Mitochondrial Involvement in Mental Disorders: Energy Metabolism and Genetic and Environmental Factors.

Mental disorders, such as major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SZ), are generally characterized by a combination of abnormal thoughts, perceptions, emotions, behavior, and relationships with others. Multiple risk factors incorporating genetic and environmental susceptibility are associated with development of these disorders. Mitochondria have a central role in the energy metabolism, and the literature suggests energy metabolism abnormalities are widespread in the brains of subjects with MDD, BPD, and SZ. Numerous studies have shown altered expressions of mitochondria-related genes in these mental disorders. In addition, environmental factors for these disorders, such as stresses, have been suggested to induce mitochondrial abnormalities. Moreover, animal studies have suggested that interactions of altered expression of mitochondria-related genes and environmental factors might be involved in mental disorders. Further investigations into interactions of mitochondrial abnormalities with environmental factors are required to elucidate of the pathogenesis of these mental disorders.

Microglia-derived neuregulin expression in psychiatric disorders.

Several studies have revealed that neuregulins (NRGs) are involved in brain function and psychiatric disorders. While NRGs have been regarded as neuron- or astrocyte-derived molecules, our research has revealed that microglia also express NRGs, levels of which are markedly increased in activated microglia. Previous studies have indicated that microglia are activated in the brains of individuals with autism spectrum disorder (ASD). Therefore, we investigated microglial NRG mRNA expression in multiple lines of mice considered models of ASD. Intriguingly, microglial NRG expression significantly increased in BTBR and socially-isolated mice, while maternal immune activation (MIA) mice exhibited identical NRG expression to controls. Furthermore, we observed a positive correlation between NRG expression in microglia and peripheral blood mononuclear cells (PBMCs) in mice, suggesting that NRG expression in human PBMCs may mirror microglia-derived NRG expression in the human brain. To translate these findings for application in clinical psychiatry, we measured levels of NRG1 splice-variant expression in clinically available PBMCs of patients with ASD. Levels of NRG1 type III expression in PBMCs were positively correlated with impairments in social interaction in children with ASD (as assessed using the Autistic Diagnostic Interview-Revised test: ADI-R). These findings suggest that immune cell-derived NRGs may be implicated in the pathobiology of psychiatric disorders such as ASD.

A case of a gastrostomy fistula reopening 21 years after spontaneously closure.

Here we report a rare case of a reopened gastrostomy fistula 21-years after spontaneous closure. A male newborn underwent gastrostomy by laparotomy because of esophageal atresia shortly after birth. The gastrostomy tube was removed at 7 months old because he could consume enough oral nutrition. At the age of 21, however, the fistula reopened to form a labial fistula. When he consulted to our hospital, we observed a large skin sore with redness at the site of the fistula, which was caused by gastric outflow. We chose to resect the fistula by open surgery as a reliable therapeutic method in consideration of his future social life. The postoperative course was unremarkable.

Mismatch in cerebral blood flow and glucose metabolism after the forced swim stress in rats.

OBJECTIVE: Neuroimaging studies of depression considered as a stress-related disorder have shown uncoupling in regional cerebral blood flow (rCBF) and regional cerebral metabolic rate for glucose (rCMRglc). We hypothesised that the mismatch change of rCBF and rCMRglc could be a stress-related phenomenon. METHODS: We exposed male rats to 15-min period of forced swim (FS), followed by the measurement of rCBF using N-isopropyl-4-[123I] iodoamphetamine (123I-IMP) and rCMRglc using 2-deoxy-2-[18F] fluoro-D-glucose (18F-FDG). RESULTS: The uptake rate of 18F-FDG in the FS group showed a significant decrease in the prefrontal cortex (0.86±0.20%ID/g, p<0.01) and thalamus (0.77±0.17%ID/g, p<0.05) and tended to be lower in the hippocampus (0.58±0.13%ID/g) and cerebellum (0.59±0.13%ID/g) without overt alteration in the uptake rate of 123I-IMP. CONCLUSIONS: The FS stress can cause mismatch change of rCBF and rCMRglc, which reflect a stress-related phenomenon.

