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This study aimed to determine whether the distance of gait training using a hybrid assistive limb (HAL) is related to the improvement of walking independence in patients with acute brain injury. This was an exploratory, observational study. Thirty patients having hemiplegia (functional ambulation category, FAC score ≤2) with acute stroke or after brain tumor surgery were included. Patients performed 4 sessions of gait training using HAL (60 min/session), 1–3 sessions/week, combined with conventional physical therapy. The gait distance achieved in the four training sessions using HAL was measured. FAC score was measured before and after intervention. Patients were divided into groups A, B, and C, for FAC score improvements of 0, 1, and ≥2, respectively. Gait distance was compared among groups using one-way analysis of variance. Gait distance in group C was significantly longer than that ingroup A [mean (standard deviation): 2527 (1725) m vs. 608 (542) m]. This study suggested that the gait distance achieved during training using the HAL may be a clinical indicator of the effectiveness of the HAL on gait training in patients with acute brain injury. Clinical trial registration number: UMIN000012764 R000014756.

Excessive accumulation of amyloid β-protein (Aβ) is one of the primary mechanisms that leads to neuronal death with phosphorylated tau in the pathogenesis of Alzheimer's disease (AD). Protofibrils, one of the high-molecular-weight Aβ oligomers (HMW-Aβo), are implicated to be important targets of disease modifying therapy of AD. We previously reported that phenolic compounds such as myricetin inhibit Aβ1-40, Aβ1-42, and α-synuclein aggregations, including their oligomerizations, which may exert protective effects against AD and Parkinson's disease. The purpose of this study was to clarify the detailed mechanism of the protective effect of myricetin against the neurotoxicity of HMW-Aβo in SH-SY5Y cells. To assess the effect of myricetin on HMW-Aβo-induced oxidative stress, we systematically examined the level of membrane oxidative damage by measuring cell membrane lipid peroxidation, membrane fluidity, and cell membrane potential, and the mitochondrial oxidative damage was evaluated by mitochondrial permeability transition (MPT), mitochondrial reactive oxygen species (ROS), and manganese-superoxide dismutase (Mn-SOD), and adenosine triphosphate (ATP) assay in SH-SY5Y cells. Myricetin has been found to increased cell viability by suppression of HMW-Aβo-induced membrane disruption in SH-SY5Y cells, as shown in reducing membrane phospholipid peroxidation and increasing membrane fluidity and membrane resistance. Myricetin has also been found to suppress HMW-Aβo-induced mitochondria dysfunction, as demonstrated in decreasing MPT, Mn-SOD, and ATP generation, raising mitochondrial membrane potential, and increasing mitochondrial-ROS generation. These results suggest that myricetin preventing HMW-Aβo-induced neurotoxicity through multiple antioxidant functions may be developed as a disease-modifying agent against AD.

Aims/Introduction The association between diabetes and periodontal disease is considered to be bidirectional. However, there is still controversy surrounding the relationship between periodontal disease and type 1 diabetes. We investigated whether insulin improves periodontitis without any local treatments for periodontitis under type 1 diabetes conditions using the ligature‐induced experimental periodontitis model. Materials and Methods Type 1 diabetic rats were induced by streptozotocin injection. Experimental periodontitis was induced by ligature in normal and diabetic rats. Half of the diabetic rats were treated with insulin. Two weeks after the ligature, periodontitis was evaluated. Results Insulin treatment significantly improved inflammatory cell infiltration and inflammatory cytokine gene expression, leading to suppression of alveolar bone loss, in the periodontitis of diabetic rats. Insulin also suppressed the periodontitis‐increased nitric oxide synthase‐positive cells in periodontal tissue of the diabetic rats. Even without induction of periodontitis, diabetic rats showed decreased gingival blood flow and an increased number of nitric oxide synthase‐positive cells in the gingiva and alveolar bone loss compared with normal rats, all of which were ameliorated by insulin treatment. We further confirmed that insulin directly suppressed lipopolysaccharide‐induced inflammatory cytokine expressions in THP‐1 cells. Conclusions There were abnormalities of periodontal tissue even without the induction of periodontitis in streptozotocin‐induced diabetic rats. Insulin treatment significantly ameliorated periodontitis without local periodontitis treatment in diabetic rats. These data suggest the therapeutic impacts of insulin on periodontitis in type 1 diabetes., There was a slight increase in the numbers of inflammatory cells in the gingiva on the periodontitis side of normal rats and on the control side of diabetic rats. The inflammatory cells were markedly increased on the periodontitis side of diabetic rats. Insulin treatment decreased the inflammatory cells in the periodontitis gingiva of diabetic rats.

D-Serine has been shown to play an important role in the expression and control of a variety of brain functions by acting as the endogenous coagonist for the N-methyl-D-aspartate type glutamate receptor (NMDAR), at least, in the forebrain. To obtain further insight into the still debatable cellular localization of the D-amino acid, we have examined the effects of the selective destruction of the neuronal cell bodies by quinolinate on the tissue or extracellular D-serine concentrations in the medial prefrontal cortex of the rat. A local quinolinate infusion into the bilateral medial prefrontal cortex produced a cortical lesion with a marked (- 65%) and non-significant alteration (- 5%) in the cortical and striatal tissue D-serine concentrations, respectively, 7 days post-infusion. In vivo microdialysis experiments in the right prefrontal lesion site 9 days after the quinolinate application revealed that the basal extracellular D-serine levels were also dramatically reduced (- 64%). A prominent reduction in the tissue levels of GABA in the interneurons of the prefrontal cortex (- 78%) without significant changes in those in the striatum (+ 12%) verified that a major lesion part was confined to the cortical portion. The lack of a significant influence of the prefrontal quinolinate lesion on its dopamine concentrations in the mesocortical dopamine projections suggests that the nerve terminals and axons in the lesion site may be spared. These findings are consistent with the perikarya-selective nature of the present quinolinate-induced lesion and further support the view that neuronal cell bodies of intrinsic neurons in the prefrontal cortical region contain substantial amounts of D-serine, which may sustain the basal extracellular concentrations of D-serine.

