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Interleukin 18 (IL18) was originally identified as an inflammation-induced cytokine that is secreted by immune cells. An increasing number of studies have focused on its non-immunological functions, with demonstrated functions for IL18 in energy homeostasis and neural stability. IL18 is reportedly required for lipid metabolism in the liver and brown adipose tissue. Furthermore, IL18 (Il18) deficiency in mice leads to mitochondrial dysfunction in hippocampal cells, resulting in depressive-like symptoms and cognitive impairment. Microarray analyses of Il18−/− mice have revealed a set of genes with differential expression in liver, brown adipose tissue, and brain; however, the impact of IL18 deficiency in these tissues remains uncertain. In this review article, we discuss these genes, with a focus on their relationships with the phenotypic disease traits of Il18−/− mice.

Background Cognitive behavioral therapy (CBT) is a first-line treatment for many mental health conditions. In Japan, patients can receive health insurance coverage for CBT treatment of major depressive disorder (MDD), social anxiety disorder (SAD), panic disorder (PD), obsessive compulsive disorder (OCD), post-traumatic stress disorder (PTSD), and bulimia nervosa; however, utilization of CBT remains insufficient. This study aimed to examine the status of CBT provision for these disorders using Japanese health insurance claims data. Methods Data for April 2015–March 2022 from the Detroit Employment Solutions Corporation (DeSC) database were analyzed. The dataset included “Kempo” (salaried workers’ insurance; large companies) and “Kokuho” (national health insurance; self-employed and their dependents) insurance, representing 2.8% and 12% of each insured population, respectively. Patients diagnosed with the above mental health conditions were identified, and their demographic characteristics, CBT session frequencies, session intervals, and psychotropic prescription status were evaluated. Results Overall, 0.50% of Kempo and 0.24% of Kokuho clients diagnosed with the relevant mental health conditions claimed insurance for CBT. Among Kempo clients, CBT was claimed by 322 (89.2%) with MDD, 8 (2.2%) with SAD, 13 (3.6%) with PD, 11 (3.1%) with OCD, 5 (1.4%) with PTSD, and 2 (0.5%) with unspecified conditions. Among Kokuho clients, CBT was claimed by 1037 (92.0%) with MDD, 11 (1.0%) with SAD, 23 (2.0%) with PD, 25 (2.2%) with OCD, 13 (1.2%) with PTSD, and 18 (1.6%) with unspecified conditions. Average intervals between MDD sessions were 34.2 days under Kempo and 71.9 days under Kokuho. Conclusions Few patients claimed insurance for CBT, and most session intervals exceeded 1 month. The findings highlight substantial unmet medical needs in CBT provision in Japan. Medical environments that support and integrate regular CBT must be established.

A close association between obsessive-compulsive disorder (OCD) and attention-deficit/hyperactivity disorder (ADHD) in children and adolescents has been investigated in previous studies. However, few studies examined the relationship between lifetime comorbidity of ADHD and OCD in adults. Therefore, we sought to investigate the clinical and psychopathological features related to comorbid ADHD in Japanese adult patients with OCD. We assessed lifetime comorbidity of ADHD in 93 adult Japanese patients with OCD. Additionally, we used the Japanese version of Conners' Adult ADHD Rating Scales to assess the characteristics and severity of ADHD in each participant. According to the results, we excluded OCD patients that did not have ADHD but who exhibited elevated levels of ADHD traits. We compared OCD patients with ADHD (ADHD+ group) and those without ADHD or its trait (ADHD− group) in terms of background profiles and clinical features, such as OCD symptomatology and psychometric test results. Additionally, the 6-month treatment outcome was compared prospectively between groups. Of the 93 OCD participants, the prevalence of lifetime comorbidity of ADHD was estimated as 16.1%. Compared with the ADHD− group, participants in the ADHD+ group had an earlier age of onset of OCD, higher frequencies of hoarding symptoms, higher levels of depressive and anxiety symptoms and lower quality of life, more elevated levels of impulsivity, and higher rates of substance or behavioral addiction and major depression. Finally, the mean improvement rate on the Yale-Brown Obsessive Compulsive Scale after 6 months of standardized OCD treatment in the ADHD+ group (16.1%) was significantly lower than that in the ADHD− group (44.6%). The lifetime comorbidity of ADHD is likely to exert a significant effect on clinical features and treatment outcome in adult patients with OCD. It is important to consider that underlying ADHD pathology may function as a facilitator for increased severity of global clinical features and treatment refractory conditions in OCD patients. Further studies are required to examine treatment strategies for such patients. •The lifetime prevalence of comorbid ADHD in adult Japanese OCD patients was 16.1%.•OCD patients with comorbid ADHD showed earlier age of OCD onset and more hoarding symptoms.•OCD patients with comorbid ADHD were more likely to have severe psychopathological features.•OCD patients with comorbid ADHD showed significantly poorer 6-month treatment outcomes.

