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Background: Although adolescent major depressive disorder (MDD) is acknowledged to be a heterogeneous disorder, no studies have reported on biological correlates of its clinical subgroups. This study addresses this issue by examining whether adolescent MDD with and without melancholic features (M-MDD and NonM-MDD) have distinct biological features in the kynurenine pathway (KP). The KP is initiated by pro-inflammatory cytokines via induction of the enzyme indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan (TRP) into kynurenine (KYN). KYN is further metabolized into neurotoxins linked to neuronal dysfunction in MDD. Hypotheses were that, compared to healthy controls and to NonM-MDD adolescents, adolescents with M-MDD would exhibit: (i) increased activation of the KP [i.e., increased KYN and KYN/TRP (reflecting IDO activity)]; (ii) greater neurotoxic loads [i.e., increased 3-hydroxyanthranilic acid (3-HAA, neurotoxin) and 3-HAA/KYN (reflecting production of neurotoxins)]; and (iii) decreased TRP. We also examined relationships between severity of MDD and KP metabolites., Methods: Subjects were 20 adolescents with M-MDD, 30 adolescents with NonM-MDD, and 22 healthy adolescents. MDD episode duration had to be >or= 6 weeks and Children's Depression Rating Scale-Revised (CDRS-R) scores were >or= 36. Blood samples were collected at AM after an overnight fast and analyzed using high-performance liquid chromatography. Group contrasts relied on analysis of covariance based on ranks, adjusted for age, gender, and CDRS-R scores. Analyses were repeated excluding medicated patients. Fisher's protected least significant difference was used for multiple comparisons., Results: As hypothesized, KYN/TRP ratios were elevated and TRP concentrations were reduced in adolescents with M-MDD compared to NonM-MDD adolescents (p = .001 and .006, respectively) and to healthy controls (p = .008 and .022, respectively). These findings remained significant when medicated patients were excluded from the analyses. Significant correlations were obtained exclusively in the M-MDD group between KYN and 3-HAA/KYN and CDRS-R., Conclusions: Findings support the notion that adolescent M-MDD may represent a biologically distinct clinical syndrome.

Objective: The Treatment for Adolescents With Depression Study (TADS) evaluates the effectiveness of fluoxetine, cognitive-behavioral therapy (CBT), and their combination in adolescents with major depressive disorder. The authors report effectiveness outcomes across a 1-year naturalistic follow-up period., Method: The randomized, controlled trial was conducted in 13 academic and community sites in the United States. Stages I, II, and III consisted of 12, 6, and 18 weeks of acute, consolidation, and continuation treatment, respectively. Following discontinuation of TADS treatments at the end of stage III, stage IV consisted of 1 year of naturalistic follow-up. The participants were 327 subjects between the ages of 12 and 17 with a primary DSM-IV diagnosis of major depressive disorder. No TADS treatment was provided during the follow-up period; treatment was available in the community. The primary dependent measures, rated by an independent evaluator blind to treatment status, were the total score on the Children's Depression Rating Scale-Revised and the rate of response, defined as a rating of much or very much improved on the Clinical Global Impressions improvement measure., Results: Sixty-six percent of the eligible subjects participated in at least one stage IV assessment. The benefits seen at the end of active treatment (week 36) persisted during follow-up on all measures of depression and suicidality., Conclusions: In contrast to earlier reports on short-term treatments, in which worsening after treatment is the rule, the longer treatment in the TADS was associated with persistent benefits over 1 year of naturalistic follow-up.

Background: A large body of evidence suggests that immune system dysregulation is associated with Major Depressive Disorder (MDD) in adults. This study extends this work to adolescent MDD to examine the hypotheses of immune system dysregulation in adolescents with MDD, as manifested by significantly: (i) elevated plasma levels of cytokines (interferon [IFN]-gamma, tumor necrosis factor-alpha, interleukin [IL]-6, IL-1beta, and IL-4); and (ii) Th1/Th2 cytokine imbalance shifted toward Th1 as indexed by increased IFN-gamma/IL-4., Method: Thirty adolescents with MDD (19 females; 13 medication-free/naïve; ages 12-19) of at least 6 weeks duration and a minimum severity score of 40 on the Children's Depression Rating Scale-Revised, and 15 healthy comparisons (8 females), group-matched for age, were enrolled. Plasma cytokines were examined using enzyme-linked immunosorbent assay. Mann-Whitney test was used to compare subjects with MDD and controls., Results: Adolescents with MDD had significantly elevated plasma IFN-gamma levels (3.38+/-11.8 pg/ml versus 0.37+/-0.64 pg/ml; p<0.003), and IFN-gamma/IL-4 ratio (16.6+/-56.5 versus 1.76+/-2.28; p=0.007). A trend for IL-6 to be elevated in the MDD group was also observed (1.52+/-2.88 pg/ml versus 0.49+/-0.90 pg/ml; p=0.09). Importantly, findings remained evident when medicated subjects were excluded., Conclusions: Findings suggest that immune system dysregulation may be associated with adolescent MDD, with an imbalance of Th1/Th2 shifted toward Th1, as documented in adult MDD. Larger studies with medication-free adolescents should follow.

