A multicenter, single-arm, open-label interventional study of adherence to brexpiprazole during switching from previous antipsychotic drugs in patients with schizophrenia or schizoaffective disorder.

The rate of medication persistence was examined in patients with schizophrenia or schizoaffective disorder during switching from previously administered antipsychotics to brexpiprazole, a new dopamine D2 receptor partial agonist. A multicenter, single-arm, open-label 24-week interventional study was conducted, consisting of two 12-week consecutive periods: an initial switch (by plateau cross-titration) with the subsequent period, followed by a second maintenance period. Prior antipsychotics were olanzapine or risperidone/paliperidone. The primary and secondary outcome measures were medication persistence rates after the first 12 weeks and changes from baseline in the Specific Levels of Functioning Scale (SLOF), Subjective Well-being under Neuroleptic drug treatment Short form (SWNS), and Positive and Negative Syndrome Scale (PANSS) scores, respectively. In total, 79 patients were administered brexpiprazole and the medication persistence rate at 12 weeks was 78.5%, which was significantly higher than the predefined threshold of 65%. Regarding the prior medication, the persistence rate at 12 weeks was 84.6% for olanzapine and 72.5% for risperidone/paliperidone. Significant improvements from baseline were observed in the SLOF, SWNS, and PANSS scores. There were no adverse events of concern. Thus, brexpiprazole appeared to be a suitable antipsychotic on switching from olanzapine, risperidone, or paliperidone.

Protocol for stratification of triple-negative breast cancer patients using in silico signaling dynamics.

Personalized kinetic models can predict potential biomarkers and drug targets. Here, we provide a step-by-step approach for building an executable mathematical model from text and integrating transcriptomic datasets. We additionally describe the steps to personalize the mechanistic model and to stratify patients with triple-negative breast cancer (TNBC) based on in silico signaling dynamics. This protocol can also be applied to any signaling pathway for patient-specific modeling. For complete details on the use and execution of this protocol, please refer to Imoto et al. (2022).

[Severe aplastic anemia exhibiting mild COVID-19 despite high serum IL-6 levels].

COVID-19 is a viral infection characterized by a cytokine storm similar to that in acute respiratory distress syndrome (ARDS). Neutrophils and monocytes are known to play an important role in tissue damage in ARDS. COVID-19 has been reported to be more severe in patients with hematological malignancies; however, there are few reports of COVID-19 in patients with aplastic anemia. Moreover, how aplastic anemia affects COVID-19 remains unclear. Here, we report the case of a COVID-19 patient with aplastic anemia who had high serum IL-6 levels but did not progress to the severe form of COVID-19. We inferred that severe neutropenia and monocytopenia due to aplastic anemia could contribute to a mild form of COVID-19, although a risk of more severe secondary bacterial infections exists.

Clonal Cytopenia of Undetermined Significance in a Patient with Congenital Wilms' Tumor 1 and Acquired DNMT3A Gene Mutations.

Congenital mutations of the Wilms' tumor 1 (WT1) gene can lead to various abnormalities, including renal/gonadal developmental disorders and cardiac malformations. Although there have been many reports of somatic WT1 mutations in patients with acute myeloid leukemia and myelodysplastic syndrome, congenital WT1 mutations have not been reported in hematological disorders. We herein report a patient with early-onset clonal cytopenia of undetermined significance that was associated with a congenital mutation of WT1 and an acquired mutation of DNMT3A [encoding DNA (cytosine-5)-methyltransferase 3A].

A Rare Case of Chronic Subdural Hematoma Coexisting With Metastatic Tumor.

