Etiological Models Research Articles

Body image facets as predictors of muscularity-oriented disordered eating in women: Findings from a prospective study

Muscularity-oriented disordered eating (MODE) is becoming increasingly common among women and is characterized by dietary alterations (e.g., blending meals into liquid form to increase caloric intake) aimed towards gaining lean muscle. In light of the mental health risks associated with these pathological eating behaviors, understanding factors that influence women’s engagement in MODE is essential for preventative efforts and for informing etiological models. Body image is a possible factor that may influence MODE in light of evidence of cross-sectional associations and its importance as a key risk factor for thinness-oriented disordered eating. However, research is yet to test for prospective relationships between the various components of body image (i.e., body dissatisfaction, body appreciation) and MODE, which was the aim of this study. Adult women completed the online study measures at baseline (Time 1 [T1]; n = 1760) and three-month follow-up (Time 2 [T2]; n = 1208). A series of univariate regressions revealed that all body image facets (i.e., preoccupation, overvaluation, dissatisfaction, body image appreciation and feeling fat) at T1 significantly predicted MODE at T2. However, multivariable models revealed that only preoccupation and body appreciation uniquely predicted MODE at T2, with a positive relationship observed for preoccupation and a negative one for body appreciation. This is the first study to establish temporal relationships between distinct body image facets and MODE. Pending replication, findings highlight possible targets for addressing MODE in women.

Impact of genetic factors on antioxidant rescue of maternal diabetes-associated congenital heart disease.

Congenital heart disease (CHD) affects ~1% of live births. Although genetic and environmental etiologic contributors have been identified, the majority of CHD lacks a definitive cause, suggesting the role of gene-environment interactions (GxE) in disease pathogenesis. Maternal diabetes mellitus (matDM) is among the most prevalent environmental risk factors for CHD. However, there is a substantial knowledge gap in understanding how matDM acts upon susceptible genetic backgrounds to increase disease expressivity. Previously, we reported a GxE between Notch1 haploinsufficiency and matDM leading to increased CHD penetrance. Here, we demonstrate a cell lineage specific effect of Notch1 haploinsufficiency in matDM-exposed embryos, implicating endothelial/endocardial derived tissues in the developing heart. We report impaired atrioventricular cushion morphogenesis in matDM exposed Notch1+/- animals and show a synergistic effect of NOTCH1 haploinsufficiency and oxidative stress in dysregulation of gene regulatory networks critical for endocardial cushion morphogenesis in vitro. Mitigation of matDM-associated oxidative stress via SOD1 overexpression did not rescue CHD in Notch1 haploinsufficient mice compared to wildtype littermates. Our results show the combinatorial interaction of matDM-associated oxidative stress and a genetic predisposition, Notch1 haploinsufficiency, on cardiac development, supporting a GxE model for CHD etiology and suggesting that antioxidant strategies maybe ineffective in genetically-susceptible individuals.

Genetically stratified Parkinson's disease with freezing of gait is related to specific pattern of cognitive impairment and non-motor dominant endophenotype.

Freezing of gait (FOG) is an important milestone in the individual disease trajectory of people with Parkinson's disease (PD). Based on the cognitive model of FOG etiology, the mechanism behind FOG implies higher executive dysfunction in PDFOG+. To test this model, we investigated the FOG-related phenotype and cognitive subdomains in idiopathic PD (iPD) patients without genetic variants linked to PD from the Luxembourg Parkinson's study. A cross-sectional analysis comparing iPDFOG+ (n = 118) and iPDFOG- (n = 378) individuals was performed, followed by the application of logistic regression models. Consequently, regression models were fitted for a subset of iPDFOG+ (n = 35) vs. iPDFOG- (n = 126), utilizing a detailed neuropsychological battery to assess the association between FOG and cognitive subdomains. Both regression models were adjusted for sociodemographic confounders and disease severity. iPDFOG+ individuals presented with more motor complications (MDS-UPDRS IV) compared to iPDFOG- individuals. Moreover, iPDFOG+ individuals exhibited a higher non-motor burden, including a higher frequency of hallucinations, higher MDS-UPDRS I scores, and more pronounced autonomic dysfunction as measured by the SCOPA-AUT. In addition, iPDFOG+ individuals showed lower sleep quality along with lower quality of life (measured by PDSS and PDQ-39, respectively). The cognitive subdomain analysis in iPDFOG+ vs. iPDFOG- indicated lower scores in Benton's Judgment of Line Orientation test and CERAD word recognition, reflecting higher impairment in visuospatial, executive function, and memory encoding. We determined a significant association between FOG and a clinical endophenotype of PD with higher non-motor burden. While our results supported the cognitive model of FOG, our findings point to a more widespread cortical impairment across cognitive subdomains beyond the executive domain in PDFOG+ with additional higher impairment in visuospatial function and memory encoding.

