A preliminary genetic association study of GAD1 and GABAB receptor genes in patients with treatment-resistant schizophrenia.

BACKGROUND: GABAergic system dysfunction has been implicated in the etiology of schizophrenia and of cognitive impairments in particular. Patients with treatment-resistant schizophrenia (TRS) generally suffer from profound cognitive impairments in addition to severe positive symptoms, suggesting that GABA system dysfunction could be involved more closely in patients with TRS. METHODS AND RESULTS: In the present study, exome sequencing was conducted on fourteen TRS patients, whereby four SNPs were identified on GAD1, GABBR1 and GABBR2 genes. An association study for five SNPs including these 4 SNPs and rs3749034 on GAD1 as then performed among 357 patients with TRS, 682 non-TRS patients and 508 healthy controls (HC). The results revealed no significant differences in allelic and/or genetic distributions for any of the five SNPs. However, several subanalyses in comparisons between schizophrenia and HC groups, as well as between the three groups, showed nominal-level significance for rs3749034 on GAD1 and rs10985765/rs3750344 on GABBR2. In particular, in comparisons of female subjects, rigorous analysis for rs3749034 showed a statistical difference between the schizophrenia and HC groups and between the TRS and HC groups. CONCLUSIONS: Several positive results in subanalyses suggested that genetic vulnerability in the GABA system to schizophrenia or TRS could be affected by sex or sampling area, and overall, that rs3749034 on GAD1 and rs10985765 on GABBR2 could be related to TRS. In the present study, only a few SNPs were examined; it is possible that other important genetic variants in other regions of GABA-related genes were not captured in this preliminary study.

Vascular risk factors and the relationships between cognitive impairment and hypoperfusion in late-onset Alzheimer's disease.

OBJECTIVE: Our recent single-photon emission computed tomography (SPECT) study of patients with late-onset Alzheimer's disease (AD) revealed that regional cerebral blood flow (rCBF) was reduced in the frontal, temporal, and limbic lobes, and to a lesser degree in the parietal and occipital lobes. Moreover, these patients' scores on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) were significantly correlated with rCBF in some gyri of the frontal, parietal, and limbic lobes. Our present study aimed to understand how vascular factors and metabolic disease influenced the relationship between rCBF and ADAS-cog scores. METHODS: We divided late-onset AD patients into two groups according to their Hachinski Ischemic Score (HIS), low vascular risk patients had values of ≤4 (n=25) and high vascular risk patients had scores ≥5 (n=15). We examined rCBF using brain perfusion SPECT data. RESULTS: The degrees and patterns of reduced rCBF were largely similar between late-onset AD patients in both groups, regardless of HIS values. Cognitive function was significantly associated with rCBF among late-onset AD patients with low vascular risk (HIS≤4), but not among those with high vascular risk (HIS≥5). Furthermore, metabolic diseases, such as hypertension and diabetes mellitus, disrupted the relationships between hypoperfusion and cognitive impairments in late-onset AD patients. CONCLUSION: Factors other than hypoperfusion, such as hypertension and diabetes mellitus, could be involved in the cognitive dysfunction of late-onset AD patients with high vascular risk.

Relationships between cognitive impairment on ADAS-cog and regional cerebral blood flow using SPECT in late-onset Alzheimer's disease.

The aim of this study was to examine brain hypoperfusion and its relationship with cognitive dysfunction in late-onset Alzheimer's disease (AD). Forty patients with late-onset AD and not receiving acetylcholinesterase inhibitors were recruited from outpatient clinics. We examined cognitive function using the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and brain perfusion using single-photon emission computed tomography, and analyzed classified gyrus level segments with three-dimensional stereotactic surface projection and the stereotactic extraction estimation method level 3. ADAS-cog subscales were grouped into three domains: language, memory, and praxis. Patients with late-onset AD showed an apparent reduction in regional cerebral blood flow (rCBF) with a z score >1.5 in the frontal, temporal, and limbic lobes, with lesser reduction in the parietal and occipital lobes. Although hypoperfusion in the orbital, rectal, and subcallosal gyri of the frontal lobe was prominent, rCBF in the inferior frontal gyrus of the frontal lobe was significantly correlated with ADAS-cog total and language and praxis subscale scores. The parahippocampal gyrus of the limbic lobe was also significantly correlated with the ADAS-cog total, language, and praxis subscale scores. Additionally, the cingulate of the limbic lobe was significantly related with ADAS-cog memory. In spite of lesser hypoperfusion, the posterior cingulate gyrus of the limbic lobe was significantly related with ADAS-cog total, language, and memory subscale scores. Further, each subdivision of ADAS-cog was found to be related with various brain regions.