Copy number variations (CNVs) in the distal 1q21.1 region, both deletion (1q del) and duplication (1q dup), are associated with autism spectrum disorder, epilepsy and schizophrenia. Besides common phenotypes, 1q del and 1q dup manifest opposite clinical phenotypes—e.g., microcephaly in 1q del and macrocephaly in 1q dup. However, molecular and cellular mechanisms are still elusive. We generate isogenic human ES (hES) cell lines with reciprocal 1q21.1 CNVs using CRISPR/Cas9 system and differentiate them into 2-dimensional (2-D) neurons and 3-D cortical organoids. Our study recapitulates opposite organoid size and shows dosage-dependent differentiation changes i.e., more mature and GABAergic components in 1q del and more proliferative state in 1q dup. In contrast, both CNVs show hyperexcitability and altered expressions of glutamate system as common features. These results demonstrate that 1q21.1 CNVs dramatically affect cell fate in the early neurodevelopmental periods. This is the first isogenic model of hES CNVs and our findings provide new insights into the underlying mechanisms of neurodevelopmental disorders.

Objectives: Recently, use of the Hybrid Assistive Limb (HAL) that is effective for improvement of gait ability in chronic stroke patients has been reported. However, how long the effects are mainta...

Background: Robotic rehabilitation has been attracting attention as a means to carry out "intensive", "repetitive", "task-specific", gait training. The newly developed robotic device, the Hybrid Assistive Limb (HAL), is thought to have the possibility of having an excellent effect on gait speed improvement over the conventional automatic programed assist robot. The purpose of this study was to investigate the spatiotemporal characteristics related to gait speed improvement using the HAL in chronic stroke patients. Research question: To investigate the effects of robotic gait training on gait speed and gait parameters. Methods: An observational study with an intervention for single group was used. Intervention was conducted in University Hospital. Eleven chronic stroke patients were enrolled in this study. The patients performed 8 gait training sessions using the HAL, 2–5 sessions/week for 3 weeks. Gait speed, stride length, cadence, time of gait cycle (double-limb stance phases and single-limb stance phases) and time asymmetry index were measured before and after intervention. Results: After intervention, gait speed, stride length, and cadence were significantly improved (Effect size = 0.39, 0.29, and 0.29), the affected initial double-limb stance phase was significantly shortened (from 15.8 ± 3.46%–13.3 ± 4.20%, p = .01), and the affected single-limb stance phase was significantly lengthened (from 21.8±7.02%–24.5±7.95%, p

Oral dysesthesia denotes a condition characterized by abnormal sensations in oral regions without a somatic basis, and is often seen in people with autistic traits, including those with autism spectrum disorder. This study aimed to examine the association between the symptoms of oral dysesthesia and the degree of autistic traits. A retrospective chart review was performed on 44 patients with oral dysesthesia, and associations among the subscales of the Oral Dysesthesia Rating Scale (Oral DRS), Autism Spectrum Quotient (AQ), and Glasgow Sensory Questionnaire (GSQ) were investigated. A Pearson correlation analysis revealed a significant, positive correlation between AQ scores and the A3 (squeezing or pulling) subscale of the Oral DRS (r = 0.37), but there were no significant correlations between the AQ and other subscale scores. There was a significant correlation between the AQ and GSQ score, but no correlation was detected between the GSQ and A3 scores or any other Oral DRS subscale scores. In conclusion, an abnormal squeezing or pulling sensation in oral regions without a somatic basis was associated with autistic traits and could be highlighted as a specific abnormality in sensory processing in autism spectrum disorder.

Excessive accumulation of amyloid β-protein (Aβ) is one of the primary mechanisms that leads to neuronal death with phosphorylated tau in the pathogenesis of Alzheimer's disease (AD). Protofibrils, one of the high-molecular-weight Aβ oligomers (HMW-Aβo), are implicated to be important targets of disease modifying therapy of AD. We previously reported that phenolic compounds such as myricetin inhibit Aβ1-40, Aβ1-42, and α-synuclein aggregations, including their oligomerizations, which may exert protective effects against AD and Parkinson's disease. The purpose of this study was to clarify the detailed mechanism of the protective effect of myricetin against the neurotoxicity of HMW-Aβo in SH-SY5Y cells. To assess the effect of myricetin on HMW-Aβo-induced oxidative stress, we systematically examined the level of membrane oxidative damage by measuring cell membrane lipid peroxidation, membrane fluidity, and cell membrane potential, and the mitochondrial oxidative damage was evaluated by mitochondrial permeability transition (MPT), mitochondrial reactive oxygen species (ROS), and manganese-superoxide dismutase (Mn-SOD), and adenosine triphosphate (ATP) assay in SH-SY5Y cells. Myricetin has been found to increased cell viability by suppression of HMW-Aβo-induced membrane disruption in SH-SY5Y cells, as shown in reducing membrane phospholipid peroxidation and increasing membrane fluidity and membrane resistance. Myricetin has also been found to suppress HMW-Aβo-induced mitochondria dysfunction, as demonstrated in decreasing MPT, Mn-SOD, and ATP generation, raising mitochondrial membrane potential, and increasing mitochondrial-ROS generation. These results suggest that myricetin preventing HMW-Aβo-induced neurotoxicity through multiple antioxidant functions may be developed as a disease-modifying agent against AD.

