that CO exposure does not lead to COHb levels above 2.0%, a target based on experimental evidence on toxicodynamic relationships between COHb and cardiac performance among persons with cardiovascular disease (CVD). The guidelines do not consider the role of pathophysiological influences on toxicokinetic relationships. Physiological deficits that contribute to increased CO uptake, decreased CO elimination, and increased COHb formation can alter relationships between CO exposures and resulting COHb levels, and consequently, the severity of outcomes. Following three fatalities attributed to CO in a long-term care facility (LTCF), we queried whether pathologies other than CVD could alter CO-COHb relationships. Our primary objective was to inform susceptibility-specific modeling that accounts for physiological deficits that may alter CO-COHb relationships, ultimately to better inform CO management in LTCFs., Methods: We reviewed experimental studies investigating relationships between CO, COHb, and outcomes related to health or physiological outcomes among healthy persons, persons with CVD, and six additional physiologically susceptible groups considered relevant to LTCF residents: persons with chronic obstructive pulmonary disease (COPD), anemia, cerebrovascular disease (CBD), heart failure, multiple co-morbidities, and persons of older age (≥ 60 years)., Results: We identified 54 studies published since 1946. Six studies investigated toxicokinetics among healthy persons, and the remaining investigated toxicodynamics, mainly among healthy persons and persons with CVD. We identified one study each of CO dynamics in persons with COPD, anemia and persons of older age, and no studies of persons with CBD, heart failure, or multiple co-morbidities. Considerable heterogeneity existed for exposure scenarios and outcomes investigated., Conclusions: Limited experimental human evidence on the effects of physiological deficits relevant to CO kinetics exists to support indoor air CO guidelines. Both experimentation and modeling are needed to assess how physiological deficits influence the CO-COHb relationship, particularly at sub-acute exposures relevant to indoor environments. Such evidence would better inform indoor air quality guidelines and CO management in indoor settings where susceptible groups are housed.

Research on nightmares has largely focused on the nightmare itself and its associated negative consequences, framing nightmare sufferers as victims of a diathesis-stress induced form of psychopathology. However, there is evidence that frequent nightmare recallers are sensitive to a wide range of sensory and emotional experiences, and report vivid, bizarre and even intensely positive dream and daydream experiences. We propose sensory processing sensitivity as a novel trait marker that underlies the unique symptoms and imaginative richness found in nightmare-prone individuals. Sensory processing sensitivity describes an increased emotional reactivity, greater depth of processing, and subtle awareness of environmental stimuli-it is a 'for better and for worse' trait that is associated with positive outcomes in conditions of support, but also confers a tendency to be easily overwhelmed by stressors and adversity. This novel approach places nightmare-prone individuals within the broader framework of Differential Susceptibility and raises the possibility that they may benefit especially from supportive environments-a possibility that is particularly relevant for developing future treatment approaches., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Patients with post-traumatic stress disorder have a heightened vulnerability to developing substance use disorders; however, the biological underpinnings of this vulnerability remain unresolved. We used the predator odor stress model of post-traumatic stress disorder with segregation of subjects as susceptible or resilient based on elevated plus maze behavior and context avoidance. We then determined behavioral and neurochemical differences across susceptible, resilient, and control populations using a panel of behavioral and neurochemical assays. Susceptible subjects showed a significant increase in the motoric and dopaminergic effects of cocaine, and this corresponded with heightened motivation to self-administer cocaine. Resilient subjects did not show differences in the motoric effects of cocaine, in dopamine signaling in vivo, or in any measure of cocaine self-administration. Nonetheless, we found that these animals displayed elevations in both the dopamine release-promoting effects of cocaine and dopamine autoreceptor sensitivity ex vivo. Our results suggest that the experience of traumatic stress may produce alterations in dopamine systems that drive elevations in cocaine self-administration behavior in susceptible subjects, but may also produce both active and passive forms of resilience that function to prevent gross changes in cocaine's reinforcing efficacy in resilient subjects., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background Altered autobiographical memory (ABM) functioning has been implicated in the pathogenesis of depression and post-traumatic stress disorder and may represent one mechanism by which childhood maltreatment elevates psychiatric risk. Aims To investigate the impact of childhood maltreatment on ABM functioning. Method Thirty-four children with documented maltreatment and 33 matched controls recalled specific ABMs in response to emotionally valenced cue words during functional magnetic resonance imaging. Results Children with maltreatment experience showed reduced hippocampal and increased middle temporal and parahippocampal activation during positive ABM recall compared with peers. During negative ABM recall they exhibited increased amygdala activation, and greater amygdala connectivity with the salience network. Conclusions Childhood maltreatment is associated with altered ABM functioning, specifically reduced activation in areas encoding specification of positive memories, and greater activation of the salience network for negative memories. This pattern may confer latent vulnerability to future depression and post-traumatic stress disorder., Competing Interests: Declaration of interestNone., (© The Royal College of Psychiatrists 2017.)

