In insulin-resistant states such as obesity, pancreatic β-cells proliferate to prevent blood glucose elevations. Failure of this β-cells proliferative response leads to the development of diabetes. On the other hand, when organs are damaged, cells proliferate to repair the organs. Therefore, these proliferations are compensatory mechanisms aimed at maintaining whole-body homeostasis. We previously discovered vagal signal-mediated systems regulating adaptive proliferation of β-cells and hepatocytes. Neuron-mediated liver-β-cell inter-organ crosstalk is involved in promotion of β-cell proliferation during obesity, and in this system, vagal signals directly stimulate β-cell proliferation. Meanwhile, in the liver, the multi-step mechanisms whereby vagal nerve signals activate hepatic resident macrophages are involved in hepatocyte proliferation after severe injury. Diabetes mellitus develops on the pathological basis of insufficient insulin action. Insulin action insufficiency is attributable to insulin resistance, i.e., the failure of insulin to exert sufficient effects, and/or to impairment of insulin secretion. Impairment of insulin secretion is attributable not only to the β-cell dysfunction but also to functional β-cell mass reduction. In this regard, there are already therapeutic options to increase insulin secretion from residual β-cells, such as sulfonyl urea and incretin-related drugs. In contrast, there are as yet no applicable therapeutic strategies to increase functional β-cell mass in vivo. Therefore, we have conducted the basic investigations to tackle this issue based on the discovery of neuron-mediated liver-β-cell inter-organ crosstalk. This review introduces vagal signal-mediated regulatory systems of adaptive cell proliferation in vivo and efforts to develop cell-increasing therapies based on vagal nerve-mediated cell proliferation.
The cytotoxic T-lymphocyte antigen-4 and programmed cell death 1 pathways are novel therapeutic targets in immune checkpoint inhibitor (ICI) therapy for cancer. However, they may cause endocrine-related adverse events, including hypophysitis, autoimmune thyroiditis and type 1 diabetes mellitus (DM). Moreover, delayed immune-related adverse events (irAEs) after discontinuation of ICI therapy have been reported. Here we report a 60-year-old female patient with advanced renal cell carcinoma with brain metastasis who was treated with nivolumab, ipilimumab and prednisolone. At the 3rd course of combination therapy, the administration was discontinued due to the onset of colitis and the dosage of prednisolone was increased. About half a year after discontinuation, she was admitted to the hospital with general malaise, hyperglycemia (330 mg/dL) and diabetic ketoacidosis. Glycated hemoglobin level was 6.5%. Islet-related autoantibodies were negative. The glucagon tolerance test showed complete depletion of insulin. Therefore, we diagnosed fulminant type 1 DM and treated with multiple daily injections of insulin. The onset of type 1 DM was rapid in many cases treated with combination therapy of ICIs. The present case is a rare case in which fulminant type 1 DM developed about half a year after discontinuation of nivolumab and ipilimumab. The literature shows two cases of type 1 DM occurring 4 months after discontinuation of ICI therapy by nivolumab or atezolizumab. The present case indicates that regular monitoring is mandatory for fulminant type 1 DM and other delayed irAEs after discontinuation of ICI therapy even under the low-dose prednisolone treatment.
Bronchiolitis obliterans is a chronic obstructive respiratory disease involving stenosis or occlusion of the bronchioles and smaller airways. The prognosis of bronchiolitis obliterans is poor, and the patient might require home oxygen therapy and/or lung transplantation. Bronchiolitis obliterans has various etiologies; in children, the most common causes are infections by respiratory pathogens like adenoviruses. In such cases, the condition is termed as postinfectious bronchiolitis obliterans. A 7-year-old girl was diagnosed with bronchial asthma at the age of 1 year and was on a regimen of a leukotriene receptor antagonist and an inhaled corticosteroid. At 1 year of age, she was admitted to our hospital with a respiratory syncytial virus infection, and despite continued treatment with the above drugs, she required frequent readmissions. At the age of 7 years, she was diagnosed with postinfectious bronchiolitis obliterans based on the following findings: mosaic perfusion on high-resolution chest computed tomography and ventilation-perfusion mismatch on ventilation-perfusion scintigraphy. A lung biopsy was not performed due to its invasiveness. It has been suggested that appropriate treatment during the early stage improves the prognosis of bronchiolitis obliterans. This disease might be misdiagnosed as bronchial asthma because of the clinical similarities. In patients who do not respond to the treatment for bronchial asthma, pediatricians should consider other diseases with similar signs and symptoms, such as bronchiolitis obliterans, in the differential diagnosis.