Using a robot for gait training in stroke patients has attracted attention for the last several decades. Previous studies reported positive effects of robot rehabilitation on gait function in the short term. However, the long-term effects of robot rehabilitation for stroke patients are still unclear. The purpose of the present study was to investigate the long-term effects of periodic gait training using the Hybrid Assistive Limb (HAL) on gait function in chronic stroke patients. Seven chronic stroke patients performed 8 gait training sessions using the HAL 3 times every few months. The maximal 10-m walk test and the 2-minute walking distance (2MWD) were measured before the first intervention and after the first, second, and third interventions. Gait speed, stride length, and cadence were calculated from the 10-m walk test. Repeated one-way analysis of variance showed a significant main effect on evaluation time of gait speed (F = 7.69, p < 0.01), 2MWD (F = 7.52, p < 0.01), stride length (F = 5.24, p < 0.01), and cadence (F = 8.43, p < 0.01). The effect sizes after the first, second, and third interventions compared to pre-intervention in gait speed (d = 0.39, 0.52, and 0.59) and 2MWD (d = 0.35, 0.46, and 0.57) showed a gradual improvement of gait function at every intervention. The results of the present study showed that gait function of chronic stroke patients improved over a year with periodic gait training using the HAL every few months.

It has been well accepted that d -serine may be an exclusive endogenous coagonist for the N -methyl- d -aspartate (NMDA)-type glutamate receptor in mammalian forebrain regions. We have recently found by using an in vivo dialysis method that an intra-medial prefrontal cortex infusion of S-α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (S-AMPA), a selective AMPA-type glutamate receptor agonist, causes a reduction in the extracellular levels of d -serine in a calcium-permeable AMPA receptor antagonist-sensitive manner. The inhibitory influence by the AMPA receptor on the extracellular d -serine, however, contradicts the data obtained from in vitro experiments that the AMPA receptor stimulation leads to facilitation of the d -serine liberation. This discrepancy appears to be due to the different cell setups between the in vivo and in vitro preparations. From the viewpoints of the previous reports indicating (1) the neuronal presence of d -serine synthesizing enzyme, serine racemase, and d -serine-like immunoreactivity and (2) the same high tissue concentrations of d -serine in the glia-enriched white matter and in the neuron-enriched gray matter of the mammalian neocortex, we have now investigated in the mouse medial prefrontal cortex, the effects of attenuation of neuronal and glial activities, by tetrodotoxin or fluorocitrate, respectively, on the S-AMPA-induced downregulation of the extracellular d -serine contents. In vivo dialysis studies revealed that a local infusion of tetrodotoxin or fluorocitrate eliminated the ability of S-AMPA given intra-cortically to cause a significant decrease in the dialysate concentrations of d -serine without affecting the elevating effects of S-AMPA on those of glycine, another intrinsic coagonist for the NMDA receptor. These findings suggest that the control by the AMPA receptor of the extracellular d -serine levels could be modulated by the neuronal and glial activities in the prefrontal cortex. It cannot be excluded that fluorocitrate would indirectly alter the modulation by changing synaptic neurotransmission via glial activity attenuation as previously reported.

Background Although several studies have shown efficacy of nanoparticle albumin-bound (nab) paclitaxel use as a neoadjuvant treatment in breast cancer, dosage and schedules were varied or used in combination and the data are still limited for weekly regimens. We evaluated the feasibility of weekly nab-paclitaxel followed by FEC (5-FU [fluorouracil], epirubicin, and cyclophosphamide) treatment feasibility as neoadjuvant chemotherapy for breast cancer. Patients and Methods Thirty-three patients with no previous chemotherapy were enrolled to receive nab-paclitaxel 150 mg/m2 the first 3 of 4 weeks (3q4w) followed by FEC as neoadjuvant treatment. The trial was powered for analyses of feasibility. Results Twenty-five patients completed the treatment as per protocol, and the completion rate was 75.8% (95% confidence interval, 59.0-87.2; P = .44). The regimen completion group was younger than those with regimen incompletion (average 45.1 vs. 56.6 years). The pathological complete response (ypT0-is/N0) rate was 30.3% in 33 patients, which was higher in triple-negative patients (58.3%). Grade 3/4 neutropenia was seen in 48.5%, although there was no febrile neutropenia. Grade 3 peripheral neuropathy was seen in 33.3%. Conclusion Our study showed that weekly nab-paclitaxel 150 mg/m2 3q4w followed by FEC as neoadjuvant regimen might be sufficient in efficacy, although with a relatively high severe adverse event occurrence rate.

Objectives The siderophore cephalosporin cefiderocol possesses in vitro activity against MDR Gram-negative bacteria. The stability of cefiderocol against serine- and metallo-type carbapenemases has been reported previously, but little is known about how cefiderocol interacts with chromosomal AmpC β-lactamases. We investigated a number of features of cefiderocol, namely antibacterial activity against AmpC overproducers, stability against AmpC β-lactamases and propensity for AmpC induction using Pseudomonas aeruginosa and Enterobacter cloacae. Methods MICs were determined by broth microdilution according to CLSI guidelines. The MIC of cefiderocol was determined in iron-depleted CAMHB. Hydrolysis of the antibiotics was determined by monitoring the changes in the absorbance in the presence of AmpC β-lactamase, and AmpC induction was evaluated by double disc diffusion and nitrocefin degradation assays. Results The MICs of ceftazidime and cefepime for PAO1 increased 4- to 16-fold with inactivation of either ampD or dacB, whereas cefiderocol MICs were little affected by these inactivations (

