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Secondary lymphedema is a common complication of lymph node dissection or radiation therapy for cancer treatment. Conventional therapies such as compression sleeve therapy, complete decongestive physiotherapy, and surgical therapies decrease edema; however, they are not curative because they cannot modulate the pathophysiology of lymphedema. Recent advances reveal that the activation and accumulation of CD4+ T cells are key in the development of lymphedema. Based on this pathophysiology, the efficacy of pharmacotherapy (tacrolimus, anti-IL-4/IL-13 antibody, or fingolimod) and cell-based therapy for lymphedema has been demonstrated in animal models and pilot studies. In addition, mesenchymal stem/stromal cells (MSCs) have attracted attention as candidates for cell-based lymphedema therapy because they improve symptoms and decrease edema volume in the long term with no serious adverse effects in pilot studies. Furthermore, MSC transplantation promotes functional lymphatic regeneration and improves the microenvironment in animal models. In this review, we focus on inflammatory cells involved in the pathogenesis of lymphedema and discuss the efficacy and challenges of pharmacotherapy and cell-based therapies for lymphedema.

Background Early diagnosis of individuals' at-risk mental state (ARMS) is important for preventing their pathogenesis or, at least, delaying onset of overt psychosis. Traditional diagnosis of ARMS subjects is mainly based on structured interviews, but future diagnosis would be carried out together with biomarkers. Aim In this study, we report urinary biopyrrins and free immunoglobin light chains κ and λ (κFLC and λFLC) as novel diagnostic biomarker candidates for screening ARMS subjects. Methods Nineteen ARMS subjects and 21 age- and sex-matched healthy controls were enrolled in this study. Inclusion criteria of the ARMS subjects were based on a comprehensive assessment of Structured Interview for Prodromal Syndromes. We compared oxidative stress and immunological markers in the urine of ARMS subjects with those of healthy controls by ELISA protocol. Results Augmentation of biopyrrins and reduction of κFLC and λFLC were found in the ARMS samples, and their diagnostic performance was evaluated by receiver operating characteristic analysis, of which area under the curve was as large as 0.915 in combination. Conclusion Our findings suggest that the ARMS subjects were under higher oxidative stress but lower in B cell activation, and that the combined assay of urinary biopyrrins and free immunoglobulin light chains would be useful for the early detection and screening of ARMS subjects among adolescents.

Background Severe neonatal hyperbilirubinemia has been known to cause the clinical syndrome of kernicterus and a milder one the syndrome of bilirubin-induced neurologic dysfunction (BIND). BIND clinically manifests itself after the neonatal period as developmental delay, cognitive impairment, and related behavioral and psychiatric disorders. The complete picture of BIND is not clear. Methods The Gunn rat is a mutant strain of the Wistar rat with the BIND phenotype, and it demonstrates abnormal behavior. We investigated serotonergic dysfunction in Gunn rats by pharmacological analyses and ex vivo neurochemical analyses. Results Ketanserin, the 5-HT2AR antagonist, normalizes hyperlocomotion of Gunn rats. Both serotonin and its metabolites in the frontal cortex of Gunn rats were higher in concentrations than in control Wistar rats. The 5-HT2AR mRNA expression was downregulated without alteration of the protein abundance in the Gunn rat frontal cortex. The TPH2 protein level in the Gunn rat raphe region was significantly higher than that in the Wistar rat. Conclusions It would be of value to be able to postulate that a therapeutic strategy for BIND disorders would be the restoration of brain regions affected by the serotonergic dysfunction to normal operation to prevent before or to normalize after onset of BIND manifestations. Impact We demonstrated serotonergic dysregulation underlying hyperlocomotion in Gunn rats. This finding suggests that a therapeutic strategy for bilirubin-induced neurologic dysfunction (BIND) would be the restoration of brain regions affected by the serotonergic dysfunction to normal operation to prevent before or to normalize after the onset of the BIND manifestations. Ketanserin normalizes hyperlocomotion of Gunn rats. To our knowledge, this is the first study to demonstrate a hyperlocomotion link to serotonergic dysregulation in Gunn rats.

Mogamulizumab (Mog), an anti-C-C motif chemokine receptor 4 (CCR4) antibody, is a therapeutic for adult T-cell leukemia/lymphoma (ATL). Injuries of normal regulatory T cells (Tregs) which express CCR4 by Mog could result in immune-related adverse events including

