Neonatal malnutrition impacts fibroblast growth factor 21-induced neuron neurite outgrowth and growth hormone-releasing hormone secretion in neonatal mouse brain.

Neonatal malnutrition is one of the most common causes of neurological disorders. However, the mechanism of action of the factors associated with neonatal nutrition in the brain remains unclear. In this study, we focused on fibroblast growth factor (FGF) 21 to elucidate the effects of malnutrition on the neonatal brain. FGF21 is an endocrine factor produced by the liver during lactation which is the main source of nutrition during the neonatal period. In this study, malnourishment during nursing mice induced decreased levels of Fgf21 mRNA in the liver and decreased levels of FGF21 in the serum. RNA-seq analysis of neonatal mouse brain tissue revealed that FGF21 controlled the expression of Kalrn-201 in the neonatal mouse brain. Kalrn-201 is a transcript of Kalirin, a Ras homologous guanine nucleotide exchange factor at the synapse. In mouse neurons, FGF21 induced the expression of Kalirin-7 (a Kalirin isoform) by down-regulating Kalrn-201. FGF21-induced Kalirin-7 stimulated neurite outgrowth in Neuro-2a cells. FGF21 also induced Growth hormone-releasing hormone (GHRH) expression in Neuro-2a cells. Kalirin-7 and GHRH expression induced by FGF21 was altered by inhibiting the activity of SH2-containing tyrosine phosphatase (SHP2) which is located downstream of the FGF receptor (FGFR). Additionally, malnourished nursing induced intron retention of the SHP2 gene (Ptpn11), resulting in the alteration of Kalirin-7 and GHRH expression by FGF21 signaling. Ptpn11 intron retention is suggested to be involved in regulating SHP2 activity. Taken together, these results suggest that FGF21 plays a critical role in the induction of neuronal neurite outgrowth and GHRH secretion in the neonatal brain, and this mechanism is regulated by SHP2. Thus, Ptpn11 intron retention induced by malnourished nursing may be involved in SHP2 activity.

Does Li-ion transport occur rapidly in localized high-concentration electrolytes?

The ionic conductivity and lithium-ion transference number of electrolytes significantly influence the rate capability of Li-ion batteries. Highly concentrated Li-salt/sulfolane (SL) electrolytes exhibit elevated Li+ transference numbers due to lithium-ion hopping via a ligand exchange mechanism within their -Li+-SL-Li+- network. However, highly concentrated electrolytes (HCEs) are extremely viscous and have an ionic conductivity that is one order of magnitude less than that of conventional electrolytes. Dilution of HCEs with a non-coordinating hydrofluoroether (HFE) lowers the viscosity and produces localized high-concentration electrolytes (LHCE). However, the mechanism of Li+ transport in LHCEs is unclear. This study investigated the transport properties of LHCEs prepared by diluting a SL-based HCE with 1,1,2,2-tetrafluoroethyl-2,2,3,3-tetrafluoropropyl ether. Electrolyte viscosity decreases dramatically upon dilution, whereas ionic conductivity increases only slightly. Ion diffusivity increases with increasing HFE content due to the decrease in electrolyte viscosity. However, the Li+ transference number declines, because the HFE interferes with conduction via the Li+ hopping mechanism. The resulting decrease in the product of ionic conductivity and Li+ transference number indicates superior lithium-ion transport in the parent HCE compared with LHCEs.

Fecal Stream Diversion Changes Intestinal Environment, Modulates Mucosal Barrier, and Attenuates Inflammatory Cells in Crohn's Disease.

BACKGROUND: The intestinal environment plays important roles in mucosal barrier homeostasis and intestinal inflammation, as clarified in studies using experimental animals but not in humans. AIMS: We investigated whether environmental changes in the fecal stream cause phenotypic changes in the human mucosal barrier. METHODS: We obtained human ileal samples after fecal stream diversions in patients with rectal cancer or Crohn's disease. We investigated the bacterial load and diversity in the human defunctioned ileum, defined as the anal side of the ileum relative to the ileostomy. We also examined the epithelium and lamina propria cell phenotypes in the defunctioned ileum. RESULTS: After fecal stream diversion, bacterial loads decreased significantly in the defunctioned ileum. Based on the Chao1, Shannon, and observed species indices, the diversity of mucosa-associated microbiota was lower in the defunctioned ileum than in the functional ileum. Moreover, the healthy defunctioned ileum showed reductions in villous height, goblet cell numbers, and Ki-67+ cell numbers. Additionally, interferon-γ+, interleukin-17+, and immunoglobulin A+ cell abundance in the lamina propria decreased. After the intestinal environment was restored with an ileostomy closure, the impaired ileal homeostasis recovered. The defunctioned ileum samples from patients with Crohn's disease also showed reductions in interferon-γ+ and interleukin-17+ cell numbers. CONCLUSIONS: Fecal stream diversion reduced the abundance and diversity of intestinal bacteria. It also altered the intestinal mucosal barrier, similar to the alterations observed in germ-free animals. In patients with Crohn's disease, Th1 and Th17 cell numbers were attenuated, which suggests that the host-microbiome interaction is important in disease pathogenesis.