Molecular Characteristics of Pancreatic Ductal Adenocarcinomas with High-Grade Pancreatic Intraepithelial Neoplasia (PanIN) Are Different from Those without High-Grade PanIN.

AIMS: We reported that pancreatic ductal adenocarcinomas (PDACs) without high-grade pancreatic intraepithelial neoplasia (PanIN) in the vicinity had worse prognoses than PDACs with high-grade PanIN. However, the molecular characteristics of PDACs with and without high-grade PanIN have not been compared. The aim of this study is to clarify the molecular characteristics of PDACs with and without high-grade PanIN. METHOD AND RESULTS: We reviewed all of a consecutive series of 100 patients with PDACs and divided them into 2 groups: the PDACs with PanIN-2 or PanIN-3 in the background (the PanIN-high group, n = 60) and the PDACs without PanIN-2 or PanIN-3 in the background (the PanIN-low group, n = 40). We evaluated the p53, p16, and SMAD4 expressions in the invasive ductal carcinoma (IDC) components by immunohistochemical staining. KRAS mutation was also analyzed in 80 tumors. The PanIN-low group showed significantly more frequent "high p53 expression" and "loss of SMAD4 expression" than the PanIN-high group (p = 0.048 and p = 0.019, respectively). Loss of p16 expression was not significantly different between the groups. The rate of KRAS wild type was significantly higher in the PanIN-low group than the PanIN-high group (p = 0.024). CONCLUSIONS: Our results demonstrated that the molecular characteristics in the PDACs with high-grade PanIN were different from those in the PDACs without high-grade PanIN. PDACs without high-grade PanIN may develop via a pathway other than the PanIN-carcinoma sequence.

Effect of mirtazapine versus selective serotonin reuptake inhibitors on benzodiazepine use in patients with major depressive disorder: a pragmatic, multicenter, open-label, randomized, active-controlled, 24-week trial.

BACKGROUND: This study aimed to evaluate whether selecting mirtazapine as the first choice for current depressive episode instead of selective serotonin reuptake inhibitors (SSRIs) reduces benzodiazepine use in patients with major depressive disorder (MDD). We concurrently examined the relationship between clinical responses and serum mature brain-derived neurotrophic factor (BDNF) and its precursor, proBDNF. METHODS: We conducted an open-label randomized trial in routine psychiatric practice settings. Seventy-seven MDD outpatients were randomly assigned to the mirtazapine or predetermined SSRIs groups, and investigators arbitrarily selected sertraline or paroxetine. The primary outcome was the proportion of benzodiazepine users at weeks 6, 12, and 24 between the groups. We defined patients showing a ≥50 % reduction in Hamilton depression rating scale (HDRS) scores from baseline as responders. Blood samples were collected at baseline, weeks 6, 12, and 24. RESULTS: Sixty-five patients prescribed benzodiazepines from prescription day 1 were analyzed for the primary outcome. The percentage of benzodiazepine users was significantly lower in the mirtazapine than in the SSRIs group at weeks 6, 12, and 24 (21.4 vs. 81.8 %; 11.1 vs. 85.7 %, both P < 0.001; and 12.5 vs. 81.8 %, P = 0.0011, respectively). No between-group difference was observed in HDRS score changes. Serum proBDNF levels were significantly decreased (χ2 = 8.5, df = 3, P = 0.036) and serum mature BDNF levels were temporarily significantly decreased (F = 3.5, df = 2.4, P = 0.027) in the responders of both groups at week 24. CONCLUSION: This study demonstrated mirtazapine as the first-choice antidepressant for current depressive episodes may reduce benzodiazepine use in patients with MDD. Trial registration UMIN000004144. Registered 2nd September 2010. The date of enrolment of the first participant to the trial was 24th August 2010. This study was retrospectively registered 9 days after the first participant was enrolled.