BACKGROUND: Incidence of chronic subdural hematoma (CSH) associated with metastases of extraneural malignancies is rare. We report a rare case of CSH wherein most of the CSH cavity was occupied with metastatic cancer cells; in addition, we review the literature. CASE DESCRIPTION: A 68-year-old man with a history of gastric cancer presented to our hospital with dysarthria and shoulder paralysis; CSH was diagnosed from preoperative imaging findings. When the hematoma was removed via a small craniotomy, besides the hematoma, we observed an abnormal mass of tissue in the capsule. Pathologically, the mass was consistent with the findings of metastatic gastric cancer. Although the symptoms immediately disappeared postoperatively, a symptomatic acute subdural hematoma with midline shift was observed on postoperative day 27. Emergency craniotomy and hematoma and tumor removal were performed. Pathologic examination showed hemorrhagic necrosis in the tumor, which had not been initially observed. The postoperative course progressed without hematoma recurrence. CONCLUSIONS: To the best of our knowledge, this is the first report of a CSH accompanied by tumor metastasis in most of the CSH cavity. Although rare, if a patient with cancer has CSH, the CSH should be treated considering the possibility of metastasis.

Morphological characteristics of infected subdural hematoma: Comparison with images of chronic subdural hematoma.

OBJECTIVES: Infected subdural hematoma (ISH) is a rare type of subdural empyema, with fewer than 50 cases reported to date. Its radiological features have not been adequately described, making diagnosis challenging. At our institution, two adults presented with ISH, which exhibited a characteristic shape on preoperative imaging. PATIENTS AND METHODS: This study examined ISH cases and chronic subdural hematoma (CSH) cases that underwent surgery at the Ishikawa Prefectural Central Hospital between January 2016 and March 2018. To distinguish ISH from CSH, we focused on three specific radiological features: the biconvex shape of the hematoma, presence of a high-density region at the lower end of the hematoma on plain computed tomography (CT), and presence of a hyper-intense signal within the hematoma on diffusion weighted imaging (DWI). RESULTS: We analyzed 30 ISH (current and previously reported) and 102 CSH cases in our study. We found no statistically significant associations between the hematoma type (ISH or CSH) and the presence of a high-density region at the lower end of the hematoma on plain CT (p = 0.13) or the presence of hyperintensity in the hematoma on DWI (p = 1.00). Conversely, a statistically significant association was found between the hematoma type and the biconvex shape of the hematoma (p < 0.01). CONCLUSION: These results suggest that the shape of the hematoma on imaging provides valuable information that can be used to differentiate ISH from CSH and optimize therapeutic approaches.

Upregulation of sphingosine-1-phosphate receptor 3 on fibroblast-like synoviocytes is associated with the development of collagen-induced arthritis via increased interleukin-6 production.

BACKGROUND: Sphingosine-1-phosphate receptor 3 (S1P3) is one of five receptors for sphingosine-1-phosphate (S1P). S1P/S1P3 signaling is involved in numerous physiological and pathological processes including bone metabolism, sepsis, cancer, and immunity. In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLSs) are activated by several factors and promote abundant proinflammatory cytokine production and bone destruction. The aim of this study was to investigate whether S1P3 is associated with the development of autoimmune arthritis and the pathogenic function of FLSs. METHODS: Wild-type (WT) and S1P3 knockout (S1P3-KO) collagen-induced arthritis (CIA) mice were evaluated with respect to clinical and histological disease severity, along with the levels of anti-collagen antibodies and expression of tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6). S1P3 expression in the synovium was analyzed by real-time reverse-transcription polymerase chain reaction (RT-PCR) and immunofluorescence staining. FLSs isolated from CIA mice were activated with TNFα and S1P3 expression was analyzed by real-time RT-PCR. The role of S1P/S1P3 signaling in activated and non-activated FLSs was investigated by measuring cell proliferation and cyto/chemokine production by real-time RT-PCR and/or enzyme-linked immunosorbent assay. RESULTS: Clinical and histological scores, and synovial IL-6 expression were significantly lower in S1P3-KO mice with CIA than in WT mice. Arthritic synovia had higher S1P3 expression than intact synovia and FLSs in arthritic joints expressed S1P3 in vivo. Primary cultured FLSs produced IL-6 in a time-dependent manner in response to S1P stimulation and exhibited higher levels of S1P3 expression after activation with TNFα. S1P3-induced production of IL-6 and MMP-3 was increased in FLSs pre-activated with TNFα. CONCLUSION: In this study, we demonstrated that S1P3 expression is associated with the development of autoimmune arthritis via inflammation-induced increases in S1P/S1P3 signaling that increase production of IL-6 in FLSs. Inhibition of S1P/S1P3 signaling could open the door to the development of new therapies for RA.