Interleukin-18 (IL18) is an inflammatory cytokine that is related to psychiatric disorders such as depression and cognitive impairment. We previously found that IL18 deficiency may cause hippocampal impairment, resulting in depression-like behavioral changes. However, the potential role of IL18 in stressful conditions remains uncertain. In the present study, we examined the effect of IL18 on neural inflammation and stress tolerance during acute stress. Littermate Il18 +/+ and Il18 −/− mice were exposed to a single restraint stress for 6 h, and all assessments were performed 18 h after the mice were released from the restraint. In Il18 −/− mice exposed to acute stress, the immobility times in both the forced swim test and tail suspension test were decreased, although no difference was observed in Il18 +/+ mice. Il1β , Il6 , and Tnfα expression levels in the hippocampus of stressed Il18 −/− mice were significantly higher than those in the other groups. Moreover, the numbers of astrocytes and microglia, including those in the active form, were also increased compared with those in other groups. Regarding the molecular mechanism, the HSF5 and TTR genes were specifically expressed in stressed Il18 −/− mice. As a potential treatment, intracerebral administration of IL18 to Il18 −/− mice resulted in partial recovery of changes in behavioral assessments. Our results revealed that IL18-deficient mice were more sensitive and had a longer response to acute stress than that in normal mice. In addition, neural inflammation and augmentation of glucocorticoid signals caused by stress were more intense and remained longer in Il18 −/− mice, resulting in behavioral changes. In conclusion, IL18 might be an indispensable factor that modulates the stress response and maintains balance between neural inflammation and glucocorticoid signaling.

Background Obsessive-compulsive disorder (OCD) present invasive thoughts and repetitive behaviors affecting 1–3% of the population, divided into 3–5 symptom dimensions. Self-contamination, a subtype within the contamination/washing dimension, remains poorly understood. This study aim is to investigate pathological features and treatment response in self-contamination subtype compared to other contamination subtype and checking symptoms. Method Seventy-one OCD patients were categorized into self-contamination ( n  = 15), contaminated ( n  = 25), and checking symptom (control, n  = 31) groups. OCD symptom severity was assessed using the Japanese version of the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) Symptom Checklist. Comorbidities were evaluated using the Structured Clinical Interview for DSM-IV. Global functioning, anxiety, and depressive symptoms were measured using DSM-IV’s Global Assessment of Functioning Scale (GAFS), State-Trait Anxiety Inventory, and Zung’s Self-rating Depression Scale, respectively. Treatment involved a standardized combination of selective serotonin reuptake inhibitors and cognitive-behavioral therapy, with treatment response assessed after 1 year. Results Subjects in the self-contamination group showed significantly lower quality of life, GAFS scores, and higher comorbidities including major depressive disorder, social anxiety disorder, body dysmorphic disorder, and olfactory reference disorder. Treatment response was notably poorer in the self-contamination group. Multiple regression analysis identified four poor treatment outcome predictors: score on the Y-BOCS and the SDS, duration of illness, and prevalence of ORD. Conclusion The identification of the self-contamination subtype in OCD patients is crucial for understanding the pathophysiological and treatment response. Further research is needed to clarify the socio-cultural effects on the development of this putative subtype of OCD.