Introduction Primary hyperparathyroidism (PHPT) is characterized by hypercalcemia and an elevated level of serum parathyroid hormone (PTH). PHPT presents with a complex set of renal, skeletal, and neuropsychological symptoms. Parathyroidectomy (PTX) is a radical treatment that is recommended for all physically symptomatic patients with PHPT. However, psychiatric symptoms are not considered as an indication for surgery. There remains an important issue from the view of perioperative management of whether PTX should be performed with the presence of uncontrolled psychiatric symptoms or deferred until severe psychiatric symptoms have been controlled. We report a case of mild hypercalcemia that caused severe psychosis in PHPT, which improved dramatically following PTX and resulted in successful postoperative management. Patient concern Our patient was a 68-year-old Japanese woman. She was diagnosed with PHPT, which was triggered by mild hypercalcemia. She was due to receive an operation for osteoporosis and kidney stones. She had severe psychosis, despite medication. Blood examinations revealed mild hypercalcemia (10.4 mg/dL, 8.8-10.1 mg/dL) and elevated serum levels of intact PTH (184.0 pg/mL, 10-65 pg/mL). Diagnosis She was diagnosed with severe psychosis caused by mild hypercalcemia in PHPT. Interventions Although she was treated with 37.5 mg quetiapine and 2 mg risperidone daily, she was excessively sedated and rejected oral treatment. Therefore, we decided to perform the operation. Outcomes Immediately following surgery, serum levels of calcium, and intact PTH were normalized. Her psychotic symptoms ceased completely 5 days after surgery. Conclusion We emphasize that PHPT presents with various severe psychiatric symptoms, even in mild hypercalcemia. Psychiatric symptoms may be the only salient symptoms in PHPT, and thus clinicians should suspect PHPT in patients with psychiatric symptoms and mild hypercalcemia. Furthermore, PTX is recommended for PHPT-even in the presence of severe uncontrolled psychiatric symptoms, which carries risks for postoperative management-because psychiatric symptoms are expected to improve and good postoperative management is possible.

Objective This study aimed to examine the effects of suvorexant on delirium prevention in a real-world setting. Previous studies have demonstrated the efficacy of suvorexant for delirium prevention in limited randomized clinical trial settings; however, its effectiveness in everyday clinical settings remains unknown. Methods A single-center, retrospective cohort study was conducted in the intensive care unit of an academic hospital. Patients (aged ≥ 3 years) admitted from January 2016 to December 2018 were eligible if they stayed in the intensive care unit for at least 72 hours. Suvorexant was prescribed by the attending physician for insomnia as part of everyday clinical practice. A Cox proportional hazards regression analysis was conducted on delirium-free survival for suvorexant users, adjusting for delirium-related covariates. As part of routine clinical practice, the Confusion Assessment Method for the Intensive Care Unit was used to detect the existence of delirium at least twice daily throughout the intensive care unit stay. Results There were 699 patients-84 suvorexant users and 615 suvorexant nonusers. Delirium was detected in 214 patients. Delirium prevalence was significantly lower in suvorexant users than in nonusers (17.9% vs 32.4%, respectively; P = .007). Cox regression analysis revealed a significantly lower hazard ratio (0.472; 95% CI, 0.268-0.832; P = .009) of delirium in suvorexant users than in nonusers. Trazodone also had a preventive effect on delirium (hazard ratio 0.345; 95% CI, 0.149-0.802; P = .013). Conclusions The present study extends to real-world settings previous findings that suvorexant is effective for delirium prevention.

Background: Fibroblast growth factor (FGF) 2 (also referred to as basic FGF) is a multifunctional growth factor that plays a pivotal role in the pro-survival, pro-migration and pro-differentiation of neurons. Method: Because alterations in FGF2 levels are suggested to contribute to the pathogenesis schizophrenia, we investigated serum levels of FGF2 in the Gunn rat, a hyperbilirubinemia animal model of schizophrenic symptoms. Results: The enzyme-linked immunosorbent assay showed that the serum levels of FGF2 in Gunn rats were 5.09 ± 0.236 pg/mL, while those in the normal strain Wistar rats were 11.90 ± 2.142 pg/mL. The serum FGF2 levels in Gunn rats were significantly lower than those in Wistar rats. We also measured serum levels of unconjugated bilirubin (UCB) and found a significant negative correlation between UCB and FGF2 at serum levels in all the rats studied. Conclusion: Since it is known that FGF2 regulates dopaminergic neurons and have anti-neuroinflammatory effects, our finding suggests that low FGF2 levels may contribute to the pathogenesis of schizophrenia, in which disbalanced dopamin-ergic signaling and neuroinflammation are supposed to play certain roles.

Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell neoplasm associated with the human T-cell leukemia virus type-I (HTLV-1); prognosis still remains very poor. We retrospectively reviewed the treatment of 198 patients with acute-, lymphoma- and unfavorable chronic-type ATL (aggressive ATL) diagnosed from 2005 to 2014 in a hospital located in an area of Japan in which HTLV-1 is highly endemic. One-hundred forty-three, and 35 patients were treated using OPEC/MPEC and VCAP-AMP-VECP, respectively. OPEC/MPEC was mainly used until around 2010, and gradually switched to VCAP-AMP-VECP, especially for younger patients. The 2-year overall survival for patients treated by VCAP-AMP-VECP was significantly higher than that using OPEC/MPEC for patients