Social defeat stress exacerbates atopic dermatitis through downregulation of DNA methyltransferase 1 and upregulation of C-C motif chemokine receptor 7 in skin dendritic cells.

DNA methylation is an epigenetic modification that regulates gene transcription. DNA methyltransferase 1 (DNMT1) plays an important role in DNA methylation. However, the involvement of DNMT1 and DNA methylation in the pathogenesis of atopic dermatitis (AD) remains unclear. In this study, microarray analysis revealed that peripheral blood mononuclear cells of AD patients with low DNMT1 expression (DNMT1-low) highly expressed dendritic cell (DC) activation-related genes. Also, DNMT1-low AD patients exhibited a higher itch score compared to AD patients with high DNMT1 expression (DNMT1-high). By using an AD-like mouse model induced by the application of Dermatophagoides farinae body ointment, we found that Dnmt1 expression was decreased, while the expression of C-C chemokine receptor type 7 (Ccr7) was upregulated in mouse skin DCs. Furthermore, mice exposed to social defeat stress exhibited Dnmt1 downregulation and Ccr7 upregulation in skin DCs. Additionally, dermatitis and itch-related scratching behavior were exacerbated in AD mice exposed to stress. The relationship between low DNMT1 and itch induction was found in both human AD patients and AD mice. In mouse bone marrow-derived DCs, Ccr7 expression was inhibited by 5-aza-2-deoxycytidine, a methylation inhibitor. Furthermore, in mouse skin DCs, methylation of CpG sites in Ccr7 was modified by either AD induction or social defeat stress. Collectively, these findings suggest that social defeat stress exacerbates AD pathology through Dnmt1 downregulation and Ccr7 upregulation in mouse skin DCs. The data also suggest a role of DNMT1 downregulation in the exacerbation of AD pathology.

Characterization of the signature of peripheral innate immunity in women with later-life major depressive disorder.

The prevalence of depression in later life is higher in women than in men. However, the sex difference in the pathophysiology of depression in elderly patients is not fully understood. Here, we performed gene expression profiling in leukocytes of middle-aged and elderly patients with major depressive disorder, termed later-life depression (LLD) in this context, and we characterized the sex-dependent pathophysiology of LLD. A microarray dataset obtained from leukocytes of patients (aged ≥50 years) with LLD (32 males and 39 females) and age-matched healthy individuals (20 males and 24 females) was used. Differentially expressed probes were determined by comparing the expression levels between patients and healthy individuals, and then functional annotation analyses (Ingenuity Pathway Analysis, Reactome pathway analysis, and cell-type enrichment analysis) were performed. A total of 1656 probes were differentially expressed in LLD females, but only 3 genes were differentially expressed in LLD males. The differentially expressed genes in LLD females were relevant to leukocyte extravasation signaling, Tec kinase signaling and the innate immune response. The upregulated genes were relevant to myeloid lineage cells such as CD14+ monocytes. In contrast, the downregulated genes were relevant to CD4+ and CD8+ T cells. Remarkable innate immune signatures are present in the leukocytes of LLD females but not males. Because inflammation is involved in the pathophysiology of depression, the altered inflammatory activity may be involved in the pathophysiology of LLD in women. In contrast, abnormal inflammation may be an uncommon feature in LLD males.

Distinctive Neuroanatomical Substrates for Depression in Bipolar Disorder versus Major Depressive Disorder.