Stress-induced overeating behaviors explained from a (transitory) relief-learning perspective

People use various behaviors to cope with stressful events. These behaviors are mostly adaptive, as they allow a successful release of stress without impacting other aspects of life: How nice is it to have a break with a few spoons of that favorite ice cream during a hectic working day? However, when excessive consumption of high-sugar/salt ultra-processed food becomes the gateway to find relief from stress, eating loses this adaptive function and may escalate to binge eating, lead to obesity, and other medical conditions linked to overweight.Several etiological models attempt to explain stress-induced eating and excessive overeating behaviors characterizing these clinical conditions. The popular Emotional Eating Theory proposes that stress-related (over-)eating, a major predictor of obesity and diagnosed binge eating disorders, develops based on negative reinforcement learning since food consumption regulates the negative affective state associated with stressful circumstances. Differently, the prominent Incentive Sensitization Theory explains overeating, binge eating disorders (including bulimia), and obesity in terms of excessive amplification of reward ‘wanting’, which is thought to emerge from overexposure to obesogenic (food)cues. The several studies oriented by these theories have paved the way to better understand stress-related (over-)eating and its clinical excesses. However, a deep mechanistic understanding of how and why stress-induced (over-)eating can escalate till clinical forms of overeating remain elusive. A well-funded connection of the mechanisms proposed by the Emotional Eating Theory and the Incentive Sensitization Theory might address this etiological open question. To avoid erroneous arguments, it is however essential to first address the internal theoretical and methodological shortcomings of each theory and connected studies. These shortcomings stem from conceptual fallacies and poorly implemented designs, which might partially explain the ‘high variability and low replicability’ problem of empirical findings. Next, the formulation of a new integrative model could provide fresh insight into the deep learning and biological mechanisms of this escalation. A successful formalization of this model could then create the much-needed impact in clinical and preventive research since excessive overeating is a behavior hard to change once established.In this opinion paper, I propose to apply recent insights we gathered on the role of relief from the field of safety learning to stress (over-)eating. I will present a new relief-based model that, as a starting point, has the potential to connect the Emotional Eating Theory with the Incentive Sensitization Theory, setting the base for more integrative science.

The role of Toll-like receptors in the etiopathogenesis and treatment of schizophrenia

In this review paper, we present current theories about the inflammatory etiopathogenesis of schizophrenia. We mentioned the biopsychosocial etiological model of the disease and stressed the importance of neuroinflammation and neurodegeneration in its biological basis. We searched the literature about innate immunity, Toll-like receptors, inflammation, and neurodegeneration, and we summarized their role in the etiopathogenetic mechanisms of schizophrenia. We also found studies on available antipsychotics that can regulate the expression of Toll-like receptors and modulate innate inflammatory mechanisms. Despite the effective properties of antipsychotics in reducing psychotic symptoms, their role in inflammatory mechanisms remains imprecise and underresearched. More specific information about how antipsychotics affect neuroinflammation could lead to the development of a wider range of possible drugs that could keep inflammatory processes working properly and improve mental abilities and, ultimately, the quality of life.

ART26.12, a novel fatty acid-binding protein 5 inhibitor, shows efficacy in multiple preclinical neuropathy models.

