Investigation of the renal injury caused by liver ischemia-reperfusion in rats

To explain the mechanism of renal injury caused by liver ischemia-reperfusion, we investigated biochemical and morphological changes in the liver and kidney in rats. After reperfusion following 60 min of liver ischemia, numerous changes were found. The level of serum transaminases and lipid peroxide formation in the liver tissue increased significantly. Electron microscopic studies revealed that most of the hepatocytes had swollen mitochondria and clumping of the nuclear chromatin. The sinusoidal endothelium was disrupted and the sinusoidal lumen was filled with numerous erythrocytes. Blood endotoxin concentration, plasma lipid peroxide levels, and serum -glucuronidase activities were significantly higher than in the control group. Biochemical and morphological renal injury was also observed. Tissue lipid peroxide levels increased in both the kidney and the liver. Microscopic examination revealed damage to the renal tubules, including interstitial edema, dilatation of the lumen, and granular casts derived from necrotic cells in the proximal convoluted tubule. The levels of urinary N-acetyl--d-glucosaminidase (NAG) in the liver ischemia-reperfusion group were also higher than in the control group. These results suggest that the renal injury was caused by an increase in endotoxin, lipid peroxide, and lysosomal enzymes in the blood following the liver injury induced by the ischemia-reperfusion.     

Manganese deposition in the globus pallidus in patients with biliary atresia

BACKGROUND: Chronic liver diseases may alter trace element contents in the brain. Among these trace elements, manganese is a ubiquitous transition metal excreted by the liver into the bile. Blood concentrations of manganese are elevated in patients with biliary atresia who have undergone hepatic portoenterostomy. The present study investigated the effects of liver transplantation on manganese deposition in the brain in such patients. METHODS: The signal intensity of the globus pallidus was calculated as an index defined as the percentile ratio of signal intensity in the globus pallidus to the subcortical frontal white-matter in sagittal T1-weighted magnetic resonance imaging planes. RESULTS: Brain magnetic resonance imaging revealed hyperintense signals in the globus pallidus due to manganese deposition in biliary atresia patients. Few neurologic symptoms related to manganese intoxication were observed. However, one 23-year-old female with biliary atresia had depressive symptoms and dyskinesia; she improved after oral administration of the dopamine precursor, L-DOPA. Manganese deposition disappeared in two patients after living-related reduced-size hepatic transplantation. CONCLUSIONS: Manganese accumulates in the brain during cholestasis associated with biliary atresia and disappears after hepatic transplantation. Manganese deposition is likely to be subclinical and reversible but may be associated with some age-related neurologic symptoms.     

Cytotoxic Mechanisms of FK317, a New Class of Bioreductive Agent with Potent Antitumor Activity

FK317 is a member of a new class of bioreductive agents that exhibit strong cytotoxicity against various human cancer cells. The effect of FK317 was found to be stronger than that of mitomycin C (MMC), adriamycin (ADR) or cisplatin (CDDP). Alkaline elution analysis indicated that FK317 formed interstrand DNA-DNA and DNA-protein cross-links in cells. On the other hand, no DNA single-strand breaks were observed in the cells treated with FK317. In a cell-free system the deacetylated metabolites produced cross-linked DNA under reductive conditions, though FK317 itself did not form DNA-DNA cross-links. In order to elucidate the metabolic activation mechanisms, we established an FK317-resistant subline from human non-small cell lung cancer cells (Lu99) by stepwise and brief exposure (1 h) to FK317. The resistant subline (Lu99/317) showed cross-resistance to MMC and carboquone (CQ), but not to ADR or CDDP. DT-diaphorase, which is one of the activation enzymes of MMC and CQ, was deficient in Lu99/317 cells as determined by enzyme activity assay. However, the levels of NADPH:cytochrome P450 reductase, which is another activation enzyme for MMC and CQ, were comparable in resistant and parent cell lines. Treatment of the cells with dicumarol, an inhibitor of DT-diaphorase, reduced the cytotoxicity of FK317 to Lu99 cells, but not to Lu99/317 cells. These results indicate that deacetylation of FK317 is necessary for its reductive activation, and deacetylated FK317 is reduced by DT-diaphorase to form an active metabolite, which produces DNA-DNA interstrand and DNA-protein cross-links that lead to cell death.     

Manganese deposits in patients with biliary atresia after hepatic porto-enterostomy

PURPOSE: The aim of this study was to determine if there is latent manganese toxicity in patients with biliary atresia. METHODS: Fifteen children with biliary atresia were examined postoperatively with regard to whole-blood manganese levels using brain magnetic resonance imaging (MRI) and I-123 iodoamphetamine (IMP) per rectal portal scintigraphy. RESULTS: Nine (60%) of the 15 had high whole-blood manganese levels (mean, 4.1 microg/dL; range, 1.2 to 9.6; normal, 0.5 to 2.5), and these 9 had hyperintense globus pallidus on T1-weighted images, with no corresponding signal change in T2 sequences. I-123 IMP per rectal portal scintigraphy was done for 13 patients to evaluate portosystemic shunt flow. 12 (92%) of these patients had an increased flow. Mean shunt ratio was estimated to be 41% (range, 0.6 to 98; normal, <5%). Encephalopathy was evident in only 1 patient. CONCLUSIONS: Some patients with biliary atresia in the postoperative period have manganese deposits in globus pallidus on T1-weighted images and high whole-blood manganese levels, possibly caused by increased portsystemic shunt, and a latent or subclinical encephalopathy is also present.     

