Chronic Ileum Obstruction, Granulation, and Ulceration With IgG4-Positive Plasma Cell Infiltration in a Six-Year-Old Girl With 21trisomy.

Patients with 21trisomy often develop congenital or acquired gastrointestinal diseases, such as duodenal or anal atresia, celiac disease, intussusception, and constipation. In these patients, it is often challenging to diagnose gastrointestinal diseases because most patients have difficulty explaining their complaints in detail. Furthermore, these patients also possess immunological disorders, such as increased type I interferon activation, innate immune hypersensitivity, and polarization to autoimmune. Here, we present a girl with 21trisomy and constipation who developed severe anemia, occult blood and elevated levels of calprotectin in stool, and chronic ileum obstruction confirmed by computed tomography. The patient underwent surgical resection of the ileum and recovered without complications. Pathological examination demonstrated intussusception, ischemia, ulceration, inflammatory granulation, and massive IgG4-positive plasma cell infiltration. After the surgery, her fecal calprotectin levels were normalized. We assumed that the ileum inflammation caused by ileum dilation generated ulcers and granulation, which could be associated with immunological, gastrointestinal, and intellectual disorders in patients with 21trisomy.

Discovery and SAR of JTE-151: A Novel RORγ Inhibitor for Clinical Development.

A number of RORγ inhibitors have been reported over the past decade. There were also several examples advancing to human clinical trials, however, none of them has reached the market yet, suggesting that there could be common obstacles for their future development. As was expected from the general homology of nuclear receptor ligands, insufficient selectivity as well as poor physicochemical properties were identified as potential risks for a RORγ program. Based on such considerations, we conducted a SAR investigation by prioritizing drug-like properties to mitigate such potential drawbacks. After an intensive SAR exploration with strong emphasis on "drug-likeness" indices, an orally available RORγ inhibitor, JTE-151, was finally generated and was advanced to a human clinical trial. The compound was confirmed to possess highly selective profiles along with good metabolic stability, and most beneficially, no serious adverse events (SAE) and good PK profiles were observed in the human clinical trial.

Status of school health programs in Asia: National policy and implementation.

BACKGROUND: The WHO's Health Promoting Schools (HPS) framework is based on an understanding of the reciprocal relationship between health and education, and the need to take a holistic approach to health promotion in schools. We aim to clarify the degree to which the HPS framework is reflected in the national policies of eight target countries and the issues surrounding its successful implementation. METHODS: Date were collected through two expert workshops with participants from eight Asian countries: Cambodia, China, Japan, Korea, Lao PDR, Nepal, the Philippines, and Thailand. In the first workshop, data collected on national policy were mapped against the HPS framework. From this, key issues were identified, and follow-up data collection was conducted in each country for a second workshop. RESULTS: We identified a policy shift toward the HPS framework in six out of the eight countries. Neither Japan nor Korea had changed their national policy frameworks to reflect an HPS approach; however, in the latter, model programs had been introduced at a local level. We identified various barriers to successful implementation, especially in relation to mental health and wellbeing. CONCLUSION: Given the recent shift toward the HPS approach in six out of the eight countries in this study, there is a need to conduct research to assess the impact of this framework on the health and wellbeing of students and school staff. At the same time, we call for more dialog in the context of Japan to explore the possible benefits of introducing the HPS framework into schools.

The effects of cumulative antipsychotic dose on brain structures in patients with schizophrenia: Observational study of multiple CT scans over a long-term clinical course.