Painful neuropathy is a pathological condition caused by numerous factors including diabetes, chemotherapy or cancer. ART26.12 is a novel fatty acid-binding protein 5 inhibitor, which our group showed could prevent and treat persistent pain in a preclinical model of oxaliplatin-induced peripheral neuropathy. In the current study, the efficacy of orally dosed ART26.12 was tested in multiple neuropathy models of different aetiology. Paw withdrawal threshold to von Frey monofilaments and latency to escape a cold plate were used as measurements of mechanical and cold sensitivity. ART26.12 (25 and 50 mg/kg BID), dosed prior to the induction of paclitaxel-induced peripheral neuropathy (PIPN), reversed mechanical allodynia induced by paclitaxel in both male and female rats, and ART26.12 (50 mg/kg BID) prevented the induction of PIPN in female rats. ART26.12 (50 mg/kg BID) also had a protective effect on body weight in the PIPN model. ART26.12 (25 and 100 mg/kg BID) reversed mechanical allodynia when treating established streptozotocin-induced diabetic neuropathy in male rats. In a model of breast cancer-induced bone pain in female rats, ART26.12 (100 mg/kg BID) reversed mechanical allodynia within 1 h of dosing. In the same model, ART26.12 (25 mg/kg BID) reversed mechanical allodynia from day 4 of treatment. Overall, these preclinical data suggest that ART26.12 is a safe and efficacious therapeutic drug for continued development towards the prevention and treatment of peripheral neuropathy. This work now shows that ART26.12, a novel and selective inhibitor of FABP5, can prevent and treat multiple preclinical models of peripheral neuropathy. Given its excellent safety profile, further work is warranted to develop ART26.12 as a potential therapeutic tool for pain management.

Induced worry increases risk aversion in patients with generalized anxiety

Generalized anxiety disorder is characterized by disruptions in decision-making, including an enhanced aversion to uncertain outcomes (i.e., risk aversion), which is not specific to negative outcomes (i.e., no loss aversion). It is unknown if this uncertainty bias is a trait-like causal factor contributing to anxiety symptoms, or a state-like feature triggered by anxiety symptoms such as worry chains. Here, in-patients with Major Depression Disorder (MDD), with (N = 16) or without (N = 24) Generalized anxiety (GA) symptoms, and healthy controls (N = 23), completed an economic decision-making task before and after worry induction. They were asked to choose between a certain monetary payoff, and an uncertain gamble, allowing for estimation of risk and loss aversion through a computational prospect-theoretic model. There were no significant differences in risk and loss aversion between any of the three groups at baseline. After worry induction, patients with GA symptoms, compared to those without, showed increased risk aversion. This increase was modulated by the severity of anxiety symptoms. These findings suggest that decision-making disruptions in anxiety disorder may be driven by anxiety symptoms such as worry, rather than causing them. This could shape etiological models, motivate standardization of emotional state in research on decision-making in anxiety disorders, support treatment strategies primarily aimed at worry management, and could guide novel interventions focusing on uncertainty exposure across aversive and appetitive domains.

The Current Research Status and Progress of Bipolar Disorder

Bipolar disorder is a common but serious mental illness with extremely high mortality and a high suicide rate. It has variable symptoms of both depression and mania and can separate into three types of sub-types---bipolar disorder type I, bipolar disorder type II and Rapid cycling bipolar disorder. So far, scientists and medical researchers had got a lot of success in the field of bipolar disorder. Therefore, this paper proposes to conclude the recent research to discuss the status and progress of bipolar disorder, which mainly discusses the history of bipolar disorder, symptoms, treatments, and possible etiology; this paper will discuss them from the view of genetic and environmental. Besides, this paper specifically focuses on the recent innovative discovery of genetic etiology and genetic model treatment methods.

An exploration of blood-based biomarkers of negative symptoms of psychosis in men

Negative symptoms in the context of psychosis are still poorly understood and diagnosed, which impairs the treatment efficacy of current therapies and patient's integration in society. In this study, we aimed to test hypothesis-based and exploratory associations of negative symptom domains, as defined by the Brief Negative Symptom Scale (BNSS), with hormonal and hematological variables, and, complementarily, with standard psychological/cognitive and psychopathological measures. Fifty-one male patients diagnosed with a psychotic disorder underwent a structured interview and blood collection. Standard Spearmen bivariate correlations were used for data analysis. We obtained evidence of hypothesis-based associations between specific negative symptoms and oxytocin, thyroid stimulating hormone levels and neutrophil-to-lymphocyte ratio; as well as novel and hypothesis-free associations with erythrocyte and lymphocyte count, mean corpuscular volume and red cell distribution width. Complementarily, we also obtained some validation of previous associations of negative symptoms with illness resolution, cognitive symptom severity and social performance, and a novel association with anger contagion. We hope our results can generate new hypotheses in psychosis research. Our work suggests further avenues in research on erythrocytic, inflammatory, thyroid and oxytocin-related markers and abnormalities in psychosis, especially in regards to specific negative symptoms, towards more precise and comprehensive etiological, diagnostic and therapeutic models.

Alcoholic Etiology, Severity of Liver Disease, and Post-Transplant Adherence Are Correlated with Worse Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) in Liver Transplant Candidates.

