Cerebral cortical structural alteration patterns across four major psychiatric disorders in 5549 individuals.

According to the operational diagnostic criteria, psychiatric disorders such as schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and autism spectrum disorder (ASD) are classified based on symptoms. While its cluster of symptoms defines each of these psychiatric disorders, there is also an overlap in symptoms between the disorders. We hypothesized that there are also similarities and differences in cortical structural neuroimaging features among these psychiatric disorders. T1-weighted magnetic resonance imaging scans were performed for 5,549 subjects recruited from 14 sites. Effect sizes were determined using a linear regression model within each protocol, and these effect sizes were meta-analyzed. The similarity of the differences in cortical thickness and surface area of each disorder group was calculated using cosine similarity, which was calculated from the effect sizes of each cortical regions. The thinnest cortex was found in SZ, followed by BD and MDD. The cosine similarity values between disorders were 0.943 for SZ and BD, 0.959 for SZ and MDD, and 0.943 for BD and MDD, which indicated that a common pattern of cortical thickness alterations was found among SZ, BD, and MDD. Additionally, a generally smaller cortical surface area was found in SZ and MDD than in BD, and the effect was larger in SZ. The cosine similarity values between disorders were 0.945 for SZ and MDD, 0.867 for SZ and ASD, and 0.811 for MDD and ASD, which indicated a common pattern of cortical surface area alterations among SZ, MDD, and ASD. Patterns of alterations in cortical thickness and surface area were revealed in the four major psychiatric disorders. To our knowledge, this is the first report of a cross-disorder analysis conducted on four major psychiatric disorders. Cross-disorder brain imaging research can help to advance our understanding of the pathogenesis of psychiatric disorders and common symptoms.

Subcortical volumetric alterations in four major psychiatric disorders: a mega-analysis study of 5604 subjects and a volumetric data-driven approach for classification.

Differential diagnosis is sometimes difficult in practical psychiatric settings, in terms of using the current diagnostic system based on presenting symptoms and signs. The creation of a novel diagnostic system using objective biomarkers is expected to take place. Neuroimaging studies and others reported that subcortical brain structures are the hubs for various psycho-behavioral functions, while there are so far no neuroimaging data-driven clinical criteria overcoming limitations of the current diagnostic system, which would reflect cognitive/social functioning. Prior to the main analysis, we conducted a large-scale multisite study of subcortical volumetric and lateralization alterations in schizophrenia, bipolar disorder, major depressive disorder, and autism spectrum disorder using T1-weighted images of 5604 subjects (3078 controls and 2526 patients). We demonstrated larger lateral ventricles volume in schizophrenia, bipolar disorder, and major depressive disorder, smaller hippocampus volume in schizophrenia and bipolar disorder, and schizophrenia-specific smaller amygdala, thalamus, and accumbens volumes and larger caudate, putamen, and pallidum volumes. In addition, we observed a leftward alteration of lateralization for pallidum volume specifically in schizophrenia. Moreover, as our main objective, we clustered the 5,604 subjects based on subcortical volumes, and explored whether data-driven clustering results can explain cognitive/social functioning in the subcohorts. We showed a four-biotype classification, namely extremely (Brain Biotype [BB] 1) and moderately smaller limbic regions (BB2), larger basal ganglia (BB3), and normal volumes (BB4), being associated with cognitive/social functioning. Specifically, BB1 and BB2-3 were associated with severe and mild cognitive/social impairment, respectively, while BB4 was characterized by normal cognitive/social functioning. Our results may lead to the future creation of novel biological data-driven psychiatric diagnostic criteria, which may be expected to be useful for prediction or therapeutic selection.

Dynamics of corticocortical brain functional connectivity relevant to therapeutic response to biologics in inflammatory arthritis.