Yojiro Umezaki,1 Anna Miura,2 Yukiko Shinohara,2 Lou Mikuzuki,2 Shiori Sugawara,2 Kaoru Kawasaki,2 Trang TH Tu,2 Takeshi Watanabe,2 Takayuki Suga,2 Motoko Watanabe,3 Miho Takenoshita,2 Tatsuya Yoshikawa,2 Akihito Uezato,4 Toru Nishikawa,4 Ken Hoshiko,5 Toru Naito,1 Haruhiko Motomura,2 Akira Toyofuku2 1Section of Geriatric Dentistry, Department of General Dentistry, Fukuoka Dental College, Fukuoka, Japan; 2Department of Psychosomatic Dentistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; 3Department of Oral and Maxillofacial Radiology, Tokyo Dental College, Tokyo, Japan; 4Department of Psychiatry and Behavioral Sciences, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; 5Department of Pharmacy, Dental Hospital, Tokyo Medical and Dental University, Tokyo, Japan Objective: Oral cenesthopathy is characterized by foreign body sensations without medical and dental evidence for them. It is thought to be a rare disease in psychiatry, but many patients are visiting dental clinics seeking treatment to remove a foreign body. Even though the features of oral cenesthopathy might be different between a psychiatric clinic and a dental clinic, there has been no clinico-statistical study from dentists. In this study, we report a clinico-statistical study of patients with oral cenesthopathy in dentistry. Methods: This is a retrospective chart review of 606 outpatients with oral cenesthopathy in Tokyo Medical and Dental University from April 2010 through to March 2015. Results: A total of 159 male and 447 female patients were included in this study. The mean age was 62.08 years, and female patients were older than male patients. The trigger of the dental treatment and the acute phase of depression at the onset were significantly related (p=0.037). Only 128 patients (36%) had clinically significant improvement after 6 months of pharmacotherapy. No history of psychiatric disorders (odds ratio [OR] 0.479 [95% confidence interval {CI}: 0.262–0.875], p=0.017) and longer duration of illness (>18 months) (OR 2.626 [95% CI: 1.437–4.799], p=0.002) were significant factors for clinical outcomes. Conclusion: Patients with oral cenesthopathy in our clinic were predominantly elderly female patients. Dental treatment in the acute phase of depression might be a risk factor for oral cenesthopathy. Therefore, comprehending the situation of psychiatric disorder and obtaining adequate informed consent might be required to prevent the trouble concerning oral cenesthopathy. Keywords: oral cenesthopathy, delusional disorder somatic type, DDST, chart review, dentistry

Aim While electroconvulsive therapy (ECT) is a well-established, safe, and effective treatment for mental illnesses, the potential for adverse effects on cognitive functions remains controversial. We aimed to evaluate multiple cognitive functions in different time periods before and after ECT in a Japanese population. Methods A battery of five neurocognitive tests was administered to patients who underwent a course of ECT treatment at three time points: before, immediately after, and 4 weeks after ECT. Results A transient but significant decline in letter fluency function was observed immediately after ECT, but had recovered well by 4 weeks. We also observed a significant improvement in the trail-making task at 4 weeks after ECT. Conclusion In a Japanese population, adverse effects of ECT on verbal fluency function-related and other cognitive impairments were transient. Over the longer term, we detected significant improvements in the performance of tasks that presumably reflected information processing speed and executive functions.

The synapse-associated protein 97/discs, large homolog 1 of Drosophila (DLG1) gene encodes synaptic scaffold PDZ proteins interacting with ionotropic glutamate receptors including the N-methyl-D-aspartate type glutamate receptor (NMDAR) that is presumed to be hypoactive in brains of patients with schizophrenia. The DLG1 gene resides in the chromosomal position 3q29, the microdeletion of which confers a 40-fold increase in the risk for schizophrenia. In the present study, we performed genetic association analyses for DLG1 gene using a Japanese cohort with 1808 schizophrenia patients and 2170 controls. We detected an association which remained significant after multiple comparison testing between schizophrenia and the single nucleotide polymorphism (SNP) rs3915512 that is located within the newly identified primate-specific exon (exon 3b) of the DLG1 gene and constitutes the exonic splicing enhancer sequence. When stratified by onset age, although it did not survive multiple comparisons, the association was observed in non-early onset schizophrenia, whose onset-age selectivity is consistent with our recent postmortem study demonstrating a decrease in the expression of the DLG1 variant in early-onset schizophrenia. Although the present study did not demonstrate the previously reported association of the SNP rs9843659 by itself, a meta-analysis revealed a significant association between DLG1 gene and schizophrenia. These findings provide a valuable clue for molecular mechanisms on how genetic variations in the primate-specific exon of the gene in the schizophrenia-associated 3q29 locus affect its regulation in the glutamate system and lead to the disease onset around a specific stage of brain development.

Cefiderocol (S-649266) is a novel parenteral siderophore cephalosporin conjugated with a catechol moiety at the third-position side chain. The in vitro activity of cefiderocol against Pseudomonas aeruginosa was enhanced under iron-depleted conditions, whereas that of ceftazidime was not affected. The monitoring of [thiazole- 14 C]cefiderocol revealed the increased intracellular accumulation of cefiderocol in P. aeruginosa cells incubated under iron-depleted conditions compared with those incubated under iron-sufficient conditions. Cefiderocol was shown to have potent chelating activity with ferric iron, and extracellular iron was efficiently transported into P. aeruginosa cells in the presence of cefiderocol as well as siderophores, while enhanced transport of extracellular ferric iron was not observed when one of the hydroxyl groups of the catechol moiety of cefiderocol was replaced with a methoxy group. We conclude that cefiderocol forms a chelating complex with iron, which is actively transported into P. aeruginosa cells via iron transporters, resulting in potent antibacterial activity of cefiderocol against P. aeruginosa .

We report a case of right uretero-external iliac artery fistula. A 46-year-old woman diagnosed with left ovarian cancer with peritoneal dissemination underwent simple hysterectomy, bilateral adnexal removal, partial omentectomy and appendectomy. Sixteen months after the operation, a computed tomography scan showed right hydronephrosis due to the development of tumor within the pelvis. A ureteral stent was placed into the right ureter in order to preserve renal function. The ureteral stent was replaced at regular intervals. Five months after the ureteral stent placement, the patient was hospitalized urgently with gross hematuria. She was diagnosed with right uretero-external iliac artery fistula based on the angiographic examination that was conducted to detect the source of hemorrhage. She was treated successfully with endovascular stent grafting in the right external iliac artery. She has since shown no episode of hematuria.