No neuroanatomical substrates for distinguishing between depression of bipolar disorder (dBD) and major depressive disorder (dMDD) are currently known. The aim of the current multicenter study was to identify neuroanatomical patterns distinct to depressed patients with the two disorders. Further analysis was conducted on an independent sample to enable generalization of results. We directly compared MR images of these subjects using voxel-based morphometry (VBM) and a support vector machine (SVM) algorithm using 1531 participants. The VBM analysis showed significantly reduced gray matter volumes in the bilateral dorsolateral prefrontal (DLPFC) and anterior cingulate cortices (ACC) in patients with dBD compared with those with dMDD. Patients with the two disorders shared small gray matter volumes for the right ACC and left inferior frontal gyrus when compared with healthy subjects. Voxel signals in these regions during SVM analysis contributed to an accurate classification of the two diagnoses. The VBM and SVM results in the second cohort also supported these results. The current findings provide new evidence that gray matter volumes in the DLPFC and ACC are core regions in displaying shared and distinct neuroanatomical substrates and can shed light on elucidation of neural mechanism for depression within the bipolar/major depressive disorder continuum.

Cumulative Inflammation Could Be a Risk Factor for Intestinal Failure in Crohn's Disease.

BACKGROUND: Intestinal failure is the most critical complication of Crohn's disease. Intestinal failure requires home parenteral nutrition, which worsens the quality of life of the patients and sometimes causes life-threatening complications. AIMS: The purpose of this study was to investigate the incidence and risk factors for intestinal failure in Crohn's disease. METHODS: We performed a retrospective analysis of Crohn's disease patients (162 cases) at Osaka University Hospital between January 2000 and December 2017. Kaplan-Meier analysis was used to investigate the cumulative incidence of intestinal failure. To identify the risk factors of intestinal failure, patient characteristics were analyzed by multivariate analysis, including disease classification, surgical history, medical treatment other than surgery, and cumulative inflammation was calculated using the average C-reactive protein value and disease duration. RESULTS: The cumulative incidence of intestinal failure 5, 10, and 15 years after Crohn's disease diagnosis was 2.6%, 3.4%, and 8.6%, respectively. Multivariate analysis identified the following as independent risk factors for intestinal failure in Crohn's disease: residual small intestinal length < 200 cm (odds ratio 7.51, 95% confidence interval 2.14-29.96), non-use of anti-tumor necrosis factor-alpha therapy (3.34, 1.22-10.74), and cumulative inflammation (1.01, 1.001-1.038). We created a new predictive nomogram consisting of these risk factors. CONCLUSIONS: Intestinal failure occasionally occurred during long-term treatment of Crohn's disease. Cumulative inflammation for the first time, in addition to short residual small intestinal length and non-use of anti-tumor necrosis factor-alpha therapy, was shown to be potential risk factors for intestinal failure in Crohn's disease.

Epigenetic mechanisms of major depression: Targeting neuronal plasticity.

Major depressive disorder is one of the most common mental illnesses as it affects more than 350 million people globally. Major depressive disorder is etiologically complex and disabling. Genetic factors play a role in the etiology of major depression. However, identical twin studies have shown high rates of discordance, indicating non-genetic mechanisms as well. For instance, stressful life events increase the risk of depression. Environmental stressors also induce stable changes in gene expression within the brain that may lead to maladaptive neuronal plasticity in regions implicated in disease pathogenesis. Epigenetic events alter the chromatin structure and thus modulate expression of genes that play a role in neuronal plasticity, behavioral response to stress, depressive behaviors, and response to antidepressants. Here, we review new information regarding current understanding of epigenetic events that may impact depression. In particular, we discuss the roles of histone acetylation, DNA methylation, and non-coding RNA. These novel mechanisms of action may lead to new therapeutic strategies for treating major depression.

Genetic Demonstration of a Role for Stathmin in Adult Hippocampal Neurogenesis, Spinogenesis, and NMDA Receptor-Dependent Memory.