[A Case of Multiple Bevacizumab-Related Colonic Perforations during Opioid Use].

We present the case ofa 54-year-old man who had been treated with bevacizumab-containing chemotherapy for a postoperative recurrence of lung cancer for 5 months; he had used opioids for cancer pain in his right lateral chest for 2 months. He was admitted to the hospital because his chest pain had worsened 5 days earlier and he was experiencing a dull pain in his lower abdomen. His condition was recognized as an aggravation of the cancer pain and his opioid dose was increased. He presented with intense abdominal pain 6 days after admission, and we diagnosed gastrointestinal perforations from an abdominal CT scan. Therefore, we undertook an emergency operation. Multiple perforations were seen on the transverse and descending colon; an extensive colectomy and a colostomy were performed. Histopathological findings showed that multiple ulcer perforations and normal mucosa coexisted throughout the resected specimen. Bevacizumab-induced ischemic changes were the suspected cause. When pain control becomes variable during opioid use, conditions such as bevacizumab-related gastrointestinal perforations should be considered, in addition to progression of the cancer pain itself, and the appropriate treatment should be administered.

[Examination of outcomes after conversion surgery for Stage IVGastric cancer in our hospital].

PURPOSE: We examined the outcomes of conversion surgery (CS) for Stage IV gastric cancer performed in our hospital. OBJECTIVE AND METHOD: We retrospectively examined the outcomes of 5 Stage IV gastric cancer patients, for whom surgical excision was possible and CS was performed after induction chemotherapy between January 2010 and December 2013. RESULTS: The median age of the patients who underwent CS was 62 years, and non-recovering factors were as follows: M1 (LYM) for 3 patients, H1 for 1 patient, and P1 for 1 patient. For all patients, the induction chemotherapy regimen consisted only of TS-1+cisplatin (CDDP). Using diagnostic imaging to determine treatment effect, we found that 2 patients showed a partial response(PR)as a result of the induction chemotherapy. As a result of CS, R0 surgery could be enforced to 3 cases and postoperative complications accepted neither. Ef-grade which of the histopathological judging of the chemotherapy were 1a: 4 cases, 2: 1 case. After adjuvant chemotherapy treatment in 3 patients, the median survival time (MST) of the CS patients was 22.5 months. In contrast, the MST of non-CS patients, who received treatments other than CS, was 4 months. These results indicate that the MST for CS patients was substantially longer compared to patients who did not receive CS (p=0.046). CONCLUSION: Although CS in response to Stage IV gastric cancer fully needed to examine selection of a case, the timing of operation introduction, etc. to be successful, a possibility of contributing to a prognosis improvement in a multidisciplinary treatment was suggested.

The human oligodendrocyte proteome.

Myelination of the CNS is performed by oligodendrocytes (OLs), which have been implicated in brain disorders, such as multiple sclerosis and schizophrenia. We have used the human oligodendroglial cell line MO3.13 to establish an OL reference proteome database. Proteins were prefractionationated by SDS-PAGE and after in-gel digestion subjected to nanoflow LC-MS analysis. Approximately 11 600 unique peptides were identified and, after stringent filtering, resulted in 2290 proteins representing nine distinct biological processes and various molecular classes and functions. OL-specific proteins, such as myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP), as well as other proteins involved in multiple sclerosis and schizophrenia were also identified and are discussed. Proteins of this dataset have also been classified according to their chromosomal origin for providing useful data to the Chromosome-centric Human Proteome Project (C-HPP). Given the importance of OLs in the etiology of demyelinating and oligodendrogial disorders, the MO3.13 proteome database is a valuable data resource. The MS proteomics data have been deposited to the ProteomeXchange with identifier PXD000263 (http://proteomecentral.proteomexchange.org/dataset/PXD000263).

[Protocol for the administration of modified FOLFOX6 (mFOLFOX6) in patients with unresectable/recurrent colorectal cancer].