Background Although growing evidence indicates that ECT affects astrocytes, the exact mechanisms of the therapeutic effect of ECT are still unknown. Astrocytic endfeet express the water channel aquaporin (AQP) 4 abundantly and ensheath brain blood vessels to form gliovascular units. It has been shown that the coverage of blood vessels by AQP4-immunostained endfeet is decreased in the prefrontal cortex (PFC) of patients with major depression. This study was made to determine whether ECT restores the astrocytic coverage of blood vessels with amelioration of depressive symptoms. Methods After electroconvulsive shock (ECS) administration to rats, the forced swimming test (FST) and Y-maze test were performed. Subsequently, immunofluorescence analysis was conducted to measure the coverage of blood vessels by astrocytic endfeet in the PFC and hippocampus by using the endothelial cell marker lectin and anti-AQP4 antibody. We also performed Western blot to examine the effects of ECS on the hippocampal expression of AQP4 and the tight junction molecule claudin-5. Results Gunn rats showed learned helplessness and impaired spatial working memory, compared to normal control Wistar rats. ECS significantly improved the depressive-like behavior. Gunn rats showed a decrease in astrocytic coverage of blood vessels, that was significantly increased by ECS. ECS significantly increased expression of AQP4 and claudin-5 in Gunn rats. Conclusions ECS increased the reduced coverage of blood vessels by astrocytic endfeet in the mPFC and hippocampus with amelioration of depressive-like behavior. Therefore, therapeutic mechanism of ECT may involve restoration of the impaired gliovascular units by increasing the astrocytic-endfoot coverage of blood vessels.

Increasing evidence suggests that infection and persistent low-grade inflammation in peripheral tissues are important pathogenic factors in major depression. Major depression is frequently comorbid with systemic inflammatory diseases/conditions such as rheumatoid arthritis, allergies of different types, multiple sclerosis, cardiovascular disease, inflammatory bowel disease, chronic liver disease, diabetes, and cancer, in which pro-inflammatory cytokines are overexpressed. A number of animal studies demonstrate that systemic inflammation induced by peripheral administration of lipopolysaccharide increases the expression of pro-inflammatory cytokines in both the periphery and brain and causes abnormal behavior similar to major depression. Systemic inflammation can cause an increase in CNS levels of pro-inflammatory cytokines associated with glial activation, namely, neuroinflammation, through several postulated pathways. Such neuroinflammation can in turn induce depressive moods and behavioral changes by affecting brain functions relevant to major depression, especially neurotransmitter metabolism. Although various clinical studies imply a causal relationship between periodontitis, which is one of the most common chronic inflammatory disorders in adults, and major depression, the notion that periodontitis is a risk factor for major depression is still unproven. Additional population-based cohort studies or prospective clinical studies on the relationship between periodontitis and major depression are needed to substantiate the causal link of periodontitis to major depression. If such a link is established, periodontitis may be a modifiable risk factor for major depression by simple preventive oral treatment.

The authors present the case of a 38-year-old man with schizophrenia and with severe insomnia, who attempted suicide twice during oral drug therapy with risperidone. The patient slept barely 2 or 3 h per night, and he frequently took half days off from work due to excessive daytime sleepiness. As a maladaptive behavior to insomnia, he progressively spent more time lying in bed without sleeping, and he repeatedly thought about his memories, which were reconstructed from his hallucinations. His relatives and friends frequently noticed that his memories were not correct. Consequently, the patient did not trust his memory, and he began to think that the hallucinations controlled his life. During his insomniac state, he did not take antipsychotic drugs regularly because of his irregular meal schedule due to his excessive daytime sleepiness. The authors started cognitive behavioral therapy for insomnia (CBT-i) with aripiprazole long acting injection (LAI). CBT-i is needed to be tailored to the patient's specific problems, as this case showed that the patient maladaptively use chlorpromazine as a painkiller, and he exercised in the middle of the night because he believed he can fall asleep soon after the exercise. During his CBT-i course, he learned how to evaluate and control his sleep. The patient, who originally wanted to be short sleeper, began to understand that adequate amounts of sleep would contribute to his quality of life. He finally stopped taking chlorpromazine and benzodiazepine as sleeping drugs while taking suvorexant 20 mg. Through CBT-i, he came to understand that poor sleep worsened his hallucinations, and consequently made his life miserable. He understood that good sleep eased his hallucinations, ameliorated his daytime sleepiness and improved his concentration during working hours. Thus, he was able to improve his self-esteem and self-efficacy by controlling his sleep. In this case report, the authors suggest that CBT-i can be an effective therapy for schizophrenia patients with insomnia to the same extent of other psychiatric and non-psychiatric patients.

POEMS syndrome is often complicated by pulmonary hypertension. The standard therapy for patients with POEMS syndrome is high-dose chemotherapy followed by autologous stem cell transplantation. However, the safety of high-dose chemotherapy for patients complicated with pulmonary hypertension remains unclear, and the optimal therapy for these patients is yet to be establishment. Herein, we report the case of a 54-year-old woman with POEMS syndrome accompanied by pulmonary hypertension. We successfully and safely performed lenalidomide and dexamethasone (Ld) therapy followed by high-dose chemotherapy and autologous stem cell transplantation, which improved her pulmonary hypertension. Thus, Ld can be considered as safe and effective for pulmonary hypertension with POEMS syndrome.