Introduction: Psychosocial pre-transplant evaluation in patients undergoing liver transplantation (LT) could help identify those patients at higher risk of pharmacological non-adherence, organ rejection, and mortality. The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) is a validated tool for assessing LT candidates' psychosocial well-being. Data on the ability of the SIPAT evaluation to predict post-transplant outcomes are sparse. Material and Methods: clinical and psychosocial data from a sample of 134 candidates for LT were analyzed. Moreover, the association between pre-transplant psychosocial evaluation and post-transplant clinical outcomes, including organ rejection, mortality, and immunosuppressant drug adherence, was calculated. Results: At the pre-transplant evaluation, patients who showed high SIPAT scores (77, 57%) also had more liver disease assessed by model for end-stage liver disease (MELD; F = 5.04; p < 0.05), alcoholic etiology (F = 35.80; p < 0.001), encephalopathy (F = 5.02; p < 0.05), and portal hypertension (F = 7.45; p < 0.01). Of the 51 transplant patients, those who had a high pre-transplant SIPAT score showed lower post-transplant immunosuppressive adherence, linked to more frequent immunological events. Conclusions: Patients with an alcoholic etiology of liver disease and more severe liver dysfunction are likelier to not adhere to medical prescriptions following transplantation. Current data suggests that this specific group of patients could benefit from early psychological pre-habilitation before undergoing liver transplantation.

Deciphering the landscape of lncRNA-driven ceRNA network in schizophrenia etiology

BackgroundThe unifying hypothesis of competing endogenous RNA (ceRNA) wherein crosstalk between coding (mRNAs) and long non-coding RNAs (lncRNAs) via microRNA (miRNA) response elements, creates a pervasive regulatory network across the transcriptome, has been implicated in complex disorders including schizophrenia. Even with a wide range of high-throughput data, the etiology of schizophrenia remains elusive, necessitating a more holistic understanding of the altered genetic landscape, shifting focus from solely candidate gene studies and protein-coding variants.ObjectiveWe developed lncRNA-associated ceRNA networks to elucidate global molecular/regulatory signatures underlying schizophrenia using diverse data in the public domain.MethodsMicroarray dataset associated with peripheral blood mononuclear cells (PBMCs) of schizophrenia and control patients was used to identify differentially expressed mRNAs. Weighted gene co-expression network analysis (WGCNA) was used to identify highly correlated hubs, and genes from these overlapping Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene ontology (GO) term genesets were considered key mRNA players. StarBase, Human MicroRNA Disease Database, and miRWalk were used to derive mRNA-miRNA and miRNA-lncRNA relationships. Finally, the key mRNAs, interacting lncRNAs and miRNAs were chosen to reconstruct sub-ceRNA networks based on network centrality scores.ResultsBioinformatics analysis revealed the involvement of three differentially expressed mRNAs, namely ADRA1A, HAP1 and HOMER3 in the schizophrenia ceRNA networks with lncRNAs NEAT1, XIST, and KCNQ1OT1 modulating their activity by a suggestive sequestering of miR-3163, miR-214-3p and miR-2467-3p, respectively.ConclusionsFurthermore, based on contextual evidence, we propose how ceRNAs could orchestrate crosstalk between neurostructural dynamics and immune/inflammatory processes and enable unifying these disparate models of schizophrenia etiology.

The analysis of the skeletal muscle metabolism is crucial for designing optimal exercise paradigms in type 2 diabetes mellitus

BackgroundType 2 diabetes mellitus (T2DM) is a chronic metabolic disease that commonly results from a high-calorie diet and sedentary lifestyle, leading to insulin resistance and glucose homeostasis perturbation. Physical activity is recommended as one first-line treatment in T2DM, but it leads to contrasted results. We hypothesized that, instead of applying standard exercise protocols, the prescription of personalized exercise programs specifically designed to reverse the potential metabolic alterations in skeletal muscle could result in better results.MethodsTo test this hypothesis, we drew the metabolic signature of the fast-twitch quadriceps muscle, based on a combined unbiased NMR spectroscopy and RT-qPCR study, in several T2DM mouse models of different genetic background (129S1/SvImJ, C57Bl/6J), sex and aetiology (high-fat diet (HFD) or HFD/Streptozotocin (STZ) induction or transgenic MKR (FVB-Tg Ckm-IGF1R*K1003R)1Dlr/J) mice. Three selected mouse models with unique muscular metabolic signatures were submitted to three different swimming-based programs, designed to address each metabolic specificity.ResultsWe found that depending on the genetic background, the sex, and the mode of T2DM induction, specific muscular adaptations occurred, including depressed glycolysis associated with elevated PDK4 expression, shift to β-oxidation, or deregulation of amino-acid homeostasis. Interestingly, dedicated swimming-based exercises designed to restore specific metabolic alterations in muscle were found optimal in improving systemic T2DM hallmarks, including a significant reduction in insulin resistance, the improvement of glucose homeostasis, and a delay in sensorimotor function alterations.ConclusionThe muscle metabolism constitutes an important clue for the design of precision exercises with potential clinical implications for T2DM patients.