Laparoscopic cholecystectomy is an effective and safe treatment for uncomplicated symptomatic cholelithiasis. However, biliary tract injury may be more common with this procedure than with open cholecystectomy. We have encountered 17 patients with a biliary leak among 465 patients undergoing laparoscopic cholecystectomy, the diagnosis being established by clinical and radiographic parameters. The most common site of leakage was the cystic duct stump. Patients underwent endoscopic sphincterotomy and biliary stent placement, with an overall success rate of 96%. No morbidity or mortality related to the endoscopic procedures was encountered. We conclude that biliary leakage after laparoscopic cholecystectomy is uncommon. When it occurs, it can be treated safely and efficaciously by endoscopic means.

Background: While several state-based studies have shown that children in foster care are more likely to be prescribed psychotropic medications and experience concomitant medication use both within and among medication class, these patterns have not been explored in the state of Nevada, which lacks state mandated oversight of psychotropic prescribing for foster care enrolled youth. Methods: Data from an electronic medical record system from a single institution were analyzed to examine the prevalence of psychotropic prescribing and concomitant medication use in children ages 2 to 19 who were enrolled and received psychotropic prescriptions between July 2019 to June 2022. Results: Out of 569 distinct psychotropic medication treatment episodes within this cohort, the most frequent psychotropic classes prescribed were non-stimulant ADHD medications (alpha-agonists and atomoxetine, 31.5%), atypical antipsychotics (22.1%), antidepressants (20.6%), and stimulants (16.0%). The use of stimulants and non-stimulant ADHD medications decreased in older age groups while the use of antidepressants and antipsychotics increased in older age groups. During the three-year period studied, 24.0% of psychotropic medications prescriptions increased in dosage. Treatments were prescribed for only one month in 43.8% of youth. In children prescribed psychotropic medications, concomitant medication use for at least 60 days occurred in 28.0% of children who had any psychotropic medication prescribed. Conclusion: Within the cohort of 273 foster care enrolled subjects aged 2 to 19 years old who received psychotropic medication prescriptions, non-stimulant ADHD medications (both alpha-agonists and atomoxetine) and atypical antipsychotics were more commonly co-prescribed additional psychotropic medication compared to other co-prescribed medication categories. This study illustrates prescribing patterns in a community mental health clinic focused on judicious prescribing of psychotropic medications in foster care enrolled youth. Despite this, 41% of the youth treated in this clinic received at least one prescription for psychotropic medication, and of those, 27.8% were prescribed more than one psychotropic medication at the same time. More studies are necessary to understand the underlying causes of high prevalence of concomitant medication use and prescribing practices of psychotropic medications use in foster care involved pediatric populations. [ABSTRACT FROM AUTHOR]

The article focuses on the challenges of diagnosing adult attention-deficit/hyperactivity disorder (ADHD), and it emphasizes the subjective nature of symptoms, the risks of over diagnosis, and the impact of poor diagnostic practices. It reports an increase in adult ADHD diagnoses and stimulant prescriptions, discusses the challenges of distinguishing ADHD from other conditions that affect attention, and it highlights the risks associated with stimulant treatment.

A pharmacokinetic (PK) bridging approach was successfully employed to support the dosing regimen and approval of brexpiprazole in pediatric patients aged 13-17 years with schizophrenia. Brexpiprazole was approved in 2015 for the treatment of schizophrenia and the adjunctive treatment of major depressive disorder in adults based on efficacy and safety data from clinical trials. On January 13, 2020, the US Food and Drug Administration issued a general advice letter to sponsors highlighting the acceptance of efficacy extrapolation of certain atypical antipsychotics from adult patients to pediatric patients considering the similarity in disease and exposure-response relationships. Brexpiprazole is the first atypical antipsychotic approved in pediatrics using this approach. The PK data available from pediatric patients aged 13-17 years have shown high variability due to the limited number of PK evaluable subjects, which limits a robust estimation of differences between adult and pediatric patients. The PK model-based approach was thus utilized to evaluate the appropriateness of the dosing regimen by comparing PK exposures in pediatric patients aged 13-17 years with exposures achieved in adults at the approved doses. In addition to exposure matching, safety data from a long-term open-label clinical study in pediatric patients informed the safety profile in pediatric patients. This report illustrates the potential of leveraging previously collected efficacy, safety, and PK data in adult patients to make a regulatory decision in pediatric patients for the indication of schizophrenia., (© 2024, The American College of Clinical Pharmacology.)

We entered 60 patients with primary biliary cirrhosis in a double-blind randomized controlled trial to determine whether colchicine is therapeutically effective. Thirty patients had early disease (Stages 1 and 2), and 30 had advanced disease (Stages 3 and 4). Fifteen patients with early disease and 15 with advanced disease received colchicine (0.6 mg twice daily), and the remainder received placebo. Patients were studied about every two months; those remaining in the blind phase at two years underwent repeat liver biopsy and were then placed on open-label colchicine (0.6 mg twice daily). With a few exceptions, the results in patients with early disease were similar to those in patients with advanced disease; hence, data on patients in all stages were combined in the main analysis. During the two-year study period the colchicine-treated patients, as compared with the placebo-treated patients, had improvement in levels of serum albumin, serum bilirubin, alkaline phosphatase, cholesterol, and aminotransferases. However, there was no such improvement in the severity of symptoms or physical findings; moreover, there was no significant difference in the histologic changes noted at liver biopsy in the two treatment groups. At four years after entry, the cumulative mortality from liver disease was 21 percent in patients given colchicine and 47 percent in those given placebo (P = 0.05). The only side effect of colchicine was diarrhea, noted in three patients. The consistent and significant improvement in a number of markers of liver disease and the apparent decreased mortality from liver disease suggest that colchicine may provide some long-term clinical benefit in patients with primary biliary cirrhosis. However, the failure of colchicine to reduce hepatic inflammation and fibrosis leaves uncertain the effect of the drug on the longterm outcome of this disease.