A 26-year-old man developed a catatonic state after his grandmother's death and the Great East Japan Earthquake. He was admitted to hospital because of the prolonged severe stupor. Electroencephalography (EEG) revealed focal (F3 electrode) and generalized epileptic abnormalities. He was administered antiepileptic agents and benzodiazepines, but his stupor did not improve in spite of a reduced frequency of epileptic EEG abnormalities. His clinical his- tory did not suggest any psychotic disorders. Thereafter, extensive physical examinations were performed, but an organic cause of the stupor was not determined. For about two years, he was unable to intake food without tubal feeding, have a conversation, or move spontaneously. One day, a generalized tonic-clonic seizure (GTC) occurred spontaneously for the first time in his life, and then his stupor markedly improved. Thereafter, he could eat food spontaneously, have a fluent conversation, and move actively. After his condition had improved, we asked his parents about his developmental history, clinical history, and present state. According to clini- cal interviews including the use of PARS (Pervasive Developmental Disorders Autism Society Japan Rating Scale), DISCO (Diagnostic Interview for Social and Communication Disorders), and WAIS-III (Wechsler Adult Intelligence Scale-third edition), he was diagnosed with autistic spectrum disorder (ASD) and mild intellectual disability. It was considered that his stupor had occurred secondary to ASD. Wing et al. reported that catatonia occurred in about 17% of ASD adolescents and young adults as a later complication. It is possible that this case, without any psychotic disorders and with ASD that has been undiagnosed until young adult, progress to such a severe and prolonged catatonic state. We report this case to show that severe catatonia is possible in adolescents and young adults during the carry-over period in ASD patients.

Aim Genome-wide association studies have revealed that single nucleotide polymorphism (SNP) of human leukocyte antigen (HLA)-DQ is associated with the clearance of hepatitis B surface antigen (HBsAg) in acute hepatitis B virus (HBV) infection. We examined the effects of the SNPs on the development of hepatocellular carcinoma (HCC) and markers of HBV in chronic HBV infection. Methods The SNPs of HLA-DQ (rs2856718 and rs7453920) were determined in 299 patients with chronic HBV infection. Results In 224 HBV envelope antigen (HBeAg)-negative patients, those with rs2856718 genotype AG + GG had significantly lower hepatitis B core-related antigen levels (p = 0.0184), less frequent treatment with nucleotide/nucleoside analogs (NAs) (p = 0.0433), and less frequent HCC development (p = 0.0256) than those with genotype AA. Multivariate analysis selected age (p = 0.0460), platelet (p = 0.0481), γ-GTP (p = 0.0030) and NAs treatment (p = 0.0003) as factors independently associated with HCC development. HBeAg-negative patients with rs7453920 genotype GG had significantly lower HBsAg levels (p

Aims/Introduction The involvement of glucose-dependent insulinotropic polypeptide (GIP) on inflammation was explored in atherosclerosis and adipose tissue. Periodontal disease is a chronic inflammatory disease, and is considered one of the diabetic complications. In the present study, to examine the effect of GIP on periodontitis, we induced experimental periodontitis in glucose-dependent insulinotropic polypeptide receptor-knockout mice (GIPRKO). We also investigated the anti-inflammatory effect of GIP in a culture system. Materials and Methods Experimental periodontitis was induced by ligature wire in GIPRKO and C57BL/C mice. Two weeks after the ligature, immunohistological evaluation and inflammatory messenger ribonucleic acid expression in the gingiva was examined. To elucidate the role of GIP in inflammation, the effects of GIP on lipopolysaccharide-induced gene expressions in THP-1 cells were evaluated. Results Periodontitis increased inflammatory cell infiltration, macrophage accumulation and tumor necrosis factor-α and nitric oxide synthase gene expressions in the gingiva. Periodontitis in GIPRKO showed a marked increase of inflammatory cells in the gingivomucosal tissue. Mac-1-positive macrophages and the inflammatory gene expressions were significantly increased in periodontitis in GIPRKO compared with C57BL/C mice periodontitis. Immunohistochemical staining confirmed that GIP receptors were expressed in residual and infiltrated Mac-1-positive macrophages. The in vitro study showed that GIP suppressed lipopolysaccharide-induced tumor necrosis factor-α and nitric oxide synthase gene expression in a dose-dependent manner. Furthermore, the inhibitory effect of GIP on lipopolysaccharide-induced inflammatory gene expressions was at least partially through cyclic adenosine monophosphate/protein kinase A pathway. Conclusions These results suggest the beneficial effects of GIP on periodontal disease. In diabetic patients, GIP is expected to have a direct anti-inflammatory effect on periodontitis in addition to its glucose-lowering effect.

Background Total knee arthroplasty is one of the most successful surgeries with respect to relieving pain and restoring function of the knee. However, some studies have reported that patients are not always satisfied with their results after total knee arthroplasty. The aim of this study was to determine whether the muscle strength around the knee joint and the walking status influence patients' expectations and satisfaction before and after total knee arthroplasty. Methods We evaluated 28 patients who underwent 30 primary total knee arthroplasties from March 2012 to June 2013. We assessed patient-reported scores using the 2011 Knee Society Scoring System, knee extensor and flexor strength, the 10-m walking test, and the timed up-and-go test. All assessments were performed preoperatively and 1 year after total knee arthroplasty. We determined the correlation between the patient-reported scores and each variable. Results Preoperative patient satisfaction was significantly correlated with knee symptoms and functional activities, but not with muscle strength or walking status. Postoperative patient satisfaction was significantly correlated with knee symptoms, functional activities, knee extensor strength, and walking status, including the 10-m walking test and timed up-and-go test, after total knee arthroplasty. In stepwise regression analysis, predictors of patient satisfaction with total knee arthroplasty were knee symptoms, functional ability, and knee extensor strength. Conclusions Our study demonstrates that pain relief and restoration of functional activity are highly correlated with increasing patient satisfaction after total knee arthroplasty. The results also indicate that the quadriceps is important for patient satisfaction and restoration of functional activity following total knee arthroplasty.