Epilepsy after pediatric traumatic brain injury (TBI) is associated with poor quality of life. This study aimed to characterize post-traumatic epilepsy in a mouse model of pediatric brain injury, and to evaluate the role of interleukin-1 (IL-1) signaling as a target for pharmacological intervention. Male mice received a controlled cortical impact or sham surgery at postnatal day 21, approximating a toddler-aged child. Mice were treated acutely with an IL-1 receptor antagonist (IL-1Ra; 100 mg/kg, s.c.) or vehicle. Spontaneous and evoked seizures were evaluated from video-EEG recordings. Behavioral assays tested for functional outcomes, postmortem analyses assessed neuropathology, and brain atrophy was detected by ex vivo magnetic resonance imaging. At 2 weeks and 3 months post-injury, TBI mice showed an elevated seizure response to the convulsant pentylenetetrazol compared with sham mice, associated with abnormal hippocampal mossy fiber sprouting. A robust increase in IL-1β and IL-1 receptor were detected after TBI. IL-1Ra treatment reduced seizure susceptibility 2 weeks after TBI compared with vehicle, and a reduction in hippocampal astrogliosis. In a chronic study, IL-1Ra-TBI mice showed improved spatial memory at 4 months post-injury. At 5 months, most TBI mice exhibited spontaneous seizures during a 7 d video-EEG recording period. At 6 months, IL-1Ra-TBI mice had fewer evoked seizures compared with vehicle controls, coinciding with greater preservation of cortical tissue. Findings demonstrate this model's utility to delineate mechanisms underlying epileptogenesis after pediatric brain injury, and provide evidence of IL-1 signaling as a mediator of post-traumatic astrogliosis and seizure susceptibility. SIGNIFICANCE STATEMENT Epilepsy is a common cause of morbidity after traumatic brain injury in early childhood. However, a limited understanding of how epilepsy develops, particularly in the immature brain, likely contributes to the lack of efficacious treatments. In this preclinical study, we first demonstrate that a mouse model of traumatic injury to the pediatric brain reproduces many neuropathological and seizure-like hallmarks characteristic of epilepsy. Second, we demonstrate that targeting the acute inflammatory response reduces cognitive impairments, the degree of neuropathology, and seizure susceptibility, after pediatric brain injury in mice. These findings provide evidence that inflammatory cytokine signaling is a key process underlying epilepsy development after an acquired brain insult, which represents a feasible therapeutic target to improve quality of life for survivors., (Copyright © 2017 the authors 0270-6474/17/377864-14$15.00/0.)

Age-dependent susceptibility to nervous necrosis virus (NNV) was demonstrated for barramundi (Lates calcarifer). The experiment used juvenile barramundi produced from a single spawning that were challenged consecutively by immersion with a redspotted grouper nervous necrosis virus (RGNNV) isolate. The dose and environmental conditions (35 ppt salinity and 30 °C) were constant. Fish and water were sampled longitudinally for histopathology and RT-qPCR analysis to examine the evolution of the disease, virus replication, immune response and release of virus into water. Viral nervous necrosis (VNN) disease occurred in barramundi challenged at 3 and 4 weeks of age while fish challenged at 5, 7 and 9 weeks of age developed subclinical infection. Replication of NNV occurred faster and the concentration of virus reached higher concentrations in the younger fish with clinical disease. Virus isolation and qPCR tests indicated that infectious NNV was released from carcasses into water when fish were affected with clinical disease but not when NNV infection was subclinical. Based on these observations, we consider that carcasses from clinically infected fish have a potentially important role in the horizontal transmission of NNV, and barramundi juveniles should be protected from exposure to NNV until they are 5 weeks of age and reach the disease resistance threshold., (© 2017 John Wiley & Sons Ltd.)