Due to the customary delay between medication approvals in adult and adolescent populations, adolescents with schizophrenia may receive off-label antipsychotic treatment, without empirically justified dosing recommendations. In order to accelerate pediatric drug development, the US Food and Drug Administration (FDA) released a general advice letter to sponsors permitting the effectiveness of atypical antipsychotics for the treatment of schizophrenia in adults to be extrapolated to adolescents based on a pharmacokinetic (PK) analysis to support dose selection, plus a safety study. The aim of the present article is to describe the population PK analysis that was submitted to the FDA to inform brexpiprazole dose selection in adolescents with schizophrenia. Using a population PK model with brexpiprazole clearance and volume of distribution allometrically scaled by body weight, PK simulations showed comparable brexpiprazole dose-exposure between adults and adolescents aged 13-17 years following oral daily doses of brexpiprazole 1-4 mg, indicating that the target brexpiprazole dose of 2-4 mg/day in adults with schizophrenia is also suitable for adolescents. Based on this population PK analysis, together with a safety study in adolescents, the FDA approved brexpiprazole for the treatment of schizophrenia in adolescents aged 13-17 years, via extrapolation of the efficacy of brexpiprazole from adults to adolescents., (© 2023 Otsuka Pharmaceutical Inc and H. Lundbeck A/S. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Background: Awareness of psychotropic medication and its adverse drug reactions (ADRs) can promote safe and rational use of medications, particularly in children and adolescents with mental problems. This study examined the prescription of psychotropic drugs and actual drug-drug interaction (DDI) and ADR for children with mental disorders under 18 years of age in a tertiary hospital in Vietnam. Methods: A cross-sectional descriptive study was performed on 257 psychiatric inpatients under 18 years of age at the National Mental Health Institute—Bach Mai Hospital in 2017. Information about the course of treatment included prescribed medications, drug interactions, side effects, drug combination, and modifications to the regimen was collected. Results: 14.8% and 59.5% of patients received a single-drug regimen and a 2-drug combination regimen upon admission, respectively. The most used regimen was antipsychotics + tranquilizers, accounting for 38.1%. Haloperidol was the most commonly prescribed drug (40.5%). Most patients were given the recommended dosage of the drug (>90%). There were 20.6% of patients having drug interactions with the largest proportion of the combination of diazepam and olanzapine (62.3%). ADRs of psychotropic drugs were detected in 46.3% of patients, with the highest rate of ADRs from antipsychotic drugs. Antipsychotics had the highest rate of replacement (91.3%), mostly replaced from a first-generation antipsychotic (FGA) to a second-generation antipsychotic (SGA). Conclusion: The appointment of psychotropic drugs to patients under 18 years of age has to comply with the recommendations, and carefully balance the benefits and risks of ADRs as well as the risk of DDI in case of the drug combination. [ABSTRACT FROM AUTHOR]

Mental health encompasses a range of mental, emotional, social, and behavioral functioning and occurs along a continuum from good to poor. Previous research has documented that mental health among children and adolescents is associated with immediate and long-term physical health and chronic disease, health risk behaviors, social relationships, education, and employment. Public health surveillance of children's mental health can be used to monitor trends in prevalence across populations, increase knowledge about demographic and geographic differences, and support decision-making about prevention and intervention. Numerous federal data systems collect data on various indicators of children's mental health, particularly mental disorders. The 2013-2019 data from these data systems show that mental disorders begin in early childhood and affect children with a range of sociodemographic characteristics. During this period, the most prevalent disorders diagnosed among U.S. children and adolescents aged 3-17 years were attention-deficit/hyperactivity disorder and anxiety, each affecting approximately one in 11 (9.4%-9.8%) children. Among children and adolescents aged 12-17 years, one fifth (20.9%) had ever experienced a major depressive episode. Among high school students in 2019, 36.7% reported persistently feeling sad or hopeless in the past year, and 18.8% had seriously considered attempting suicide. Approximately seven in 100,000 persons aged 10-19 years died by suicide in 2018 and 2019. Among children and adolescents aged 3-17 years, 9.6%-10.1% had received mental health services, and 7.8% of all children and adolescents aged 3-17 years had taken medication for mental health problems during the past year, based on parent report. Approximately one in four children and adolescents aged 12-17 years reported having received mental health services during the past year. In federal data systems, data on positive indicators of mental health (e.g., resilience) are limited. Although no comprehensive surveillance system for children's mental health exists and no single indicator can be used to define the mental health of children or to identify the overall number of children with mental disorders, these data confirm that mental disorders among children continue to be a substantial public health concern. These findings can be used by public health professionals, health care providers, state health officials, policymakers, and educators to understand the prevalence of specific mental disorders and other indicators of mental health and the challenges related to mental health surveillance. [ABSTRACT FROM AUTHOR]