Enfacement illusions: Filling a knowledge gap in eating disorder risk assessment, prevention, and intervention?

Body image disturbance (BID) is central to eating disorders (EDs), yet the role of self-face perception has received limited empirical attention despite rising sociocultural pressures emphasizing facial appearance through technologies such as social media. Emerging evidence suggests impairments in self-face recognition accuracy and distorted perceptions of facial appearance among individuals with EDs. Enfacement illusions, involving the experimental induction of perceived ownership over another's face, offer a novel paradigm to comprehensively investigate the perceptual multisensory integration processes underlying self-face perception disturbances in ED populations. Such an approach may hold promise for elucidating core pathological mechanisms contributing to BID and ED psychopathology. We discuss how rigorous investigation of self-face perception through the enfacement illusion paradigm represents an innovative direction of research and/or clinical application that may advance etiological models of EDs and possibly inform interventions targeting the potentially multidimensional nature of body and facial image disturbances characterizing EDs. PUBLIC SIGNIFICANCE STATEMENT: Body image disturbance is central to eating disorders (EDs), yet, the role of face-related disturbances remains critically under-investigated. After summarizing findings on face-related disturbances in EDs we propose how enfacement illusions (i.e., the experimental induction of ownership over another's face) may elucidate self-face perception disturbances in EDs, and their underlying mechanisms. Enfacement illusions may also offer an intervention to potentially address multifaceted face and body image disturbances characterizing EDs.

Microbial diagnostics in periodontal diseases.

Microbial analytical methods have been instrumental in elucidating the complex microbial etiology of periodontal diseases, by shaping our understanding of subgingival community dynamics. Certain pathobionts can orchestrate the establishment of dysbiotic communities that can subvert the host immune system, triggering inflammation and tissue destruction. Yet, diagnosis and management of periodontal conditions still rely on clinical and radiographic examinations, overlooking the well-established microbial etiology. This review summarizes the chronological emergence of periodontal etiological models and the co-evolution with technological advances in microbial detection. We additionally review the microbial analytical approaches currently accessible to clinicians, highlighting their value in broadening the periodontal assessment. The epidemiological importance of obtaining culture-based antimicrobial susceptibility profiles of periodontal taxa for antibiotic resistance surveillance is also underscored, together with clinically relevant analytical approaches to guide antibiotherapy choices, when necessary. Furthermore, the importance of 16S-based community and shotgun metagenomic profiling is discussed in outlining dysbiotic microbial signatures. Because dysbiosis precedes periodontal damage, biomarker identification offers early diagnostic possibilities to forestall disease relapses during maintenance. Altogether, this review highlights the underutilized potential of clinical microbiology in periodontology, spotlighting the clinical areas most conductive to its diagnostic implementation for enhancing prevention, treatment predictability, and addressing global antibiotic resistance.

Early maladaptive schemas, distress tolerance and self-injury in Iranian adolescents: serial mediation model of transdiagnostic factors.

