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The metabolism of L-tryptophan (TRP) regulates homeostasis, immunity, and neuronal function. Altered TRP metabolism has been implicated in the pathophysiology of various diseases of the central nervous system. TRP is metabolized through two main pathways, the kynurenine pathway and the methoxyindole pathway. First, TRP is metabolized to kynurenine, then kynurenic acid, quinolinic acid, anthranilic acid, 3- hydroxykynurenine, and finally 3-hydroxyanthranilic acid along the kynurenine pathway. Second, TRP is metabolized to serotonin and melatonin along the methoxyindole pathway. In this review, we summarize the biological properties of key metabolites and their pathogenic functions in 12 disorders of the central nervous system: schizophrenia, bipolar disorder, major depressive disorder, spinal cord injury, traumatic brain injury, ischemic stroke, intracerebral hemorrhage, multiple sclerosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Furthermore, we summarize preclinical and clinical studies, mainly since 2015, that investigated the metabolic pathway of TRP, focusing on changes in biomarkers of these neurologic disorders, their pathogenic implications, and potential therapeutic strategies targeting this metabolic pathway. This critical, comprehensive, and up-to-date review helps identify promising directions for future preclinical, clinical, and translational research on neuropsychiatric disorders. [ABSTRACT FROM AUTHOR]

Modulators of the sphingosine-1-phosphate receptor (S1PR) have been proposed as a promising strategy for treating stroke. However, the detailed mechanisms and the potential translational value of S1PR modulators for intracerebral hemorrhage (ICH) therapy warrant exploration. Using collagenase VII-S-induced ICH in the left striatum of mice, we investigated the effects of siponimod on cellular and molecular immunoinflammatory responses in the hemorrhagic brain in the presence or absence of anti-CD3 monoclonal antibodies (Abs). We also assessed the severity of short- and long-term brain injury and evaluated the efficacy of siponimod in long-term neurologic function. Siponimod treatment significantly decreased brain lesion volume and brain water content on day 3 and the volume of the residual lesion and brain atrophy on day 28. It also inhibited neuronal degeneration on day 3 and improved long-term neurologic function. These protective effects may be associated with a reduction in the expression of lymphotactin (XCL1) and T-helper 1 (Th1)-type cytokines (interleukin 1β and interferon-γ). It may also be associated with inhibition of neutrophil and lymphocyte infiltration and alleviation of T lymphocyte activation in perihematomal tissues on day 3. However, siponimod did not affect the infiltration of natural killer cells (NK) or the activation of CD3-negative immunocytes in perihematomal tissues. Furthermore, it did not influence the activation or proliferation of microglia or astrocytes around the hematoma on day 3. Siponimod appears to have a profound impact on infiltration and activation of T lymphocytes after ICH. The effects of neutralized anti-CD3 Abs-induced T-lymphocyte tolerance on siponimod immunomodulation further confirmed that siponimod alleviated the cellular and molecular Th1 response in the hemorrhagic brain. This study provides preclinical evidence that encourages future investigation of immunomodulators, including siponimod, which target the lymphocyte-related immunoinflammatory reaction in ICH therapy. [ABSTRACT FROM AUTHOR]

A series of regioregular poly(3-alkylthiophene)s, Rg(Th- m,n/p) ( m= 5, 8, 11; n= 4; p= 4, 8, 12), with alternating alkyl and semifluoroalkyl substituents has been synthesized by the GRIM polymerization method. Compared with their regiorandom analogues, Rn(Th- m,n/p), the regioregular analogues exhibit a red shift in electronic transitions in both solution and the solid state as well as considerably higher melting and crystallization temperatures. Increasing the length of alkyl side chains decreases the melting and crystallization transitions significantly. X-ray diffraction indicates that Rg(Th- m,n/p) polymers form highly ordered bilayer lamellar structures based on the assembly of the amphiphilic Janus-type structure. This supramolecular architecture can be tuned readily by varying the lengths of alkyl ( p) and alkylene ( m) fragments, affording interlayer distances of 40.1 Å for Rg(Th-5,4/4)and 57.8 Å for Rg(Th-11,4/8). Charge mobility was measured in organic field-effect transistors fabricated using Rg(Th-5,4/12)as the semiconductor layer. Hole mobilities of up to 1.45 × 10 −2cm 2/(V s) were measured in FET devices after thermal annealing of the organic semiconductor. [ABSTRACT FROM AUTHOR]