Enlargement of Langerhans cell histiocytosis of the hypothalamus with progression into the basal ganglia and white matter.

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disease that may affect the central nervous system; it is caused by dendritic cell proliferation, and typically occurs in children. LCH frequently appears in the pituitary stalk and rarely results in multiple enhanced lesions in the brain parenchyma. CASE DESCRIPTION: We present a case of a 40-year-old woman who deveolped panhypopituitarism and central diabetes insipidus in the postpartum period requiring hormone replacement therapy. At first, magnetic resonance imaging only revealed thickening of the pituitary stalk; while 6 months later, a single enhanced mass lesion was detected in the hypothalamus. Another 5 months later, the lesion had enlarged with appearance of multiple, enhanced satellite lesions in the basal ganglia and white matter. The patient underwent successful craniotomy to obtain a biopsy sample; LCH of the hypothalamus was definitively diagnosis by histopathological examination. Steroids were administrated and resulted in significant reduction of all lesions. CONCLUSIONS: Definitive histopathological diagnosis and subsequent appropriate therapy, such as steroid administration, are required when LCH lesions in the hypothalamus become progressively enlarged and new lesions appear in the brain parenchyma.

Comparative effectiveness of switching paroxetine formulation for treatment of major depressive disorder: an open-label multicenter study.

AIM: To assess the effectiveness and safety of switching the antidepressant formulation from immediate-release (IR) to controlled-release (CR) paroxetine in patients with major depressive disorder (MDD). PATIENTS AND METHODS: A total of 113 outpatients with MDD diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, and treated with a stable dose of IR paroxetine for at least 6 months were enrolled. Patients were then switched to CR paroxetine for 8 weeks. Effectiveness was evaluated by scores on the Himorogi Self-Rating Depression/Anxiety Scales (HSDS/HSAS) and the Clinical Global Impression - Severity (CGI-S). Safety was evaluated based on the reported adverse drug reactions (ADRs). Medication satisfaction and preference were assessed based on questionnaire responses using Likert-type scales. RESULTS: The overall patient HSDS/HSAS scores significantly improved after switching from IR to CR paroxetine (P<0.001). Furthermore, CR paroxetine was superior to IR paroxetine (P<0.001) according to the results of the CGI-S evaluation. ADRs were experienced by 14 (12.4%) patients, including dry mouth, nausea/vomiting, somnolence/drowsiness, and wakefulness/arousal during sleep. Satisfaction and preference for paroxetine improved after switching to the CR formulation (P<0.001; chi-square test). CONCLUSION: These results suggest that switching the treatment from IR to CR paroxetine could improve depressive symptoms and decrease ADRs. However, these results may have been caused by the psychological effect of drug switching. Hence, future studies with blinded evaluation methods are required to confirm and expand our findings.

Role of allograft inflammatory factor-1 in bleomycin-induced lung fibrosis.

Allograft inflammatory factor-1 (AIF-1) is a protein expressed by macrophages infiltrating the area around the coronary arteries in a rat ectopic cardiac allograft model. We previously reported that AIF-1 is associated with the pathogenesis of rheumatoid arthritis and skin fibrosis in sclerodermatous graft-versus-host disease mice. Here, we used an animal model of bleomycin-induced lung fibrosis to analyze the expression of AIF-1 and examine its function in lung fibrosis. The results showed that AIF-1 was expressed on lung tissues, specifically macrophages, from mice with bleomycin-induced lung fibrosis. Recombinant AIF-1 increased the production of TGF-ß which plays crucial roles in the mechanism of fibrosis by mouse macrophage cell line RAW264.7. Recombinant AIF-1 also increased both the proliferation and migration of lung fibroblasts compared with control group. These results suggest that AIF-1 plays an important role in the mechanism underlying lung fibrosis, and may provide an attractive new therapeutic target.