Multiple lines of evidence indicate that antipsychotic agents could affect brain structures of schizophrenia patients. However, the effect of antipsychotic dosage or type on brain structure is uncertain. The present study retrospectively analyzed brain computed tomography (CT) images from a psychiatric hospital to examine the relationship between cumulative dose of antipsychotics and brain volume reduction in schizophrenia patients. A total of 43 patients with repeated relapse episode of psychosis were included and CT scans that were performed an average of 3.2 times per patient during nearly 13 years of follow-up were analyzed. The results revealed significant positive relationships of expansion of cerebrospinal fluid space with cumulative dosage of all antipsychotics and that of typical antipsychotics. Patients treated with antipsychotics including typical antipsychotics exhibited a greater volume reduction compared to patients treated with only atypical antipsychotics. The present study was one of the longest longitudinal studies examining the effects of antipsychotics on brain volume in schizophrenia patients. These results suggest a relation between cumulative lifetime antipsychotic dosage and progressive brain volume reduction in patients with schizophrenia. However, the effects of specific agent on brain structure are still uncertain, and more detailed analysis is needed.

SAR study of small molecule inhibitors of the programmed cell death-1/programmed cell death-ligand 1 interaction.

The development of small molecule inhibitors of programmed cell death-1/programmed cell death-ligand 1 (PD-1/PD-L1) has drawn research interest for the treatment of cancer. Recently, we reported the discovery of a novel dimeric core small molecule PD-1/PD-L1 inhibitor. In an effort to discover more potent inhibitors, we further explored the dimeric core scaffold. Our investigations of the structure-activity-relationship revealed that introduction of lipophilic substituents onto one of the di-alkoxylated phenyl rings improved binding affinities to PD-L1, and inhibitory activities of PD-1/PD-L1 in cellular assays. Furthermore, conversion of the ether linker part to an olefin linker not only improved binding affinity but also led to slow dissociation binding kinetics. We also explored more potent, as well as downsized, scaffolds. Compounds bearing a linear chain in place of one of the di-alkoxylated phenyl rings exhibited good binding affinity with improved ligand efficiency (LE). Representative compounds demonstrated potent inhibitory activities of PD-1/PD-L1 in the submicromolar range in cellular assays as well as cellular function in the mixed lymphocyte reaction (MLR) assay with efficacy comparable to anti-PD-1 antibody. Our results provide applicable information for the design of more potent inhibitors targeting PD-1/PD-L1 pathway.

First Report of Fatal Infection Caused by Community-acquired Methicillin-resistant Staphylococcus aureus USA300 Clone in a Collegiate Athlete.

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is prevalent around the world and is a causative agent of skin and soft tissue infections in healthy individuals. Particularly, Panton-Valentine leukocidin (PVL)-positive CA-MRSA strains occasionally cause life-threatening infections, such as septic pulmonary emboli (SPE) and infectious endocarditis. However, severe infections caused by PVL-positive CA-MRSA strains have rarely been reported in Japan. For the first time, this study reports the case of a 20-year-old Japanese college athlete with life-threatening PVL-positive CA-MRSA USA300 clone infection, including sepsis, SPE, and skin and soft tissue infections with iliofemoral deep venous thrombosis.

The effectiveness of very slow switching to aripiprazole in schizophrenia patients with dopamine supersensitivity psychosis: a case series from an open study.

Dopamine supersensitivity psychosis (DSP) in patients with schizophrenia is induced by treatment with a high dosage of antipsychotics for a long time period, and it is characterized by unstable psychotic symptoms. The upregulation of dopamine D2 receptor (DRD2) provoked by antipsychotics underlies DSP. Aripiprazole does not cause an excessive blockade of DRD2 and is less likely to upregulate DRD2 by aripiprazole's dopamine partial agonistic profile. Aripiprazole; however, has a potential risk of inducing severe rebound psychosis in patients who have already developed dopamine supersensitivity. Recently, an animal model study suggested that aripiprazole could attenuate established dopamine supersensitivity. The present study was conducted to examine whether very slowly switching to aripiprazole could help patients with schizophrenia with dopamine supersensitivity while avoiding rebound psychosis. This study was a single-armed and open-labeled study in which patients were observed over a period of 2 years. Only 11 patients were ultimately recruited. Five patients were successfully switched to a sufficient dose of aripiprazole and completed the study protocol. These five patients did not present with severe DSP over the study period, but only one patient showed a large improvement in psychopathology. Five patients dropped out of the study, and one of these five showed a severe worsening of psychosis. The present study indicated that the introduction of aripiprazole in patients with DSP was difficult, but suggested that aripiprazole could contribute to attaining a stable state in psychosis if it was applied with careful observation.