Introduction: Recent studies imply that glial activation plays a role in the pathogenesis of psychiatric disorders, such as schizophrenia and major depression. We previously demonstrated that Gunn rats with hyperbilirubinemia show congenital gliosis and schizophrenia-like behavior. Methods: As it has been suggested that major depression involves glial activation associated with neuroinflammation, we examined whether Gunn rats show depression-like behavior using the forced swimming test (FST) and the tail suspension test (TST). In addition, we quantitatively evaluated both microgliosis and astrogliosis in the hippocampus of Gunn rats using immunohistochemistry analysis of the microglial marker ionized calcium-binding adaptor molecule (Iba) 1 and the astrocytic marker S100B. Results: Both the FST and TST showed that immobility time of Gunn rats was significantly longer than that of normal control Wistar rats, indicating that Gunn rats are somewhat helpless, a sign of depression-like behavior. In the quantification of immunohistochemical analysis, Iba1immunoreactivity in the dentate gyrus (DG), cornu ammonis (CA) 1, and CA3 and the number of Iba1-positive cells in the CA1 and CA3 were significantly increased in Gunn rats compared to Wistar rats. S100B immunoreactivity in the DG, CA1, and CA3 and the number of S100B-positive cells in the DG and CA3 were significantly increased in Gunn rats compared to Wistar rats. Conclusion: Our findings suggest that both microglia and astrocyte are activated in Gunn rats and their learned helplessness could be related to glial activation.

Background. Dysfunction of the autonomic nervous system (ANS) in schizophrenia has been detected by electrophysiological methods, but the underlying mechanisms remain unknown. Several studies have suggested that measuring salivary alpha-amylase activity levels is useful for evaluating the ANS activity and that sAA levels increase in schizophrenia and correlate with Brief Psychiatric Rating Scale (BPRS) scores. However, no study has examined the relationship between sAA activity levels and symptoms of schizophrenia with catatonic state. Methods. We present the case of a 59-year-old female with persistent catatonic schizophrenia treated by electroconvulsive therapy. We evaluated the ANS activity by measuring sAA activity levels before and after ECT, and we evaluated her symptoms using the BPRS and Bush–Francis Catatonia Rating Scale (BFCRS). Results. ECT was highly effective and BPRS and BFCRS scores substantially decreased. sAA activity levels decreased from 125 kU/l to 33 kU/l. Conclusions. sAA activity levels could be a potential biomarker of schizophrenia with catatonic state.

Objective: In this study, we evaluated the long- term effects of memantine on cognitive function, BPSD, and the care burden in patients with moderate to severe Alzheimer’s disease (AD) for 72 weeks. Further, we examined the association between the long-term effects of memantine and brain blood flow using near-infrared spectroscopy (NIRS). Methods: We evaluated the effects of memantine administration from baseline using the Clinical Global Impression - Improvement scale (CGI-I) , Mini-Mental State Examination (MMSE), Clock Drawing Test (CDT), Neuropsychiatric Inventory (NPI), Japanese version of the Zarit Burden Interview (J-ZBI), and NIRS on two groups; a combined donepezil and memantine administration group (combination group, n=19), and donepezil only administration group (control group, n=18) were assessed at weeks 0, 4, 12, 24, 48 and 72. Results: A significant difference was found between the combination group and the control group in the scores of CGI-I after 4 weeks, CDT after 24 weeks, and NPI and J-ZBI after 12 weeks. A significant correlation was observed between the irritability subscore of NPI and total score of J-ZBI. In the NIRS measurements, there was no significant interaction in total value of Oxy- Hb integral from of all channels at the 72nd week, although oxyhemoglobin suppression was observed in CH5, CH7, and CH8 at 12th and 24th week. Conclusions: In this study, long-term administration of memantine to AD patients improved clinical symptoms overall, cognitive function, and BPSD, thereby reducing the burden of caregivers and inhibited transiently the reduction of cerebral blood flow in the prefrontal area.

Adult T-cell leukemia/lymphoma (ATL) is caused by human T-lymphotrophic virus type 1 infection and is one of the most refractory malignant T-cell lymphomas. Improvement of ATL therapy options requires the establishment of appropriate ATL animal models. In this study, we successfully generated an ATL mouse model by xenotransplantation of primary peripheral blood mononuclear cells (PBMCs) isolated from ATL patients (ATL cells) into nonobese diabetic/severe combined immunodeficiency/ Jak3 -null mice (NOJ mice). To generate the model, the ATL S1T cell line was subcutaneously injected into mice. Primary ATL cells were then transplanted subcutaneously, intraperitoneally, or intravenously. ATL cells infiltrated multiple organs, and elevated human soluble interleukin 2 receptor (IL-2R) levels were detected in peripheral blood. Injection of one million primary ATL cells was needed for successful engraftment into host mice. Thawed cells, frozen long-term in liquid nitrogen, could also be transplanted; however, more cells were required to achieve similar results. The median mouse survival time was proportional to the number of cells injected. Successful secondary transplantation of ATL cells from one NOJ mouse into another was achieved and confirmed by T-cell receptor analysis. Finally, we examined the effects of the antioxide pyrrolidine dithiocarbamate (PDTC) as an antitumor agent in vivo. PDTC administration inhibited the increase of soluble IL-2R and improved mouse survival, suggesting that this compound has potential as an anti-ATL agent. We demonstrated that ATL cells could be stably xenotransplanted into NOJ mice using primary cells. This model will be useful in the establishment of novel therapies to treat ATL.