Objective: This preliminary study investigated electrophysiological and microstructural features of sleep in children and adolescents 4-18 years of age who were born to depressed mothers., Methods: A total of 31 healthy subjects (15 male and 16 female) participated in the study. In this sample, 20 children born to mothers diagnosed with Major Depressive Disorder (MDD) were designated as "high-risk"; 11 children born to mothers without a personal history of depression were designated as "low-risk." Polysomnography including three-channel electroencephalography (EEG) was recorded for one night at the Pediatric Sleep Unit of the University Hospital of Lyon, France. Clinical and demographic data were collected. Sleep architectural parameters were analyzed. Sleep microstructure was assessed with the scoring of cyclic alternating pattern (CAP) and CAP measures were calculated. Spectral analysis was performed, and mean EEG band power was computed for each sleep stage. Sleep electrophysiological features (slow waves and sleep spindles) were detected, and related parameters were analyzed. Data were compared between high- and low-risk groups using Student t tests., Results: A reduction in low-frequency spindle activity and slow spindles spatio-temporal characteristics over frontal and central derivations, and an altered distribution of CAP phase A subtypes (reduction of A1 over A2-3 ratio) were observed in the high-risk group relative to the low-risk group., Conclusion: Limited spindles generation and increased non-rapid eye movement sleep instability, observed in children born to depressed mothers, might reflect functional anomalies in cortical plasticity that could represent a pathogenic factor or an epiphenomenon for MDD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In 1890, Robert Koch has formulated postulates describing what criteria a parasite has to fulfil to qualify as an aetiological agent for an infectious disease. Since then Koch's postulates have experienced reformulations by nearly every generation of microbiologists reflecting new discoveries changing the understanding of infectious diseases pathogenesis. The latest addition to this discussion is the role of the host commensal microbiota in turning infections into disease. After an overview of the historical developments of the postulates, data on diarrhoea aetiology from Bangladesh with respect to Koch's postulates were analysed. In countries with a low environmental hygiene standard, some recognized bacterial enteropathogens appear as a necessary, but not sufficient condition for diarrhoea. The possibility emerges that the loss of a physiological commensal gut microbiota equilibrium ('dysbiosis') is an important co-factor for some bacterial pathogens to induce diarrhoea. Koch's hypothesis '1 pathogen + 1 host = 1 disease' is therefore better formulated as 'X (pathogen/s) + Y (local milieu) + Z (individual host susceptibility) = disease'., (© 2017 Society for Applied Microbiology and John Wiley & Sons Ltd.)

Differences of Sex Development (DSD) includes a wide spectrum of etiologies and phenotypes. A subset of individuals with DSDs are predisposed to gonadal germ cell tumor (GCT). In this setting, GCT risk varies widely, depending on the DSD molecular etiology and penetrance. Prognostication based on molecular diagnosis remains challenging, as natural history data specific to recently identified molecular causes of DSD is lacking. In this review, we provide a framework for the clinical geneticist to consider GCT tumor risk in the patient with DSD. We discuss germ cell development and etiology of GCT growth, along with parameters to consider when recommending prophylactic gonadectomy including fertility, hormonal output, and malignant GTC treatment outcomes. Shortly after the 2006 reorganization of DSD nomenclature, literature reviews of natural history publications stratified GCT risk by a chromosomal, pathological, and hormonal taxonomy. Our 2017 literature review reveals a larger body of publications. However, the broad DSD GCT risk stratification within the 2006 taxonomy remains stable. We discuss precise GCT risk assessment for specific diagnoses, including androgen insensitivity, Smith-Lemli-Opitz, and 46,XY with MAP3K1 mutations and gonadal dysgenesis, as examples. We also examine the GCT risk in non-DSD syndromes, in addition to the cancer risks in DSD patients with dimorphic gonads and genitalia. This review is intended to provide a nuanced assessment of relative germ cell tumor risk in the DSD patient, including modern precise molecular diagnosis, for use by the clinical geneticist., (© 2017 Wiley Periodicals, Inc.)