Neurogenesis and memory formation are essential features of the dentate gyrus (DG) area of the hippocampus, but to what extent the mechanisms responsible for both processes overlap remains poorly understood. Stathmin protein, whose tubulin-binding and microtubule-destabilizing activity is negatively regulated by its phosphorylation, is prominently expressed in the DG. We show here that stathmin is involved in neurogenesis, spinogenesis, and memory formation in the DG. tTA/tetO-regulated bitransgenic mice, expressing the unphosphorylatable constitutively active Stathmin4A mutant (Stat4A), exhibit impaired adult hippocampal neurogenesis and reduced spine density in the DG granule neurons. Although Stat4A mice display deficient NMDA receptor-dependent memory in contextual discrimination learning, which is dependent on hippocampal neurogenesis, their NMDA receptor-independent memory is normal. Confirming NMDA receptor involvement in the memory deficits, Stat4A mutant mice have a decrease in the level of synaptic NMDA receptors and a reduction in learning-dependent CREB-mediated gene transcription. The deficits in neurogenesis, spinogenesis, and memory in Stat4A mice are not present in mice in which tTA/tetO-dependent transgene transcription is blocked by doxycycline through their life. The memory deficits are also rescued within 3 d by intrahippocampal infusion of doxycycline, further indicating a role for stathmin expressed in the DG in contextual memory. Our findings therefore point to stathmin and microtubules as a mechanistic link between neurogenesis, spinogenesis, and NMDA receptor-dependent memory formation in the DG. SIGNIFICANCE STATEMENT: In the present study, we aimed to clarify the role of stathmin in neuronal and behavioral functions. We characterized the neurogenic, behavioral, and molecular consequences of the gain-of-function stathmin mutation using a bitransgenic mouse expressing a constitutively active form of stathmin. We found that stathmin plays an important role in adult hippocampal neurogenesis and spinogenesis. In addition, stathmin mutation led to impaired NMDA receptor-dependent and neurogenesis-associated memory and did not affect NMDA receptor-independent memory. Moreover, biochemical analysis suggested that stathmin regulates the synaptic transport of NMDA receptors, which in turn influence CREB-mediated gene transcription machinery. Overall, these data suggest that stathmin is an important molecule for neurogenesis, spinogenesis, and NMDA receptor-dependent learning and memory.

Hippocampal MicroRNA-124 Enhances Chronic Stress Resilience in Mice.

UNLABELLED: Chronic stress-induced aberrant gene expression in the brain and subsequent dysfunctional neuronal plasticity have been implicated in the etiology and pathophysiology of mood disorders. In this study, we examined whether altered expression of small, regulatory, noncoding microRNAs (miRNAs) contributes to the depression-like behaviors and aberrant neuronal plasticity associated with chronic stress. Mice exposed to chronic ultra-mild stress (CUMS) exhibited increased depression-like behaviors and reduced hippocampal expression of the brain-enriched miRNA-124 (miR-124). Aberrant behaviors and dysregulated miR-124 expression were blocked by chronic treatment with an antidepressant drug. The depression-like behaviors are likely not conferred directly by miR-124 downregulation because neither viral-mediated hippocampal overexpression nor intrahippocampal infusion of an miR-124 inhibitor affected depression-like behaviors in nonstressed mice. However, viral-mediated miR-124 overexpression in hippocampal neurons conferred behavioral resilience to CUMS, whereas inhibition of miR-124 led to greater behavioral susceptibility to a milder stress paradigm. Moreover, we identified histone deacetylase 4 (HDAC4), HDAC5, and glycogen synthase kinase 3ß (GSK3ß) as targets for miR-124 and found that intrahippocampal infusion of a selective HDAC4/5 inhibitor or GSK3 inhibitor had antidepressant-like actions on behavior. We propose that miR-124-mediated posttranscriptional controls of HDAC4/5 and GSK3ß expressions in the hippocampus have pivotal roles in susceptibility/resilience to chronic stress. SIGNIFICANCE STATEMENT: Depressive disorders are a major public health concern worldwide. Although a clear understanding of the etiology of depression is still lacking, chronic stress-elicited aberrant neuronal plasticity has been implicated in the pathophysiology of depression. We show that the hippocampal expression of microRNA-124 (miR-124), an endogenous small, noncoding RNA that represses gene expression posttranscriptionally, controls resilience/susceptibility to chronic stress-induced depression-like behaviors. These effects on depression-like behaviors may be mediated through regulation of the mRNA or protein expression levels of histone deacetylases HDAC4/5 and glycogen synthase kinase 3ß, all highly conserved miR-124 targets. Moreover, miR-124 contributes to stress-induced dendritic hypotrophy and reduced spine density of dentate gyrus granule neurons. Modulation of hippocampal miR-124 pathways may have potential antidepressant effects.

Tryptophan protects hepatocytes against reactive oxygen species-dependent cell death via multiple pathways including Nrf2-dependent gene induction.