Alterations of Dopamine D2 Receptors and Related Receptor-Interacting Proteins in Schizophrenia: The Pivotal Position of Dopamine Supersensitivity Psychosis in Treatment-Resistant Schizophrenia.

Although the dopamine D2 receptor (DRD2) has been a main target of antipsychotic pharmacotherapy for the treatment of schizophrenia, the standard treatment does not offer sufficient relief of symptoms to 20%-30% of patients suffering from this disorder. Moreover, over 80% of patients experience relapsed psychotic episodes within five years following treatment initiation. These data strongly suggest that the continuous blockade of DRD2 by antipsychotic(s) could eventually fail to control the psychosis in some point during long-term treatment, even if such treatment has successfully provided symptomatic improvement for the first-episode psychosis, or stability for the subsequent chronic stage. Dopamine supersensitivity psychosis (DSP) is historically known as a by-product of antipsychotic treatment in the manner of tardive dyskinesia or transient rebound psychosis. Numerous data in psychopharmacological studies suggest that the up-regulation of DRD2, caused by antipsychotic(s), is likely the mechanism underlying the development of the dopamine supersensitivity state. However, regardless of evolving notions of dopamine signaling, particularly dopamine release, signal transduction, and receptor recycling, most of this research has been conducted and discussed from the standpoint of disease etiology or action mechanism of the antipsychotic, not of DSP. Hence, the mechanism of the DRD2 up-regulation or mechanism evoking clinical DSP, both of which are caused by pharmacotherapy, remains unknown. Once patients experience a DSP episode, they become increasingly difficult to treat. Light was recently shed on a new aspect of DSP as a treatment-resistant factor. Clarification of the detailed mechanism of DSP is therefore crucial, and a preventive treatment strategy for DSP or treatment-resistant schizophrenia is urgently needed.

Pancreatic intraepithelial neoplasia in the background of invasive ductal carcinoma of the pancreas as a prognostic factor.

AIMS: Of the recognized precursor lesions of pancreatic adenocarcinoma, pancreatic intraepithelial neoplasia (PanIN) is the most common form. However, little is known about the relationship between the grade of PanIN and prognosis for patients with invasive ductal carcinoma. METHODS AND RESULTS: In 124 patients with invasive ductal carcinoma, we examined the grade and number of PanIN lesions in all slides of resected pancreas. The prevalence rates of PanIN-1A, PanIN-1B, PanIN-2 and PanIN-3 were 86%, 84%, 57% and 30%, respectively. We allocated PanIN-2 and PanIN-3 cases into a PanIN-high group, and cases showing PanIN-1A, PanIN-1B or absence of PanIN into a PanIN-low group. In clinicopathological analysis, PanIN-high status was significantly correlated with the number of PanIN lesions (P < 0.0001). Disease-free and overall survival were statistically better in the PanIN-high group than in the PanIN-low group (P = 0.0005 and P = 0.0003). Univariate and multivariate analyses revealed that tumour size and PanIN-low status were statistically significant factors for a poorer prognosis (P = 0.042 and P = 0.007). CONCLUSIONS: In a pathological examination, it is important to evaluate the grade and number of PanINs in assessing the prognosis of pancreatic cancer.

A retrospective clinical practice study comparing the usefulness of dual-orexin receptor antagonists and a melatonin receptor agonist in patients switching from long-term benzodiazepine receptor agonists.

