Frequency of infiltrating regulatory T-cells in the portal tract of biliary atresia.

PURPOSE: Immunological abnormalities have been hypothesized as a pathogenesis of biliary atresia (BA). We previously investigated the frequency and function of circulating regulatory T-cells (Tregs) and reported no differences compared to controls. However, the local Treg profile remains uncertain. We aimed to investigate the frequency of Tregs in BA liver tissues. METHODS: The number of lymphocytes, CD4+ cells, and CD4+FOXP3+ Tregs infiltrating the portal tract and the percentage of Tregs among CD4+ cells of BA and control patients were visually counted. The correlation between these data and clinical indicators was also examined. RESULTS: The number of lymphocytes, CD4+ cells, and CD4+FOXP3+ Tregs was higher in the BA group. However, the percentage of Tregs among CD4+ cells was similar in both groups. Each parameter was correlated with serum γ-GTP, but there was no clear association with liver fibrosis, jaundice clearance, and native liver survival. CONCLUSION: The number of Tregs infiltrating the portal tract was higher in BA patients. However, the infiltration of lymphocytes was also generally increased. Tregs appear to be unsuccessful in suppressing progressive inflammation in BA patients, despite recruitment to local sites. Investigation of Treg function in the local environment is warranted.

[A case of myopathy, myocarditis, and encephalitis with nonconvulsive status epileptics after immune checkpoint inhibitor therapy for ureter cancer].

A 72-year-old man, who had received pembrolizumab of immune checkpoint inhibitor (ICI) over 6 months for ureter cancer, developed progressive skeletal muscle weakness, dysarthria, dyspnea, and consciousness disturbance over the past two weeks. The systemic work-up tests documented an encephalitis, myopathy, and myocarditis. Multiple autoimmune antibodies of anti-Tr, anti-titin, anti-kv1.4, anti-GM1 and anti-GD1a were positive in the serum. Although myopathy and myocarditis responded to high-dose steroid pulse therapy, encephalopathy deteriorated. Electroencephalogram showed a fluctuated pattern of rhythmic delta activity with fast waves, and a rapid response to intravenous diazepam revealed a condition of nonconvulsive status epileptics (NCSE). The patient had an uneventful course after anti-epileptic medication. The ICIs therapy may trigger a broader activation of multiple autoimmune mechanisms. When an encephalitis by immune-related adverse events does not respond to standard immunotherapy, NCSE may be a main pathophysiological mechanism, thereby anti-epileptics being an alternative treatment option.

Anti-Ma2-Associated Limbic Encephalitis after Termination of Immune Checkpoint Inhibitor Therapy for Malignant Pleural Mesothelioma.

Neurological adverse events of immune checkpoint inhibitor (ICI) therapy mostly develop within 3 months after initiation of ICI treatment. An 82-year-old male with malignant pleural mesothelioma developed anti-Ma2-associated limbic encephalitis at a delay of 18 months after the start of nivolumab therapy (3 months after termination of a 15-month course of ICI treatment). Immunotherapy with steroids and immunoglobulins resulted in moderate neurological improvement. Over the next year, malignant pleural mesothelioma gradually worsened, while the anti-Ma2 antibody test remained positive. Anti-Ma2 paraneoplastic encephalitis may occur after a delay following the discontinuation of ICI therapy.

Multi-distance surface-emitting beam profile calculation method based on the FDTD method and the diffraction theory.

A hybrid method to calculate a multi-distance beam profile emitted perpendicular from a surface of a photonic crystal (PhC) is proposed here based on the finite-domain time-difference (FDTD) method and the diffraction theory. Although the FDTD method is available to calculate a near-field emitted from the PhC, it needs too many voxels to calculate mid- and far-fields. Thus, the diffraction theory is additionally applied to obtain the mid- and far-fields using the near-field calculated by the FDTD method. A surface-emitting quantum cascade laser (QCL) that consists of a PhC and an edge-emitting laser source is fabricated to demonstrate the validity of the hybrid method. A measured beam profile of the QCL agrees with that calculated using the hybrid method, which validates applicability of the method to a surface-emitting device.

[Successful treatment of Guillain-Barré syndrome-like acute inflammatory demyelinating polyneuropathy caused by pembrolizumab with a combination of corticosteroid and immunoglobulins: a case report].

A 74-year-old man, who received pembrolizumab for the treatment for non-small cell lung cancer, developed quadriparesis 10 days after the first course of treatment accompanied by gait disturbance. Dysesthesia was observed in the distal extremities, and tendon reflexes were absent. Neurological examination and peripheral nerve conduction study supported the diagnosis of Guillain-Barré syndrome-like acute inflammatory demyelinating polyneuropathy caused by pembrolizumab. The administration of pembrolizumab was discontinued. Moreover, he was initially treated with intravenous immunoglobulin therapy, followed by intravenous methylprednisolone therapy and oral prednisolone. The limb weakness improved to a degree that he could walk alone on discharge. Pembrolizumab, which is an immune checkpoint inhibitor with a high anti-tumor effect, is reported to cause various adverse events. However, neuromuscular complications following cancer treatment with immune checkpoint inhibitors are relatively rare. Treatment with corticosteroids is considered to be effective for treating immune-related adverse events. Corticosteroids were effective in treating peripheral neuropathy caused by immune checkpoint inhibitors in this patient. Thorough treatment should be considered with a combination of corticosteroids and immunoglobulin therapy, in addition to discontinuation of immune checkpoint inhibitors, for this rare entity, which differs from that for idiopathic Guillain-Barré syndrome.