High-altitude pulmonary edema (HAPE) is a potentially fatal condition affecting high-altitude sojourners. The biggest predictor of HAPE development is a history of prior HAPE. Magnetic resonance imaging (MRI) shows that HAPE-susceptible (with a history of HAPE), but not HAPE-resistant (with a history of repeated ascents without illness) individuals develop greater heterogeneity of regional pulmonary perfusion breathing hypoxic gas (O 2 = 12.5%), consistent with uneven hypoxic pulmonary vasoconstriction (HPV). Why HPV is uneven in HAPE-susceptible individuals is unknown but may arise from regionally heterogeneous ventilation resulting in an uneven stimulus to HPV. We tested the hypothesis that ventilation is more heterogeneous in HAPE-susceptible subjects ( n = 6) compared with HAPE-resistant controls ( n = 7). MRI specific ventilation imaging (SVI) was used to measure regional specific ventilation and the relative dispersion (SD/mean) of SVI used to quantify baseline heterogeneity. Ventilation heterogeneity from conductive and respiratory airways was measured in normoxia and hypoxia (O 2 = 12.5%) using multiple-breath washout and heterogeneity quantified from the indexes S cond and S acin , respectively. Contrary to our hypothesis, HAPE-susceptible subjects had significantly lower relative dispersion of specific ventilation than the HAPE-resistant controls [susceptible = 1.33 ± 0.67 (SD), resistant = 2.36 ± 0.98, P = 0.05], and S acin tended to be more uniform (susceptible = 0.085 ± 0.009, resistant = 0.113 ± 0.030, P = 0.07). S cond was not significantly different between groups (susceptible = 0.019 ± 0.007, resistant = 0.020 ± 0.004, P = 0.67). S acin and S cond did not change significantly in hypoxia ( P = 0.56 and 0.19, respectively). In conclusion, ventilation heterogeneity does not change with short-term hypoxia irrespective of HAPE susceptibility, and lesser rather than greater ventilation heterogeneity is observed in HAPE-susceptible subjects. This suggests that the basis for uneven HPV in HAPE involves vascular phenomena. NEW & NOTEWORTHY Uneven hypoxic pulmonary vasoconstriction (HPV) is thought to incite high-altitude pulmonary edema (HAPE). We evaluated whether greater heterogeneity of ventilation is also a feature of HAPE-susceptible subjects compared with HAPE-resistant subjects. Contrary to our hypothesis, ventilation heterogeneity was less in HAPE-susceptible subjects and unaffected by hypoxia, suggesting a vascular basis for uneven HPV.

Obesity and its consequences can damage the kidney over time. However, less is known about the impact of developing overweight/obesity during childhood on the kidney in adulthood and the renal impact of a superimposed acute kidney injury (AKI). This study evaluated the effect of obesity induced by a high-fat diet initiated soon after weaning on the adult life of mice and their response to superimposed nephrotoxic effects of cisplatin. C57BL/6 post-weaning mice (3 weeks old) were divided into a control group (CT, n = 12) and a high-fat diet group (HF, n = 12). After 9 weeks, animals were further divided into the following groups: CT, CT treated with a single dose of cisplatin (CTCis, 20 mg/kg, i.p.), HF and HF treated with cisplatin (HFCis). The HF group exhibited higher body weight gain compatible with a moderate obesity. Obese mice presented increased visceral adiposity, hyperkalemia, sodium retention, glomerular hyperfiltration and proteinuria, without any significant changes in blood pressure and glycemia. AKI induced by cisplatin was exacerbated in obese animals with a 92% reduction in the GFR versus a 31% decrease in the CTCis group; this sharp decline resulted in severely elevated serum creatinine and urea levels. Acute tubular necrosis induced by cisplatin was worsened in obese mice. The HFCis group exhibited robust systemic and intrarenal inflammation that was significantly higher than that in the CTCis group; the HFCis group also showed a higher degree of renal oxidative stress. In conclusion, the moderate degree of obesity induced shortly after weaning resulted in mild early renal alterations, however, obese young animals were prone to develop a much more severe AKI induced by cisplatin.