STUDY OBJECTIVES: Although novel hypnotics have recently emerged, there are currently no data comparing the clinical potency of benzodiazepine receptor agonists (BZRAs) and novel hypnotics, or the effectiveness of different methods of switching between them. This study examined how novel hypnotics might help reduce BZRA use in real-world practice. METHODS: 289 patients with psychiatric disorders who took BZRAs for over 1 year before switching to either of 2 dual-orexin receptor antagonists (DORAs; suvorexant [SUV] or lemborexant [LEM]) or a melatonin receptor agonist (ramelteon [RMT]) were enrolled. We collected data on BZRAs at baseline and 3 months after commencement of SUV/LEM/RMT. RESULTS: Significant reductions in BZRAs were observed for all 3 agents: -4.10, -2.80, and -1.65 mg in diazepam-equivalent doses in the SUV, LEM, and RMT groups, respectively. Dose reduction was significantly greater in the DORA than the RMT group (F = 15.053, P < .001). Within the DORA group, dose reduction was significantly greater in patients taking SUV than those taking LEM (F = 4.337, P = .043). The switching success rate did not differ among the switching methods for any of the hypnotics. CONCLUSIONS: The reduction rate of BZRAs achieved by the switch fell into their equivalent-potency range estimated from clinical trials. The results suggest that DORAs can replace approximately 1 tablet of a BZRA. The difference in dose reduction between DORAs and RMT reflected the greater sleeping potency of the DORAs, whereas that between SUV and LEM might have reflected patient backgrounds: patients taking LEM may have been more strongly dependent on BZRAs. CITATION: Tachibana M, Kanahara N, Oda Y, Hasegawa T, Kimura A, Iyo M. A retrospective clinical practice study comparing the usefulness of dual-orexin receptor antagonists and a melatonin receptor agonist in patients switching from long-term benzodiazepine receptor agonists. J Clin Sleep Med. 2024;20(4):603-613.

Cerebellar and Occipital Alterations in Brain Perfusion in a Patient With Post-acute COVID-19 Encephalopathy Misdiagnosed As Primary Psychotic Disorder.

We describe the case of an unvaccinated 21-year-old Japanese male who experienced psychotic symptoms attributed to encephalopathy, known as post-acute COVID-19 syndrome (PACS). One week after his discharge following the remission of a SARS-CoV-2 infection, he experienced hyperactive delirium and unexpected movements of his limbs. As COVID-19-associated encephalopathy was suspected as a cause of the psychotic symptoms, he was admitted to the Department of Neurology. He received antiviral and steroid pulse therapy, but his psychiatric symptoms did not improve completely. Consequently, he was admitted to our psychiatric ward with a diagnosis of a primary psychotic disorder. Although he did not take psychopharmacotherapy, he gradually achieved a remission of psychiatric symptoms. At three months post-SARS-CoV-2 infection, single-photon emission computed tomography (SPECT) revealed hypoperfusion in the bilateral cerebellar dentate nuclei and occipital lobes. However, no abnormal findings were observed on fluorine-18 fluoro-deoxy-glucose positron emission tomography (18F-FDG PET) at six months after the infection. This case indicates that (1) brain perfusion SPECT can be effective for detecting functional alterations in post-acute COVID-19-associated encephalopathy, and (2) it is necessary to carefully monitor patients' progress instead of quickly diagnosing a primary psychotic disorder.

Successful Challenge With Brexpiprazole for Idiopathic Hypersomnia in a Patient With Bipolar Disorder: A Case Report.

We describe a 32-year-old Japanese female with hypersomnia and bipolar disorder. She had developed hypersomnia and sleep attacks in her teens. She was misdiagnosed with narcolepsy at a neurology department and then received methylphenidate (MPH) for many years. After giving birth, she developed postpartum depression and suffered from mood swings and irritability. Following 10-year treatment with methylphenidate, she experienced MPH-induced psychosis when she was in a manic state. Her psychosis improved rapidly with the cessation of methylphenidate. Furthermore, brexpiprazole treatment ameliorated her manic symptoms and hypersomnolence. Post-discharge, she was diagnosed with idiopathic hypersomnia based on nocturnal polysomnography and a multiple sleep latency test. This case indicates that brexpiprazole as a serotonin dopamine activity modulator might provide therapeutic effects against not only the patient's manic symptoms but also idiopathic hypersomnia.