Aims Previous studies have supported the claim that psychological stress induces the production of reactive oxygen species. Several authors have suggested that patients with psychiatric disorders show high levels of oxidative stress markers. We examined different oxidative stress markers in patients with chronic schizophrenia. Methods This study included 29 patients with chronic schizophrenia and 30 healthy volunteers. The concentration of urinary biopyrrins and 8-hydroxydeoxyguanosine (8-OHdG), as measured by enzyme-linked immunosorbent assay, were normalized to the urinary concentration of creatinine. Psychiatric symptoms were assessed by the administration of the Brief Psychiatric Rating Scale (BPRS). Results The concentration of biopyrrins in patients with chronic schizophrenia was significantly higher when compared with healthy volunteers. The correlation between biopyrrin level and the duration of illness was highly significant. There were no significant differences in the levels of urinary 8-OHdG between the two groups. In schizophrenic patients, the level of urinary biopyrrins showed correlations with BPRS scores, while the level of urinary 8-OHdG did not show correlations with BPRS. Conclusions Urinary biopyrrins are increased in patients with chronic schizophrenia while urinary 8-OHdG is not increased. These findings suggest that patients with chronic schizophrenia are under the condition of certain oxidative stresses.

Adult T cell leukemia/lymphoma (ATL) is an aggressive peripheral T cell neoplasm with very poor prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) has been reported as a curative treatment modality for ATL. However, there are no reports comparing chemotherapy alone with allo-HSCT in ATL. In this report, we retrospectively analyzed data for patients treated with (n = 29, median age 55 years) or without allo-HSCT (n = 37, median age 58 years) for ATL in Kagoshima University Hospital, located in one of the most endemic areas of human T cell lymphotropic leukemia virus type 1 infection. Forty patients (61%) started coordination for allo-HSCT. Ten patients (34.4%) received allo-HSCT while in complete remission (CR), whereas the others were not in CR. Twenty-five patients (86.2%) received reduced-intensity conditioning, and the others received myeloablative conditioning. With a median follow-up period for survivors of 41 months (range, 5 to 125 months), the 3-year overall survival (OS) rate from first chemotherapy for all patients (with or without allo-HSCT) was 35.2%. The 3-year OS from first chemotherapy for patients who received allo-HSCT or only chemotherapy was 44.9% and 27.7%, respectively. Univariate analyses revealed that high serum soluble IL-2 receptor (sIL-2R) levels (≥2000 U/mL) just before the conditioning regimen and progressive disease (PD) status at HSCT (according to Japan Clinical Oncology Group Study 0907 criteria) were significant risk factors for OS in the allo-HSCT group. Multivariate analyses revealed that PD status was a significant risk factor for OS in the allo-HSCT group. In the chemotherapy-only group, the 3-year OS rate was 61.5% (95% CI, 30.8% to 81.8%) in patients with serum sIL-2R levels < 2000 U/mL for >3 months. In contrast, the 3-year OS rate was 5.7% (95% CI, .4% to 22.4%) in patients who did not achieve serum sIL-2R levels < 2000 U/mL for >3 months. Our single-center cohort experience indicates that chemosensitivity is the most important prognostic factor for OS in ATL patients and the use of allo-HSCT is limited in chemorefractory patients with aggressive ATL disease. In the chemosensitive patients, allo-HSCT demonstrated a tendency toward better OS. Further clinical studies are warranted to determine optimal treatments for patients who are less sensitive to conventional chemotherapy.

ALD, which is the X-linked adrenoleukodystrophy (X-ALD), is a rare inherited metabolic disease caused by an enzyme deficiency leading to accumulation of saturated very long chain fatty acid (VLCFA), especially in brain and adrenal cortex. Its prevalence is currently estimated at 1:30,000 to 50,000 in males in Japan. We report a 34-year-old man, who acts of theft, peep and obscenity with adult onset cerebral adrenoleukodystrophy (ALD). An elevated VLCFA and a point mutation in the ABCD1 gene confirmed the diagnosis of ALD. Diffusion-weighted MRI revealed a high intensity area in the white matter of the frontal lobes. T2-weighted image revealed diffuse high signal intensity in the deep white matter. MR diffusion-weighted image revealed high signal intensity area in the white matter of the frontal lobes. Proton magnetic resonance spectroscopy (H-MRS) of the white matter of the frontal lobes revealed an extreme decrease of N-acetylaspartate (NAA) and an increase of the choline (Cho)/creatinine (Cr) ratio. The mild hypoperfusion was detected in the both cerebral hemispheres by the single photon emission CT (SPECT). The genetic phenotype was detected and he was diagnosed adult onset ALD. The only neurological sign was deviant behaviors as frontal lobe symptoms; despite a diffuse high signal intensity was detected in the deep white matter in the MRI examination. Psychiatric symptomatology is presented and may be one of the earliest manifestations of ALD. Psychiatrists as well as and physicians may encounter ALD.