In patients undergoing FOLFOX6 therapy for the treatment of unresectable/recurrent colorectal cancer, control of cumulative peripheral neuropathy is problematic. In our department, we stop using mFOLFOX6 as a primary therapy after 6 to 8 courses. Instead, we use mFOLFOX6 as a secondary therapy, and re-introduce mFOLFOX6 as a tertiary therapy; the patients undergoing this treatment protocol were included in Group A. We have studied the degree of neurotoxicity and the time of its occurrence in these patients compared to those undergoing the standard method (Group B; 12 cases). Grade 3 peripheral neuropathy was observed in both the groups. In Group B, peripheral neuropathy occurred in the primary treatment period, whereas in Group A, it appeared in the tertiary treatment period. Moreover, in Group A, we observed Grade 2 peripheral neuropathy in the primary treatment period in 3 cases, but this was promptly resolved after the therapy was shifted to the secondary treatment period. The period with neurological toxicities was shorter in Group A compared to Group B. When treating colorectal cancer with chemotherapy, it is important to elucidate how the prognosis can be improved while maintaining the quality of life( QOL). In our department, we place a greater emphasis on the QOL of the patient.

[A case of recurrent breast cancer that responded to bevacizumab].

We report a case of a 59-year-old woman who was forced to undergo mastectomy of the right breast (Rt Bt) plus axillary lymph node (Ax) dissection for right breast cancer at another hospital. The pathological diagnosis was invasive ductal carcinoma( scirrhou[s sci], pT2N2M0, Stage IIIA, estrogen recepto[r ER[]+], progesterone recepto[r PgR[]+], human epidermal growth factor receptor-2[HER2][2+]). Although no recurrence was observed after postoperative adjuvant chemotherapy and endocrine therapy, skin metastasis on the left back and pleuritis carcinomatosa were detected at our hospital 9 years and 6 months after the operation. Thereafter, bone metastasis, contralateral lymph node metastasis, and frequent occurrence of hepatic metastasis were sequentially detected. The patient was treated with chemotherapy (a total of 4 regimens) and endocrine therapy in addition to radiation therapy for lymph node metastasis over a period of approximately 2 years and 3 months; however, disease control was poor. Therefore, combined chemotherapy with paclitaxel and bevacizumab was initiated from February 2012. Soon after the initiation of combination therapy, the serum carcinoembryonic antigen (CEA) level gradually reduced and computed tomography (CT) revealed that the multiple-organ metastases had remarkably reduced in size. The response was classified as a clinical partial response (cPR). Although adverse events such as peripheral neuropathy, nose bleeding, and high blood pressure were observed, these were all of lesser that Grade 2 severity. The efficacy of chemotherapy was noted for 11 months.

Measurement of Mitochondrial Respiration in Cryopreserved Human Peripheral Blood Mononuclear Cells (PBMCs).

Inflammatory diseases caused by infectious agents such as the SARS-CoV-2 virus can lead to impaired reductive-oxidative (REDOX) balance and disrupted mitochondrial function. Peripheral blood mononuclear cells (PBMCs) provide a useful model for studying the effects of inflammatory diseases on mitochondrial function but can be limited by the need to store these cells by cryopreservation prior to assay. Here, we describe a method for improving and determining PBMC viability with normalization of values to number of living cells. The approach can be applied not only to PBMC samples derived from patients with diseases marked by an altered inflammatory response such as viral infections.

Altering the expression balance of hnRNP C1 and C2 changes the expression of myelination-related genes.

The expression level of hnRNP C1/C2 protein has been reported to be significantly decreased in the post-mortem brain of schizophrenic patients. In this study, we investigated whether overexpression of the hnRNP C variants hnRNP C1 and C2 changed the expression of myelination-related genes in the human neuroblastoma cell line SK-N-SH. In both hnRNP C1- and C2-overexpressing cells, the expression of quaking (QKI)-6 and QKI-7 significantly increased or decreased compared to the control, respectively. Intriguingly, QKI-5 and myelin basic protein were markedly up- or down-regulated by overexpressing hnRNP C2, respectively. Our findings are the first to demonstrate distinct functions of hnRNP C1 and C2, and may be helpful in understanding the functions of these molecules. These findings indicate that altered expression levels of hnRNP C in the brain of patients with schizophrenia could be involved in the pathophysiology of this disease through alteration of the QKI isoform and myelin basic protein expression.