Reduction of claudin-5 and aquaporin-4 in the rat hippocampal CA-1 and CA-3 regions of a learned helplessness model of depression.

BACKGROUND: Although findings from both animal and clinical research indicate that the blood-brain barrier (BBB) contributes to the pathogenesis of various psychiatric disorders (including depression), the underlying mechanisms are unknown. We investigated the levels of the tight-junction proteins claudin-5 and aquaporin-4 (AQP-4) in astrocytes of learned helplessness (LH) rats (an animal model of depression) and non-LH rats (a model of resilience). METHODS: We administered inescapable mild electric shock to rats and then identified the LH and non-LH rats by a post-shock test. The expressions of claudin-5 and AQP-4 in several brain regions of the LH and non-LH rats were then evaluated by a western blot analysis. RESULTS: The levels of both claudin-5 and AQP-4 in the CA-1 and CA-3 hippocampal areas of the LH group were significantly lower than those of the control group, whereas those of the non-LH rats were not significantly different from those of the control and LH rats. CONCLUSIONS: These results suggest that LH rats but not non-LH rats experienced down-regulations of claudin-5 and AQP-4 in the CA-1 and CA-3. It is possible that a region-specific modulation of claudin-5 and AQP-4 is involved in the mechanisms of vulnerability but not resilience in depression.

Intraductal papillary mucinous neoplasms of the pancreas with distinct pancreatic ductal adenocarcinomas are frequently of gastric subtype.

OBJECTIVE: To identify a high-risk group of patients with pancreatic ductal adenocarcinoma (PDAC), independently arising in the pancreas with intraductal papillary mucinous neoplasm (IPMN), using histopathologic subtypes. BACKGROUND: Pathologic features of IPMN with distinct PDAC, including histopathologic subtypes of IPMN and PDAC phenotypes, have not been well characterized. Mucin expression patterns and the mutational status of GNAS and KRAS are useful to explore the relationship between these 2 lesion types. METHODS: Clinicopathologic data of 179 resected IPMNs and 180 resected PDACs without IPMNs as a control group were reviewed. IPMNs were classified into 4 grades (low-grade, intermediate-grade, high-grade dysplasia, and an associated invasive carcinoma) and 4 subtypes (gastric, intestinal, pancreatobiliary, and oncocytic). The expression of MUC1, MUC2, MUC5AC, MUC6, and CDX2 was investigated by immunohistochemistry in IPMNs and PDACs with and without IPMNs. The mutational status of GNAS and KRAS was evaluated by cycle sequencing in PDACs and pre-/coexisting IPMNs. RESULTS: Twenty-six synchronous or metachronous PDACs were identified in 20 patients (11.2%) with IPMNs. Occurrence of concomitant PDACs was more frequently observed in gastric-type IPMNs (18/110, 16.4%) compared with intestinal (1/49, 2.0%), pancreatobiliary (1/17, 5.9%), or oncocytic-type (0/3, 0%) (P = 0.047). Both PDACs with and without IPMNs were frequently positive for MUC1, MUC5AC, and MUC6 expression, as assessed by immunohistochemistry, but were negative for MUC2 and CDX2. The mucin-staining patterns were similar to those of invasive tubular adenocarcinoma arising from gastric-type IPMNs. Mutation of GNAS within codon 201 was not detected in PDACs and gastric-type IPMNs, whereas most of these exhibited KRAS mutations. However, the R201H GNAS mutation was detected in 1 intestinal-type IPMN with distinct PDAC. CONCLUSIONS: Mucin expression patterns demonstrate that PDAC without GNAS mutations of an aggressive phenotype frequently arise in the pancreas with benign gastric-type IPMN in the absence of GNAS mutations.

Adaptor protein is essential for insect cytokine signaling in hemocytes.