Disasters frequently occur in Turkey. Although there is comprehensive disaster legislation in Turkey, it has not been well studied in terms of gender sensitivity. This study aimed to evaluate the disaster legislation of Turkey in the context of gender equality. We investigated 17 non-technical disaster legislations to determine in what context and to what level disaster management is gender-sensitive in Turkey. We also carried out a workshop with experts from governmental bodies and nongovernmental organizations (NGOs), and academics to discuss the gender sensitivity of the legislations. We found that only two of the 17 legislations included a gender perspective. One legislation addressed gender equality and equity very well, while one was partially gender-sensitive and the others 5 were gender blind. The workshop was conducted in collaboration with the Disaster and Emergency Management Presidency (AFAD) and 33 participants from 19 organizations. The participants agreed that the disaster legislation did not include a gender perspective and acknowledged the importance of integrating a gender perspective into the disaster policies of Turkey. They recommended that the AFAD and emergency response units should have at least one female president or vice president, gender equality training should be provided to officers and managers of government and non-governmental disaster institutions, and a working group should be established to develop strategies that integrate gender perspectives into disaster and emergency policies. The disaster legislation of Turkey is not gender sensitive. It is important to incorporate language terminologies, understanding, and approaches that are sensitive to gender into disaster-related legislation and regulations.
Ultrasonography and fetal heart rate monitoring are subjective assessments of fetal condition, which warrants the need for objective markers to predict fetal condition. Urinary L-type fatty acid-binding protein (L-FABP) levels correlate with hypoperfusion. Elevated amniotic fluid L-FABP levels may represent fetal tissue hypoperfusion since the amniotic fluid contains fetal urine. In this study, we aimed to analyze the effectiveness of amniotic fluid L-FABP as a predictor of fetal condition. We classified singleton pregnancies into groups based on fetal growth restriction (FGR) with and without fetal blood flow abnormalities (FGR and healthy-FGR groups, respectively) and the non-FGR group (control group). We collected amniotic fluid at the time of vaginal delivery, cesarean section and amniocentesis, and compared the patient characteristics, clinical outcomes and amniotic fluid levels of L-FABP between the groups. We analyzed 153 singleton pregnancies and 186 amniotic fluid samples (FGR group, 6 (3.9%) pregnancies and 23 (12.4%) samples; healthy-FGR group, 15 (9.8%) pregnancies and 20 (10.7%) samples; control group, 132 (86.3%) pregnancies and 143 (76.9%) samples). The amniotic fluid L-FABP level was significantly higher in the FGR group compared to that in the healthy-FGR and control groups. Multivariate analysis revealed that the amniotic fluid L-FABP level was not affected by fetal body weight. Additionally, the amniotic fluid L-FABP levels increased significantly in cases with fetal blood flow abnormalities or early gestational age. Therefore, amniotic fluid L-FABP level may be an objective and accurate predictive marker of fetal condition.
Nephrotoxicity occasionally occurs during treatment with immune checkpoint inhibitors (ICIs). Few related studies compare the differences between these drugs. This study aimed to systematically characterize nephrotoxicity after ICI initiation. Data were extracted from the US FDA Adverse Event Reporting System (FAERS) database. Disproportionality analysis, including information components (ICs) and reporting odds ratios (RORs), was performed to determine the potential renal toxicity of ICIs. A total of 7,204 reports of renal adverse events (AEs) were identified in the FAERS database. Renal AEs were most commonly reported for nivolumab (46.84%). Strong signals were detected in male patients combined with ICIs. In the clinical application of ICIs, attention should be paid to patients, especially male patients, with acute kidney injury, nephritis, autoimmune nephritis and other nephrotoxic AEs. The use of ICIs is likely to aggravate their condition.
Behçet’s disease is an inflammatory disease which manifests itself as various symptoms, such as uveitis, oral and genital aphthae, erythema nodosa, gastro-intestinal ulcerations and encephalopathy. Among the manifestations, renal dysfunction is reported in some percentage of the patients with this disorder. We experienced a middle-aged male with Behçet’s disease who showed an extremely high level of urinary β2-microglulin, which is one of the markers of renal dysfunction, despite normal serum creatinine levels. The patient was on non-steroidal anti-inflammatory drug (NSAID) therapy for 7 weeks, and this could have affected his renal dysfunction. The present report suggests that renal injury should not be underestimated in patients with Behçet’s disease, especially in patients using NSAIDs.
The length of hospital stay is an important outcome measure in patients who have undergone pancreaticoduodenectomy. Although postoperative complications are known to adversely affect the length of hospital stay (LOS), the influence of early mobilization on LOS has not been clarified yet. This study aimed to examine the impact of the initial ambulation day, which is one of the components of early mobilization, on LOS after pancreaticoduodenectomy. We retrospectively enrolled patients who underwent pancreaticoduodenectomy between January 2013 and December 2017. Postoperative complications were evaluated using the Clavien–Dindo classification (CDC) system. Patients were divided into two groups based on the median LOS (early and late-discharge groups) and compared to determine their characteristics. Multivariate logistic regression analysis was performed with LOS as the dependent variable. Patients in the late-discharge group were significantly older, had an initial ambulation delay, and had higher rates of advanced disease stages and a CDC grade ≥ IIIa than those in the early discharge group. In the multivariate logistic regression analysis, CDC grade ≥ IIIa, initial ambulation day, and age were found to be significant independent factors associated with LOS. Our results demonstrated that not only postoperative complications, but also the initial ambulation day, could affect LOS after pancreaticoduodenectomy, emphasizing the importance of early ambulation for patients who undergo this surgery.