Impacts of Recombinant Human Erythropoietin Treatment During Predialysis Periods on the Progression of Chronic Kidney Disease in a Large‐Scale Cohort Study (Co‐JET study)

The effect of recombinant human erythropoietin (rHuEPO) treatment on the progression of chronic kidney disease (CKD) has not been fully evaluated in Japan. We therefore retrospectively evaluated this in a sub‐cohort of a prospective multicenter study to investigate optimal hemoglobin (Hb) level of CKD patients on hemodialysis (HD) treated with rHuEPO; Japan Erythropoietin Treatment Study for Target Hb and Survival (JET study). Effect of rHuEPO treatment during predialysis period to delay initiation of HD was retrospectively assessed in 2434 patients from the JET study comparing groups with and without rHuEPO treatment. The assessment was done by Cox proportional hazards regression analysis and inverse probability‐weighted (IPW) analysis to adjust for time‐dependent confounders. The weights used in the IPW analysis were calculated using a logistic model that included baseline confounders and time‐dependent variables. During the predialysis period, 71.7% (1746 patients) were treated with rHuEPO (mean Hb level of 8.7 g/dL at initiation of rHuEPO treatment). Covariates significantly associated with initiation of rHuEPO treatment were Hb level, serum creatinine level, age, diabetes, cardiac insufficiency, and hypertension. The adjusted hazard ratio for time until HD initiation under rHuEPO treatment was 0.272 (95% CI, 0.223–0.331; P < 0.001) in the Cox analysis and 0.63 (95% CI, 0.53–0.76; P < 0.0001) in the IPW analysis. This retrospective study suggests that rHuEPO treatment during the predialysis period has preventive effects on the progression of CKD although further prospective investigation on the efficacy is needed.     

Direct ESR Measurement of Free Radicals in Mouse Pancreatic Lesions

In this experiment, free radicals in the pancreas of endotoxemia and ethionine induced acute pancreatitis in mice were attempted to be detected directly by ESR spectroscopy, using 77 freeze-trapping and 25 °C DMPO spin trapping techniques. In the 77 K freeze-trapping method, Mn (II) ion and R-00’ radical were detected in endotoxemia and ethionine induced pancreatic lesions. The heme-NO radical was observed at 6 and 24 h after isolation of the normal pancreas, and signal intensity was increased with time. This finding supports that ESR spectroscopy is a useful method for detecting the tissue degeneration process from ischemia to necrosis. Using the DMPO spin trapping technique (25 °C), 6-line was detected at 6 h after intraperitoneal administration ofE. coli in the model of endotoxemia, and 3- and 6-lines and a signal suggestive of DMPO-OH adduct were noted at 12 and 24 h in ethionine pancreatitis. These findings suggest that impaired, pancreatic tissues exist in a considerably oxidative environment and oxygen derived free radicals may be considered to play an important role in the development of pancreatic lesions.     

Bile flow in a mutant Sprague-Dawley rat with defective biliary excretion of glutathione

The Eisai hyperbilirubinemic rat is a mutant strain of Sprague-Dawley origin with hereditary defects in the biliary excretion of bilirubin glucuronide, glutathione, and several other organic anions. The correlation between bile flow and bile acid excretion rates during taurocholate infusion revealed that bile acid-independent flow was smaller in the mutant than in intact Sprague-Dawley rats (19.3 vs 56.0 μl/kg per min), while bile acid-dependent flow was similar. The correlation between bile flow and glutathione excretion rates in Sprague-Dawley rats with modified hepatic glutathione levels revealed that a certain portion of bile flow was proportional to the biliary excretion of glutathione, with a coefficient of 551 bile per 1 mol glutathione. One-third of bile acid-independent bile flow in intact Sprague-Dawley rats was accounted for by glutathione osmosis, which feature was absent in the mutant rats.     

Intravenous administration of class I antiarrhythmic drug induced T wave alternans in an asymptomatic Brugada syndrome patient

A 53-year-old man with an abnormal ECG was referred to the Nihon University School of Medicine. The 12-lead ECG showed right bundle branch block and saddleback-type ST elevation in leads V1-V3 (Brugada-type ECG). Signal-averaged ECG showed positive late potentials. Double ventricular extrastimuli (S1: 500 ms, S2: 250 ms, S3: 210 ms) induced VF. Amiodarone (200 mg/day) was administered for 6 months and programmed ventricular stimulation was repeated. VF was induced again by double ventricular stimuli (S1: 600 ms, S2: 240 ms, S3: 170 ms). Intravenous administration of class Ic antiarrhythmic drug, pilsicainide (1 mg/kg), augmented ST-T elevation in leads V1-V3, and visible ST-T alternans that was enhanced by atrial pacing was observed in leads V2 and V3. Visible ST-T wave alternans disappeared in 15 minutes. However, microvolt T wave alternans was present during atrial pacing at a rate of 70/min without visible ST-T alternans.     