Growth-blocking peptide (GBP) is an insect cytokine that stimulates a class of immune cells called plasmatocytes to adhere to one another and to foreign surfaces. Although extensive structure-activity studies have been performed on the GBP and its mutants in Lepidoptera Pseudaletia separata, the signaling pathway of GBP-dependent activation of plasmatocytes remains unknown. We identified an adaptor protein (P77) with a molecular mass of 77 kDa containing SH2/SH3 domain binding motifs and an immunoreceptor tyrosine-based activation motif (ITAM)-like domain in the cytoplasmic region of the C terminus. Although P77 showed no capacity for direct binding with GBP, its cytoplasmic tyrosine residues were specifically phosphorylated within seconds after GBP was added to a plasmatocyte suspension. Tyrosine phosphorylation of P77 also was observed when hemocytes were incubated with Enterobactor cloacae or Micrococcus luteus, but this phosphorylation was found to be induced by GBP released from hemocytes stimulated by the pathogens. Tyrosine phosphorylation of the integrin beta subunit also was detected in plasmatocytes stimulated by GBP. Double-stranded RNAs targeting P77 not only decreased GBP-dependent tyrosine phosphorylation of the integrin beta subunit, but also abolished GBP-induced spreading of plasmatocytes on foreign surfaces. P77 RNAi larvae also showed significantly higher mortality than control larvae after infection with Serratia marcescens, indicating that P77 is essential for GBP to mediate a normal innate cellular immunity in insects. These results demonstrate that GBP signaling in plasmatocytes requires the adaptor protein P77, and that active P77-assisted tyrosine phosphorylation of integrins is critical for the activation of plasmatocytes.

Feasibility of laparoscopic gastrectomy for advanced gastric cancer with positive peritoneal cytology.

PURPOSE: The role of gastrectomy for patients with positive peritoneal cytology, but a negative macroscopic peritoneal implant (P-/cy+), remains unclear. The aim of this study was to evaluate laparoscopic gastrectomy for P-/cy+ patients. METHODS: This study reviewed a prospectively maintained gastric cancer database of gastric-cancer patients those underwent surgical resection. P-/cy+ gastric cancer that had invaded the subserosa, or deeper layers, of the stomach wall without distant organ metastases was considered operable in this institution. P-/cy+ patients underwent either open or laparoscopic gastrectomy with D2 lymphadenectomy. The short-term results were examined to assess differences in outcome between the two groups. RESULTS: Eighteen P-/cy+ patients without distant organ metastases underwent surgery between 2000 and 2010. Laparoscopic gastrectomy was performed in nine patients and open gastrectomy in nine patients. The estimated blood loss was significantly smaller, the resumption of food intake earlier, and the length of postoperative hospital stay shorter in the patients that underwent laparoscopic gastrectomy than in the patients that underwent open gastrectomy. There were no significant differences in the 2-year survival rates between the groups. CONCLUSION: Laparoscopic gastrectomy for P-/cy+ patients is a minimally invasive and safe oncologic procedure with good short-term results.

Hybrid large hepatitis B surface protein composed of two viral genotypes C and D induces strongly cross-neutralizing antibodies.

Hepatitis B virus (HBV) vaccination is known to effectively decrease the risk of HBV infection. However, several issues need to be addressed in order to develop an improved HBV vaccine. Although the HBV vaccine has been shown to be effective, this vaccine needs to be more efficacious in defined groups, including non-responders (i.e., individuals who do not develop a protective response even after vaccination) and in health care workers and travelers who require rapid protection. Furthermore, it has been reported that universal HBV vaccination has accelerated the appearance of vaccine-escape mutants resulting from the accumulation of mutations altering the "a" determinant of the hepatitis B surface (HBs) protein. To address these problems, we have been focusing on the large HBs (LHBs) protein, which consists of three domains: pre-S1, pre-S2, and S (in N- to C-terminal order). To enhance the immunogenicity of LHBs, we developed a yeast-derived hybrid LHBs (hy-LHBs) antigen composed of the LHBs proteins from two distinct genotypes (Genotypes C and D). The levels of antibodies induced by hy-LHBs immunization were high not only against S, but also against the pre-S1 and pre-S2 domains. Additionally, hy-LHBs immunization induced significantly more strongly cross-reactive neutralizing antibodies than did small HBs (SHBs) or LHBs of any genotype alone. These findings suggested that hy-LHBs might serve as a candidate antigen for use in an improved prophylactic HBV vaccine.