Aberrant functional connectivity (FC) of the brain regions, evaluated by functional magnetic resonance imaging (fMRI), affects clinical courses in inflammatory arthritis (IA). The static analysis methods would be simplistic to estimate the whole picture of resting-state brain function because blood oxygen level-dependent (BOLD) signals fluctuate over time. The effects of FC dynamics on clinical course are unknown in IA. Therefore, we aimed to evaluate dynamic FC for therapeutic responsiveness to biologics in IA patients. We analyzed resting-state fMRI data of 64 IA patients in 2 cohorts. Dynamic FC was derived as a correlation coefficient of the windowed BOLD signal time series. We determined representative whole-brain dynamic FC patterns by k-means++ cluster analysis, leading to 4 distinct clusters. In the first cohort, occurrence probability of the distinct cluster was associated with favorable therapeutic response in disease activity and patients' global assessment, which was validated by the second cohort. The whole-brain FC of the distinct cluster indicated significantly increased corticocortical connectivity, and probabilistically decreased after therapy in treatment-effective patients compared with -ineffective patients. Taken together, frequent emergence of corticocortical connections was associated with clinical outcomes in IA. The coherence of corticocortical interactions might affect pain modulation, possibly relevant to therapeutic satisfaction.

Polyimidazolium Protects against an Invasive Clinical Isolate of Salmonella Typhimurium.

Frequent outbreaks of Salmonella Typhimurium infection, in both animal and human populations and with the potential for zoonotic transmission, pose a significant threat to the public health sector. The rapid emergence and spread of more invasive multidrug-resistant clinical isolates of Salmonella further highlight the need for the development of new drugs with effective broad-spectrum bactericidal activities. The synthesis and evaluation of main-chain cationic polyimidazolium 1 (PIM1) against several Gram-positive and Gram-negative bacteria have previously demonstrated the efficacy profile of PIM1. The present study focuses on the antibacterial and anti-biofilm activities of PIM1 against Salmonella in both in vitro and in ovo settings. In vitro, PIM1 exhibited bactericidal activity against three strains of Salmonella at a low dosage of 8 µg/mL. The anti-biofilm activity of PIM1 was evident by its elimination of planktonic cells within preformed biofilms in a dose-dependent manner. During the host cell infection process, PIM1 reduces the extracellular bacterial load, which reduces adhesion and invasion to limit the establishment of infection. Once intracellular, Salmonella strains were tolerant and protected from PIM1 treatment. In a chicken egg infection model, PIM1 exhibited therapeutic activity for both Salmonella strains, using stationary-phase and exponential-phase inocula. Moreover, PIM1 showed a remarkable efficacy against the stationary-phase inocula of drug-resistant Salmonella by eliminating the bacterial burden in >50% of the infected chicken egg embryos. Collectively, our results highlight the potential for PIM1 as a replacement therapy for existing antibiotic applications on the poultry farm, given the efficiency and low toxicity profile demonstrated in our agriculturally relevant chicken embryo model.

Aberrant functional connectivity between anterior cingulate cortex and left insula in association with therapeutic response to biologics in inflammatory arthritis.

BACKGROUND: Brain activity is reported to be associated with individual pain susceptibility and inflammatory status, possibly contributing to disease activity assessment in inflammatory arthritis (IA) including rheumatoid arthritis (RA) and spondyloarthritis (SpA). However, what alteration of brain function associated with disease activity and therapeutic effectiveness in IA remains unclear. We aimed to identify the alterations of brain functional connectivity (FC) shared in both RA and SpA, and evaluate its relationship to anti-rheumatic treatment response using functional magnetic resonance imaging (MRI). PATIENTS AND METHODS: Structural and resting-state functional MRI data were acquired from patients with IA, patients with osteoarthritis (OA) and heathy controls (HCs). Two datasets were adopted to derive (51 IA, 56 OA, and 17 HCs) and validate (31 IA) the observations. 33 IA patients in the derivation dataset and all the patients in validation dataset required biological treatment and were clinically evaluated before and after therapy. Via whole-brain pair-wise FC analyses, we analyzed IA-specific FC measures relevant to therapeutic response to biologics. RESULTS: The value of FC between left insular cortex (IC) and anterior cingulate cortex (ACC) was significantly low in IA patients compared with OA patients and HCs. We demonstrated that the FC between left anterior long insular gyrus as a subdivision of IC and ACC was significantly associated with therapeutic response to biologics regarding the improvement of patients' global assessment (PGA) in both derivation and validation datasets. CONCLUSION: Disease-specific resting-state FC provides a means to assess the therapeutic improvement of PGA and would be a clinical decision-making tool with predictability for treatment response in both RA and SpA.

