Successful Pregnancy Outcome in a Patient with Juvenile Idiopathic Arthritis in Adulthood, Amyloid A Amyloidosis, and Chronic Kidney Disease Using Tocilizumab with Strict Blood Pressure Control.

Pregnancies with chronic kidney disease (CKD) and high disease activity in rheumatic diseases are high-risk events with adverse outcomes for both the mother and fetus. We herein report a 35-year-old woman with juvenile idiopathic arthritis (JIA), amyloid A (AA) amyloidosis related to JIA, and CKD stage G4A2 who wished to have children. She achieved a successful pregnancy, even in the presence of these multiple risk factors, using tocilizumab to control the disease activity of JIA and AA amyloidosis, along with antihypertensive drugs to control her blood pressure before and during pregnancy.

Efficient detection of somatic UBA1 variants and clinical scoring system predicting patients with variants in VEXAS syndrome.

OBJECTIVES: To efficiently detect somatic UBA1 variants and establish a clinical scoring system predicting patients with pathogenic variants in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. METHODS: Eighty-nine Japanese patients with clinically suspected VEXAS syndrome were recruited [81 males and 8 females; median onset age (IQR) 69.3 years (62.1-77.6)]. Peptide nucleic acid-clamping PCR (PNA-PCR), regular PCR targeting exon 3 clustering UBA1 variants, and subsequent Sanger sequencing were conducted for variant screening. Partitioning digital PCR (pdPCR) or targeted amplicon deep sequencing (TAS) was also performed to evaluate the variant allele frequency (VAF). We developed our clinical scoring system to predict UBA1 variant-positive and ­negative patients and assessed the diagnostic value of our system using receiver operating characteristic (ROC) curve analysis. RESULTS: Forty patients with reported pathogenic UBA1 variants (40/89, 44.9%) were identified, including a case having a variant with VAF of 1.7%, using a highly sensitive method. Our clinical scoring system considering >50 years of age, cutaneous lesions, lung involvement, chondritis, and macrocytic anaemia efficiently predicted patients with UBA1 variants (the area under the curve for the scoring total was 0.908). CONCLUSIONS: Genetic screening with the combination of regular PCR and PNA-PCR detected somatic UBA1 variants with high sensitivity and specificity. Our scoring system could efficiently predict patients with UBA1 variants.

Effects of dedifferentiated fat cells on neurogenic differentiation and cell proliferation in neuroblastoma cells.

PURPOSE: Mesenchymal stem cells (MSCs) can induce differentiation of neuroblastoma (NB) cells. Properties of dedifferentiated fat cells (DFATs) are similar to those of MSCs. Here, we investigated whether DFATs can induce NB cell differentiation and suppress cell proliferation. METHODS: DFATs were obtained from mature adipocytes isolated from adipose tissue from a ceiling culture. NB cells were cultured in a medium with or without DFATs and, subsequently, cultured in a DFAT-conditioned medium (CM) with or without phosphatidylinositol 3-kinase (PI3K) inhibitor. The neurite lengths were measured, and mRNA expression levels of the neurofilament (NF) and tubulin beta III (TUBß3) were assessed using quantitative real-time RT-PCR. Cell viability was assessed using the WST-1 assay. RESULTS: NB cells cultured with DFATs caused elongation of the neurites and upregulated the expression of NF and Tubß3. NB cells cultured in DFAT-CM demonstrated increased cell viability. NB cells cultured with DFAT-CM and PI3K inhibitors suppressed cell viability. NB cells cultured with DFAT-CM and PI3K inhibitor demonstrated increased neurite length and expression, and upregulation of Tubß3. CONCLUSION: The combined use of DFAT-CM and PI3K inhibitors suppresses the proliferation of NB cells and induces their differentiation. Thus, DFAT may offer new insights into therapeutic approaches in neuroblastoma.

Successful laparoscopic-assisted partial splenectomy and splenopexy with umbilical approach to wandering spleen with an enlarged cyst in a pediatric patient.

A 10-year-old girl with a wandering spleen with an enlarged cyst was successfully treated by laparoscopic-assisted partial splenectomy and splenopexy. The patient visited our hospital with a complaint of a lower abdominal mass. Abdominal computed tomography showed malposition of the spleen and the presence of a 10 cm diameter splenic cyst (SC) in the lower pole. In surgery, the navel was opened with an inverted Y-shaped incision. The SC was punctured and aspirated the contents of the cyst, the migrating spleen was pulled out of navel and the partial splenectomy was done. The residual spleen was laparoscopically fixed by creating an extraperitoneal pocket. Pathologically, the cyst was covered with a vitrified fibrotic capsule and was diagnosed as a pseudocyst. We considered it a traumatic cyst. The postoperative course was uneventful. This minimally invasive laparoscopic procedure was feasible and effective for treating wandering spleen with a large SC in a pediatric patient.