Effectiveness of Brexpiprazole in a Patient With Bipolar Disorder and Comorbid Persistent Genital Arousal Disorder/Genito-Pelvic Dysesthesia: A Case Report.

Although the symptoms of persistent genital arousal disorder/genito-pelvic dysesthesia (PGAD/GPD) can have negative impacts on patients' lives, it is an under-recognized clinical entity. We describe the case of a 61-year-old Japanese female who suffered simultaneously from bipolar disorder and PGAD/GPD. She developed PGAD/GPD approx. 10 years after being diagnosed with bipolar disorder. Despite 20 years of various drug treatments, her bipolar disorder and PGAD/GPD symptoms showed little improvement. She had also undergone multiple sessions of cognitive behavioral therapy (CBT) and mindfulness, nerve block, botulinum toxin injections, and laser treatment for PGAD/GPD. Her PGAD/GPD symptoms remained with no significant improvement, and her bipolar disorder symptoms had also not responded well to medication. With the administration of brexpiprazole, she achieved remission of her bipolar disorder. Her PGAD/GPD symptoms also eventually improved. When PGAD/GPD is comorbid with bipolar disorder, the improvement of bipolar disorder may also lead to relief of PGAD/GPD symptoms. This case reveals that brexpiprazole, which has a unique profile, may be effective for PGAD/GPD.

Infusions of beta-hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, produce antidepressant-like effects on learned helplessness rats through BDNF-TrkB signaling and AMPA receptor activation, and strengthen learning ability.

Beta-hydroxybutyrate (BHB), an endogenous NLRP3 inflammasome inhibitor, has been shown to be associated with the pathophysiology of depression in rodents. However its active mechanism has not been revealed. Herein, we probed both the pathways and brain regions involved in BHB's antidepressant-like effects in a learned helplessness (LH) rat model of depression. A single bilateral infusion of BHB into the cerebral ventricles induced the antidepressant-like effects on the LH rats. The antidepressant-like effects of BHB were blocked by the TrkB inhibitor ANA-12 and the AMPA receptor antagonist NBQX, indicating that the antidepressant-like effects of BHB involve BDNF-TrkB signaling and AMPA receptor activation. Further, infusions of BHB into the prelimbic and infralimbic portions of medial prefrontal cortex, the dentate gyrus of hippocampus, and the basolateral region of amygdala produced the antidepressant-like effects on LH rats. However, infusions of BHB into the central region of amygdala, the CA3 region of hippocampus, and the shell and core regions of nucleus accumbens had no effect. Finally, a single bilateral infusion of BHB into the cerebral ventricles of naive rats strengthened learning ability on repeated active avoidance test where saline-infused animals failed to increase avoidance responses.

Association of SLC6A3 variants with treatment-resistant schizophrenia: a genetic association study of dopamine-related genes in schizophrenia.