Development of localized cul-de-sac endometrioid carcinoma associated with deep infiltrating endometriosis during remission of early endometrial cancer.

•A cul-de-sac endometrioid carcinoma adjacent to extraovarian endometriosis was identified during remission of endometrial cancer.•The origin of the cul-de-sac tumor was malignant transformation of deep infiltrating endometriosis.•Endometriosis-related cancer was identified in a woman with endometrial cancer during remission.•Hyperestrogenism due to infertility treatment may contribute to malignant transformation of deep infiltrating endometriosis.

Canagliflozin improves obesity and insulin resistance in a diabetic patient with Cushings disease undergoing postoperative steroid therapy: A case report.

A 47-year-old woman with diabetes treated with high-dose insulin was admitted to Mie University Hospital, Tsu, Japan, for screening of secondary diabetes mellitus and obesity. Laboratory tests and imaging studies were consistent with Cushing's disease (CD). The patient underwent trans-sphenoidal pituitary surgery. The patient exhibited loss of body weight (85.9 to 80.0 kg), improved glycated hemoglobin (HbA1c) (11.2 to 7.8%) and required lower doses of insulin (112 to 46 U/day) 6 months after surgery. The patient's body weight and daily insulin dose remained stable during the following 5 months (6-11 months after surgery). At that point, the patient was administered with canagliflozin, a sodium-glucose cotransporter 2 inhibitor. The patient required lower daily insulin dose without decreasing the dose of postoperative hydrocortisone concurrent to the administration of canagliflozin (100 mg/day). The patient's body weight decreased to 69.5 kg and withdrawal of insulin therapy was possible 8 months after initiation of canagliflozin. Despite withdrawal of insulin therapy, the HbA1c levels remained at <7.0%. Although surgical treatment is the first-choice treatment for CD, obesity-related metabolic disorders including diabetes are frequent in CD patients following surgery. Canagliflozin may be an effective treatment to reduce body weight and improve insulin resistance following surgical treatment of CD.

A case of type 2 diabetes mellitus with metformin-associated lactic acidosis initially presenting the appearance of a sulfonylurea-related hypoglycemic attack.

Case: A 64-year-old Japanese woman with diabetes mellitus was admitted for hypoglycemia. Her diabetes had been under good control with glimepiride, voglibose, exenatide, and metformin for a few years. Although overt proteinuria was observed, the serum creatinine values were within normal range during the routine outpatient follow-up. Hypoglycemic attack caused by glimepiride and loss of appetite by urinary tract infection were diagnosed. Then, metformin-associated lactic acidosis with acute renal failure caused by dehydration was detected. Outcome: Her condition was improved by continuous veno-venous hemodiafiltration and hemodialysis, known to be useful to remove metformin. Conclusion: We reported a case of metformin-associated lactic acidosis with hypoglycemia during routine treatment of diabetes that was successfully rescued by early renal replacement therapy.

Sudachitin, a polymethoxylated flavone, improves glucose and lipid metabolism by increasing mitochondrial biogenesis in skeletal muscle.

BACKGROUND: Obesity is a major risk factor for insulin resistance, type 2 diabetes, and stroke. Flavonoids are effective antioxidants that protect against these chronic diseases. In this study, we evaluated the effects of sudachitin, a polymethoxylated flavonoid found in the skin of the Citrus sudachi fruit, on glucose, lipid, and energy metabolism in mice with high-fat diet-induced obesity and db/db diabetic mice. In our current study, we show that sudachitin improves metabolism and stimulates mitochondrial biogenesis, thereby increasing energy expenditure and reducing weight gain. METHODS: C57BL/6 J mice fed a high-fat diet (40% fat) and db/db mice fed a normal diet were treated orally with 5 mg/kg sudachitin or vehicle for 12 weeks. Following treatment, oxygen expenditure was assessed using indirect calorimetry, while glucose tolerance, insulin sensitivity, and indices of dyslipidemia were assessed by serum biochemistry. Quantitative polymerase chain reaction was used to determine the effect of sudachitin on the transcription of key metabolism-regulating genes in the skeletal muscle, liver, and white and brown adipose tissues. Primary myocytes were also prepared to examine the signaling mechanisms targeted by sudachitin in vitro. RESULTS: Sudachitin improved dyslipidemia, as evidenced by reduction in triglyceride and free fatty acid levels, and improved glucose tolerance and insulin resistance. It also enhanced energy expenditure and fatty acid ß-oxidation by increasing mitochondrial biogenesis and function. The in vitro assay results suggest that sudachitin increased Sirt1 and PGC-1α expression in the skeletal muscle. CONCLUSIONS: Sudachitin may improve dyslipidemia and metabolic syndrome by improving energy metabolism. Furthermore, it also induces mitochondrial biogenesis to protect against metabolic disorders.