Basement membranes (BMs) are thin, dense sheets of specialized, self-assembled extracellular matrix that surround most animal tissues (Figure 1, top). The emergence of BMs coincided with the origin of multicellularity in animals, suggesting that they were essential for the formation of tissues. Their sheet-like structure derives from two independent polymeric networks - one of laminin and one of type IV collagen (Figure 1, bottom). These independent collagen and laminin networks are thought to be linked by several additional extracellular matrix proteins, including nidogen and perlecan (Figure 1, bottom). BMs are usually associated with cells and are anchored to cell surfaces through interactions with adhesion receptors and sulfated glycolipids (Figure 1, bottom). Various combinations of other proteins, glycoproteins, and proteoglycans - including fibulin, hemicentin, SPARC, agrin, and type XVIII collagen - are present in BMs, creating biochemically and biophysically distinct structures that serve a wide variety of functions. BMs have traditionally been viewed as static protein assemblies that provide structural support to tissues. However, recent studies have begun to uncover dynamic, active roles for BMs in many developmental processes. Here, we discuss established and emerging roles of BMs in development, tissue construction, and tissue homeostasis. We also explore how cells traverse BM barriers, the roles of BMs in human diseases, and future directions for the field., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: The liver stages of Plasmodium parasites are important targets for the discovery and development of prophylactic drugs., Methods: A real-time in vivo imaging system was used to determine the level of luminescence measured from firefly luciferase expression by sporozoites developing in hepatocytes in different strains of mice., Results: The luminescence values (photon counts/sec) measured from the anatomical liver location in the untreated mice infected with 10,000 Plasmodium berghei sporozoites were 8.15 × 10 5 for C57BL/6 Albino, 2.12 × 10 5 for C3H/HeNCrL, 0.91 × 10 5 for C57BL/6 WT, 0.28 × 10 5 for BALB/c, and 0.16 × 10 5 for ICR/CD-1 mice. This data suggests that the C57BL/6 Albino strain is most susceptible to luminescent photon, mainly because the less light scattering and absorption from deeper tissues and the skin in the strain of mouse. The photon count observed in black C57BL/6 wild type mice was shown to be 88.83% lower compared to C57BL/6 Albino mice. Although the highest growth rate of sporozoites in hepatocytes was found for C57BL/6 wild type mice in this study, the black skin of this mouse significantly reduced parasite-associated bioluminescence., Conclusions: The minimal light scattering and absorption and also enhanced susceptibility to liver infection of C57BL/6 Albino mice makes this strain preferable sensitivity for discovery and development of prophylactic antimalarial drugs., (Reprint & Copyright © 2017 Association of Military Surgeons of the U.S.)

More than 5 million Americans are living with Alzheimer's disease (AD) today, and nearly two-thirds of Americans with AD are women. This sex difference may be due to the higher longevity women generally experience; however, increasing evidence suggests that longevity alone is not a sufficient explanation and there may be other factors at play. The Alzheimer's Association convened an expert think tank to focus on the state of the science and level of evidence around gender and biological sex differences for AD, including the knowledge gaps and areas of science that need to be more fully addressed. This article summarizes the think tank discussion, moving forward a research agenda and funding program to better understand the biological underpinnings of sex- and gender-related disparities of risk for AD., (Copyright © 2016 The Alzheimer's Association. All rights reserved.)

While several epidemiological studies have investigated the relationship between height and risk for thyroid cancer, the results were inconsistent. In the present study, a systematic review and meta-analysis of prospective cohort studies was conducted to assess the impact of height on thyroid cancer risk. Online databases were searched up to December 30, 2014, for prospective cohort studies on the association between height and thyroid cancer risk. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a random-effects model of meta-analysis. In all, 11 articles were included in this meta-analysis, including 15 prospective cohort studies, containing 6,695,593 participants and 7,062 cases of thyroid cancer. By comparing the highest versus the lowest categories of height, we reported that risk of thyroid cancer was increased with height in both men (summary RR = 1.40, 95%CI 1.09-1.78, p = 0.008) and women (summary RR = 1.54, 95%CI 1.30-1.83, p < 0.001). The summary RR of thyroid cancer per 5-cm increase in height was 1.16 (95%CI 1.09-1.23, p < 0.001). The results were similar among men (per 5-cm increase RR = 1.13, 95%CI 1.03-1.23, p = 0.011) and women (per 5-cm increase RR = 1.18, 95%CI 1.10-1.27, p < 0.001). No obvious risk of publication bias was observed. Our meta-analysis provides strong evidence for a dose-response relationship between height and risk of thyroid cancer in both men and women., (© 2015 UICC.)