Pediatric labeling information for novel atypical antipsychotics can be significantly delayed as the result of time lag between initial drug approval in adults and the completion of pediatric clinical trials. This delay can lead health care providers to rely on limited evidence‐based literature to make critical therapeutic decisions for pediatric patients. Effective and scientifically justified dosing recommendations are needed to improve treatment outcomes in pediatric patients with schizophrenia and bipolar I disorder. Extrapolation‐based drug development strategies rely on leveraging prior data to reduce evidentiary requirements for newer data in establishing drug efficacy. On January 13, 2020, the US Food and Drug Administration (FDA) released a general advice letter to sponsors highlighting the acceptance of extrapolating efficacy of atypical antipsychotics to pediatric patients. This review provides insight into the FDA's justification for extrapolating efficacy from adult to pediatric patients and provides a rationale for dose selection in pediatric patients with schizophrenia and bipolar I disorder. [ABSTRACT FROM AUTHOR]

Several lines of evidence indicate that immune-inflammatory alterations are widely observed in various mental disorders. Genetic syndromes with high risk of psychiatric disorders may constitute a model for studies investigating this phenomenon. One of such genetically determined neurodevelopmental disorders is the Prader–Willi syndrome (PWS). Therefore, we aimed to profile a broad panel of immune-inflammatory markers in patients with PWS, taking into account co-morbid psychopathology. Participants were 20 children with PWS, and 20 healthy children matched for age, sex and body mass index. Behavioural symptoms and co-occurring psychopathological symptoms were assessed using the Child Behaviour Checklist (CBCL). We found significantly elevated levels of interleukin (IL)-1β and IL-13 in patients with PWS. There were significant positive correlations between the levels of IL-1β and scores of the following externalizing and internalizing CBCL domains: withdrawn/depressed, social problems, thought problems, attention problems, delinquent and aggressive behaviour in PWS children. Moreover, higher levels of IL-13 were associated with more severe psychopathology in terms of social and attention problems as well as delinquent and aggressive behaviour. Our findings imply that subclinical inflammation, observed as elevated IL-1β and IL-13 levels, appears only in PWS patients and is correlated to several psychopathological symptoms. [ABSTRACT FROM AUTHOR]

Rationale: Stress is related to cognitive impairments which are observed in most major brain diseases. Prior studies showed that the brain concentration of the tryptophan metabolite kynurenic acid (KYNA) is modulated by stress, and that changes in cerebral KYNA levels impact cognition. However, the link between these phenomena has not been tested directly so far. Objectives: To investigate a possible causal relationship between acute stress, KYNA, and fear discrimination. Methods: Adult rats were exposed to one of three acute stressors—predator odor, restraint, or inescapable foot shocks (ISS)—and KYNA in the prefrontal cortex was measured using microdialysis. Corticosterone was analyzed in a subset of rats. Another cohort underwent a fear discrimination procedure immediately after experiencing stress. Different auditory conditioned stimuli (CSs) were either paired with foot shock (CS+) or were non-reinforced (CS−). One week later, fear was assessed by re-exposing rats to each CS. Finally, to test whether stress-induced changes in KYNA causally impacted fear discrimination, a group of rats that received ISS were pre-treated with the selective KYNA synthesis inhibitor PF-04859989. Results: ISS caused the greatest increase in circulating corticosterone levels and raised extracellular KYNA levels by ~ 85%. The two other stressors affected KYNA much less (< 25% increase). Moreover, only rats that received ISS were unable to discriminate between CS+ and CS−. PF-04859989 abolished the stress-induced KYNA increase and also prevented the impairment in fear discrimination in animals that experienced ISS. Conclusions: These findings demonstrate a causal connection between stress-induced KYNA increases and cognitive deficits. Pharmacological manipulation of KYNA synthesis therefore offers a novel approach to modulate cognitive processes in stress-related disorders. [ABSTRACT FROM AUTHOR]

Drugs are prescribed to manage or prevent symptoms and diseases, but may sometimes cause unexpected toxicity to muscles. The symptomatology and clinical manifestations of the myotoxic reaction can vary significantly between drugs and between patients on the same drug. This poses a challenge on how to recognize and prevent the occurrence of drug-induced muscle toxicity. The key to appropriate management of myotoxicity is prompt recognition that symptoms of patients may be drug related and to be aware that interindividual differences in susceptibility to drug-induced toxicity exist. The most prevalent and welldocumented drug class with unintended myotoxicity are the statins, but even today new classes of drugs with unintended myotoxicity are being discovered. This review will start off by explaining the principles of drug-induced myotoxicity and the different terminologies used to distinguish between grades of toxicity. The main part of the review will focus on the most important pathogenic mechanisms by which drugs can cause muscle toxicity, which will be exemplified by drugs with high risk of muscle toxicity. This will be done by providing information on key clinical and laboratory aspects, muscle electromyography patterns and biopsy results, and pathological mechanism and management for a specific drug from each pathogenic classification. In addition, rather new classes of drugs with unintended myotoxicity will be highlighted. Furthermore, we will explain why it is so difficult to diagnose drug-induced myotoxicity, and which tests can be used as a diagnostic aid. Lastly, a brief description will be given of how to manage and treat drug-induced myotoxicity. [ABSTRACT FROM AUTHOR]