The authors present the case of a 24-year-old male with treatment-resistant schizophrenia, with predominant severe delusion and hallucination, who received bone marrow transplantation (BMT) for acute myeloid leukemia (AML). After BMT, he showed a remarkable reduction in psychotic symptoms without administration of neuroleptics. He also showed drastic improvement in social functioning. Follow-up evaluations two and four years after BMT showed persistent significant improvement of the psychotic state and social functioning. Recent findings show that the major underlying pathogenic mechanism of schizophrenia is immune dysregulation. Thus, conceptually, BMT, a cellular therapy, that facilitates the counteractive processes of balancing inflammation by immune regulation, could produce beneficial clinical effects in patients with treatment-resistant schizophrenia. Further studies are required to define the true benefits of BMT for the possible curative treatment of schizophrenia.

Emerging evidence indicates that the kynurenine pathway (KP) contributes to neurodegenerative diseases associated with glial activation. Interferon (IFN)-γ is a potent activator of indole-2,3-dioxygenase, the first and rate-limiting enzyme of the KP. Our previous studies have shown that adult human astrocytes become neurotoxic when activated by IFN-γ. We now used high performance liquid chromatographymass spectrometry in both the positive- and negative- ionization mode of electrospray interface, to examine whether the IFN-γ-activated adult human astrocytes secrete neurotoxic KP metabolites, such as quinolinic acid (QUIN), 3-hydroxykynurenine (3-HK) and 3-hydroxyanthranilic acid (3-HAA). Kynurenine was detected in cell culture supernatants of IFN-γ-stimulated astrocytes, but not in supernatants of unstimulated astrocytes. On the other hand, QUIN, 3-HK and 3-HAA were not detected in samples from either IFN-γ- stimulated or unstimulated cells. These results indicate that the KP may not be involved in the IFN-γ-induced neurotoxicity of adult human astrocytes. Therefore, neurotoxins other than KP metabolites could be responsible for the IFN-γ-induced astrocyte neurotoxicity.