Transurethral resection of bladder tumor (TURBT) was performed on the bladder tumor of a 68-yearold male patient. Bacillus Calmette-Guérin (BCG) intravesical therapy was performed to prevent recurrence (Immunobladder : ○R 80 mg once/week×6 times). A 40 mm tumor was noted in the left kidney by renal ultrasound performed two months after the completion of BCGintravesical therapy. Computed tomography (CT) showed non-enhanced multiple mass lesions in the left kidney. Renal tuberculous granuloma, hypovascular renal cell carcinoma or malignant lymphoma was suspected and CT-guided needle biopsy was performed. The patient was diagnosed with renal tuberculous granuloma that developed after BCGintravesical therapy as epithelioid cell granulomas were noted in the biopsy results. Treatment with anti-tuberculosis drugs was started and the tumor showed signs of shrinkage.

Objectives Contrast-enhanced ultrasonography can evaluate microcirculation. Thus, we used contrast-enhanced ultrasonography in evaluating pancreas graft perfusion and examined the relationship between graft circulation and function. Methods Contrast-enhanced ultrasonography was performed in 17 cases within 24 hours and at 1, 3, 5, 7, 14, 21, and 28 days after transplantation (Tx). The time between the time to peak intensity in the parenchyma and that in the vein was defined as delta-Tp(P-V). Graft function was evaluated with oral glucose tolerance test (OGTT) at 1 and 3 months after Tx, and glucagon stimulation test at 1 month after Tx. Results Differences in delta-Tp(P-V) between individual cases were more significant early after Tx, and delta-Tp(P-V) within 24 hours (delta-Tp[P-V]24h) was used in the subsequent analysis. Delta-Tp(P-V)24 hours showed a negative correlation with C-peptide increment in the glucagon stimulation test and the area under the curve of insulin level in oral glucose tolerance test. The cases were divided into the following 2 groups: the standard group (delta-Tp[P-V]24h ≤6.10 seconds) and the delayed group (>6.10 seconds). The area under the curve of insulin level increased significantly from 1 to 3 months after Tx in the standard group only. Conclusions These results suggest that delta-Tp(P-V)24 hours affects insulin secretion after Tx. Contrast-enhanced ultrasonography is useful in predicting endocrine function of the graft.

The structure-activity relationship (SAR) for a novel series of catechol conjugated siderophore cephalosporins is described with their in vitro activities against multi-drug resistant Gram-negative pathogens including Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia and Enterobacteriaceae. Cefiderocol (3) was one of the best molecules which displayed well-balanced and potent activities against multi-drug resistant Gram-negative pathogens including carbapenem resistant bacteria among the prepared compounds with the modified C-7 side chain and the modified C-3 side chain. Cefiderocol (3) is a highly promising parenteral cephalosporin for the treatment of multi-drug resistant Gram-negative infection.

Schizophrenia and schizophrenia-like symptoms induced by the dopamine agonists and N-methyl-D aspartate type glutamate receptor antagonists occur only after the adolescent period. Similarly, animal models of schizophrenia by these drugs are also induced after the critical period around postnatal week three. Based upon the development-dependent onsets of these psychotomimetic effects, by using a DNA microarray technique, we identified the WD repeat domain 3 (WDR3) and chitobiosyldiphosphodolichol beta-mannosyltransferase (ALG1) genes as novel candidates for schizophrenia-related molecules, whose mRNAs were up-regulated in the adult (postnatal week seven), but not in the infant (postnatal week one) rats by an indirect dopamine agonist, and phencyclidine, an antagonist of the NMDA receptor. WDR3 and other related proteins are the nuclear proteins presumably involved in various cellular activities, such as cell cycle progression, signal transduction, apoptosis, and gene regulation. ALG1 is presumed to be involved in the regulation of the protein N-glycosylation. To further elucidate the molecular pathophysiology of schizophrenia, we have evaluated the genetic association of WDR3 and ALG1 in schizophrenia. We examined 21 single nucleotide polymorphisms [SNPs; W1 (rs1812607)-W16 (rs6656360), A1 (rs8053916)-A10 (rs9673733)] from these genes using the Japanese case-control sample (1,808 schizophrenics and 2,170 matched controls). No significant genetic associations of these SNPs were identified. However, we detected a significant association of W4 (rs319471) in the female schizophrenics (allelic P = 0.003, genotypic P = 0.008). Based on a haplotype analysis, the observed haplotypes consisting of W4 (rs319471)–W5 (rs379058) also displayed a significant association in the female schizophrenics (P = 0.016). Even after correction for multiple testing, these associations remained significant. Our findings suggest that the WDR3 gene may likely be a sensitive factor in female patients with schizophrenia, and that modification of the WDR3 signaling pathway warrants further investigation as to the pathophysiology of schizophrenia.

Cefiderocol (CFDC; S-649266), a novel parenteral siderophore cephalosporin conjugated with a catechol moiety, has a characteristic antibacterial spectrum with a potent activity against a broad range of aerobic Gram-negative bacterial species, including carbapenem-resistant strains of Enterobacteriaceae and nonfermenting bacteria such as Pseudomonas aeruginosa and Acinetobacter baumannii . Cefiderocol has affinity mainly for penicillin-binding protein 3 (PBP3) of Enterobacteriaceae and nonfermenting bacteria similar to that of ceftazidime. A deficiency of the iron transporter PiuA in P. aeruginosa or both CirA and Fiu in Escherichia coli caused 16-fold increases in cefiderocol MICs, suggesting that these iron transporters contribute to the permeation of cefiderocol across the outer membrane. The deficiency of OmpK35/36 in Klebsiella pneumoniae and the overproduction of efflux pump MexA-MexB-OprM in P. aeruginosa showed no significant impact on the activity of cefiderocol.