Hepatocyte apoptosis plays a key role in the pathogenesis of immune-mediated hepatitis. However, the detailed mechanisms of apoptosis signaling are still unclear and effective therapeutic drugs for hepatitis have been explored. Here, we show that tryptophan (Trp) suppressed IFN-γ-mediated hepatic apoptosis in vitro. Trp inhibited the downstream apoptotic events of mitochondria disruption, such as cell death and caspase-3 activation, while it did not influence upstream signaling including STAT1 activation and IRF1 expression. Trp suppressed reactive oxygen species (ROS) generation at the mitochondria. IFN-γ induced ROS in mitochondria by inhibiting complex I and III, but not II. This ROS generation by IFN-γ required de novo protein synthesis. Trp showed relatively weak direct scavenging activity but antagonized IFN-γ against the suppression of complex I. In addition, Trp increased the expression of the Nrf2-dependent antioxidant genes NQO1, HO-1 and GCS in hepatocytes both in vitro and in vivo. Finally, the administration of Trp in an acetaminophen-induced ROS-dependent hepatitis model suppressed the liver injury in vivo. Thus, Trp protects hepatocytes from ROS-dependent cell injury via multiple pathways. This study suggests Trp as a therapeutic antioxidant drug for hepatitis and a regulator for Nrf2-dependent genes.

[The Report of the Survey to the Members of the Society about the Functional Dissociation of the Psychiatric Hospital beds].

In 2014, Japanese Ministry of Health, Labour and Welfare published the guideline on the policy of the psychiatric hospitals. We executed a survey to the members of "The Japanese Society of Psychiatry and Neurology" about the impression of this guideline, especially about "The functional differentiation of psychiatric hospital beds". Nine questions were notified on the home page of the society. 862 answers (5.3% of the members) were corrected by website from 1st to 30th of May in 2015. Attribution of the answers : doctors working at the psychiatric hospitals (70.9%), the psychiatric clinics (20%), the others (9.1%). The questions which more than 80% of the answers agreed were "The reduction of the psychiatric beds should be stepwise under the rule of check & balance in the improvement of the psychiatric community treatment", "Improve the function of the recovery phase treatment" and "The adequate treat- ment for the patients of the severe and chronic phases". The questions more than 55% of the answers agreed were "The reduction of the chronic phase beds for the improvement of the function of the acute phase beds". The questions which opposites exceeded (almost 47%) were "The assessment of the psychiatric symptoms in the patients of the chronic phase should be done by the third party" and "The facility for social skill treatment should be placed in the community". We could know the mind of the members about the revolution of the psychiatric.

Nonaqueous Dispersion Formed by an Emulsion Solvent Evaporation Method Using Block-Random Copolymer Surfactant Synthesized by RAFT Polymerization.

As surfactants for preparation of nonaqueous microcapsule dispersions by the emulsion solvent evaporation method, three copolymers composed of stearyl methacrylate (SMA) and glycidyl methacrylate (GMA) with different monomer sequences (i.e., random, block, and block-random) were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. Despite having the same comonomer composition, the copolymers exhibited different functionality as surfactants for creating emulsions with respective dispersed and continuous phases consisting of methanol and isoparaffin solvent. The optimal monomer sequence for the surfactant was determined based on the droplet sizes and the stabilities of the emulsions created using these copolymers. The block-random copolymer led to an emulsion with better stability than obtained using the random copolymer and a smaller droplet size than achieved with the block copolymer. Modification of the epoxy group of the GMA unit by diethanolamine (DEA) further decreased the droplet size, leading to higher stability of the emulsion. The DEA-modified block-random copolymer gave rise to nonaqueous microcapsule dispersions after evaporation of methanol from the emulsions containing colored dyes in their dispersed phases. These dispersions exhibited high stability, and the particle sizes were small enough for application to the inkjet printing process.

[A Case of Anorexia Nervosa with Chewing and Spitting Improved by Treatment with Selective Serotonin Reuptake Inhibitors].

Chewing and spitting (CHSP) is the symptom of chewing and spitting out food without swallowing. CHSP is fairy common among patients with eating disorders, but no report has been published on drug treatment for it. We report a patient with anorexia nervosa showing extreme weight loss due to CHSP. After admission, CHSP was improved by treatment with Selective Serotonin Reuptake Inhibitors, leading to marked recovery of the body weight CHSP may represent a marker for illness severity, so its early treatment is critical to prevent the increasing severity of eating disorders.