Objectives: Peripheral inflammation has been associated with multiple psychiatric disorders, particularly with depression. However, findings remain inconsistent and unreproducible, most likely due to the disorder's heterogeneity in phenotypic presentation. Therefore, in the present study, in an effort to account for inter-individual differences in symptom severity, we utilised a dimensional approach to assess the relationships between a broad panel of inflammatory cytokines and key psychiatric symptoms (i.e. depression, anhedonia, anxiety, fatigue and suicidality) in adolescents across psychiatric disorders. We hypothesised that only anhedonia (reflecting deficits of reward function) will be associated with inflammation. Methods: Participants were 54 psychotropic medication-free adolescents with diverse psychiatric conditions and 22 healthy control (HC) adolescents, aged 12–20. We measured 41 cytokines after in vitro lipopolysaccharide stimulation. Mann-Whitney U and Spearman correlation tests examined group comparison and associations, respectively, while accounting for multiple comparisons and confounds, including depression severity adolescent. Results: There were no group differences in cytokine levels. However, as hypothesised, within the psychiatric group, only anhedonia was associated with 19 cytokines, including haematopoietic growth factors, chemokines, pro-inflammatory cytokines, and anti-inflammatory cytokines. Conclusions: Our findings suggest that general inflammation may induce reward dysfunction, which plays a salient role across psychiatric conditions, rather than be specific to one categorical psychiatric disorder. [ABSTRACT FROM AUTHOR]

Objectives: Patients affected by major depression (MDD) are at high risk of suicide. The metabolism of tryptophan (Trp) along the serotonin (5-HT) and kynurenine (Kyn) pathways was found dysfunctional in MDD and in suicide. However, a clear biological framework linking dysfunctions in Trp metabolism via 5-HT and Kyn, cortisol, and the activities of tryptophan and indoleamino 2,3-dioxygenase (TDO, IDO) enzymes has not been yet clarified in MDD with or without suicidal behaviours. Methods: We analysed peripheral markers of Trp via 5-HT and Kyn pathways, Kyn/Trp ratio as a measure of TDO/IDO activities, cortisol, and psychopathology in 73 non-suicidal and 56 suicidal MDD patients, and in 40 healthy controls. Results: Plasma Trp levels were lower and the ratio Kyn/Trp higher in suicidal MDD than in non-suicidal MDD patients and controls. Trp levels and the ratio Kyn/Trp correlated with suicidal ideation, and cortisol with the Kyn/Trp ratio. Finally, Trp levels discriminated controls from non-suicidal and suicidal MDD patients, and also non-suicidal from suicidal MDD patients. Conclusions: Reduced availability of Trp for 5-HT synthesis and increased activation of the Kyn pathway and cortisol correlate with depression and suicide. Low plasma Trp levels may be a biomarker of MDD and suicide in MDD. [ABSTRACT FROM AUTHOR]

Treatment of primary biliary cholangitis (PBC) with ursodeoxycholic acid (UDCA) is not always sufficient to prevent progression to hepatic decompensation and/or need for liver transplant. Adjuvant therapy with obeticholic acid may provide additional biochemical improvements in some patients, but it is not well-tolerated by patients with significant itch or advanced cirrhosis. Thus, new and creative approaches to treating patients with PBC are important to identify. This review discusses major potential therapeutic targets in PBC and provides examples of some specific agents currently in development for the treatment of PBC. Targets are broadly classified into those which strive to modify bile, inflammation, cell survival, or fibrosis. In bile, shrinking the size of the bile acid pool or modifying the quality of the bile by making it more hydrophilic or enriched in phosphatidylcholine may ameliorate cholestatic injury. Biliary epithelial cell survival may be extended by fortifying the bicarbonate umbrella or improving cell membrane integrity. Autoimmunity and cholangitis have the potential to be improved via regulation of the immune system. Targeting cytokines, immune checkpoints, and anti-mitochondrial antibodies are examples of a more focused immunosuppression approach. Stem cell therapy and lymphocyte trafficking inhibition are more novel methods of broad immune regulation. Anti-fibrotic therapies are also potentially useful for preventing progression of PBC. The nuclear hormone receptors, farnesoid X receptor (FXR) and peroxisome proliferator-activated receptor (PPAR) regulate many of these pathways: cholestasis, inflammation, and fibrosis, which is why they are being enthusiastically pursued as potential therapeutic targets in PBC., (© 2022 American Association for the Study of Liver Diseases.)

Objective: Neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and monocyte/lymphocyte ratio (MLR) are practical inflammation parameters. In bipolar disorder (BD) and major depressive disorder (MDD), these parameters were reported higher than in healthy controls (HC). We aim to compare NLR, PLR, MLR in HC and patients with MDD and BB-manic episode. Method: Forty-six patients with MDD and 43 patients with BD hospitalized between 2013 and 2017 and 40 HC were included in the study. White blood cell, neutrophil, lymphocyte, platelet, and monocyte numbers were entered retrospectively from complete blood counts made at the time of admission, and NLR, PLR, and MLR were calculated from these. Results: NLR and PLR were revealed higher in MDD than HC. NLR and neutrophil values were higher in BD than HC, and there was a positive correlation between NLR and hospitalization period of patients with BD. Conclusion: Findings of our study supported the inflammation hypothesis for MDD and BD in adolescents. Larger-scale studies are necessary to confirm these findings. [ABSTRACT FROM AUTHOR]