How to avoid unnecessary surgical treatment for neonatal small left colon syndrome.

We report a case of neonatal small left colon syndrome (NSLCS) that underwent surgery. A female infant was born at 38 weeks of gestation. The mother had gestational diabetes requiring insulin therapy. The baby was admitted for respiratory distress. Abdominal distension was observed, and the gastric residue increased. Contrast enema revealed a small caliber of the left colon up to the splenic flexure. At 14 days, the full-thickness biopsy of the sigmoid and transverse colons was performed. Pathological diagnosis showed that the sigmoid colon had few ganglion cells, therefore the transverse colostomy was performed. At 6 months of age, a rectal biopsy was performed to confirm the diagnosis of Hirschsprung's disease; the intestinal plexus and ganglion cells were normal. The surgery was changed from a pull-through to a stoma closure. The postoperative diagnosis was NSLCS, and the course up to 3 years was good without defecation or growth problems.

Relationship between pedestrian detection specifications of parking sensor and potential safety benefits.

Measures to protect vulnerable road users during low-speed maneuvers are required. For example, systems that use cameras to display the vehicle's rearview are popular. However, some vehicles are difficult to equip with a rear view camera system. To avoid a crash when driving in reverse, it is also effective to identify the presence of pedestrians via an audible warning using a device (e.g., clearance sonar). It may be cheaper to install than a rearview camera system. Installation cost is also important for the spread of equipment that reduces a crash. It is necessary to clarify the minimum specifications that balance cost and reduce crashes. Device specifications (e.g., detection distance and response delay) may affect the crash reduction rate. There should be a detection distance required for the sonar to have the same crash reduction effect as the rear view camera system. Thus, in this study, we conducted experiments and obtained data about how a vehicle moves and driver reactions to audible warnings when driving in reverse. Based on the acquired data, a numerical simulation was performed to determine whether a driver could avoid a crash under various circumstances. As a result, it was shown that the clearance sonar must have a detection distance of 0.8 m or more to expect the same effect as a rearview camera system. In other words, to expect sonar to have the same performance as a rearview camera, a detection distance of at least 0.8 m should be set as a specification.

Diagnosis and management of genital injuries in girls: 14-year experience.

BACKGROUND: Pediatric patients with genital injuries are often recommended to receive an examination under general anesthesia; however, detailed clinical data of such patients are rarely reported. METHODS: A single-center retrospective review was conducted in 45 girls less than 16 years of age with genital injuries between January 2005 and December 2018. RESULTS: The median patient age was 5.0 years. Forty-two patients were hospitalized, of whom 38 required an examination under general anesthesia and all consequently required surgical repair. The diagnosis obtained after a thorough examination under general anesthesia was inconsistent with the diagnosis obtained at the emergency room in five patients. In 20 patients, the source of bleeding was not clarified at the time of initial examination at the emergency room; four of these patients were later revealed to have vaginal or rectal injuries that had been overlooked during the examination at the emergency room. Injuries occurring in the bathroom were the most frequent and tended to be serious. Multiple injuries were found in 10 patients. The exterior of the labia minora was the most commonly injured site, found in 18 patients. CONCLUSIONS: We analyzed the clinical data of girls with genital injuries in detail, which allowed us to find a detailed classification of injured sites and the characteristics of serious cases, and to re-recognize the importance of a thorough examination under general anesthesia.

Therapeutic potential of mature adipocyte-derived dedifferentiated fat cells for inflammatory bowel disease.