A risk as an infection route: Nasal colonization of methicillin-resistant Staphylococcus aureus USA300 clone among contact sport athletes in Japan.

Panton-Valentine leukocidin (PVL)-positive USA300 clone is a highly pathogenic and global epidemic community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) clone. Athletes are particularly vulnerable to CA-MRSA infection because of the frequency of skin trauma, close-contact situations, and sharing of equipment that is customary in the athletic setting. We experienced a case of Japanese collegiate football player with septic pulmonary emboli secondary to infectious iliofemoral deep venous thrombosis caused by the USA300 clone. Here, we screened the nasal carriage of USA300 clone colonization among asymptomatic teammate of the patient to elucidate the infection route. Among 69 nasal samples, CA-MRSA strains were found in 5.8% (four samples). Molecular epidemiological analyses showed that three of the CA-MRSA strains were USA300 clone. Furthermore, pulsed-field gel electrophoresis revealed that all nasal USA300 clones showed 100% identity with the USA300 clone isolated from their teammate with critical infection. Our findings indicate that nasal colonization of the PVL-positive CA-MRSA, especially USA300 clone, pose a threat among contact sport athletes in Japan likewise other countries. An immediate infection control strategy for contact sport athletes is necessary to prevent outbreaks of PVL-positive CA-MRSA infections.

Discovery of a Janus Kinase Inhibitor Bearing a Highly Three-Dimensional Spiro Scaffold: JTE-052 (Delgocitinib) as a New Dermatological Agent to Treat Inflammatory Skin Disorders.

Dermatologic disorders such as atopic dermatitis arise from genetic and environmental causes and are complex and multifactorial in nature. Among possible risk factors, aberrant immunological reactions are one of the leading etiologies. Immunosuppressive agents including topical steroids are common treatments for these disorders. Despite their reliability in clinical settings, topical steroids display side effects, typified by skin thinning. Accordingly, there is a need for alternate effective and well-tolerated therapies. As part of our efforts to investigate new immunomodulators, we have developed a series of JAK inhibitors, which incorporate novel three-dimensional spiro motifs and unexpectedly possess both excellent physicochemical properties and antidermatitis efficacy in the animal models. One of these compounds, JTE-052 (ent-60), also known as delgocitinib, has been shown to be effective and well-tolerated in human clinical trials and has recently been approved in Japan for the treatment of atopic dermatitis as the first drug among Janus kinase inhibitors.

Symmetry-based ligand design and evaluation of small molecule inhibitors of programmed cell death-1/programmed death-ligand 1 interaction.

The development of small molecule inhibitors of PD-1/PD-L1 is eagerly anticipated for treatment of cancer. We focused on the symmetry of the ternary complex structure of reported small molecule ligands and hPD-L1 homodimers, and designed partially- or fully-symmetric compounds for more potent inhibitors. The design of the new compounds was guided by our hypothesis that the designed symmetric compound would induce a flip of sidechain of ATyr56 protein residue to form a new cavity. The designed compound 4 exhibited substantially increased binding affinity to hPD-L1, as well as PD-1/PD-L1 inhibitory activity in physiological conditions. Compound 4 also showed a dose-dependent increase in IFN-γ secretion levels in a mixed lymphocyte reaction assay. These results not only indicate the feasibility of targeting the PD-1/PD-L1 pathway with small molecules, but illustrate the applicability of the symmetry-based ligand design as an attractive methodology for targeting protein-protein interaction stabilizers.

Intracranial Hemorrhaging Following Cardiobacterium hominis Endocarditis.