The MAPK/ERK (mitogen-activated protein kinases/extracellular signal-regulated kinase) pathway is a cardinal regulator of synaptic plasticity, learning, and memory in the hippocampus. One of major endpoints of this signaling cascade is the 5+ mRNA cap binding protein eIF4E (eukaryotic Initiation Factor 4E), which is phosphorylated on Ser 209 by MNK (MAPK-interacting protein kinases) and controlsmRNAtranslation. The precise role of phospho-eIF4E in the brain is yet to be determined. Herein, we demonstrate that ablation of eIF4E phosphorylation in male mice (4Eki mice) does not impair long-term spatial or contextual fear memory, or the late phase of LTP. Using unbiased translational profiling in mouse brain, we show that phospho-eIF4E differentially regulates the translation of a subset of mRNAs linked to inflammation, the extracellular matrix, pituitary hormones, and the serotonin pathway. Consequently, 4Eki male mice display exaggerated inflammatory responses and reduced levels of serotonin, concomitant with depression and anxiety-like behaviors. Remarkably, eIF4E phosphorylation is required for the chronic antidepressant action of the selective serotonin reuptake inhibitor fluoxetine. Finally, we propose a novel phospho-eIF4E-dependent translational control mechanism in the brain, via the GAIT complex (gamma IFN activated inhibitor of translation). In summary, our work proposes a novel translational control mechanism involved in the regulation of inflammation and depression, which could be exploited to design novel therapeutics. [ABSTRACT FROM AUTHOR]

Recent reports show that the worldwide incidence of autism spectrum disorder (ASD) is dramatically increasing, although ASD etiology and pathogenesis are still far to be fully elucidated. Some dietary-derived essential compounds, such as the amino acid tryptophan, appear to be impaired in patients with ASD. Tryptophan (Trp) plays a significant role in the human organism and serves as a precursor for a wide range of bioactive compounds, including major neurotransmitters. Research indicates that tryptophan might be deficient in subjects with ASD. Deficiency in the tryptophan level can be retrieved by investigating Trp levels or its major metabolite kynurenine in urines. The purpose of the present study is to quantify tryptophan content in urine samples ( n = 236) of ASD patients, who underwent a supplemented dietary panel with B vitamins and magnesium, compared to controls (without this diet regimen). The samples were analyzed with gas chromatography-mass spectrometry. Additionally, the correlation between body mass index (BMI) and the level of this amino acid in urine was accomplished. Basic parameters of urine samples were also evaluated. Statistical evaluations in the concentration of tryptophan in ASD patients with different severity of symptoms were reported. A significant difference in tryptophan levels in all groups was observed. Supplementation with B vitamins and magnesium has an influence on the Trp concentration. Furthermore, no correlation between BMI and tryptophan levels was found. These results assess that the Trp level in ASD subjects is critical and that intake of B vitamins and magnesium with diet might influence its metabolic homeostasis. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is not a single disease, but a number of various ailments that form one entity. Psychomotor retardation, anhedonia, sleep disorders, an increased suicide risk, and anxiety are the main symptoms that often define the clinical diagnosis of depression. Interleukin-6 (IL-6), as one of the proinflammatory cytokines, seems to be overexpressed during certain mental disorders, including MDD. Overexpression of IL-6 in depression is thought to be a factor associated with bad prognosis and worse disease course. IL-6 may directly affect brain functioning and production of neurotransmitters; moreover, its concentration is correlated with certain clinical symptoms within the wide range of depressive symptomatology. Furthermore, there is a strong correlation between IL-6 synthesis and psychosomatic functioning of the patient. This article discusses potential sources and significance of IL-6 in the pathogenesis of depression. [ABSTRACT FROM AUTHOR]

HIV-infection is associated with neuroinflammation and greater psychopathological symptoms, which may be mediated by imbalances in the kynurenic pathway (KP). Two key KP enzymes that catabolize kynurenine include kynurenine-aminotransferase II (KATII), which yields antioxidative kynurenine acid [KYNA] in astrocytes, and kynurenine-3-monooxygenase (KMO), which produces neurotoxic metabolites in microglia. The relationships between polymorphisms in KMO and KATII, psychopathological symptoms, and cerebrospinal fluid (CSF) [KYNA] were evaluated in subjects with and without HIV-infection. Seventy-two HIV-positive and 72-seronegative (SN) participants were genotyped for KATII-rs1480544 and KMO-rs1053230. Although our participants were not currently diagnosed with depression or anxiety, they were assessed for psychopathological distress with Center for Epidemiologic Studies-Depression scale and Symptom Checklist-90-Revised. CSF-[KYNA] was also measured in 100 subjects (49 HIV/51 SN). HIV-participants had more psychopathological distress than SN, especially for anxiety. KATII-by-HIV interactions were found on anxiety, interpersonal sensitivity and obsessive compulsivity; KATII-C-carriers had lower scores than TT-carriers in SN but not in HIV. In contrast, the KMO-polymorphism had no influence on psychopathological symptoms in both groups. Overall, CSF-[KYNA] increased with age independently of HIV-serostatus, except KATII-TT-carriers tended to show no age-dependent variations. Therefore, the C-allele in KATII-rs1480544 appears to be protective against psychopathological distress in SN but not in HIV individuals, who had more psychopathological symptoms and likely greater neuroinflammation. The age-dependent increase in CSF-[KYNA] may reflect a compensatory response to age-related inflammation, which may be deficient in KATII-TT-carriers. Targeted treatments that decrease neuroinflammation and increase KYNA in at risk KATII-TT-carriers may reduce psychopathological symptoms in HIV. [ABSTRACT FROM AUTHOR]

An essay is presented on Samson Raphael Hirsch, German Orthodox Bible translator and commentator, and his contribution to German Jewish community by his revolutionary concepts such as establishing relationship between the oral and written "Torah." Topics include his written works such as "Der Pentateuch," beliefs on practical application of torah and use of biblical commandments. Also mentioned are his aversion towards using Wissenschaft methods to study biblical and rabbinic writings.