Nipple-sparing mastectomy (NSM) is an advantageous treatment option, providing a complete cure and good cosmetic results. We tested whether NSM is a surgically and oncologically safe technique. We evaluated the oncological outcome of 425 breasts in 413 patients who underwent NSM between January 2000 and March 2013. We retrospectively reviewed patient data and analyzed all patient characteristics as potential risk factors of recurrence at the nipple–areola complex (NAC). To confirm the oncological safety of NSM, we compared outcomes of NSM and conventional total mastectomy. The median follow-up time after surgery was 46.8 months (range 6–158 months). Nipple necrosis was observed in 6 cases (1.4 %). The cumulative local recurrence rate after NSM was 5.8 % (25/425 cases), similar to that of conventional total mastectomy in the same period (5.6 %, 49/878 cases). Furthermore, the cumulative local recurrence rate at the NAC was 2.3 % (10 cases). HER2-enriched tumors and young age (

In the hippocampus of mice lacking the gene for serine racemase (SR), a D-serine synthesizing enzyme, in the CaMKIIα-expressing neurons, we observed a significant decrease in the extracellular concentration of D-serine, a coagonist for the N-methyl-D-aspartate type glutamate receptor (NMDAR), and NMDAR hypofunction as revealed by diminished extracellular taurine concentrations after an intra-hippocampal NMDA infusion when compared to the wild type controls. Therefore, the neuronal SR could regulate the extracellular D-serine signaling responsible for NMDAR activation in the hippocampus.

Delayed encephalopathy (DE) affects not only the cerebral white matter and globus pallidus but also the cortex and thalamus. However, it remains unknown whether these brain lesions alter sleep along with clinical manifestations of DE. A 46-year-old man with DE underwent repetitive hyperbaric oxygen therapy. The patient was evaluated by not only neuropsychological and neuroimaging testing but polysomnography over the clinical course. Neurological symptoms improved markedly; however, profound frontal cognitive deficits continued. The polysomnography revealed prolonged absence and delayed recovery of sleep spindles across recordings. Alterations in spindle oscillations in DE could provide further insight into sleep regulatory networks.

Although several studies have shown efficacy of nanoparticle albumin-bound (nab) paclitaxel use as a neoadjuvant treatment in breast cancer, dosage and schedules were varied or used in combination and the data are still limited for weekly regimens. We evaluated the feasibility of weekly nab-paclitaxel followed by FEC (5-FU [fluorouracil], epirubicin, and cyclophosphamide) treatment feasibility as neoadjuvant chemotherapy for breast cancer.Thirty-three patients with no previous chemotherapy were enrolled to receive nab-paclitaxel 150 mg/mTwenty-five patients completed the treatment as per protocol, and the completion rate was 75.8% (95% confidence interval, 59.0-87.2; P = .44). The regimen completion group was younger than those with regimen incompletion (average 45.1 vs. 56.6 years). The pathological complete response (ypT0-is/N0) rate was 30.3% in 33 patients, which was higher in triple-negative patients (58.3%). Grade 3/4 neutropenia was seen in 48.5%, although there was no febrile neutropenia. Grade 3 peripheral neuropathy was seen in 33.3%.Our study showed that weekly nab-paclitaxel 150 mg/m

Diminished glutamate neurotransmission via the N-methyl-d-aspartate type glutamate receptor (NMDAR) has been considered to be involved in the pathophysiology of schizophrenia based upon the observation that the antagonists and autoantibodies of NMDAR cause positive, negative and cognitive symptomatologies similar to those of schizophrenia. The possible reduced extracellular levels of d-serine by overstimulation of the calcium-permeable α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate glutamate receptor (CP-AMPAR) following the NMDAR hypofunction-induced compensatory increase in the glutamate release could aggravate the NMDAR hypofunction in the brain of the drug- or antibody-associated psychoses and schizophrenia, because d-serine is an intrinsic coagonist for the NMDAR. To obtain an insight into the therapeutic approach to such a glutamate-linked psychotic state, we have studied the effects of the systemic administration of the CP-AMPAR-selective antagonist, IEM 1460 (N,N,N-trimethyl-5- [(tricyclo[3.3.1.13,7]dec-1-ylmethyl)amino]-1-pentanaminium bromide hydrobromide), on the hyperactivity following an injection of a schizophrenomimetic NMDAR antagonist, phencyclidine, in the mouse. The subcutaneous IEM 1460 application produced a dose-dependent inhibition of the increased movement counts after the subcutaneous injection of phencyclidine. This inhibiting influence was also seen on the hyperactivity elicited by another NMDAR antagonist, dizocilpine. Moreover, the IEM 1460 administration attenuated the ability of a schizophrenomimetic dopamine agonist, methamphetamine, to increase spontaneous movements. These findings indicate that dysregulation of the CP-AMPAR could, at least in part, be implicated in the glutamate pathology of schizophrenia and/or related psychotic symptoms and be a potential target for the development of their novel treatment.