Prefrontal activation in response to emotional words in patients with bipolar disorder and major depressive disorder.

Abnormal emotional processing is involved in the pathophysiology of bipolar disorder (BD) and major depressive disorder (MDD). However, whether the neural mechanism underlying this deficit is a trait characteristic of BD and MDD is unclear. The aim of this study was to elucidate the similarities and differences in processing of emotional stimuli between patients with BD and MDD in remission, using functional near-infrared spectroscopy (fNIRS). Thirty-two patients (16 with BD and 16 with MDD) and 20 healthy control subjects matched for age, sex, handedness, and years of education were included. An emotional Stroop task, including happy, sad, and threat words, was used. The relative oxygenated and deoxygenated hemoglobin concentration ([oxy-Hb] and [deoxy-Hb]) changes in the frontal region were measured using 52-channels of NIRS. During the threat task, compared to healthy control subjects, patients with BD showed significantly increased [oxy-Hb] in the left inferior frontal region whereas patients with MDD showed significantly increased [oxy-Hb] in the left middle frontal region. During the happy task, compared to healthy control subjects, patients with BD showed significantly decreased [oxy-Hb] in the middle frontal region in both hemispheres. Moreover, patients with BD exhibited decreased [oxy-Hb] and increased [deoxy-Hb] in the superior frontal and middle frontal regions compared to MDD in response to the happy stimulus. No significant differences in [oxy-Hb] or [deoxy-Hb] were seen between the groups during the sad task. These results suggest that abnormal neural responses to emotional stimuli in patients with mood disorders in remission may be a trait characteristic, that negative emotional stimuli are associated with similar prefrontal responses, and that positive emotional stimuli are associated with different prefrontal responses in patients with BD and MDD. These findings indicate that different neural circuits play a role in emotional processing in BD and MDD; this may aid the elucidation of the pathophysiology of these two disorders.

Different and shared brain volume abnormalities in late- and early-onset schizophrenia.

The differences in clinical characteristics between late- (LOS) and early-onset schizophrenia (EOS) are well documented. However, very little is known about the neural mechanisms underlying these differences. Here, we compared morphometric abnormalities between patients with EOS and those with LOS. A total of 22 patients with LOS, 24 patients with EOS and 41 healthy control subjects were included in this magnetic resonance imaging study. Brain images were analyzed using DARTEL preprocessing for voxel-based morphometry in SPM8. We tested a main effect of diagnosis in the whole-brain analysis and compared the results among the three groups. We also carried out correlation analyses between regional volumes and clinical variables. Patients with LOS showed larger gray matter (GM) volume of the left precuneus compared with healthy subjects and patients with EOS. Patients with LOS and EOS showed decreased GM volumes in the right insula, left superior temporal gyrus and left orbitofrontal gyrus compared with healthy subjects. A longer duration of illness was associated with reduced GM volume in the temporal pole in patients with EOS. Our findings may help improve our understanding of schizophrenia pathophysiology and shed light on the different and shared neurobiological underpinnings of LOS and EOS.

Impaired hippocampal spinogenesis and neurogenesis and altered affective behavior in mice lacking heat shock factor 1.

Aberrant transcriptional regulation in the brain is thought to be one of the key components of the pathogenesis and pathophysiology of neuropsychiatric disorders. Heat shock factors (HSFs) modulate cellular homeostasis through the control of gene expression. However, the roles of HSFs in brain function have yet to be elucidated fully. In the present study, we attempted to clarify the role of HSF1-mediated gene regulation in neuronal and behavioral development using HSF1-deficient (HSF1(-/-)) mice. We found granule neurons of aberrant morphology and impaired neurogenesis in the dentate gyrus of HSF1(-/-) mice. In addition, HSF1(-/-) mice showed aberrant affective behavior, including reduced anxiety and sociability but increased depression-like behavior and aggression. Furthermore, HSF1 deficiency enhanced behavioral vulnerability to repeated exposure to restraint stress. Importantly, rescuing the HSF1 deficiency in the neonatal but not the adult hippocampus reversed the aberrant anxiety and depression-like behaviors. These results indicate a crucial role for hippocampal HSF1 in neuronal and behavioral development. Analysis of the molecular mechanisms revealed that HSF1 directly modulates the expression of polysialyltransferase genes, which then modulate polysialic acid-neural cell adhesion molecule (PSA-NCAM) levels in the hippocampus. Enzymatic removal of PSA from the neonatal hippocampus resulted in aberrant behavior during adulthood, similar to that observed in HSF1(-/-) mice. Thus, these results suggest that one role of HSF1 is to control hippocampal PSA-NCAM levels through the transcriptional regulation of polysialyltransferases, a process that might be involved in neuronal and behavioral development in mice.