Acute infectious endocarditis (IE) is a complex disease that presents as a serious clinical condition associated with a high mortality rate, especially due to intracranial hemorrhaging (ICH). The most common causative organism is Staphylococcus aureus. We herein report a patient with ICH following subacute IE with a positive blood culture for Cardiobacterium hominis. A review of the existing literature revealed that acute IE associated with Cardiobacterium has been reported to cause ICH in only seven previous cases. Prolonged culture-specific antibiotic therapy along with extended surveillance of blood culture is therefore essential for timely intervention.

First-episode psychosis in treatment-resistant schizophrenia: a cross-sectional study of a long-term follow-up cohort.

BACKGROUND: Approximately one-third of schizophrenia patients eventually develop treatment-resistant schizophrenia (TRS). Although the time course of TRS development varies from patient to patient, the details of these variations have not been clarified. The present study compared the duration of time required to achieve control of the first-episode psychosis (FEP) between patients who went on to develop TRS and those who did not, in order to determine whether a bifurcation point exists for the transition to TRS. METHODS: The present study included 271 schizophrenia patients. Based on the clinical assessment, each patient was assigned to a TRS (n = 79) or Non-TRS group (n = 182). Clinical factors relating to FEP treatment such as the duration of initial hospital admission and the degree of improvement were retrospectively identified. RESULTS: There was no significant difference in the duration of initial hospital admission (defined as the time from treatment introduction to successful discharge) between the two groups (mean of 87.9 days for TRS vs. 53.3 days for Non-TRS). The degree of improvement during initial hospital admission of the TRS group was significantly lower than that of the Non-TRS group (Global Assessment of Functioning (GAF) of 50 points for TRS vs. 61 points for Non-TRS). Approximately half of the TRS patients showed an acute onset pattern and longer hospital admission (mean 169 days) for their FEP. The other half of TRS patients needed no hospital admission, indicating an insidious onset pattern with no clear psychotic episode and treatment introduction without hospital admission. CONCLUSIONS: Future TRS patients can have difficulty in improvement during their FEP. There appear to be two distinct patterns for the development of TRS. One pattern is characterized by refractory positive symptoms and a longer period to control the first psychosis; the other shows latent or insidious onset and poor response to the initial treatment.

Identifying improvable employment-related factors in schizophrenia patients.

Although many studies report various factors related to future employment of schizophrenia patients, few identify the treatable or improvable ones. The responses to the first year of treatment and daily antipsychotic drug doses may be the treatable and improvable factors. We surveyed 235 schizophrenia outpatients in three facilities, of whom 129 and 106 were employed and unemployed, respectively. Through face-to-face interviews and medical record reviews, we investigated symptomatic and social functioning responses to the first year of treatment using the Global Assessment of Psychopathology Scale (GAPS) and the Social and Occupational Functioning Assessment Scale (SOFAS). We investigated daily antipsychotic drug doses and other clinical assessments at the interview time. Finally, we used multivariable logistic regression analysis. SOFAS-measured improvements in the period 6 to 12 months after beginning treatment and daily antipsychotic drug doses equivalent to less than 600 mg of chlorpromazine were identified as an employment-related factor, but GAPS-measure improvements were not. Social functioning improvements in the period 6 to 12 months after beginning treatment and low-to-moderate daily antipsychotic drug doses were detected as employment-related factors, suggesting that early efforts to improve social functioning and optimize antipsychotic drug doses could lead to future employment for schizophrenia patients.

Emergency endovascular treatment of a ruptured external carotid artery pseudoaneurysm caused by a cervical stab wound: A case report and literature review.

The formation of external carotid artery (ECA) pseudoaneurysms caused by stab wounds is a rare vascular anomaly. Although the surgical exploration of the ECA segment is the standard treatment, endovascular treatment (EVT) can be considered if there is difficulty in identifying the source of bleeding in the injured regions that are difficult to operatively access. Here we treated a young patient who had hemorrhagic instability with hemorrhage-induced coagulopathy caused by a zone III cervical stab wound with a pseudoaneurysm from the main trunk of the ECA; the patient underwent EVT and successful hemostasis. A literature review based on the data available on PubMed was conducted, and 15 published reports of 82 penetrating ECA injuries treated by EVT were identified. We concluded that EVT appears to be an effective surgical alternative for patients with hemorrhage-induced coagulopathy caused by a ruptured ECA pseudoaneurysm after a cervical stab wound.