Major depression is a serious psychiatric disorder; however, the precise biological basis of depression still remains elusive. A large body of evidence implicates a dysregulated endocrine and inflammatory response system in the pathogenesis of depression. Despite this, given the heterogeneity of depression, not all depressed patients exhibit dysregulation of the inflammatory and endocrine systems. Evidence suggests that inflammation is associated with depression in certain subgroups of patients and that those who have experienced stressful life events such as childhood trauma or bereavement may be at greater risk of developing depression. Consequently, prolonged exposure to stress is thought to be a key trigger for the onset of a depressive episode. This review assesses the relationship between stress and the immune system, with a particular interest in the mechanisms by which stress impacts immune function, and how altered immune functioning, in turn, may lead to a feed forward cascade of multiple systems dysregulation and the subsequent manifestation of depressive symptomology. The identification of stress-related immune markers and potential avenues for advances in therapeutic intervention is vital. Changes in specific biological markers may be used to characterize or differentiate depressive subtypes or specific symptoms and may predict treatment response, in turn facilitating a more effective, targeted, and fast-acting approach to treatment. [ABSTRACT FROM AUTHOR]

Background: Continuous ambulatory peritoneal dialysis is a successful treatment modality for patients with end-stage renal disease. Peritoneal fibrosis (PF) is the most critical complication of long-term peritoneal dialysis (PD). Aims: In our study, we aimed to compare the effects of colchicine and sirolimus on PF induced by hypertonic peritoneal dialysis solutions in rats. Study Design: Animal experiment. Methods: Twenty-four rats were randomly divided into three groups. The control group received an intraperitoneal injection (ip) of saline. The sirolimus group received the PD solution, plus 1.0 mg/kg/day Rapamune ®. The colchicine group received the PD solution ip plus 1.0 mg/kg/day of colchicine. Blood samples were taken to measure the serum levels of VEGF, TGF-β, and TNF-α. Peritoneal tissue samples were taken for histopathological evaluation. Results: TGF-β and TNF-α values in the sirolimus group were found to be statistically significantly lower than in the control and colchicine groups, but the differences between the control and colchicine groups were not statistically significant. No statistically significant differences were found between the groups regarding the VEGF values. Vascular neogenesis and peritoneal thickness were compared; the values in the sirolimus group were statistically reduced compared to the values in the control group. Mild fibrosis developed in 75% of all animals in the sirolimus group; there was no moderate or severe fibrosis observed. Fibrosis developed to varying degrees in 100% of the animals in the control and colchicine groups. Conclusion: The present study demonstrates that sirolimus might be beneficial for preventing or delaying the progression of PF and neoangiogenesis. These alterations in the peritoneal membrane may be connected with reduced TNF-α and TGF-β levels. [ABSTRACT FROM AUTHOR]

Background Soyo-san is a traditional oriental medicinal formula, a mixture of 9 crude drugs, and it has been clinically used for treating mild depressive disorders. The role of pro- and antiinflammatory cytokines in psychiatric disorders has been the focus of great research attention in recent years. In the present study, we detected the antidepressant effect of soyo-san in the ovariectomized and repeated stressed female rats. Methods This study was designed to evaluate the antidepressant-like effect of soyo-san on the forced swimming test (FST). The rats were randomly divided into the following groups: the nonoperated and nonstressed group (non-op), the nonoperated and stressed group (non-op + ST), the ovariectomized and stress group (OVX) and sham operated and stressed group (sham), the ovariectomized and stressed group (OVX + ST), the ovariectomized, stressed and soyo-san 100 mg/kg treated group (SOY100) and the ovariectomized, stressed and soyo-san 400 mg/kg treated group (SOY400). The rats were exposed to immobilization stress (IMO) for 14day (2 h/14day), and soyo-san (100 mg/kg and 400 mg/kg) was administrated during the same time. In the same animals, the levels of corticosterone and interleukin-1-beta (IL- 1β) were examined in the serum. Also, the change of IL-1β expression in brain regions was examined after behavior test. Results In the FST, the lower dose (100 mg/kg) of extract was effective in reducing immobility, along with an increase in swimming time. The serum levels of corticosterone and IL-1β in the SOY groups were significantly lower than that in the control group. In the brain, the expression of IL-1β positive neurons in the control group significantly increased in the paraventricular nucleus (PVN) and hippocampus compared to the non-op. However, soyo-san groups significantly reduced the IL-1β-ir neurons in the PVN and hippocampal regions compared to the control. Conclusion The present results demonstrated that soyo-san effectively reduced behavioral and pathophysiological depression-like responses. Trial registration: Our results suggest that soyo-san may be useful for an immune promoter in repeated stress-induced ovariectomized female rats. [ABSTRACT FROM AUTHOR]

Experienced acute and critical care nurses are poised to be high-impact leaders in the current, ever-changing health care landscape.These professionals need new skills to carry them to the next level, as they are called on to lead in a new age filled with increasing complexities.This article provides strategies for nurses to consider and reflect on throughout their leadership journey [ABSTRACT FROM AUTHOR]