Autistic-Like Behavior and Impairment of Serotonin Transporter and AMPA Receptor Trafficking in N-Ethylmaleimide Sensitive Factor Gene-Deficient Mice.

Autism spectrum disorder (ASD), characterized by profound impairment in social interactions and communication skills, is the most common neurodevelopmental disorder. Many studies on the mechanisms underlying the development of ASD have focused on the serotonergic system; however, these studies have failed to completely elucidate the mechanisms. We previously identified N-ethylmaleimide-sensitive factor (NSF) as a new serotonin transporter (SERT)-binding protein and described its importance in SERT membrane trafficking and uptake in vitro. In the present study, we generated Nsf +/- mice and investigated their behavioral, neurotransmitter, and neurophysiological phenotypes in vivo. Nsf +/- mice exhibited abnormalities in sociability, communication, repetitiveness, and anxiety. Additionally, Nsf loss led to a decrease in membrane SERT expression in the raphe and accumulation of glutamate alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors at the synaptic membrane surface in the hippocampal CA1 region. We found that postsynaptic density and long-term depression were impaired in the hippocampal CA1 region of Nsf +/- mice. Taken together, these findings demonstrate that NSF plays a role in synaptic plasticity and glutamatergic and serotonergic systems, suggesting a possible mechanism by which the gene is linked to the pathophysiology of autistic behaviors.

Abnormal social behavior and altered gene expression in mice lacking NDRG2.

N-myc downstream-regulated gene 2 (NDRG2), a member of the NDRG family, has multiple functions in cell proliferation, differentiation, and stress responses, and is predominantly expressed by astrocytes in the central nervous system. Previous studies including ours demonstrated that NDRG2 is involved in various central nervous system pathologies. However, the significance of NDRG2 in neurodevelopment is not fully understood. Here, we investigated the expression profile of NDRG2 during postnatal brain development, the role of NDRG2 in social behavior, and transcriptome changes in the brain of NDRG2-deficient mice. NDRG2 expression in the brain increased over time from postnatal day 1 to adulthood. Deletion of NDRG2 resulted in abnormal social behavior, as indicated by reduced exploratory activity toward a novel mouse in a three-chamber social interaction test. Microarray analysis identified genes differentially expressed in the NDRG2-deficient brain, and upregulated gene expression of Bmp4 and Per2 was confirmed by quantitative PCR analysis. Expression of both these genes and the encoded proteins increased over time during postnatal brain development, similar to NDRG2. Gene expression of Bmp4 and Per2 was upregulated in cultured astrocytes isolated from NDRG2-deficient mice. These results suggest that NDRG2 contributes to brain development required for proper social behavior by modulating gene expression in astrocytes.

Dietary spermidine improves cognitive function.

Decreased cognitive performance is a hallmark of brain aging, but the underlying mechanisms and potential therapeutic avenues remain poorly understood. Recent studies have revealed health-protective and lifespan-extending effects of dietary spermidine, a natural autophagy-promoting polyamine. Here, we show that dietary spermidine passes the blood-brain barrier in mice and increases hippocampal eIF5A hypusination and mitochondrial function. Spermidine feeding in aged mice affects behavior in homecage environment tasks, improves spatial learning, and increases hippocampal respiratory competence. In a Drosophila aging model, spermidine boosts mitochondrial respiratory capacity, an effect that requires the autophagy regulator Atg7 and the mitophagy mediators Parkin and Pink1. Neuron-specific Pink1 knockdown abolishes spermidine-induced improvement of olfactory associative learning. This suggests that the maintenance of mitochondrial and autophagic function is essential for enhanced cognition by spermidine feeding. Finally, we show large-scale prospective data linking higher dietary spermidine intake with a reduced risk for cognitive impairment in humans.

Significance of prevention and early treatment of a postoperative twisted neck: atlantoaxial rotatory subluxation after head and neck surgery.