PURPOSE: Our previous studies demonstrated that mature adipocyte-derived dedifferentiated fat (DFAT) cells possess similar multipotency as mesenchymal stem cells. Here, we examined the immunoregulatory potential of DFAT cells in vitro and the therapeutic effect of DFAT cell transplantation in a mouse inflammatory bowel disease (IBD) model. METHODS: The effect of DFAT cell co-culture on T cell proliferation and expression of immunosuppression-related genes in DFAT cells were evaluated. To create IBD, CD4+CD45RBhigh T cells were intraperitoneally injected into SCID mice. One week later, DFAT cells (1 × 105, DFAT group) or saline (Control group) were intraperitoneally injected. Subsequently bodyweight was measured every week and IBD clinical and histological scores were evaluated at 5 weeks after T cell administration. RESULTS: The T cell proliferation was inhibited by co-cultured DFAT cells in a cell density-dependent manner. Gene expression of TRAIL, IDO1, and NOS2 in DFAT cells was upregulated by TNFα stimulation. DFAT group improved IBD-associated weight loss, IBD clinical and histological scores compared to Control group. CONCLUSION: DFAT cells possess immunoregulatory potential and the cell transplantation promoted recovery from colon damage and improved clinical symptoms in the IBD model. DFAT cells could play an important role in the treatment of IBD.

Lysosomal Protein Lamtor1 Controls Innate Immune Responses via Nuclear Translocation of Transcription Factor EB.

Amino acid metabolism plays important roles in innate immune cells, including macrophages. Recently, we reported that a lysosomal adaptor protein, Lamtor1, which serves as the scaffold for amino acid-activated mechanistic target of rapamycin complex 1 (mTORC1), is critical for the polarization of M2 macrophages. However, little is known about how Lamtor1 affects the inflammatory responses that are triggered by the stimuli for TLRs. In this article, we show that Lamtor1 controls innate immune responses by regulating the phosphorylation and nuclear translocation of transcription factor EB (TFEB), which has been known as the master regulator for lysosome and autophagosome biogenesis. Furthermore, we show that nuclear translocation of TFEB occurs in alveolar macrophages of myeloid-specific Lamtor1 conditional knockout mice and that these mice are hypersensitive to intratracheal administration of LPS and bleomycin. Our observation clarified that the amino acid-sensing pathway consisting of Lamtor1, mTORC1, and TFEB is involved in the regulation of innate immune responses.

Supersonic gas streams enhance the formation of massive black holes in the early universe.

The origin of super-massive black holes in the early universe remains poorly understood. Gravitational collapse of a massive primordial gas cloud is a promising initial process, but theoretical studies have difficulty growing the black hole fast enough. We report numerical simulations of early black hole formation starting from realistic cosmological conditions. Supersonic gas motions left over from the Big Bang prevent early gas cloud formation until rapid gas condensation is triggered in a protogalactic halo. A protostar is formed in the dense, turbulent gas cloud, and it grows by sporadic mass accretion until it acquires 34,000 solar masses. The massive star ends its life with a catastrophic collapse to leave a black hole-a promising seed for the formation of a monstrous black hole.

Lamtor1 Is Critically Required for CD4+ T Cell Proliferation and Regulatory T Cell Suppressive Function.

Mechanistic target of rapamycin complex (mTORC)1 integrates intracellular sufficiency of nutrients and regulates various cellular functions. Previous studies using mice with conditional knockout of mTORC1 component proteins (i.e., mTOR, Raptor, and Rheb) gave conflicting results on the roles of mTORC1 in CD4+ T cells. Lamtor1 is the protein that is required for amino acid sensing and activation of mTORC1; however, the roles of Lamtor1 in T cells have not been investigated. In this article, we show that Lamtor1-deficient CD4+ T cells exhibited marked reductions in proliferation, IL-2 production, mTORC1 activity, and expression of purine- and lipid-synthesis genes. Polarization of Th17 cells, but not Th1 and Th2 cells, diminished following the loss of Lamtor1. Accordingly, CD4-Cre-driven Lamtor1-knockout mice exhibited reduced numbers of CD4+ and CD8+ T cells at rest, and they were completely resistant to experimental autoimmune encephalomyelitis. In contrast, genetic ablation of Lamtor1 in Foxp3+ T cells resulted in severe autoimmunity and premature death. Lamtor1-deficient regulatory T cells survived ex vivo as long as wild-type regulatory T cells; however, they exhibited a marked loss of suppressive function and expression of signature molecules, such as CTLA-4. These results indicate that Lamtor1 plays essential roles in CD4+ T cells. Our data suggest that Lamtor1 should be considered a novel therapeutic target in immune systems.

Semaphorin 4D inhibits neutrophil activation and is involved in the pathogenesis of neutrophil-mediated autoimmune vasculitis.