Interleukin-18 (IL-18) is an inflammatory cytokine that has been linked to energy homeostasis and psychiatric symptoms such as depression and cognitive impairment. We previously revealed that deficiency in IL-18 led to hippocampal abnormalities and resulted in depression-like symptoms. However, the impact of IL-18 deficiency on other brain regions remains to be clarified. In this study, we first sought to confirm that IL-18 expression in neural cells can be found in human brain tissue. Subsequently, we examined the expression of genes in the prefrontal cortex of Il18−/− mice and compared it with gene expression in mice subjected to a chronic mild stress model of depression. Extracted genes were further analyzed using Ingenuity® Pathway Analysis, in which 18 genes common to both the chronic mild stressed model and Il18−/− mice were identified. Of those, 16 were significantly differentially expressed between Il18+/+ and Il18−/− mice. We additionally measured protein expression of α-2-HS-glycoprotein (AHSG) and transthyretin (TTR) in serum and the brain. In the prefrontal cortex of Il18−/− mice, TTR but not AHSG was significantly decreased. Conversely, in the serum of Il18−/− mice, AHSG was significantly increased but not TTR. Therefore, our results suggest that in IL-18-deficit conditions, TTR in the brain is one of the mediators causally related to depression, and AHSG in peripheral organs is one of the regulators inducing energy imbalance. Moreover, this study suggests a possible “signpost” to clarify the molecular mechanisms commonly underlying the immune system, energy metabolism, neural function, and depressive disorders.

Objective: Polycystic ovary syndrome (PCOS) is a prevalent hormonal and metabolic disorder, wherein the adipose tissue and gut microbiome have been demonstrated to contribute to its pathogenesis. This study aims to assess the concentrations of the adipokine, meteorin-like protein (Metrnl) and the protein, zonulin, related to intestine permeability, in individuals with PCOS with a particular emphasis on their relationship with obesity, clinical manifestations, hormonal profiles, and metabolic parameters. Methods: A cohort comprising 58 women with PCOS, classified according to the Rotterdam criteria, was enrolled. The study also considered age, body mass index (BMI), and ethnicity-matched controls (n = 30). Comprehensive anthropometric and clinical evaluations, hormonal assays, and biochemical analyses were conducted during the follicular phase. Subsequent subgroup analyses were executed within the PCOS cohort based on waist-to-height ratio (WHtR), insulin resistance (IR), and free androgen index (FAI). Serum concentrations of Metrnl and zonulin were quantified via the enzyme-linked immunosorbent assay (ELISA) technique. Results: The Metrnl and zonulin levels exhibited no significant disparity between PCOS patients and controls. Nevertheless, within the entire participant cohort and the PCOS group exclusively, overweight/obese participants demonstrated higher Metrnl concentrations relative to their normal-weight counterparts (p < 0.001, p = 0.001, respectively). Furthermore, higher Metrnl concentrations were identified in subgroups characterized by high WHtR and IR in comparison to those with low WHtR (p = 0.001) and without IR (p = 0.001), respectively. A correlation emerged between Metrnl levels and various anthropometric and metabolic parameters, as well as sex-hormone-binding globulin (SHBG) and interleukin-18 (IL-18) within the PCOS group. Multiple linear regression analysis identified HOMA-IR as the sole independent predictor of Metrnl levels. Conclusion: While Metrnl and zonulin levels do not serve as diagnostic indicators of PCOS, elevated Metrnl concentrations exhibited robust associations with proinflammatory and metabolic irregularities within the PCOS population.

Delirium is a multifactorial medical condition of waxing and waning impairment across various domains of mental functioning over time. Importantly, delirium is also one of the greatest risk factors for prolonged hospitalization, morbidity, and mortality. Studying this important condition is challenging due to the difficulty in both objective diagnosis in patients and validation of laboratory models. As a result, there is a lack of protective treatments for delirium. Our recent studies report the efficacy of bispectral electroencephalography (BSEEG) in diagnosing delirium in patients and predicting patient outcomes, advancing the concept that this simple measure could represent an additional vital sign for patients. Here, we applied BSEEG to characterize and validate a novel lipopolysaccharide (LPS) mouse model of infection-related delirium. We then applied this model to evaluate the protective efficacy of three putative therapeutic agents: the conventional antipsychotic medication haloperidol, the neuroprotective compound P7C3-A20, and the antibiotic minocycline. Aged mice were more susceptible than young mice to LPS-induced aberration in BSEEG, reminiscent of the greater vulnerability of older adults to delirium. In both young and old mice, P7C3-A20 and minocycline administration prevented LPS-induced BSEEG abnormality. By contrast, haloperidol did not. P7C3-A20 and minocycline have been shown to limit different aspects of LPS toxicity, and our data offers proof of principle that these agents might help protect patients from developing infection-related delirium. Thus, utilization of BSEEG in a mouse model for infection-related delirium can identify putative therapeutic agents for applications in patient clinical trials.