Divergent effects of lithium and sodium valproate on brain-derived neurotrophic factor (BDNF) production in human astrocytoma cells at therapeutic concentrations

Mood stabilizers such as lithium (Li) or valproic acid (VPA) are used in the therapy of bipolar disorders, but the mechanisms by which these medicines work is unclear. Recently, neuroprotection has attracted attention as a potential action for VPA and Li. The close spatial relationship of the pre- and post-synapse with an astrocyte process within a 'tripartite synapse' suggests that mood stabilizer actions on astrocytes may be important. Therefore, we examined the effect of Li and VPA, at therapeutic concentrations, on brain-derived neurotrophic factor (BDNF) production in cultured human astrocytoma cells over an extended period of exposure. Released (extracellular) and intracellular BDNF was measured with sandwich-ELISA. Intracellular BDNF mRNA was also quantified using RT-PCR. VPA treatment potentiated the level of extracellular BDNF, whereas Li reduced it. Furthermore, VPA caused increased intracellular levels of BDNF protein and mRNA, while exposure to Li led to no significant differences compared to control cells. We suggest the possibility that VPA and Li have divergent effects on astrocyte BDNF production. Mood stabilizers play an essential role in regulating BDNF not only in neurons, but also in astrocytes. These findings could form the basis of a new astrocyte-targeted approach towards developing effective medications to treat bipolar disorders.     

Clinicopathological Significance of Nuclear Accumulation of Tumor Suppressor Gene p53 Product in Primary Lung Cancer

Since the nuclear accumulation of p53 protein is known to correspond well with mutation of the p53 tumor suppressor gene, the authors examined 88 primary lung cancer specimens immunohistochemically using anti-p53 mouse monoclonal antibody, pAb1801, and analyzed the relationship between the immunohistochemical results and clinicopathological features. Nuclear localization of p53 protein was found in 43/88 (49%) tumor specimens, but not in the corresponding normal lung tissues. The percentage of cases showing nuclear p53 localization varied according to the histological type. In squamous cell carcinoma, nuclear p53 localization was found in 15/26 (57%), appearing more frequently than in other histologic types. However, no obvious correlation was observed between nuclear p53 localization and patients' age, sex, history of smoking, TNM factor, degree of differentiation, or any other clinicopathological features analyzed. In adenocarcinoma, nuclear p53 localization was found in 20/46 (43%). Incidence of positive cases was significantly correlated with regional lymph node metastasis, distant metastasis, and pathological stage ( P < 0.05). These results indicate that mutation of the p53 tumor suppressor gene plays an important role in the development of primary lung cancer, and that nuclear accumulation of p53 protein is a potential prognostic factor in adenocarcinoma of the lung.     

Increased intestinal absorption of insulin in a micellar solution: Water-in-oil-in-water insulin micelles

Summary Water-in-oil-in-water (W/O/W) insulin micelles were prepared, and the possibility of insulin absorption in a micellar form was examined. In this preparation, insulin was trapped in oil droplets of oleic acid in glyceryl-α-monooleate. (1) W/O/W insulin micelles were absorbed from the ligated jejunal loop of rabbits to the order of 12.3 to 58.5% of the dose given (10 U/kg body weight) during the 3-h experimental period. (2) Alloxan diabetic rats were treated with intrajejunal administration of W/O/W insulin micelles at a dosage of either 25 or 50 U/100 g body weight, three times daily for as longs as 14 days. During treatment, a significant reduction in the daily excretion of urinary glucose was observed, concomitant with a decrease in fasting blood glucose. Quantitative estimates suggested that the effectiveness of 25 U/100 g of intrajejunal W/O/W insulin micelles was comparable to that of regular insulin at a dosage of 1 U/100 g i.m. These results would indicate that W/O/W insulin micelles, when given enterally, are more effective in lowering blood and urinary glucose levels than W/O/W insulin emulsions in which insulin was trapped in oil droplets of triglyceride.     

Clinical experience of emergency coronary artery bypass grafting following failed percutaneous transulminal coronary angioplasty

From July, 1981 to December, 1988, 2431 percutaneous transluminal coronary angioplasties were performed on 1901 patients at the Heart Institute of Sào Paulo University Medical School. Seventy-six patients (4.0 per cent) underwent emergency coronary artery bypass grafting for failed angioplasty. The incidence of failed angioplasty was significantly higher in the impending myocardial infarction group (11.5 per cent) than in the angina group (4.8 per cent) and the acute myocardial infarction group (1.3 per cent). The mean age of the seventy-six patients was 54.4 years, and 54 patients were male. The operative mortality was 15.8 per cent, being 9 males and 3 females. Patients who had had a left main trunk dissection during angioplasty and those who were hemodynamically unstable following the failed angioplasty or who had had a cardiac arrest necessistating a cardiac massage during transportation to the operating room, had a higher mortality than patients in whom the failure occurred in other sites and those who were hemodynamically stable. Perioperative myocardial infarction was documented in 50 per cent of the patients. Patients who had had a cardiac arrest during the procedure had a higher rate of perioperative myocardial infarction than those whose preoperative hemodynamic condition was stable.     

Soluble Programmed Cell Death Ligand 1 as a Novel Biomarker for Nivolumab Therapy for Non–Small-cell Lung Cancer

Background

Biomarkers for predicting the effect of anti–programmed cell death 1 (PD-1) monoclonal antibody against non–small-cell lung cancer (NSCLC) are urgently required. Although it is known that the blood levels of soluble programmed cell death ligand 1 (sPD-L1) are elevated in various malignancies, the nature of sPD-L1 has not been thoroughly elucidated. We investigated the significance of plasma sPD-L1 levels as a biomarker for anti–PD-1 monoclonal antibody, nivolumab therapy.