Pleiotropic Effects of Linagliptin Monotherapy on Levels of Nitric Oxide, Nitric Oxide Synthase, and Superoxide Dismutase in Hemodialysis Patients with Diabetes

Linagliptin is an anti-diabetic drug and the only bile-excreted dipeptidyl peptidase-4 inhibitor. Malnutrition-inflammation-atherosclerosis syndrome is an important prognostic factor for hemodialysis patients, and we previously reported anti-inflammatory effects of linagliptin in hemodialysis patients with diabetes. Inflammation can accelerate oxidative stress, vasoconstriction, and platelet aggregation. However, few studies have investigated the pleiotropic effects of linagliptin treatment on inflammation in hemodialysis patients. In this study, we have extended our previous investigations of these effects in a longer and more thorough follow-up of hemodialysis patients with diabetes. We examined 20 hemodialysis patients with diabetes who were not receiving oral diabetes drugs or insulin therapy and who exhibited inadequate glycemic control (glycated albumin levels＞20%). Linagliptin (5mg) was administered daily, and we evaluated the patients’ superoxide dismutase, 8-hydroxydeoxyguanosine, nitric oxide, nitric oxide synthase, and asymmetric dimethylarginine levels in serum at baseline and after 1, 3, and 6 months of treatment. After 6 months of treatment, superoxide dismutase levels had significantly decreased from 8.8±0.5U/ml to 7.0±0.5U/ml. Nitric oxide synthase levels were significantly increased at 3 and 6 months (maximum, 94.2±13.2µg/ml; baseline, 31.6±5.5µg/ml). After 3 months of treatment, nitric oxide levels had significantly increased from 64.5±6.6µmol/l to 104±15.4µmol/l, and remained significantly elevated at 6 months. Asymmetric dimethylarginine and 8-hydroxydeoxyguanosine levels did not change during the 6-month treatment course, and no patients exhibited hypoglycemia or other significant adverse effects. Linagliptin treatment significantly changed various markers of inflammation relevant to the atherosclerosis in malnutrition-inflammation-atherosclerosis syndrome. Therefore, linagliptin monotherapy has pleiotropic effects on inflammation in hemodialysis patients with diabetes, and may improve their prognosis

Effect of Hydrogen Peroxide and High Glucose on the Glucose Metabolism of Lymphoma-derived U937 Cells

Our study aimed to clarify specific oxidative stress and glucose metabolic disorders in hemodialysis patients, by examining hydrogen peroxide (H2O2) - and high glucose-induced oxidative stress, glucose transport and the failure of glycolysis. As an in vitro blood cell model of end-stage renal disease (ESRD) in patients with diabetes, human monocytic U937 cells of malignant lymphoma origin were exposed to high glucose (28.9mM) for 6 days, with 5mM H2O2 added on the last day. The generation of intracellular reactive oxygen species (ROS), glucose levels, lactate levels, AMP-activated protein kinase (AMPK) activity and Glut4 levels were examined. Exposure of U937 cells to H2O2 resulted in a significant increase in intracellular ROS generation and glucose levels. Under high glucose conditions, treatment with H2O2 significantly promoted these actions. In H2O2-induced U937 cells, AMPK activity and Glut4 levels were significantly increased, but lactate and pyruvate levels were significantly decreased. Thus, exposure of U937 cells to H2O2 and a high glucose load promoted an increase in intracellular ROS, and exposure to H2O2 induced increased glucose transport and high intracellular glucose due to reduced glycolytic metabolism. This suggests that reduced glycolytic metabolism might be induced in states of high oxidative stress in hemodialysis patients with diabetes

The Effectiveness of Combined Medical Therapy and Hemodialysis for Hypercalcemia in Anaplastic Lymphoma Kinase-negative Anaplastic Large Cell Lymphoma

A 71-year-old man with a right lower abdominal quadrant epithelial tumor developed gradually worsening lumbago and dysbasia. He became comatose and was admitted to our hospital. He had swelling of the left axillary lymph nodes and necrosis of the 4.0-cm diameter abdominal tumor, which infiltrated the subcutaneous tissues. He was hypercalcemic (16.7mg/dl), and had elevated levels of soluble interleukin-2 receptor (24,090U/ml) and parathyroid hormone-related protein (5.4pmol/l). Computerized tomography (CT) showed left axillary lymphadenopathy, splenomegaly, and a right abdominal-wall mass that was described as anaplastic large cell lymphoma upon pathology. Brain radiography and CT revealed multiple lesions infiltrating the cranium. Magnetic resonance imaging showed diffuse low signal intensity throughout the vertebral spine. The patient was diagnosed with anaplastic lymphoma kinase (ALK) -negative anaplastic large cell lymphoma with hypercalcemia. Fluid replacement and drug therapies including calcitonin had no effect on the hypercalcemia or the coma. The patient\u27s serum calcium concentration decreased after hemodialysis (calcium dialysate concentration, 5mg/dl) and subsequent zoledronic acid hydrate therapy. His consciousness improved by the fifth day of treatment. This rare case of hypercalcemia in ALK-negative anaplastic large cell lymphoma improved with combined medical and hemodialysis therapy

Effects of ferric citrate on intracellular oxidative stress markers after hydrogen peroxide treatment of human U937 monocytes