Background: Congenital long QT syndrome (LQTS) is a familial arrhythmogenic cardiac channelopathy characterized by prolonged ventricular repolarization and increased risk of torsades de pointes-mediated syncope, seizures, and sudden cardiac death (SCD). QT prolongation corrected for heart rate (QTc) is an important diagnostic and prognostic feature in LQTS. Obstructive sleep apnea (OSA) has been increasingly implicated in the pathogenesis of cardiovascular disease, including arrhythmias and SCD. We tested the hypothesis that the presence of concomitant OSA in patients with LQTS is associated with increased QT intervals, both during sleep and while awake., Methods and Results: Polysomnography with simultaneous overnight 12-lead electrocardiography (ECG) was recorded in 54 patients with congenital LQTS and 67 control subjects. OSA was diagnosed as apnea-hypopnea index (AHI) ≥ 5 events/h for adults and AHI > 1 event/h for children. RR and QT intervals were measured from the 12-lead surface ECG. QTc was determined by the Bazett formula. Respiratory disturbance index, AHI, and arousal index were significantly increased in patients with LQTS and with OSA compared to those without OSA and control subjects. QTc during different sleep stages and while awake was also significantly increased in patients with LQTS and OSA compared to those without OSA. Severity of OSA in patients with LQTS was directly associated with the degree of QTc., Conclusions: The presence and severity of obstructive sleep apnea (OSA) in patients with congenital long QT syndrome (LQTS) is associated with increased QT prolongation corrected for heart rate, which is an important biomarker of sudden cardiac death (SCD). Treatment of OSA in LQTS patients may reduce QT prolongation, thus reducing the risk of LQT-triggered SCD., (© 2015 Associated Professional Sleep Societies, LLC.)

In the study reported here, we examined the effects of fetal exposure to a synthetic stress hormone (synthetic glucocorticoids) on children's susceptibility to postnatal sociodemographic adversity. We recruited children who were born healthy and at term. Twenty-six had been treated with steroid hormones (glucocorticoids) during the prenatal period, and 85 had not. Only children exposed to both prenatal stress hormones and postnatal sociodemographic adversity showed impaired performance on standardized tests of memory function. The association was specific to long-term memory. General intellectual functioning and expressive language were not affected by fetal glucocorticoid exposure. Results were independent of maternal intelligence and maternal depression at the time of the study. These findings are consistent with a vulnerability-stress model: Prenatal exposure to synthetic stress hormones is associated with increased susceptibility to subsequent adversity, with consequences for cognitive functioning that persist 6 to 10 years after birth., (© The Author(s) 2015.)

A study of broiler breeder eggs differing in eggshell matrix optical density was conducted to determine the association of eggshell structural quality and the risk of disease in broilers. A total of 10 000 eggs from a broiler breeder flock were examined according to the pre-established criteria, and allocated to groups classified as having a high or low density shell matrix. The eggs from respective groups were incubated and hatched in a commercial hatchery. Samples of unhatched eggs from each group were subjected to detailed examination to establish the cause of reproductive failure. First, quality chicks from each group were raised as separate flocks in a commercial broiler barn. Group performance, morbidity, and mortality were monitored throughout the growth period. All birds were processed in a commercial plant, and condemnation data were compiled. There were significantly more unhatched eggs, and fewer quality chicks in the group classified as having a low density eggshell matrix, in comparison to the high-density group. Embryo pathology accounted for a large proportion of the overall reproductive failure in both groups, with a large proportion of embryos showing anatomical anomalies. The eggs and embryos from the low-density eggshell matrix group were three times more likely to be infected. Significantly higher production losses associated with mortality/morbidity, and condemnations of carcasses at processing were observed in broilers from the low-density eggshell group compared with the high-density eggshell group. It is concluded that common metabolic/physiological changes in breeder hens associated with eggshell pathology may be also risk factors linked with predisposition of broiler chicks to some health problems.