Risperidone long-acting injectable in the treatment of treatment-resistant schizophrenia with dopamine supersensitivity psychosis: Results of a 2-year prospective study, including an additional 1-year follow-up.

UNLABELLED: Dopamine supersensitivity psychosis (DSP) resulting from antipsychotic treatment is related to treatment-resistant schizophrenia (TRS), and its treatment has not been established to date. Maintaining thoroughly stable occupancy of the dopamine D2 receptor by risperidone long-acting injectable (RLAI) is one strategy for treatment. In this study, RLAI was given as an adjunctive medication to oral antipsychotic(s), which were switched partially and gradually to RLAI in 108 treatment-resistant patients for an additional 1-year follow-up in a 2-year study, and to compare the effects in 72 patients with a DSP history (DSP group) and 36 patients without this history (NonDSP group). Although both groups showed significant improvements in the total Brief Psychotic Rating Scale (BPRS) score during the follow-up period, greater improvement was observed for the DSP group than the NonDSP group. High doses (> 850 mg chlorpromazine-dose combined of oral antipsychotics and RLAI) did not significantly change in both groups throughout the study period; however, extrapyramidal symptoms, including tardive dyskinesia, were significantly improved only in the patients with DSP. This study strongly suggested that the RLAI treatment, even with only partial switching, provides relief from refractory symptoms, particularly for patients with a history of DSP. CLINICAL TRIAL REGISTRATION: http://www.umin.ac.jp/:UMIN000008487.

Resuscitative endovascular balloon occlusion of the aorta for uncontrolled haemorrahgic shock as an adjunct to haemostatic procedures in the acute care setting.

BACKGROUND: Haemorrhagic shock is a major cause of death in the acute care setting. Since 2009, our emergency department has used intra-aortic balloon occlusion (IABO) catheters for resuscitative endovascular balloon occlusion of the aorta (REBOA). METHODS: REBOA procedures were performed by one or two trained acute care physicians in the emergency room (ER) and intensive care unit (ICU). IABO catheters were positioned using ultrasonography. Collected data included clinical characteristics, haemorrhagic severity, blood cultures, metabolic values, blood transfusions, REBOA-related complications and mortality. RESULTS: Subjects comprised 25 patients (trauma, n = 16; non-trauma, n = 9) with a median age of 69 years and a median shock index of 1.4. REBOA was achieved in 22 patients, but failed in three elderly trauma patients. Systolic blood pressure significantly increased after REBOA (107 vs. 71 mmHg, p < 0.01). Five trauma patients (20 %) died in ER, and mortality rates within 24 h and 60 days were 20 % and 12 %, respectively. No REBOA-related complications were encountered. The total occlusion time of REBOA was significantly lesser in survivors than that in non-survivors (52 vs. 97 min, p < 0.01). Significantly positive correlations were found between total occlusion time of REBOA and shock index (Spearman's r = 0.6) and lactate concentration (Spearman's r = 0.7) in survivors. CONCLUSION: REBOA can be performed in ER and ICU with a high degree of technical success. Furthermore, correlations between occlusion time and initial high lactate levels and shock index may be important because prolonged occlusion is associated with a poorer outcome.

Impact of dopamine supersensitivity psychosis in treatment-resistant schizophrenia: An analysis of multi-factors predicting long-term prognosis.