Efficacy of abatacept in patients with rheumatoid arthritis, as assessed by magnetic resonance imaging of bilateral hands.

AIM: To examine the efficacy of abatacept in patients with rheumatoid arthritis (RA) using magnetic resonance imaging (MRI) of bilateral hands. METHOD: This prospective study included 35 RA patients. MRI of bilateral hands was performed at baseline and after 12 months of treatment with intravenous abatacept. MRI images were scored for synovitis, osteitis, erosion and joint space narrowing (JSN) according to the RA MRI Scoring System (RAMRIS). The primary endpoint was the change in RAMRIS score from baseline. Repair of erosion was defined as a negative change in the erosion score that was greater than the smallest detectable changes (SDCs). RESULTS: Thirty-one patients completed the study. Median synovitis and osteitis scores showed statistically significant reductions at Month 12 when compared to baseline (synovitis score, -5.5 [P < 0.0001]; osteitis score, -0.5 [P = 0.03]). However, median erosion and JSN scores did not significantly change. At Month 12, 83% of patients showed no progression of erosion scores and repair of erosion was observed in 11% of patients. All patients with repair of erosion achieved functional remission (Health Assessment Questionnaire-Disability Index ≤ 0.5). The Simplified Disease Activity Index response rate at Month 1 was identified as an independent factor predicting changes in the erosion scores at Month 12. CONCLUSION: Abatacept treatment reduced synovitis and osteitis scores and did not worsen erosion and JSN scores at Month 12. Over 10% of patients experienced repair of erosion.

Convenient chirality transfer from organics to titania: construction and optical properties.

Polyethyleneimine (PEI) complexed with chiral d- (or l-) tartaric acid (tart) in water can self-organize into chiral and crystalline PEI/tart assemblies. It has been previously confirmed that the complexes of PEI/tart could work as catalytic/chiral templates to induce the deposition of SiO2 nanofibres with optical activity but without outwards shape chirality such as helices. In this work, we found that the templating functions of PEI/tart were still effective to prompt the deposition of TiO2 to form chiral PEI/tart@TiO2 hybrid nanofibres under aqueous and room temperature conditions within two hours. Furthermore, the co-deposition of TiO2 and SiO2 was also fulfilled to yield chiral PEI/tart@TiO2/SiO2 nanofibres. These TiO2-containing hybrid nanofibres showed non-helical shapes on the length scale; however, chiroptical signals with mirror relation around the UV-Vis absorption band of TiO2 remarkably appeared on their circular dichroism (CD) spectra. By means of the protocols of XRD, TEM, SEM, UV-Vis, CD and XPS, structural features and thermoproperties of the chiral TiO2 and SiO2/TiO2 were investigated.

Once-weekly teriparatide improves glucocorticoid-induced osteoporosis in patients with inadequate response to bisphosphonates.

BACKGROUND: Patients with glucocorticoid-induced osteoporosis (GIOP) are at very high risk of fracture, and patients with severe GIOP often experience fractures during treatment with bisphosphonates. Teriparatide (TPTD) is the only currently available anabolic agent expected to be effective for GIOP. Once-weekly TPTD decreased bone resorption marker with primary osteoporosis different from daily TPTD, but it has not yet been tested with GIOP. OBJECTIVES: To evaluate the efficacy of once-weekly TPTD for patients with GIOP and inadequate response to bisphosphonates. METHODS: Patients with GIOP and collagen diseases treated with prednisolone for at least 6 months with inadequate responses to bisphosphonates were administered once-weekly TPTD. Bone density of the lumbar spine and femoral neck, measured as percent young adult mean (YAM); serum concentrations of cross-linked N-terminal telopeptides of type I collagen (NTx), bone alkaline phosphatase (BAP), and calcium; and FRAX were measured at baseline and 6, 12 and 18 months after starting TPTD. RESULTS: Of the 12 GIOP patients with collagen diseases enrolled, nine (seven females, two males; mean age 57.4 ± 11.1 years) completed treatment, including six with systemic lupus erythematosus, two with rheumatoid arthritis, and one with adult onset still disease. Only one new fracture event, a lumbar compression fracture, occurred during the study period, although seven patients experienced eight fracture events within 18 months before starting TPTD (p = 0.04). Lumbar spine YAM significantly improved at 18 months (p = 0.04), whereas femoral neck YAM did not (p = 0.477). Serum NTx, BAP, Ca, and FRAX were not significantly affected by TPTD treatment. CONCLUSIONS: Once-weekly TPTD reduces fracture events and increases bone density of the lumbar spine of GIOP patients with inadequate response to bisphosphonates.