Background It has been reported that drugs which promote the N-Methyl-D-aspartate-type glutamate receptor function by stimulating the glycine modulatory site in the receptor improve negative symptoms and cognitive dysfunction in schizophrenia patients being treated with antipsychotic drugs. Methods We performed a placebo-controlled double-blind crossover study involving 41 schizophrenia patients in which D-cycloserine 50 mg/day was added-on, and the influence of the onset age and association with white matter integrity on MR diffusion tensor imaging were investigated for the first time. The patients were evaluated using the Positive and Negative Syndrome Scale (PANSS), Scale for the Assessment of Negative Symptoms (SANS), Brief Assessment of Cognition in Schizophrenia (BACS), and other scales. Results D-cycloserine did not improve positive or negative symptoms or cognitive dysfunction in schizophrenia. The investigation in consideration of the onset age suggests that D-cycloserine may aggravate negative symptoms of early-onset schizophrenia. The better treatment effect of D-cycloserine on BACS was observed when the white matter integrity of the sagittal stratum/ cingulum/fornix stria terminalis/genu of corpus callosum/external capsule was higher, and the better treatment effect on PANSS general psychopathology (PANSS-G) was observed when the white matter integrity of the splenium of corpus callosum was higher. In contrast, the better treatment effect of D-cycloserine on PANSS-G and SANS-IV were observed when the white matter integrity of the posterior thalamic radiation (left) was lower. Conclusion It was suggested that response to D-cycloserine is influenced by the onset age and white matter integrity. Trial registration UMIN Clinical Trials Registry (number UMIN000000468 ). Registered 18 August 2006

Aim The aetiology of progressive periodontitis in diabetes has not yet been elucidated. We previously demonstrated that nitrosative stress is increased in diabetic rats with periodontitis. Nitrosative stress induces poly(ADP-ribose) polymerase (PARP) activation. Here, we demonstrated the involvement of PARP activation in diabetic periodontitis and detailed the therapeutic effects of PARP inhibitor. Materials and methods Experimental periodontitis was induced by placing a nylon thread ligature. Half of the normal and diabetic rats received the PARP inhibitor, 1,5-isoquinolinediol, for 2 weeks. Gingival PARP activation was detected by immunostaining for poly(ADP-ribose). Periodontitis was evaluated by gingival inflammatory cell infiltration, inflammatory gene expressions and micro-CT analyses. Results Although both periodontitis and the presence of diabetes increased PARP activation in the gingiva, diabetic rats with periodontitis had the highest activation of PARP. Diabetic rats with periodontitis also showed significant increases in monocyte/macrophage invasion into the gingiva, inflammatory gene expressions, nitrotyrosine-positive cells in the gingiva and alveolar bone loss, all of which were suppressed by treatment with the PARP inhibitor. Conclusions These results indicate the involvement of PARP activation in the pathogenesis and aggravation of periodontal disease in diabetes and suggest the therapeutic potential of PARP inhibition for treating periodontal disease, especially in patients with diabetes.

Background D -serine is an endogenous co-agonist of N-methyl-D-aspartate receptor (NMDAR) and plays an important role in glutamate neurotransmission. Several studies suggested the possible involvement of D -serine related in the pathophysiology of psychiatric disorders including major depression disorders (MDD). We tried to examine whether cerebrospinal fluid (CSF) or plasma D -serine concentrations are altered in MDD and whether D -serine concentrations correlated with disease severity. Methods 26 MDD patients and 27 healthy controls matched for age, sex and ethnicity were enrolled. We measured amino acids in these samples using by high-performance liquid chromatography with fluorometric detection. Results D -serine and L -serine, precursor of D -serine, levels in CSF or plasma were not significantly different in patients of MDD compared to controls. Furthermore, a significant correlation between D -serine levels in CSF and Hamilton Depression Rating Scale (HAMD)-17 score was observed (r = −0.65, p = 0.006). Furthermore, we found a positive correlation between CSF D -serine and HVA concentrations in MDD patients (r = 0.54, p = 0.007). CSF D -serine concentrations were correlated with those of plasma in MDD (r = 0.61, p = 0.01) but not in controls. In CSF, we also confirmed a significant correlation between D -serine and L -serine levels in MDD (r = 0.72, p Conclusions The study has some limitations; sample size was relatively small and most patients were medicated. We revealed that CSF D -serine concentrations were correlated with depression severity and HVA concentrations and further investigation were required to reveal the effect of medication and disease heterogeneity.

While electroconvulsive therapy (ECT) is a well-established, safe, and effective treatment for mental illnesses, the potential for adverse effects on cognitive functions remains controversial. We aimed to evaluate multiple cognitive functions in different time periods before and after ECT in a Japanese population.A battery of five neurocognitive tests was administered to patients who underwent a course of ECT treatment at three time points: before, immediately after, and 4 weeks after ECT.A transient but significant decline in letter fluency function was observed immediately after ECT, but had recovered well by 4 weeks. We also observed a significant improvement in the trail-making task at 4 weeks after ECT.In a Japanese population, adverse effects of ECT on verbal fluency function-related and other cognitive impairments were transient. Over the longer term, we detected significant improvements in the performance of tasks that presumably reflected information processing speed and executive functions.

Background Suicidal behavior accounts for at least 40,000 admissions per year to emergency departments in Japan; however, little is known about emergency admissions owing to suicidal behavior in metropolitan areas. Therefore, we examined the clinical characteristics of suicidal behavior using psychosocial assessments performed by experienced psychiatrists in an intensive care unit. Methods Participants were 971 patients admitted to a university hospital’s intensive care unit for suicidal behavior between July 2006 and June 2013. Physicians and psychiatrists regularly assessed the participants using a standard data extraction form while the participants were in the intensive care unit. As suicidal behavior involving drug overdose is generally less fatal than other methods, we predicted that clinical characteristics would differ between patients with and without overdose. We classified participants into drug overdose or other method groups (ns = 732 and 239, respectively) to compare suicide methods. Results In the overdose group, participants’ median age was approximately 5 years lower, and the following proportions were larger: female participants (77%) and participants with borderline personality disorders (21% vs. 10%), no clear suicidal ideation (30% vs. 15%), impulsively attempted self-harm (86% vs. 62%), and interpersonal problems (26% vs. 16%). Conclusion Ameliorating interpersonal problems and improving stress coping skills would benefit people who attempt suicide via overdose.