OBJECTIVES: Inappropriate activation of neutrophils plays a pathological role in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The aim of this study was to investigate the functions of semaphorin 4D (SEMA4D) in regulation of neutrophil activation, and its involvement in AAV pathogenesis. METHODS: Serum levels of soluble SEMA4D were evaluated by ELISA. Blood cell-surface expression of membrane SEMA4D was evaluated by flow cytometry. To determine the functional interactions between neutrophil membrane SEMA4D and endothelial plexin B2, wild-type and SEMA4D-/- mice neutrophils were cultured with an endothelial cell line (MS1) stained with SYTOX green, and subjected to neutrophil extracellular trap (NET) formation assays. The efficacy of treating human neutrophils with recombinant plexin B2 was assessed by measuring the kinetic oxidative burst and NET formation assays. RESULTS: Serum levels of soluble SEMA4D were elevated in patients with AAV and correlated with disease activity scores. Cell-surface expression of SEMA4D was downregulated in neutrophils from patients with AAV, a consequence of proteolytic cleavage of membrane SEMA4D. Soluble SEMA4D exerted pro-inflammatory effects on endothelial cells. Membranous SEMA4D on neutrophils bound to plexin B2 on endothelial cells, and this interaction decreased NET formation. Recombinant plexin B2 suppressed neutrophil Rac1 activation through SEMA4D's intracellular domain, and inhibited pathogen-induced or ANCA-induced oxidative burst and NET formation. CONCLUSIONS: Neutrophil surface SEMA4D functions as a negative regulator of neutrophil activation. Proteolytic cleavage of SEMA4D as observed in patients with AAV may amplify neutrophil-mediated inflammatory responses. SEMA4D is a promising biomarker and potential therapeutic target for AAV.

Continuous transanal decompression for infants with long- and total-type Hirschsprung's diseases as a bridge to curative surgery: a single-center experience.

BACKGROUND: The purpose of this study is to assess the usefulness of continuous bowel decompression using an indwelling transanal tube (ITT) for preoperative management in infants with long-segment (L)- or total (T)-type Hirschsprung's disease (HD). CASE PRESENTATION: Between 2012 and 2015, seven patients with L- or T-type HD underwent preoperative bowel management by continuous bowel decompression using an ITT during waiting period for curative surgery. Continuous bowel decompression was done using an ITT, a 10-12F flexible dual lumen tube placed through the rectum up to the dilated colon under fluoroscopic guidance and secured to the bilateral buttocks. The ITT tips were located at least in a dilated colon or the cecum if there was no radiographic transitional zone. The ITT was left open for continuous drainage, and its patency was checked by regular suction until the curative operation. The patient status and complications of this preoperative management were reviewed retrospectively. RESULTS: The median duration of decompression management was 65 (17-137) days. During decompression period, neither abdominal distention, enterocolitis, nor other complications occurred and six patients could stay at home until the curative operation. The weight-for-age Z-score at curative surgery was the same as or higher than that at birth in five patients. ITT replacement was needed three times per patient on an average for accidental ITT removal, ITT stenosis, or ITT hardening. CONCLUSIONS: Bowel management by continuous bowel decompression using an ITT is easy, safe, and effective for preoperative management in patients with L- or T-type HD and may permit single-stage surgery rendering colostomy or enterostomy unnecessary.

Polarization of M2 macrophages requires Lamtor1 that integrates cytokine and amino-acid signals.

Macrophages play crucial roles in host defence and tissue homoeostasis, processes in which both environmental stimuli and intracellularly generated metabolites influence activation of macrophages. Activated macrophages are classified into M1 and M2 macrophages. It remains unclear how intracellular nutrition sufficiency, especially for amino acid, influences on macrophage activation. Here we show that a lysosomal adaptor protein Lamtor1, which forms an amino-acid sensing complex with lysosomal vacuolar-type H+-ATPase (v-ATPase), and is the scaffold for amino acid-activated mTORC1 (mechanistic target of rapamycin complex 1), is critically required for M2 polarization. Lamtor1 deficiency, amino-acid starvation, or inhibition of v-ATPase and mTOR result in defective M2 polarization and enhanced M1 polarization. Furthermore, we identified liver X receptor (LXR) as the downstream target of Lamtor1 and mTORC1. Production of 25-hydroxycholesterol is dependent on Lamtor1 and mTORC1. Our findings demonstrate that Lamtor1 plays an essential role in M2 polarization, coupling immunity and metabolism.

LRRK1 is critical in the regulation of B-cell responses and CARMA1-dependent NF-κB activation.