BACKGROUND: Although a variety of factors are known to be significantly related to poor prognosis in schizophrenia, their interactions remain unclear. Dopamine supersensitivity psychosis (DSP) is a clinical concept related to long-term pharmacotherapy and could be one of the key factors contributing to the development of treatment-resistant schizophrenia (TRS). The present study aims to explore the effect of DSP on progression to TRS. METHODS: Two-hundreds and sixty-five patients were classified into either a TRS or Non-TRS group based on retrospective survey and direct interview. The key factors related to prognosis, including the presence or absence of DSP episodes, were extracted, and each factor was compared between the two groups. RESULTS: All parameters except for the duration of untreated psychosis (DUP) were significantly worse in the TRS group compared to the Non-TRS group. In particular, the TRS group presented with a significantly higher rate of DSP episodes than the Non-TRS group. Regression analysis supported the notion that DSP plays a pivotal role in the development of TRS. In addition, deficit syndrome was suggested to be a diagnostic subcategory of TRS. CONCLUSIONS: Our data confirmed that the key predicting factors of poor prognosis which have been established would actually affect somehow the development of TRS. In addition, the occurrence of a DSP episode during pharmacotherapy was shown to promote treatment refractoriness.

Dopamine supersensitivity psychosis as a pivotal factor in treatment-resistant schizophrenia.

There may be subtypes in treatment-resistant schizophrenia (TRS), and one of the subtypes may be related to dopamine supersensitivity psychosis (DSP). In developing strategies for prevention and treatment TRS, it is important to clarify the role of DSP in TRS. TRS patients were recruited from 3 hospitals for the present study. Through chart reviews, all patients were judged as either TRS or not, and then possible TRS patients were investigated about their past/present histories of DSP episode(s) by direct interviews. We then compared each factor between the groups with and without DSP episode(s). Out of 611 patients screened, 147 patients met the criteria for TRS and were included in the present analysis. These were divided into groups with and without DSP, comprising 106 (72.1%) and 41 patients (27.9%), respectively. Clinical characteristics in the two groups were similar, except for drug-induced movement disorders (DIMDs), which were significantly more important in DSP patients. Of the DSP patients, 42% and 56% experienced rebound psychosis and tolerance to antipsychotic effects, respectively. The present study revealed that approximately 70% of TRS patients experienced one or more DSP episodes, which may have a strong impact on the long-term prognosis of patients with schizophrenia.

A prospective comparative study of risperidone long-acting injectable for treatment-resistant schizophrenia with dopamine supersensitivity psychosis.

OBJECTIVE: Dopamine supersensitivity psychosis (DSP) is considered to be one cause of treatment-resistant schizophrenia (TRS). The authors investigated the efficacy of risperidone long-acting injections (RLAI) in patients with TRS and DSP. METHOD: This is a multicenter, prospective, 12-month follow-up, observational study that included unstable and severe TRS patients with and without DSP. 115 patients with TRS were recruited and divided into two groups according to the presence or absence of DSP which was judged on the basis of the clinical courses and neurological examinations. RLAI was administered adjunctively once every 2weeks along with oral antipsychotics. We observed changes in scores for the Brief Psychiatric Rating Scales (BPRS), Clinical Global Impression-Severity of Illness (CGI-S), Global Assessment of Functioning Scale (GAF), and Extrapyramidal Symptom Rating Scale (ESRS) during the study. Of the assessed 94 patients, 61 and 33 were categorized into the DSP and NonDSP groups, respectively. RESULTS: While baseline BPRS total scores, CGI-S scores and GAF scores did not differ, the ESRS score was significantly higher in the DSP group compared with the NonDSP group. Treatment significantly reduced BPRS total scores and CGI-S scores, and increased GAF scores in both groups, but the magnitudes of change were significantly greater in the DSP group relative to the NonDSP group. ESRS scores were also reduced in the DSP group. Responder rates (≥20% reduction in BPRS total score) were 62.3% in the DSP group and 21.2% in the NonDSP group. CONCLUSIONS: It is suggested that DSP contributes to the etiology of TRS. Atypical antipsychotic drugs in long-acting forms, such as RLAI, can provide beneficial effects for patients with DSP. CLINICAL TRIALS REGISTRATION: UMIN (UMIN000008487).