Non-suicidal self-injury (NSSI) is prevalent behaviour among adolescents. Although there are different etiological models of NSSI, there is a general lack of evidence-based, comprehensive and transdiagnostic models of NSSI in adolescents. The aim of this study was to investigate a model of transdiagnostic factors of NSSI in adolescents, testing a serial mediation model of the relationship between early maladaptive schemas (EMS), distress tolerance and NSSI through experiential avoidance and rumination. A community sample was identified of 1014 adolescents aged 13-17, of whom 425 had a history of NSSI. A serial mediation path analytic method was utilised to examine the relationships between NSSI and its associated functions as criterion variables, EMS and distress tolerance as predictors, experiential avoidance as the first mediator and rumination as the second mediator. The path analytic model fit indices were good (X2/d.f. = 2.25, goodness of fit index = 0.98, normed fit index = 0.97, comparative fit index = 0.98, root mean square error of approximation = 0.054, standardised root mean squared residual = 0.028). Rumination significantly mediated the relationship between schemas of 'vulnerability to harm', 'emotional deprivation', 'social isolation', 'insufficient self-control', and NSSI frequency and intrapersonal functions. In serial fashion, experiential avoidance mediated the role of rumination in the relationship between social isolation, and insufficient self-control and NSSI frequency and intrapersonal functions. All indirect effects were significant. Key indirect effects were found linking maladaptive schemas and distress tolerance to NSSI frequency, and NSSI intrapersonal functions via experiential avoidance and rumination. Thus, it is important to address these transdiagnostic factors with particular emphasis on the sequential mediating role of experiential avoidance and rumination in conceptualisation and therapeutic interventions for NSSI.

Blood Adhesion Molecules as Biomarkers in Children with Chronic Urticaria.

The prevailing etiological model of both acute and chronic urticaria implicates specific allergen exposure that triggers the local release of vasoactive factors and inflammatory adhesion molecules, including vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), endothelial leukocyte adhesion molecule 1 (ELAM-1), P-selectin and E-selectin in the superficial dermis. This study focused on the possible role of VCAM-1 and ICAM-1 as biomarkers in children with acute and chronic urticaria. This study involved 184 children, 40 with acute urticaria, 71 with chronic urticaria, and 73 matched comparison subjects. The serum levels of ICAM-1 and VCAM-1 were determined in venous blood in all the participants on enrollment. Antihistamine treatment was administered to all the patients. In the children with chronic urticaria, the Urticaria Activity Score Questionnaire (UAS7) was completed daily by the parents. In 16 of the patients with acute urticaria and 43 with chronic urticaria, the serum levels of ICAM-1 and VCAM-1 were determined at follow-up after 6-8 weeks of treatment. The mean serum levels of both VCAM-1 and ICAM-1 were higher in both groups of children with urticaria than in the comparison subjects at the start of the study. In the chronic urticaria group, the levels decreased significantly (p = 0.03 and p = 0.01, respectively) following treatment. Similarly, the acute urticaria group exhibited significant reduction in the mean levels of VCAM and ICAM (p < 0.001). In both groups, the mean level of ICAM after treatment was comparable with that of the comparison group. VCAM-1 and ICAM-1 are suggested as promising biomarkers for monitoring both acute and chronic urticaria in children. Future research should explore their utility in larger cohorts and investigate their role in personalized treatment strategies.

Premorbid body weight predicts weight loss in both anorexia nervosa and atypical anorexia nervosa: Further support for a single underlying disorder.

For adolescents, DSM-5 differentiates anorexia nervosa (AN) and atypical AN with the 5th BMI-centile-for-age. We hypothesized that the diagnostic weight cut-off yields (i) lower weight loss in atypical AN and (ii) discrepant premorbid BMI distributions between the two disorders. Prior studies demonstrate that premorbid BMI predicts admission BMI and weight loss in patients with AN. We explore these relationships in atypical AN. Based on admission BMI-centile < or ≥5th, participants included 411 female adolescent inpatients with AN and 49 with atypical AN from our registry study. Regression analysis and t-tests statistically addressed our hypotheses and exploratory correlation analyses compared interrelationships between weight loss, admission BMI, and premorbid BMI in both disorders. Weight loss in atypical AN was 5.6 kg lower than in AN upon adjustment for admission age, admission height, premorbid weight and duration of illness. Premorbid BMI-standard deviation scores differed by almost one between both disorders. Premorbid BMI and weight loss were strongly correlated in both AN and atypical AN. Whereas the weight cut-off induces discrepancies in premorbid weight and adjusted weight loss, AN and atypical AN overall share strong weight-specific interrelationships that merit etiological consideration. Epidemiological and genetic associations between AN and low body weight may reflect a skewed premorbid BMI distribution. In combination with prior findings for similar psychological and medical characteristics in AN and atypical AN, our findings support a homogenous illness conceptualization. We propose that diagnostic subcategorization based on premorbid BMI, rather than admission BMI, may improve clinical validity. Because body weights of patients with AN must drop below the 5th BMI-centile per DSM-5, they will inherently require greater weight loss than their counterparts with atypical AN of the same sex, age, height and premorbid weight. Indeed, patients with atypical AN had a 5.6 kg lower weight loss after controlling for these variables. In comparison to the reference population, we found a lower and higher mean premorbid weight in patients with AN and atypical AN, respectively. Considering previous psychological and medical comparisons showing little differences between AN and atypical AN, we view a single disorder as the most parsimonious explanation. Etiological models need to particularly account for the strong relationship between weight loss and premorbid body weight.