Phosphate binders, such as iron （III） citrate hydrate （FCH）, are essential medications for hemodialysis patients. Some in vivo studies have demonstrated that FCH prevented induction of oxidative stress in the presence of transferrin. However, how FCH affects iron-related oxidative stress in the absence of transferrin remains unclear. In the current study, we investigated the effects of ferric citrate （FC） on oxidative stress in the absence of transferrin in vitro to address this question. Human U937 monocytes were pretreated with FC, iron （II） chloride tetrahydrate （FeCl2・4H2O）, iron （III） chloride hexahydrate （FeCl3・6H2O）, or saccharated ferric oxide for 24 h and then treated with 10-mM hydrogen peroxide （H2O2） for 30 min. The final Fe concentrations were adjusted to approximately 200µg/dl. Iron concentration, intracellular reactive oxygen species （ROS） levels, and intracellular lipid peroxidation of the cell membrane were measured. After treatment with FC, iron concentration and ROS levels increased. Change in lipid peroxidation after treatment with FC was not observed. However, after treatment with H2O2, no change was observed in the intracellular ROS levels in FC-pretreated cells, whereas lipid peroxidation of the cell membrane was decreased. Despite the high iron concentration in FC-pretreated cells, neither intracellular ROS nor cell membrane lipid peroxidation levels were increased with H2O2 treatment. Their results might represent antioxidative effects of FC. The results of this study may contribute to a better understanding of the effects of oxidative stress in hemodialysis patients treated with FCH

Denosumab for Male Hemodialysis Patients with Low Bone Mineral Density: A Case-Control Study

Denosumab increases bone mineral density (BMD) in patients not receiving hemodialysis therapy. However, limited data are available in the literature concerning the use of denosumab in hemodialysis patients. We treated male hemodialysis patients with low radius BMD with denosumab therapy for 1 year and evaluated its effect on radius BMD. Seventeen patients were treated with denosumab 60 mg every 6 months, and 20 patients were not treated with denosumab (control group). At seven days, the mean corrected calcium level decreased from 9.2±0.5 mg to 8.5±0.5 mg (P<0.01), and mean serum phosphorus decreased from 5.0±1.3 mg/dl to 4.2±0.9 mg/dl (P<0.01). At 1 month, the corrected calcium and serum phosphorus levels were 9.2±0.9 mg/dl and 4.0±1.1 mg/dl, respectively. At 1 year, BMD increased by 2.6%  ± 4.4% in the denosumab group and decreased by 4.5%  ± 7.7% in the control group (P<0.001). In our observational study, denosumab therapy represents an effective treatment for male dialysis patients with low BMD

Mass media information can facilitate early diagnose of hereditary angioedema: Case series study

Background: A patient’s motivation for consulting a physician is paramount to the first steps of achieving an early diagnosis of hereditary angioedema (HAE). Understanding what triggers this motivation can help in the design of strategies to increase the number of visits to a specialist physician following early symptoms of HAE. The aim of the present study was to identify the reasons that led patients to seek the opinion of an HAE expert physician.Methods: The number of patients who had visited a specialist outpatient clinic for HAE was determined. All patients were asked what motivated them to seek medical consultation. Clinical data and blood samples were collected to establish a diagnosis.&nbsp;Results: Seventy patients visited the clinic within a 30-month period between August 2015 and January 2018. Seven of these patients were diagnosed with HAE. The main source of evidence that prompted the visit to the specialist clinic was websites (67.1%), followed by newspapers (15.7%) and information provided by the home doctor (14.2%). The number of patients per month increased after a rise in the number of publications about HAE in newspapers and websites.Conclusion: Mass media publications are an efficient way to motivate patients to visit an HAE expert physician.</p

Soy isoflavones inducing overt hypothyroidism in a patient with chronic lymphocytic thyroiditis: a case report

Abstract Background Many people have thyroid conditions that make them susceptible to hypothyroidism. If the foods they eat may interfere with the production of thyroid hormone, which can lead to development of serious hypothyroidism. The danger of health drinks should always be noted. Case presentation A 72-year-old Japanese woman was previously diagnosed with chronic lymphocytic thyroiditis caused by a goiter and had an elevated thyroid-stimulating hormone level (6.56 μIU/ml), a high anti-thyroid peroxidase antibody level (>600 IU/ml), and a high antithyroglobulin level (> 4000 IU/ml) but normal levels of free triiodothyronine (3.08 pg/ml) and thyroxine (1.18 ng/ml). She presented to our hospital with sudden-onset general malaise, edema, and hoarseness with an elevated thyroid-stimulating hormone (373.3 μIU/ml) level and very low triiodothyronine (< 0.26 pg/ml) and thyroxine (0.10 ng/ml) levels. It was determined that for 6 months she had been consuming a processed, solved health drink (“barley young leaf”) in amounts of 9 g/day, which included soybean and kale powder extract. Hypothyroidism might be affected by ingredients of health drinks. She discontinued consumption of the health drink immediately and began taking 12.5 μg of levothyroxine. The amount of levothyroxine was gradually increased every 3 days up to 100 μg. At day 61, her thyroid-stimulating hormone level had decreased (6.12 μIU/ml), her free triiodothyronine (2.69 pg/ml) and thyroxine (1.56 ng/ml) levels had increased, and her general condition was improved. Among risky foods lowering thyroid function, some experimental studies have revealed that isoflavones reduce thyroid function. Therefore, we measured the presence of isoflavones in the patient’s frozen serum with thin-layer chromatography. After she discontinued consumption of the health drink, two components quickly disappeared, and the other three components gradually decreased. On the basis of developing solvent composition and a positive ferric chloride reaction in thin-layer chromatography experiment, the five ingredients that disappeared or decreased were highly suspected to be soy isoflavones. Conclusions This case emphasizes that consuming health drinks that include soy isoflavone powder extracts can lead to severe hypothyroidism