Allograft inflammatory factor-1 in the pathogenesis of bleomycin-induced acute lung injury.

Allograft inflammatory factor-1 (AIF-1) is a protein expressed by macrophages infiltrating the area around the coronary arteries of rats with an ectopic cardiac allograft. Some studies have shown that expression of AIF-1 increased in a mouse model of trinitrobenzene sulfonic acid-induced acute colitis and in acute cellular rejection of human cardiac allografts. These results suggest that AIF-1 is related to acute inflammation. The current study used bleomycin-induced acute lung injury to analyze the expression of AIF-1 and to examine its function in acute lung injury. Results showed that AIF-1 was significantly expressed in lung macrophages and increased in bronchoalveolar lavage fluid from mice with bleomycin-induced acute lung injury in comparison to control mice. Recombinant AIF-1 increased the production of IL-6 and TNF-α from RAW264.7 (a mouse macrophage cell line) and primary lung fibroblasts, and it also increased the production of KC (CXCL1) from lung fibroblasts. These results suggest that AIF-1 plays an important role in the mechanism underlying acute lung injury.

Inhibition of osteoclastogenesis by osteoblast-like cells genetically engineered to produce interleukin-10.

Bone destruction at inflamed joints is an important complication associated with rheumatoid arthritis (RA). Interleukin-10 (IL-10) may suppress not only inflammation but also induction of osteoclasts that play key roles in the bone destruction. If IL-10-producing osteoblast-like cells are induced from patient somatic cells and transplanted back into the destructive bone lesion, such therapy may promote bone remodeling by the cooperative effects of IL-10 and osteoblasts. We transduced mouse fibroblasts with genes for IL-10 and Runx2 that is a crucial transcription factor for osteoblast differentiation. The IL-10-producing induced osteoblast-like cells (IL-10-iOBs) strongly expressed osteoblast-specific genes and massively produced bone matrix that were mineralized by calcium phosphate in vitro and in vivo. Culture supernatant of IL-10-iOBs significantly suppressed induction of osteoclast from RANKL-stimulated Raw264.7 cells as well as LPS-induced production of inflammatory cytokine by macrophages. The IL-10-iOBs may be applicable to novel cell-based therapy against bone destruction associated with RA.

Knock out of S1P3 receptor signaling attenuates inflammation and fibrosis in bleomycin-induced lung injury mice model.

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in many critical cellular processes, including proliferation, migration, and angiogenesis, through interaction with a family of five G protein-coupled receptors (S1P1-5). Some reports have implicated S1P as an important inflammatory mediator of the pathogenesis of airway inflammation, but the role of S1P3 in the pathogenesis of lung diseases is not completely understood. We used S1P3-deficient (knockout (KO)) mice to clarify the role of S1P3 receptor signaling in the pathogenesis of pulmonary inflammation and fibrosis using a bleomycin-induced model of lung injury. On the seventh day after bleomycin administration, S1P3 KO mice exhibited significantly less body weight loss and pulmonary inflammation than wild-type (WT) mice. On the 28th day, there was less pulmonary fibrosis in S1P3 KO mice than in WT mice. S1P3 KO mice demonstrated a 56% reduction in total cell count in bronchoalveolar lavage fluid (BALF) collected on the seventh day compared with WT mice; however, the differential white blood cell profiles were similar. BALF analysis on the seventh day showed that connective tissue growth factor (CTGF) levels were significantly decreased in S1P3 KO mice compared with WT mice, although no differences were observed in monocyte chemotactic protein-1 (MCP-1) or transforming growth factor ß1 (TGF-ß1) levels. Finally, S1P levels in BALF collected on the 7th day after treatment were not significantly different between WT and S1P3 KO mice. Our results indicate that S1P3 receptor signaling plays an important role in pulmonary inflammation and fibrosis and that this signaling occurs via CTGF expression. This suggests that this pathway might be a therapeutic target for pulmonary fibrosis.