Atlantoaxial rotatory subluxation (AARS) is an infrequent condition that occurs most commonly in children for unknown reasons. Pediatric surgery, otopharyngeal inflammation, general anesthesia, and extreme rotation of the head are risk factors for development of postsurgical AARS, but AARS can often occur unnoticed, and the syndrome is not well known. We encountered three cases of postoperative AARS that occurred within 7 months; therefore, we have developed guidelines for prevention and early treatment of postoperative AARS. Postoperative AARS cannot be eliminated completely, but informed consent, a preoperative check, an appropriate surgical position, and a postoperative check may reduce the risk and damage related to this condition.

Failure to confirm genetic association of the FXYD6 gene with schizophrenia: the Japanese population and meta-analysis.

The FXYD domain-containing ion transport regulator 6 (FXYD6) gene encodes phosphohippolin that regulates cellular ion transport by altering the kinetic properties of Na,K-ATPase. Phosphohippolin is highly expressed in brain regions that are relevant to schizophrenia. The FXYD6 gene is located at chromosome 11q22-24, one of the most established linkage regions for schizophrenia. Therefore, it may be possible that genetic variants in FXYD6, including the regulatory genomic elements could cause abnormal function or expression of phosphohippolin and increase the genetic risk for schizophrenia. A previous study suggested that polymorphisms in FXYD6 are associated with schizophrenia in UK samples. However, conflicting results have been reported in the Japanese population. In this study, we aimed to test the prior genetic association findings using different samples from the ethnically homogeneous Japanese population (1,060 schizophrenic patients and 1,060 age- and sex-matched controls). From the FXYD6 gene, we examined six single nucleotide polymorphisms (rs11216573, rs555577, rs1815774, rs4938445, rs4938446, and rs497768), all of which were previously analyzed for association. We did not detect any significant allelic, genotypic or haplotypic association in our Japanese samples. Meta-analysis incorporating previous and the present studies also showed that the FXYD6 gene is not associated with schizophrenia. We conclude that the FXYD6 gene does not have a major influence on susceptibility to schizophrenia across populations.

＜Editors' Choice＞ Efficacy of pectoral nerve block type-2 (Pecs II block) versus serratus plane block for postoperative analgesia in breast cancer surgery: a retrospective study.

Thoracic wall nerve blocks reduce postoperative acute pain after breast cancer surgery (BCS); however, their short-term effects and the most effective technique remain unclear. To compare the effects of pectoral nerve block type-2 (Pecs II block) and serratus plane block for postoperative short-term analgesia, we retrospectively reviewed 43 BCS patients who underwent Pecs II block (n=22) or serratus plane block (n=21). The primary outcome was the proportion of patients with no complaints of pain 2 months post-BCS. The odds ratio (OR) was assessed, adjusting for axillary lymph node dissection. The secondary outcomes were pain severity 24 hours and 2 months post-operation using the numerical rating scale score, and morphine consumption within 24 hours. The proportion of patients without pain 2 months post-BCS was significantly less with Pecs II block than in patients with serratus plane block (55% vs. 19%, adjusted OR, 5.04; 95% confidence interval, 1.26-20.07; P=0.02); the median [interquartile range] score for pain 2 months post-operation was also significantly lower with Pecs II block (Pecs II block 0.5 [0-1] vs. serratus plane block 1 [1-2]); P=0.03). Regarding post-BCS acute analgesia, the median [interquartile range] postoperative 24-hour pain score was 2 [1-3] and 3 [1.5-3.5], and the median morphine consumption within 24 hours was 1.5 [0.75-5.5] and 3 [1.5-10] mg in Pecs II block and serratus plane block (P=0.47 and P=0.11), respectively. This study suggests that Pecs II block prevents short-term post-BCS pain better than serratus plane block. However, further studies are needed in order to support this finding.

Inhibition of autophagy curtails visual loss in a model of autosomal dominant optic atrophy.