[Successful treatment of metastatic hepatocellular carcinoma with sorafenib combined with transcatheter arterial chemoembolization/hepatic arterial infusion chemotherapy].

We report the long-term survival of a patient with metastatic hepatocellular carcinoma (HCC), successfully treated with transcatheter arterial chemoembolization (TACE)/hepatic arterial infusion chemotherapy (HAIC) combined with long-term administration of sorafenib. A 74-year-old man underwent hepatectomy for a huge hepatocellular carcinoma, measuring 19 × 13 cm. Multiple intrahepatic HCCs that recurred 5 months post-surgery were treated with TACE. After 3 cycles of TACE, however, sorafenib was administered to treat progressive disease. Six months after sorafenib treatment, TACE combined with sorafenib was administered for treatment of refractory intrahepatic lesions. Following further disease progression, TACE was replaced by up to 11 rounds of HAIC. We report successfully treatment of refractory metastatic HCC with sorafenib for more than 30 months along with a review of the literature.

[Clinical examination of 3 patients with delayed neuropsychiatric encephalopathy induced by carbon monoxide poisoning, who recovered from severe neurocognitive impairment by repetitive hyperbaric oxygen therapy].

We performed hyperbaric oxygen (HBO) therapy for 3 patients with delayed neuropsychiatric encephalopathy induced by carbon monoxide (CO) poisoning. All patients were male and around 50 years old, and they had not received HBO therapy within 24 h after CO poisoning, even though they showed severe consciousness disturbance. In these patients, delayed neuropsychiatric encephalopathy appeared about 25 days after acute CO poisoning, and HBO therapy was initiated within 8 days after disease onset. Although the condition of 2 of the patients worsened initially, they showed significant improvement of neurocognitive impairment after 30 sessions of HBO therapy. The clinical courses of these patients suggest that the effect of HBO therapy can be evaluated after 30 sessions. To evaluate the validity of the indices of the clinical effect of HBO therapy, we performed brain magnetic resonance imaging, single photon emission computed tomography, electroencephalography (EEG), and neurocognitive tests (HDS-R, and Wechsler Adult Intelligence Scale-Revised or III). Our results showed that changes in EEG signals and neurocognitive tests were closely correlated with the patients' clinical courses.

Antidepressant Response and Stress Resilience Are Promoted by CART Peptides in GABAergic Neurons of the Anterior Cingulate Cortex.

Background: A key challenge in the understanding and treatment of depression is identifying cell types and molecular mechanisms that mediate behavioral responses to antidepressant drugs. Because treatment responses in clinical depression are heterogeneous, it is crucial to examine treatment responders and nonresponders in preclinical studies. Methods: We used the large variance in behavioral responses to long-term treatment with multiple classes of antidepressant drugs in different inbred mouse strains and classified the mice into responders and nonresponders based on their response in the forced swim test. Medial prefrontal cortex tissues were subjected to RNA sequencing to identify molecules that are consistently associated across antidepressant responders. We developed and used virus-mediated gene transfer to induce the gene of interest in specific cell types and performed forced swim, sucrose preference, social interaction, and open field tests to investigate antidepressant-like and anxiety-like behaviors. Results: Cartpt expression was consistently upregulated in responders to four types of antidepressants but not in nonresponders in different mice strains. Responder mice given a single dose of ketamine, a fast-acting non-monoamine-based antidepressant, exhibited high CART peptide expression. CART peptide overexpression in the GABAergic (gamma-aminobutyric acidergic) neurons of the anterior cingulate cortex led to antidepressant-like behavior and drove chronic stress resiliency independently of mouse genetic background. Conclusions: These data demonstrate that activation of CART peptide signaling in GABAergic neurons of the anterior cingulate cortex is a common molecular mechanism across antidepressant responders and that this pathway also drives stress resilience.