Tolerogenic Immunoregulation towards Salmonella Enteritidis Contributes to Colonization Persistence in Young Chicks.

Long-term survival and the persistence of bacteria in the host suggest either host unresponsiveness or induction of an immunological tolerant response to the pathogen. The role of the host immunological response to persistent colonization of Salmonella Enteritidis (SE) in chickens remains poorly understood. In the current study, we performed a cecal tonsil transcriptome analysis in a model of SE persistent infection in 2-week-old chickens to comprehensively examine the dynamics of host immunological responses in the chicken gastrointestinal tract. Our results revealed overall host tolerogenic adaptive immune regulation in a major gut-associated lymphoid tissue, the cecal tonsil, during SE infection. Specifically, we observed consistent downregulation of the metallothionein 4 gene at all four postinfection time points (3, 7, 14, and 21 days postinfection [dpi]), which suggested potential pathogen-associated manipulation of the host zinc regulation as well as a possible immune modulatory effect. Furthermore, delayed activation in the B cell receptor signaling pathway and failure to sustain its active state during the lag phase of infection were further supported by an insignificant production of both intestinal and circulatory antibodies. Tug-of-war for interleukin 2 (IL-2) regulation between effector T cells and regulatory T cells appears to have consequences for upregulation in the transducer of ERBB2 (TOB) pathway, a negative regulator of T cell proliferation. In conclusion, this work highlights the overall host tolerogenic immune response that promotes persistent colonization by SE in young layer chicks.

Microstructural Alterations in Bipolar and Major Depressive Disorders: A Diffusion Kurtosis Imaging Study.

BACKGROUND: Identifying structural and functional abnormalities in bipolar (BD) and major depressive disorders (MDD) is important for understanding biological processes. HYPOTHESIS: Diffusion kurtosis imaging (DKI) may be able to detect the brain's microstructural alterations in BD and MDD and any differences between the two. STUDY TYPE: Prospective. SUBJECTS: In all, 16 BD patients, 19 MDD patients, and 20 age- and gender-matched healthy volunteers. FIELD STRENGTH/SEQUENCE: DKI at 3.0T. ASSESSMENT: The major DKI indices of the brain were compared voxel-by-voxel among the three groups. Significantly different voxels were tested for correlation with clinical variables (ie, Young Mania Rating Scale [YMRS], 17-item Hamilton Depression Rating Scale [17-HDRS], Montgomery-Åsberg Depression Rating Scale, total disease duration, duration of current episode, and the number of past manic/depressive episodes). The performance of the DKI indices in identifying microstructural alterations was estimated. STATISTICAL TESTS: One-way analysis of variance (ANOVA) was used for group comparison of DKI indices. The performance of these indices in detecting microstructural alterations was determined by receiver operating characteristic (ROC) analysis. Pearson's product-moment correlation analyses were used to test the correlations of these indices with clinical variables. RESULTS: DKI revealed widespread microstructural alterations across the brain in each disorder (P < 0.05). Some were significantly different between the two disorders. Mean kurtosis (MK) in the gray matter of the right inferior parietal lobe was able to distinguish BD and MDD with an accuracy of 0.906. A strong correlation was revealed between MK in that region and YMRS in BD patients (r = -0.641, corrected P = 0.042) or 17-HDRS in MDD patients (r = -0.613, corrected P = 0.030). There were also strong correlations between a few other DKI indices and disease duration (r = -0.676 or 0.626, corrected P < 0.05). DATA CONCLUSION: DKI detected microstructural brain alterations in BD and MDD. Its indices may be useful to distinguish the two disorders or to reflect disease severity and duration. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 3 J. Magn. Reson. Imaging 2020;52:1187-1196.