B-cell receptor (BCR) signaling plays a critical role in B-cell activation and humoral immunity. In this study, we discovered a critical function of leucine-rich repeat kinase 1 (LRRK1) in BCR-mediated immune responses. Lrrk1(-/-) mice exhibited altered B1a-cell development and basal immunoglobulin production. In addition, these mice failed to produce IgG3 antibody in response to T cell-independent type 2 antigen due to defects in IgG3 class-switch recombination. Concomitantly, B cells lacking LRRK1 exhibited a profound defect in proliferation and survival upon BCR stimulation, which correlated with impaired BCR-mediated NF-κB activation and reduced expression of NF-κB target genes including Bcl-xL, cyclin D2, and NFATc1/αA. Furthermore, LRRK1 physically interacted and potently synergized with CARMA1 to enhance NF-κB activation. Our results reveal a critical role of LRRK1 in NF-κB signaling in B cells and the humoral immune response.

Successful resection of metachronous para-aortic, Virchow lymph node and liver metastatic recurrence of rectal cancer.

A 66-year-old female presented with the main complaint of defecation trouble and abdominal distention. With diagnosis of rectal cancer, cSS, cN0, cH0, cP0, cM0 cStage II, Hartmann's operation with D3 lymph node dissection was performed and a para-aortic lymph node and a disseminated node near the primary tumor were resected. Histological examination showed moderately differentiated adenocarcinoma, pSS, pN3, pH0, pP1, pM1 (para-aortic lymph node, dissemination) fStage IV. After the operation, the patient received chemotherapy with FOLFIRI regimen. After 12 cycles of FOLFIRI regimen, computed tomography (CT) detected an 11 mm of liver metastasis in the postero-inferior segment of right hepatic lobe. With diagnosis of liver metastatic recurrence, we performed partial hepatectomy. Histological examination revealed moderately differentiated adenocarcinoma as a metastatic rectal cancer with cut end microscopically positive. After the second operation, the patient received chemotherapy with TS1 alone for 2 years. Ten months after the break, CT detected a 20 mm of para-aortic lymph node metastasis and a 10 mm of lymph node metastasis at the hepato-duodenal ligament. With diagnosis of lymph node metastatic recurrences, we performed lymph node dissection. Histological examination revealed moderately differentiated adenocarcinoma as metastatic rectal cancer in para-aortic and hepato-duodenal ligament areas. After the third operation, we started chemotherapy with modified FOLFOX6 regimen. After 2 cycles of modified FOLFOX6 regimen, due to the onset of neutropenia and liver dysfunction, we switched to capecitabine alone and continued it for 6 mo and then stopped. Eleven months after the break, CT detected two swelling 12 mm of lymph nodes at the left supraclavicular region. With diagnosis of Virchow lymph node metastatic recurrence, we started chemotherapy with capecitabine plus bevacizumab regimen. Due to the onset of neutropenia and hand foot syndrome (Grade 3), we managed to continue capecitabine administration with extension of interval period and dose reduction. After 2 years and 2 mo from starting capecitabine plus bevacizumab regimen, Virchow lymph nodes had slowly grown up to 17 mm. Because no recurrence had been detected besides Virchow lymph nodes for this follow up period, considering the side effects and quality of life, surgical resection was selected. We performed left supraclavicular lymph node dissection. Histological examination revealed moderately differentiated adenocarcinoma as a metastatic rectal cancer. After the fourth operation, the patient selected follow up without chemotherapy. Now we follow up her without recurrence and keep her quality of life high.

Esophageal intramural pseudodiverticulosis of the residual esophagus after esophagectomy for esophageal cancer.

A 91-year-old man was referred to our hospital with intermittent dysphagia. He had undergone esophagectomy for esophageal cancer (T3N2M0 Stage III) 11 years earlier. Endoscopic examination revealed an anastomotic stricture; signs of inflammation, including redness, erosion, edema, bleeding, friability, and exudate with white plaques; and multiple depressions in the residual esophagus. Radiographical examination revealed numerous fine, gastrografin-filled projections and an anastomotic stricture. Biopsy specimens from the area of the anastomotic stricture revealed inflammatory changes without signs of malignancy. Candida glabrata was detected with a culture test of the biopsy specimens. The stricture was diagnosed as a benign stricture that was caused by esophageal intramural pseudodiverticulosis. Accordingly, endoscopic balloon dilatation was performed and anti-fungal therapy was started in the hospital. Seven weeks later, endoscopic examination revealed improvement in the mucosal inflammation; only the pseudodiverticulosis remained. Consequently, the patient was discharged. At the latest follow-up, the patient was symptom-free and the pseudodiverticulosis remained in the residual esophagus without any signs of stricture or inflammation.