Background: Most genetic analyses that have attempted to identify a locus or loci that can distinguish patients with treatment-resistant schizophrenia (TRS) from those who respond to treatment (non-TRS) have failed. However, evidence from multiple studies suggests that patients with schizophrenia who respond well to antipsychotic medication have a higher dopamine (DA) state in brain synaptic clefts whereas patients with TRS do not show enhanced DA synthesis/release pathways. Patients and methods: To examine the contribution (if any) of genetics to TRS, we conducted a genetic association analysis of DA-related genes in schizophrenia patients (TRS, n = 435; non-TRS, n = 539) and healthy controls (HC: n = 489). Results: The distributions of the genotypes of rs3756450 and the 40-bp variable number tandem repeat on SLC6A3 differed between the TRS and non-TRS groups. Regarding rs3756450, the TRS group showed a significantly higher ratio of the A allele, whereas the non-TRS group predominantly had the G allele. The analysis of the combination of COMT and SLC6A3 yielded a significantly higher ratio of the putative low-DA type (i.e., high COMT activity + high SLC6A3 activity) in the TRS group compared to the two other groups. Patients with the low-DA type accounted for the minority of the non-TRS group and exhibited milder psychopathology. Conclusion: The overall results suggest that (i) SLC6A3 could be involved in responsiveness to antipsychotic medication and (ii) genetic variants modulating brain DA levels may be related to the classification of TRS and non-TRS.

Identification of a novel gene, anorexia, regulating feeding activity via insulin signaling in Drosophila melanogaster.

Feeding activities of animals, including insects, are influenced by various signals from the external environment, internal energy status, and physiological conditions. Full understanding of how such signals are integrated to regulate feeding activities has, however, been hampered by a lack of knowledge about the genes involved. Here, we identified an anorexic Drosophila melanogaster mutant (GS1189) in which the expression of a newly identified gene, Anorexia (Anox), is mutated. In Drosophila larvae, Anox encodes an acyl-CoA binding protein with an ankyrin repeat domain that is expressed in the cephalic chemosensory organs and various neurons in the central nervous system (CNS). Loss of its expression or disturbance of neural transmission in Anox-expressing cells decreased feeding activity. Conversely, overexpression of Anox in the CNS increased food intake. We further found that Anox regulates expression of the insulin receptor gene (dInR); overexpression and knockdown of Anox in the CNS, respectively, elevated and repressed dInR expression, which altered larval feeding activity in parallel with Anox expression levels. Anox mutant adults also showed significant repression of sugar-induced nerve responses and feeding potencies. Although Anox expression levels did not depend on the fasting and feeding states cycle, stressors such as high temperature and desiccation significantly repressed its expression levels. These results strongly suggest that Anox is essential for gustatory sensation and food intake of Drosophila through regulation of the insulin signaling activity that is directly regulated by internal nutrition status. Therefore, the mutant strain lacking Anox expression cannot enhance feeding potencies even under starvation.

Liver-intestine cadherin expression is associated with intestinal differentiation and carcinogenesis in intraductal papillary mucinous neoplasm.

OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMN) are classified into four phenotypes according to the WHO classification. Recently, intestinal-type IPMN has been suggested to grow with a distinct carcinogenetic pathway. Like mucin 2, oligomeric mucus/gel forming (MUC2) and caudal-related homeobox 2 (CDX2), liver-intestine cadherin (LI cadherin) is an intestine-specific marker. We aimed to investigate the roles of LI cadherin expression in IPMN. METHODS: We examined LI cadherin expression in 135 cases of IPMN by immunohistochemical staining and the quantitative real-time reverse-transcription polymerase chain reaction. RESULTS: LI cadherin protein and mRNA levels were significantly higher in intestinal-type IPMN than in nonintestinal-type IPMN (protein level, p < 0.001; mRNA level, p = 0.0312). A positive correlation was found between protein and mRNA of LI cadherin (p = 0.0037). The positivity rates of LI cadherin expression were significantly higher in CDX2-positive cases than in CDX2-negative cases (p < 0.001). In 41 intestinal-type IPMNs, LI cadherin-positive rates tended to increase gradually, from IPMN with low-grade dysplasia (IPMN-L) to IPMN with an associated invasive carcinoma (IPMN-IC) [IPMN-L vs. IPMN with high-grade dysplasia (IPMN-H); p = 0.0357, IPMN-L vs. IPMN-IC; p = 0.0230] and positively correlated with the Ki-67 labeling index (p = 0.0408), whereas this tendency was not recognized in nonintestinal-type IPMNs. CONCLUSIONS: LI cadherin is associated with an intestinal phenotype and an 'intestinal pathway' of carcinogenesis in IPMN.