Background: Laparoscopic cholecystectomy is one of the most common surgical procedures in Europe (and the world) and has become the standard procedure for the management of symptomatic cholelithiasis or acute cholecystitis in patients without specific contraindications. Bile duct injuries (BDI) are rare but serious complications that can occur during a laparoscopic cholecystectomy. Prevention and management of BDI has given rise to a host of publications but very few recommendations, especially in Europe. Methods: A systematic research of the literature was performed. An international expert panel was invited to appraise the current literature and to develop evidence-based recommendations. Statements and recommendations were drafted after a consensus development conference in May 2011, followed by presentation and discussion at the annual congress of the EAES held in Torino in June 2011. Finally, full guidelines were consented and adopted by the expert panel via e-mail and web conference. Results: A total of 1,765 publications were identified through the systematic literature search and additional submission by panellists; 671 publications were selected as potentially relevant. Only 46 publications fulfilled minimal methodological criteria to support Clinical Practice Guidelines recommendations. Because the level of evidence was low for most of the studies, most statements or recommendations had to be based on consensus of opinion among the panel members. A total of 15 statements and recommendations were developed covering the following topics: classification of injuries, epidemiology, prevention, diagnosis, and management of BDI. Conclusions: Because BDI is a rare event, it is difficult to generate evidence for prevention, diagnosis, or the management of BDI from clinical studies. Nevertheless, the panel has formulated recommendations. Due to the currently limited evidence, a European registry should be considered to collect and analyze more valid data on BDI upon which recommendations can be based. [ABSTRACT FROM AUTHOR]

To address the heterogeneous nature of adolescent major depression (MDD), we investigated anhedonia, a core symptom of MDD. We recently reported activation of the kynurenine pathway (KP), a central neuroimmunological pathway which metabolizes tryptophan (TRP) into kynurenine (KYN) en route to several neurotoxins, in a group of highly anhedonic MDD adolescents. In this study, we aimed to extend our prior work and examine the relationship between KP activity and anhedonia, measured quantitatively, in a group of MDD adolescents and in a combined group of MDD and healthy control adolescents. Thirty-six adolescents with MDD (22 medication-free) and 20 controls were included in the analysis. Anhedonia scores were generated based on clinician- and subject-rated assessments and a semi-structured clinician interview. Blood KP metabolites, collected in the AM after an overnight fast, were measured using high-performance liquid chromatography. The rate-limiting enzyme of the KP, indoleamine 2,3-dioxygenase (IDO), was estimated by the ratio of KYN/TRP. Pearson correlation tests were used to assess correlations between anhedonia scores and KP measures while controlling for MDD severity. IDO activity and anhedonia scores were positively correlated in the group psychotropic medication-free adolescents with MDD ( r = 0.42, P = 0.05) and in a combined group of MDD subjects and healthy controls (including medicated patients: r = 0.30, P = 0.02; excluding medicated patients: r = 0.44, P = 0.004). In conclusions, our findings provide further support for the role for the KP, particularly IDO, in anhedonia in adolescent MDD. These results emphasize the importance of dimensional approaches in the investigation of psychiatric disorders. [ABSTRACT FROM AUTHOR]

The article discusses the symptomatic and behavioral similarities and dissimilarities between both clinical depression and sickness behavior. It looks into the staging of depression compared to the course of sickness behavior and the shared immuno-inflammatory pathways that both support the two conditions. It also explores the etiological factors in both conditions.

Background. Colchicine poisoning is potentially life-threatening. Deaths generally result from hypovolemic shock and cardiovascular collapse or secondary to rapidly progressive multiorgan failure. Objective. The purpose of this study is to discuss the clinical effects, treatments and outcomes of pediatric colchicine poisoning and highlight the possible benefits of urgent plasma and whole blood exchange therapy for those patients who were believed to ingest potentially lethal doses of the drug. Methods. Current study was designed as an observational case series study. The medical records of children aged 0-16 years who were hospitalized for colchicine poisoning at the Pediatric Intensive Care Unit of, between November 1985 and March 2011 were retrospectively evaluated. Results. We present twenty-three children with colchicine poisoning. Nausea and vomiting were the most common presenting complaint, in 70% of patients. Sixteen of the 23 cases presented after ingesting sub-toxic doses of colchicine (< 0.5 mg/kg), whereas 3 patients had consumed toxic doses of the drug (0.5-0.8 mg/kg). The remaining 4 patients were hospitalized after taking colchicine at a lethal dose (> 0.8 mg/kg). Three patients (13%) died. Conclusions. Any patient suspected of ingesting high doses of colchicine should prompt immediate fluid and electrolyte resuscitation and invasive hemodynamic monitorization in a pediatric intensive care unit. Although there is lack of strong evidence, early initiation of either whole blood or plasma exchange may be considered in patients presenting with lethal-dose colchicine intoxication. These reported experience of us put forth further research for consideration. [ABSTRACT FROM AUTHOR]

The article presents a study on the recovery from and recurrence of major depressive disorder (MDD) during an extended naturalistic follow-up of participants in the Treatment for Adolescents with Depression Study (TADS) in the U.S. The researchers studied the different predictors of recovery and recurrence including family income, sex and ethnicity. They found that all predictors of recovery by two years were linked to clinical status following short-term treatment and that the female sex was the strongest predictor of recurrence.