Myeloid-derived suppressor cells play crucial roles in the regulation of mouse collagen-induced arthritis.

Myeloid-derived suppressor cells (MDSCs) are of myeloid origin and are able to suppress T cell responses. The role of MDSCs in autoimmune diseases remains controversial, and little is known about the function of MDSCs in autoimmune arthritis. In this study, we clarify that MDSCs play crucial roles in the regulation of proinflammatory immune response in a collagen-induced arthritis (CIA) mouse model. MDSCs accumulated in the spleens of mice with CIA when arthritis severity peaked. These MDSCs inhibited the proliferation of CD4(+) T cells and their differentiation into Th17 cells in vitro. Moreover, MDSCs inhibited the production of IFN-γ, IL-2, TNF-α, and IL-6 by CD4(+) T cells in vitro, whereas they promoted the production of IL-10. Adoptive transfer of MDSCs reduced the severity of CIA in vivo, which was accompanied by a decrease in the number of CD4(+) T cells and Th17 cells in the draining lymph nodes. However, depletion of MDSCs abrogated the spontaneous improvement of CIA. In conclusion, MDSCs in CIA suppress the progression of CIA by inhibiting the proinflammatory immune response of CD4(+) T cells. These observations suggest that MDSCs play crucial roles in the regulation of autoimmune arthritis, which could be exploited in new cell-based therapies for human rheumatoid arthritis.

Sciatica caused by pyomyositis of the piriformis muscle in a pediatric patient.

Because the sciatic nerve leaves the pelvis through the greater sciatic notch underneath the piriformis muscle, any pathology of the piriformis muscle could result in entrapment of the sciatic nerve; this is widely known as piriformis muscle syndrome. Pyomyositis of the piriformis muscle may be a cause of piriformis muscle syndrome. Piriformis muscle syndrome caused by pyomyositis of the piriformis muscle in pediatric patients is rare. This article describes a case of sciatica caused by pyomyositis of the piriformis muscle in a pediatric patient. A 6-year-old boy presented with right buttock and thigh pain following a mild fever and sore throat. The pain worsened, and he became unable to walk. On admission, his temperature was 38.4°C. He reported severe right-sided buttock and lateral thigh pain. Positive Freiberg sign was observed. Laboratory examination revealed elevated white blood cell count and C-reactive protein level. T2-weighted magnetic resonance images of the pelvis revealed high-intensity changes of the piriformis muscle and iliosacral joint. Thus, piriformis syndrome caused by pyomyositis of the piriformis muscle was diagnosed. Oral antibiotics (10 mg/kg per day of cefdinir) were administered. Pain gradually decreased, and the patient was able to walk. Final follow-up examination at 6 months after symptom onset revealed no sciatic pain. Follow-up magnetic resonance imaging revealed normalized intensities of the piriformis muscle. The endopelvic fascia provides a route for infection from the pelvis to the piriformis. The pyomyositis of the piriformis muscle in the current case may have occurred secondary to the pyoarthritis of the sacroiliac joint. Endopelvic infections involving the piriformis muscle may mimic hip diseases in pediatric patients.

The rapid efficacy of abatacept in a patient with rheumatoid vasculitis.

We report a case of rheumatoid vasculitis (RV) that responded well to abatacept, a cytotoxic T lymphocyte-associated antigen 4 (CTLA4)-immunoglobulin fusion protein. A 38-year-old woman developed RV despite treatment with methotrexate and tumor necrosis factor (TNF) inhibitors. The effects of steroid therapy, immunoabsorption plasmapheresis, and interleukin-6 inhibitor were insufficient, however, administration of abatacept rapidly improved her clinical symptoms with almost normalization of the immunological findings. This is the first published case report of the successful treatment of RV with abatacept.