Introduction: Mogamulizumab (Mog) is an anti-CCR4 (C-C motif chemokine receptor 4) antibody, which induce antibody dependent cellular cytotoxicity against cells expressing CCR4. Administration of Mog before allogeneic hematopoietic stem cell transplantation (allo-HSCT) for patients with adult T-cell leukemia/lymphoma (ATL) is considered to raise the risk of graft versus host disease (GVHD). Since not only ATL cells but regulatory T cells (Tregs) express CCR4, both are targeted by Mog. Tregs play a crucial role in maintaining and suppressing excessive immune responses especially in GVHD, and the depletion of Tregs by Mog is considered to result in the progression of GVHD. The aim of this study is to elucidate the characteristics of GVHD observed in patients treated by Mog, and further tried to predict the risk of GVHD by incorporating the information of serum concentration of Mog, the number of Tregs, and the alteration in Treg fractions (naïve/resting Treg; nTreg, effector Treg; eTreg). Patients and Methods: In this study, we analyzed 25 ATL patients who received allo-HSCT. The serum concentration of Mog was measured by SRL Medisearch (Tokyo, Japan). The fraction of Tregs in peripheral blood mononuclear cells (PBMNCs) were analyzed by flow cytometry (BD FACSCalibur, BD biosciences). Statistical analysis (the cumulative incidence of Grade II-IV GVHD and the number of Tregs) were performed with EZR (Easy R) software (Jichi Medical University, Saitama, Japan). Results: In comparison to allo-HSCT without Mog (Mog-, n=14), the risk of Grade II-IV GVHD was increased in the allo-HSCT with Mog (Mog+, n=11). Stage 3 or more skin GVHD was observed in 4 patients of Mog+ (36 %) and 1 patient of Mog- (7 %), respectively. Notably, stage 3 or more gut GVHD was observed in 6 patients of Mog+ (54 %), and 4 patients died with GVHD or infectious complications, whereas 3 Mog- (21 %) experienced non-fatal gut GVHD. Moreover, cytomegalovirus enteritis was observed only in the Mog+ cases. Mog was detectable in serum for approximately 6 months after the last administration (cut off level; 5.0 ng/ml), and the number of Tregs, especially eTreg (Foxp3 high, CD45RA low) was continuously suppressed during this period. In the Mog+ case, the number of eTregs recovered 180 days after allo-HSCT in most cases. Among 7 patients who received Mog before allo-HSCT, 5 patients who developed gut GVHD were performed allo-HSCT on average 52 (19-87) days after the last administration of Mog. The serum level of Mog was 100-1000 ng/ml in the period, and this concentration of Mog was considered to be critical for the onset of severe GVHD. Conclusion: Use of mogamulizumab before allo-HSCT for ATL patient is a significant risk for severe GVHD, especially gut GVHD. Although the number of patients in this study is limited, our results suggest that the serum concentration of mogamulizumab (≥10 ng/ml) and the number of eTregs in PB at the time of allo-HSCT may enable to predict the risk of developing GVHD. Disclosures Yoshimitsu: Sanofi: Speakers Bureau; Chugai: Speakers Bureau; Takeda: Speakers Bureau; Bristol-Myer-Squibb,: Speakers Bureau; Shire: Speakers Bureau; Novartis: Speakers Bureau. Ishitsuka:Daiichi Sankyo: Consultancy, Honoraria; Alexion: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria; Eisai: Honoraria, Research Funding; MSD: Research Funding; Asahi kasei: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; mundiharma: Honoraria; MSD: Research Funding; Celgene: Honoraria; Shire: Honoraria; Mochida: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria, Research Funding; Eli Lilly: Research Funding; Genzyme: Honoraria; sanofi: Honoraria; Bristol-Myers Squibb: Honoraria; sanofi: Honoraria; Chugai Pharmaceutical: Honoraria, Research Funding; Genzyme: Honoraria; Alexion: Honoraria; Takeda Pharmaceutical: Honoraria, Research Funding; Sumitomo Dainippon Pharma: Honoraria, Research Funding; mundiharma: Honoraria; Eisai: Honoraria, Research Funding; Taiho Pharmaceutical: Honoraria, Research Funding; Mochida: Honoraria, Research Funding; Janssen Pharmaceutical: Honoraria; Shire: Honoraria; Otsuka Pharmaceutical: Honoraria; Novartis: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Teijin Pharma: Research Funding; Pfizer: Honoraria; Yakult: Research Funding; Astellas Pharma: Honoraria, Research Funding; Asahi kasei: Research Funding; Eli Lilly: Research Funding; Janssen Pharmaceutical: Honoraria; Celgene: Honoraria; Teijin Pharma: Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Taiho Pharmaceutical: Honoraria, Research Funding; Yakult: Research Funding.

Increasing evidence implies a possible causal link between periodontitis and neuropsychiatric disorders, such as Alzheimer’s disease (AD) and major depression (MD). A possible mechanism underlying such a link can be explained by neuroinflammation induced by chronic systemic inflammation. This review article focuses on an overview of the biological and epidemiological evidence for a feasible causal link of periodontitis to neuropsychiatric disorders, including AD, MD, Parkinson’s disease, and schizophrenia, as well as the neurological event, ischemic stroke. If there is such a link, a broad spectrum of neuropsychiatric disorders associated with neuroinflammation could be preventable and modifiable by simple daily dealings for oral hygiene. However, the notion that periodontitis is a risk factor for neuropsychiatric disorders remains to be effectively substantiated.

Aceruloplasminemia is an autosomal recessive disorder of iron metabolism caused by mutations in the ceruloplasmin gene. Its prevalence is 1 in 2,000,000 people in Japan. This is a disorder of neurodegeneration with iron accumulation in the brain revealed by MRI. The iron overload induces oxidative stress and generation of reactive oxygen species, which triggers a cascade of pathological events that lead to neuronal death. Intravenous administration of an iron chelator, deferoxamine has been proposed as a method of inhibiting the accumulation of iron. The patient was a 46-year-old Japanese woman. She was diagnosed at the age of 33 years. Deferoxamine was administrated for 6 months but was discontinued due to adverse effects. On admission at the age of 46, psychomotor excitement was acute in onset. The extrapyramidal symptoms reflected iron deposition in the basal ganglia and substantia nigra in the midbrain. Ataxia and a wide-based gate reflected iron deposition in the dentate nuclei of the cerebellum. An antibiotic, minocycline at 150 mg/day successfully ameliorated the clinical symptoms. Minocycline, a second generation tetracycline, has a direct radical scavenging property due to its chemical structure. It has been reported that minocycline is similar to deferoxamine in its ability to chelate iron. Minocycline is also involved in preventing the upregulation of proinflammatory cytokines. The iron-chelating, antioxidant, and anti-inflammatory effects of minocycline were involved in this case.