Background: Injectable hormonal contraception may increase women's risk of HIV acquisition and can affect biological risk factors in animal models of HIV. We established, for the first time, a model to investigate whether combined oral contraceptives (COC) alter SHIV susceptibility in macaques., Methods: Seven pigtail macaques were administered a monophasic levonorgestrel (LNG)/ethinyl estradiol (EE) COC at 33% or 66% of the human dose for 60 days. Menstrual cycling, vaginal epithelial thickness, and other SHIV susceptibility factors were monitored for a mean of 18 weeks., Results: Mean vaginal epithelial thicknesses were 290.8 μm at baseline and 186.2 μm during COC (P = 0.0141, Mann-Whitney U-test). Vaginal pH decreased from 8.5 during treatment to 6.5 post-treatment (0.0176 two-tailed t-test). Measured microflora was unchanged., Conclusions: COC caused thinning of the vaginal epithelium and vaginal pH changes, which may increase SHIV susceptibility. 0.033 mg LNG + .0066 mg EE appeared effective in suppressing ovulation., (Published 2014. This article is a U.S. Government work and is in the public domain in the USA.)

The schizotypy construct focuses attention on the liability to develop schizophrenia-spectrum disorders, yet traditionally, the schizotypy models have put more emphasis on stress-vulnerability interactions rather than developmental dynamics of emerging risk for psychopathology. Indeed, developmental accounts of this emerging personality trait have rarely been explicitly formulated. In this position article, we wish to convey some of the basic developmental tenets of schizotypy, and how they can inform high-risk research. Firstly, we tackle the state vs trait issue to outline the possible relationship between high-risk states and trait schizotypy. Second, we review the evidence suggesting that the consolidation of schizotypy, encompassing its 3 main dimensions, could be considered as a developmental mediator between very early risk factors and transition into high-risk states. Importantly, developmental dynamics between endophenotypes, as well as transactional and epigenetics mechanisms should enter modern conceptualizations of schizotypy. Finally, we present a developmental psychopathology perspective of schizotypy sensitive to both the multifinality and equifinality of schizophrenia-spectrum disorders. We conclude that schizotypy represents a crucial construct in a fully-developmental study of schizophrenia-spectrum disorders., (© The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Introduction: Modifications of hearth rate variability (HRV) constitute a marker of the autonomic nervous system (ANS) deregulation, a promising pathway linking job strain (JS) and cardiovascular diseases (CVD). The study objective is to assess whether exposures to recent and prolonged JS reduce time-domain HRV parameters on working days (WD) among CVD-susceptible nurses and whether the association also persists on resting days (RD)., Material and Methods: 313 healthy nurses were investigated twice with one year interval to assess JS based on the demand-control and the effort-reward models. 36, 9 and 16 CVD-susceptible nurses were classified as low JS in both surveys (stable low strain - SLS), recent high JS (high JS at the second screening only-RHS) and prolonged high JS (high strain in both surveys-PHS), respectively. In 9, 7 and 10 of them, free from comorbidities/treatments interfering with HRV, two 24-h ECG recordings were performed on WD and RD. Differences in the time domain HRV metrics among JS categories were assessed using ANCOVA, adjusted for age and smoking., Results: In the entire sample (mean age: 39 years, 83% females) the prevalence of high job strain was 38.7% in the second survey. SDNN (standard deviation of all normal RR intervals) on WD significantly declined among JS categories (p = 0.02), with geometric mean values of 169.1, 145.3 and 128.9 ms in SLS, RHS, PHS, respectively. In the PHS group, SDNN remained lower on RD as compared to the low strain subjects (142.4 vs. 171.1 ms, p = 0.02). Similar findings were found for the SDNN&#95;Index, while SDANN (standard deviation of average RR intervals in all 5 min segments of registration) mean values reduced in the PHS group during WD only., Conclusions: Our findings suggest that persistent JS lowers HRV time-domain parameters, supporting the hypothesis that the ANS disorders may play an intermediate role in the relationship between work stress and CVD., (This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.)