In autosomal dominant optic atrophy (ADOA), caused by mutations in the mitochondrial cristae biogenesis and fusion protein optic atrophy 1 (Opa1), retinal ganglion cell (RGC) dysfunction and visual loss occur by unknown mechanisms. Here, we show a role for autophagy in ADOA pathogenesis. In RGCs expressing mutated Opa1, active 5' AMP-activated protein kinase (AMPK) and its autophagy effector ULK1 accumulate at axonal hillocks. This AMPK activation triggers localized hillock autophagosome accumulation and mitophagy, ultimately resulting in reduced axonal mitochondrial content that is restored by genetic inhibition of AMPK and autophagy. In C. elegans, deletion of AMPK or of key autophagy and mitophagy genes normalizes the axonal mitochondrial content that is reduced upon mitochondrial dysfunction. In conditional, RGC specific Opa1-deficient mice, depletion of the essential autophagy gene Atg7 normalizes the excess autophagy and corrects the visual defects caused by Opa1 ablation. Thus, our data identify AMPK and autophagy as targetable components of ADOA pathogenesis.

Simultaneous evaluation of antioxidative serum profiles facilitates the diagnostic screening of autism spectrum disorder in under-6-year-old children.

This case-control study aimed to assess oxidative stress alterations in autism spectrum disorder (ASD). We used the MULTIS method, an electron spin resonance-based technique measuring multiple free radical scavenging activities simultaneously, in combination with conventional oxidative stress markers to investigate the ability of this MULTIS approach as a non-behavioural diagnostic tool for children with ASD. Serum samples of 39 children with ASD and 58 age-matched children with typical development were analysed. The ASD group showed decreased hydroxyl radical (·OH) and singlet oxygen scavenging activity with increased serum coenzyme Q10 oxidation rate, indicating a prooxidative tendency in ASD. By contrast, scavenging activities against superoxide (O2·-) and alkoxyl radical (RO·) were increased in the ASD group suggesting antioxidative shifts. In the subgroup analysis of 6-year-olds or younger, the combination of ·OH, O2·-, and RO· scavenging activities predicted ASD with high odds ratio (50.4), positive likelihood (12.6), and percentage of correct classification (87.0%). Our results indicate that oxidative stress in children with ASD is not simply elevated but rather shows a compensatory shift. MULTIS measurements may serve as a very powerful non-behavioural tool for the diagnosis of ASD in children.

VLDL-specific increases of fatty acids in autism spectrum disorder correlate with social interaction.

BACKGROUND: Abnormalities of lipid metabolism contributing to the autism spectrum disorder (ASD) pathogenesis have been suggested, but the mechanisms are not fully understood. We aimed to characterize the lipid metabolism in ASD and to explore a biomarker for clinical evaluation. METHODS: An age-matched case-control study was designed. Lipidomics was conducted using the plasma samples from 30 children with ASD compared to 30 typical developmental control (TD) children. Large-scale lipoprotein analyses were also conducted using the serum samples from 152 children with ASD compared to 122 TD children. Data comparing ASD to TD subjects were evaluated using univariate (Mann-Whitney test) and multivariate analyses (conditional logistic regression analysis) for main analyses using cofounders (diagnosis, sex, age, height, weight, and BMI), Spearman rank correlation coefficient, and discriminant analyses. FINDINGS: Forty-eight significant metabolites involved in lipid biosynthesis and metabolism, oxidative stress, and synaptic function were identified in the plasma of ASD children by lipidomics. Among these, increased fatty acids (FAs), such as omega-3 (n-3) and omega-6 (n-6), showed correlations with clinical social interaction score and ASD diagnosis. Specific reductions of very-low-density lipoprotein (VLDL) and apoprotein B (APOB) in serum of ASD children also were found by large-scale lipoprotein analysis. VLDL-specific reduction in ASD was correlated with APOB, indicating VLDL-specific dyslipidaemia associated with APOB in ASD children. INTERPRETATION: Our results demonstrated that the increases in FAs correlated positively with social interaction are due to VLDL-specific degradation, providing novel insights into the lipid metabolism underlying ASD pathophysiology. FUNDING: This study was supported mainly by MEXT, Japan.