Many active pharmaceutical ingredients (APIs) exhibit a highly variable pharmacokinetic (PK) profile. This behavior may be attributable to pre-absorptive, absorptive and/or post-absorptive factors. Pre-absorptive factors are those related to dosage form disintegration, drug dissolution, supersaturation, precipitation and gastric emptying. Absorptive factors are involved with drug absorption and efflux mechanisms, while drug distribution and clearance are post-absorptive factors. This study aimed to investigate the relative influence of the aforementioned parameters on the pharmacokinetic profile of atazanavir, a poorly soluble weakly basic compound with highly variable pharmacokinetics. The pre-absorptive behavior of the drug was examined by applying biorelevant in vitro tests to reflect upper gastrointestinal behavior in the fasted and fed states. The in vitro results were implemented, along with permeability and post-absorptive data obtained from the literature, into physiologically based pharmacokinetic (PBPK) models. Sensitivity analysis of the resulting plasma profiles revealed that the pharmacokinetic profile of atazanavir is affected by an array of factors rather than one standout factor. According to the in silico model, pre-absorptive and absorptive factors had less impact on atazanavir bioavailability compared to post-absorptive parameters, although active drug efflux and extraction appear to account for the sub-proportional pharmacokinetic response to lower atazanavir doses in the fasted state. From the PBPK models it was concluded that further enhancement of the formulation would bring little improvement in the pharmacokinetic response to atazanavir. This approach may prove useful in assessing the potential benefits of formulation enhancement of other existing drug products on the market. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to examine the clinical validities and efficiencies of the Child Behavior Checklist (CBCL) and the ADHD Rating Scale-IV (ARS) in identifying children with attention-deficit hyperactivity disorder (ADHD) in Korean community-based samples. Method: A large sample of elementary school students (n = 1668) participated in this study. We used the CBCL and the ARS as the screening instruments. Diagnoses were determined by clinical psychiatric interviews and confirmed by DSM-IV-based structured interviews. Results: Of the 46 subjects who underwent clinical psychiatric interviews, 33 were diagnosed as having ADHD. A T score of 60 with regard to the Attention Problems profile of the CBCL resulted in a reasonable level of sensitivity or positive predictive value in the diagnosis of ADHD. In both the parent and teacher reports of the ARS, 90th percentile cut-off points resulted in a high level of predictive value. The highest levels of specificity and positive predictive value were obtained when we combined the CBCL (T ≥ 60 in Attention Problems) and the ARS (parent-teacher total ≥ 90th percentile) reports. Conclusions: These findings suggest that the combined use of the CBCL and the ARS could serve as a rapid and useful clinical method of predicting or even diagnosing children with ADHD in epidemiologic case definitions. [ABSTRACT FROM AUTHOR]

The purpose of this study is to examine the behavioral and developmental characteristics of children with inv(9). This case control study included 12 inv(9) subjects and 45 normal students. All of the subjects, together with their parents, underwent a psychiatric interview and parent questionnaire consisting of a Child Behavior Checklist (CBCL). The mean scores with regard to the social problems and total problems profiles of the CBCL were significantly higher in the inv(9) group than in the normal control group. The inv(9) group exhibited language and motor developmental delay. These findings suggest that there is a possibility of inv(9) being associated with child developmental or behavioral problems. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine tHe psychiatric characteristics of children with Prader-Willi syndrome in Korea, focusing particularly on their behavioral problems and obsessive-compulsive spectrum symptoms. Fourteen patients with Prader-Willi syndrome, together with their parents, underwent a psychiatric interview and parent questionnaire consisting of a Child Behavior Checklist. Twenty-four patients with mental retardation and 45 normal students were selected as control groups. Compared with the normal control group, the rates of inclusion in the clinical range and the mean scores with regard to social problems, thought problems, attention problems, delinquent behavior, aggressive behavior, externalizing problems, and total problems profiles were significantly higher (P < .01) in the Prader-Willi syndrome group according to the results of the Child Behavior Checklist. Compared with the mental retardation group, there was a statistically significant (P < .05) difference in the delinquent behavior profile. Comparing selected Child Behavior Checklist items related to obsessive-compulsive spectrum symptoms, the Prader-Willi syndrome group showed significantly more (P < .05) compulsion, skin picking, and stealing than the mental retardation or normal control groups. These findings suggest that children with Prader-Willi syndrome in Korea have many behavioral problems, including obsessive-compulsive spectrum symptoms, needing proper psychiatric attention and treatment. This is the first study in Korea to evaluate the psychiatric and behavioral characteristics of children with Prader-Willi syndrome. (J Child Neurol 2005;20:134-138). [ABSTRACT FROM AUTHOR]

Advances in medical imaging have enabled patient-specific biomechanical modelling of arterial lesions such as atherosclerosis and aneurysm. Geometry acquired from in-vivo imaging is already pressurized and a zero-pressure computational start shape needs to be identified. The backward displacement algorithm was proposed to solve this inverse problem, utilizing fixed-point iterations to gradually approach the start shape. However, classical fixed-point implementations were reported with suboptimal convergence properties under large deformations. In this paper, a dynamic learning rate guided by the deformation gradient tensor was introduced to control the geometry update. The effectiveness of this new algorithm was demonstrated for both idealized and patient-specific models. The proposed algorithm led to faster convergence by accelerating the initial steps and helped to avoid the non-convergence in large-deformation problems. [ABSTRACT FROM AUTHOR]