Major depressive disorder (MDD) is a common psychiatric disorder that involves marked disabilities in global functioning, anorexia, and severe medical comorbidities. MDD is associated with not only psychological and sociocultural problems, but also pervasive physical dysfunctions such as metabolic, neurobiological and immunological abnormalities. Nevertheless, the mechanisms underlying the interactions between these factors have yet to be determined in detail. The aim of the present study was to identify the molecular mechanisms responsible for the interactions between MDD and dysregulation of physiological homeostasis, including immunological function as well as lipid metabolism, coagulation, and hormonal activity in the brain. We generated depression-like behavior in mice using chronic mild stress (CMS) as a model of depression. We compared the gene expression profiles in the prefrontal cortex (PFC) of CMS and control mice using microarrays. We subsequently categorized genes using two web-based bioinformatics applications: Ingenuity Pathway Analysis and The Database for Annotation, Visualization, and Integrated Discovery. We then confirmed significant group-differences by analyzing mRNA and protein expression levels not only in the PFC, but also in the thalamus and hippocampus. These web tools revealed that hepatocyte nuclear factor 4 alpha (Hnf4a) may exert direct effects on various genes specifically associated with amine synthesis, such as genes involved in serotonin metabolism and related immunological functions. Moreover, these genes may influence lipid metabolism, coagulation, and hormonal activity. We also confirmed the significant effects of Hnf4a on both mRNA and protein expression levels in the brain. These results suggest that Hnf4a may have a critical influence on physiological homeostasis under depressive states, and may be associated with the mechanisms responsible for the interactions between MDD and the dysregulation of physiological homeostasis in humans.

Background The cytokine, interleukin-18 (IL-18), was originally identified as an interferon-γ-inducing proinflammatory factor; however, there is increasing evidence suggesting that it has non-immunological effects on physiological functions. We have previously investigated the potential pathophysiological relationship between IL-18 and dyslipidemia, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis, which were mediated by lipid energy imbalance. Therefore, herein we focused on brown adipocytes (BAs) and brown adipose tissue (BAT) related to energy consumption as non-shivering thermogenesis. Methods Il18 −/− male mice were generated on the C57Bl/6 background, and littermate C57Bl/6 Il18 +/+ male mice were used as controls. To reveal the direct effect of IL-18, primary cell cultures derived from both mice were established. Moreover, for molecular analysis, microarray, quantitative reverse transcription PCR and western blotting were performed using 6 and 12 weeks old mice. To evaluate the short- and long-term effects of IL-18 on BAT, recombinant IL-18 was administered for 2 and 12 weeks, respectively. Results Compared with Il18 +/+ mice, BAT of Il18 −/− mice showed earlier differentiation and lipid accumulation. To examine the direct effect of IL-18 on BAT, BA cell cultures were established. Myogenic factor 5 -expressing adipose precursor cells were extracted from Il18 +/+ and Il18 −/− mice. PR domain containing 16 (PRDM16), a differentiation inducer, was strongly expressed in Il18 −/− BAs, and uncoupling protein 1, a thermogenic and differentiation marker, was upregulated, resulting in the promotion of BA differentiation. Moreover, PRDM16-dependent and independent molecules related to BAT function, such as fibroblast growth factor 21, were activated. These findings were confirmed by comparing Il18 +/+ and Il18 −/− mice at 6 and 12 weeks of age. Additional analyses of the molecular mechanisms influencing the ‘Quantity of adipocytes’ identified three associated genes, apolipoprotein C3 ( Apoc3 ), insulin-induced gene 1 ( Insig1 ) and vitamin D (1,25-dihydroxyvitamin D3) receptor ( Vdr ). Intravenous administration of IL-18 not only significantly improved the expression of some of these genes, but it also significantly decreased the adipocytes’ size. Conclusions This study demonstrated the critical function of IL-18 in differentiation and lipid metabolism in BAs. Furthermore, IL-18 may contribute to novel treatments by improving the energy imbalance.