CRISPR editing of anti-anemia drug target rescues independent preclinical models of retinitis pigmentosa

Retinitis pigmentosa (RP) is one of the most common forms of hereditary neurodegeneration. It is caused by one or more of at least 3,100 mutations in over 80 genes that are primarily expressed in rod photoreceptors. In RP, the primary rod-death phase is followed by cone death, regardless of the underlying gene mutation that drove the initial rod degeneration. Dampening the oxidation of glycolytic end products in rod mitochondria enhances cone survival in divergent etiological disease models independent of the underlying rod-specific gene mutations. Therapeutic editing of the prolyl hydroxylase domain-containing protein gene (PHD2, also known as Egln1) in rod photoreceptors led to the sustained survival of both diseased rods and cones in both preclinical autosomal-recessive and dominant RP models. Adeno-associated virus-mediated CRISPR-based therapeutic reprogramming of the aerobic glycolysis node may serve as a gene-agnostic treatment for patients with various forms of RP.

Divergent effects of sex on hippocampal subfield alterations in drug-naive patients with major depressive disorder

BackgroundThe hippocampus is a crucial brain structure in etiological models of major depressive disorder (MDD). It remains unclear whether sex differences in the incidence and symptoms of MDD are related to differential illness-associated brain alterations, including alterations in the hippocampus. This study investigated divergent the effects of sex on hippocampal subfield alterations in drug-naive patients with MDD. MethodsHigh-resolution structural MR images were obtained from 144 drug-naive individuals with MDD early in their illness course and 135 age- and sex-matched healthy controls (HCs). Hippocampal subfields were segmented using FreeSurfer software and analyzed in terms of both histological subfields (CA1–4, dentate gyrus, etc.) and more integrative larger functional subregions (head, body and tail). ResultsWe observed a significant overall reduction in hippocampal volume in MDD patients, with deficits more prominent deficits in the posterior hippocampus. Differences in anatomic alterations between male and female patients were observed in the CA1-head, presubiculum-body and fimbria in the left hemisphere. Exploratory analyses revealed different patterns of clinical and memory function correlations with histological subfields and functional subregions between male and female patients primarily in the hippocampal head and body. LimitationsThis cross-sectional study cannot clarify the causality of hippocampal alterations or their association with illness risk or onset. ConclusionsThese findings represent the first reported sex-specific alterations in hippocampal histological subfields in patients with MDD early in the illness course prior to treatment. Sex-specific hippocampal alterations may contribute to diverse sex differences in the clinical presentation of MDD.

Pluripotent Stem Cells as a Preclinical Cellular Model for Studying Hereditary Spastic Paraplegias.

Hereditary spastic paraplegias (HSPs) comprise a family of degenerative diseases mostly hitting descending axons of corticospinal neurons. Depending on the gene and mutation involved, the disease could present as a pure form with limb spasticity, or a complex form associated with cerebellar and/or cortical signs such as ataxia, dysarthria, epilepsy, and intellectual disability. The progressive nature of HSPs invariably leads patients to require walking canes or wheelchairs over time. Despite several attempts to ameliorate the life quality of patients that have been tested, current therapeutical approaches are just symptomatic, as no cure is available. Progress in research in the last two decades has identified a vast number of genes involved in HSP etiology, using cellular and animal models generated on purpose. Although unanimously considered invaluable tools for basic research, those systems are rarely predictive for the establishment of a therapeutic approach. The advent of induced pluripotent stem (iPS) cells allowed instead the direct study of morphological and molecular properties of the patient's affected neurons generated upon in vitro differentiation. In this review, we revisited all the present literature recently published regarding the use of iPS cells to differentiate HSP patient-specific neurons. Most studies have defined patient-derived neurons as a reliable model to faithfully mimic HSP in vitro, discovering original findings through immunological and -omics approaches, and providing a platform to screen novel or repurposed drugs. Thereby, one of the biggest hopes of current HSP research regards the use of patient-derived iPS cells to expand basic knowledge on the disease, while simultaneously establishing new therapeutic treatments for both generalized and personalized approaches in daily medical practice.