Background Patients with schizophrenia show a significantly higher frequency of hyperbilirubinemia than patients suffering from other psychiatric disorders and the general healthy population. We examined the hyperbilirubinemia on behavioral and neuropathological changes in rats as a possible animal model of schizophrenia. Methods Gunn rats with severe hyperbilirubinemia (j/j), Gunn rats without severe hyperbilirubinemia (+/j), and Wistar rats were examined by open-field, social interaction, and prepulse inhibition tests. TUNEL, AgNOR and Ki-67 were also assayed on paraffin-embedded brain sections of these rats. Results Compared to Wistar rats, both Gunn j/j and +/j rats showed hyperlocomotion, high sniffing scores, and low defecation scores. They showed significantly more aggressive behaviors and impaired prepulse inhibition. The numbers of Ki-67-labeled cells and AgNOR were lower and the number of TUNEL-positive cells was higher than that of Wistar rats. Conclusions These results might support the neurodevelopmental hypothesis of schizophrenia. Both Gunn j/j and +/j rats may be a useful animal model and provide clues to the role of hyperbilirubinemia in schizophrenia.

Minocycline is a caspase inhibitor, decreases inducible nitric oxide synthase, and has been shown to delay disease in a mouse model of neuropsychiatric disorders. Recently, we reported the antipsychotic effects of minocycline in patients with schizophrenia. In a pilot investigation, we administered minocycline (150 mg/d) for 4 weeks as an open-label adjunct to antipsychotic medication to 22 patients with schizophrenia. The Positive and Negative Syndrome Scale for schizophrenia showed statistically significant and robust clinical improvements with minocycline treatment, which were maintained at follow-up evaluation 4 weeks after the end of minocycline treatment. There were no adverse events. These results suggest that minocycline may be a safe and effective adjunct to antipsychotic medications, and that augmentation with minocycline may prove to be a viable strategy for "boosting" antipsychotic efficacy and for treating schizophrenia.

During periods of psychological stress, excess amounts of free radicals are produced, and they play an important role in the pathophysiological process. Bilirubin oxidative metabolites, biopyrrins, are generated from bilirubin as a result of this scavenging action against free radicals. We investigated whether the urinary excretion of biopyrrin is altered during the psychotic state in patients with schizophrenia. Biopyrrin concentrations in urine of 15 patients with schizophrenia and 100 age-matched healthy subjects were measured by enzyme-linked immunosorbent assay with an anti-bilirubin antibody. Urine samples were obtained from the patients on first admission (acute state), 1 month after admission (sub-acute state), and on discharge (remission state). Urinary concentrations of biopyrrins in patients with schizophrenia on admission were significantly higher than those in the controls. Response to treatment was associated with a significant decrease in the concentrations of biopyrrins. Moreover, urinary concentrations of biopyrrins were still significantly higher in patients with schizophrenia in the sub-acute and remission states than in the controls. These results demonstrated an increase in urinary biopyrrins in patients with schizophrenia and a decrease with recovery from the psychotic state. These findings indicate that the urinary biopyrrin level is a possible indicator that can be useful in the continuous monitoring of psychotic states in clinical practice.

Selective mono-deallylation of O,O'-diallylcatechols using 10% Pd/C was investigated to give the correspond-ing allylphenols. A similar reaction of 3-methylene-1,5-benzodioxepanes afforded O-methacryl catecohols. When substrates bearing various substituents on the benzene ring were subjected to the reaction, regioselective cleavage of an ether bond occurred at the side of para position to an electron-withdrawing group on the aromatic ring. On the other hand, an electron-donating group did not cause any selectivity.

ResumenAntecedentesLos pacientes con esquizofrenia muestran una frecuencia significativamente más alta de hiperbilirrubinemia que los pacientes que sufren de otros trastornos psiquiátricos y la población general sana. El objetivo del actual estudio fue determinar si los pacientes con hiperbilirrubinemia no conjugada idiopática (síndrome de Gilbert, SG) asociada a la esquizofrenia tienen cambios especificos en las intensidades de señal en imagénes de resonancia magnética (RM) de inversión-recuperación con atenuación de fluido (FLAIR).MétodosSe comparó imágenes de RM FLAIR axiales de 5 mm de grosor de pacientes de esquizofrenia con SG (n = 18) y pacientes de esquizofrenia sin SG (n = 18), diagnosticados todos ellos según los criterios del DSM-IV, con controles no psiquiátricos emparejados por la edad y el sexo (n = 18). Se graduaron las intensidades de señal en el hipocampo, la amígdala, el caudado, el putamen, el tálamo, el giro cingulado y la ínsula en relación con la intensidad de la señal cortical en el lóbulo frontal.ResultadosComparado con los pacientes de esquizofrenia sin SG y los controles normales, los pacientes de esquizofrenia con SG mostraron aumentos significativos de la intensidad de señal en casi todas las regiones estudiadas.ConclusiónLos pacientes con SG asociado a esquizofrenia tienen cambios específicos de las intensidades de señal en las imágenes de RM FLAIR, indicando que la esquizofrenia con SG produce cambios en la corteza frontotemporal, el sistema límbico y los ganglios basales.

Allyl aryl ethers can be easily cleaved by the use of 10% Pd/C under mild and basic conditions. The present reaction would involve a SET process rather than a π-allyl-palladium complex. The scope and limitation of this new deprotective methodology is also described.