Integrative analysis of gut microbiome and metabolites revealed novel mechanisms of intestinal Salmonella carriage in chicken.

Intestinal carriage of Salmonella Enteritidis (SE) in the chicken host serves as a reservoir for transmission of Salmonella to humans through the consumption of poultry products. The aim of the current study was to examine the three-way interaction that occurred between host metabolites, resident gut microbiota and Salmonella following inoculation of SE in two-week-old layer chicks. Our results revealed an overall alteration in gut microbiome and metabolites in association with SE infection. Enriched colonization by different microbial members throughout the course of experimental infection highlighted significant fluctuation in the intestinal microbial community in response to Salmonella infection. As changes in community membership occurred, there was also subsequent impact on differential regulation of interlinked predicted functional activities within the intestinal environment dictated by Salmonella-commensal interaction. Alteration in the overall microbial community following infection also has a ripple effect on the host regulation of cecum-associated metabolic networks. The findings showed that there was differential regulation in many of the metabolites in association with SE colonization in chickens. Perturbation in metabolic pathways related to arginine and proline metabolism as well as TCA cycle was most prominently detected. Taken together, the present findings provided a starting point in understanding the effect of intestinal Salmonella carriage on the microbiome and metabolome of developing young layer chicks.

Level of Seven Neuroblastoma-Associated mRNAs Detected by Droplet Digital PCR Is Associated with Tumor Relapse/Regrowth of High-Risk Neuroblastoma Patients.

Monitoring of several sets of neuroblastoma-associated mRNAs (NB-mRNAs) by real-time quantitative PCR (qPCR) can be used to evaluate minimal residual disease in NB patients. Droplet digital PCR (ddPCR) is an adaption of qPCR that potentially provides simpler and more reproducible detection of low levels of mRNAs. However, whether minimal residual disease in NB patients can be monitored by ddPCR using a set of NB-mRNAs is not yet tested. In this study, 208 bone marrow (BM) and 67 peripheral blood samples were retrospectively collected from 20 high-risk NB patients with clinical disease evaluation at two Japanese centers between 2011 and 2018, and level of each NB-mRNA (CRMP1, DBH, DDC, GAP43, ISL1, PHOX2B, and TH mRNAs) was determined by ddPCR. Level of 7NB-mRNAs (defined as the combined signature of each NB-mRNA) was higher in BM than peripheral blood, but correlated significantly with each other. In accordance with disease burden, it varied with disease status (remission, stable, or progression) and collection time point (diagnosis, treatment, post-treatment, or relapse). In 73 post-treatment BM samples, it was significantly higher in 17 relapsed/regrown samples than in 56 nonrelapsed/nonregrown samples. Furthermore, ddPCR had a better prognostic value than qPCR in detecting 7NB-mRNAs in the same 73 post-treatment BM samples. This study suggests that ddPCR detection of 7NB-mRNAs is significantly associated with tumor relapse/regrowth in high-risk NB patients.

Commensal Enterobacteriaceae Protect against Salmonella Colonization through Oxygen Competition.

Neonates are highly susceptible to infection with enteric pathogens, but the underlying mechanisms are not resolved. We show that neonatal chick colonization with Salmonella enterica serovar Enteritidis requires a virulence-factor-dependent increase in epithelial oxygenation, which drives pathogen expansion by aerobic respiration. Co-infection experiments with an Escherichia coli strain carrying an oxygen-sensitive reporter suggest that S. Enteritidis competes with commensal Enterobacteriaceae for oxygen. A combination of Enterobacteriaceae and spore-forming bacteria, but not colonization with either community alone, confers colonization resistance against S. Enteritidis in neonatal chicks, phenocopying germ-free mice associated with adult chicken microbiota. Combining spore-forming bacteria with a probiotic E. coli isolate protects germ-free mice from pathogen colonization, but the protection is lost when the ability to respire oxygen under micro-aerophilic conditions is genetically ablated in E. coli. These results suggest that commensal Enterobacteriaceae contribute to colonization resistance by competing with S. Enteritidis for oxygen, a resource critical for pathogen expansion.