The relationship between fibromyalgia and depression,anxiety, anxiety sensitivity,fear avoidance beliefs,and quality of life in female patients

The study aims to determine whether there is a relationship between fibromyalgia (FM) disease and depression, anxiety, anxiety sensitivity, fear-avoidance beliefs, and quality of life in female patients with a diagnosis of fibromyalgia. 37 female patients followed up with FM diagnosis in pain medicine clinic and a control group consisting of 37 healthy women were included in the study. Sociodemographic and Clinical Characteristics Data Form, Quality of Life Form, fear-avoidance beliefs questionnaire, Anxiety Sensitivity Index-3, Beck Anxiety Inventory, Beck Depression Inventory, and Visual Analogue Scale was applied to the participants. When the patients in the FM group were compared to the control group; Statistically lower scores in all Quality of Life Form subscales except emotional role difficulty and social functionality scores; statistically higher scores in both physical and work activity subscales in fear-avoidance beliefs questionnaire; statistically higher scores in cognitive symptoms subscale in Anxiety Sensitivity Index-3, Beck Anxiety Inventory, Beck Depression Inventory, and Visual Analogue Scale scores were found. In FM patients, it has been determined that anxiety, depression and perceived pain severity reduce social functionality and quality of life in areas such as mental health, physical function, and emotional role difficulties. It was determined that the functionality and quality of life of patients diagnosed with FM decreased in daily life. An important contribution of the study to the literature is that it shows that the behavior of avoiding activity due to pain-induced fear exacerbates the pain and even contributes to its chronicity. These results, which show the effects of anxiety, depression, anxiety sensitivity, and fear-avoidance behavior on the prognosis of the disease in FM patients, indicate that psychiatric evaluation and treatment in FM patients is an important factor that determines the functionality and quality of life.     

Phospholamban p.Arg14del Cardiomyopathy: A Japanese Case Series

Phospholamban p.Arg14del is reported to cause hereditary cardiomyopathy with malignant ventricular tachycardia (VT) and advanced heart failure. However, the clinical courses of Japanese cardiomyopathy patients with phospholamban p.Arg14del remain uncharacterized. We identified five patients with this variant. All patients were diagnosed with dilated cardiomyopathy (DCM), developed end-stage heart failure and experienced VT requiring implantable cardioverter defibrillator discharge. Four patients survived after implantation of a left ventricular assist device (LVAD), while one patient who refused LVAD implantation died of heart failure. Based on the severe course of the disease, we propose genetic screening for phospholamban p.Arg14del in DCM patients.     

Predictive Factors for the Development or Regression of Fatty Liver in Japanese Adults

Fatty liver is commonly associated with alcohol or metabolic syndrome. We aimed to examine the longitudinal aspects of fatty liver, and clarify the independent predictors for the development or regression of fatty liver. In the present study, the clinical features of 1578 Japanese adults (1208 men and 370 women; 35 to 69 years of age) who visited our center both in 2000 and 2007–2008 were recorded and compared, including liver status diagnosed by ultrasonography. Of the 1578 participants, 217 (13.8%) showed fatty liver development, and 74 (4.7%) showed fatty liver regression. Logistic regression analysis revealed that body mass index and percentage body fat were strongly associated with the development or regression of fatty liver. Metabolic syndrome-related disorders such as serum levels of total cholesterol, triglyceride, uric acid, and fasting blood glucose were also associated with clinical course to some degree. However, the history of alcohol intake, the presence of metabolic syndrome, blood pressure, and habitual physical exercise were not independent predictors for the development or regression of fatty liver. Our present data suggest that control of body weight in men and the percentage body fat in women are particularly important for the prevention or treatment of fatty liver.     

A case of rapid development of arc welder's lung during the course of a year]

A 57-year-old man who had worked as a welder for about 40 years was admitted to our hospital. Every year he had had medical examinations in his workplace. On March 17, 1999, there was no finding of pneumoconiosis, but he had worked in a tunnel on a special arc welding project from December 20, 1999 to January 10, 2000. On admission, chest radiography revealed reticular shadows in the middle and lower lung fields. CT scans showed ground-glass opacities in both lungs. Serum iron was high (231 micrograms/dl) and serum ferritin was extremely high (2,309 ng/ml). Many iron particles were detected in the alveoli of the transbronchial biopsy specimen, and also in the sputum. A pathological diagnosis of siderosis was therefore made, and, considering the patient's occupation, the condition was termed arc welder's lung. This rapidly developing case was characterized by reticular shadows on chest radiography.     

Blockade of menstrual cycle by thyroidectomy in Japanese monkeys (Macaca fuscata fuscata)

To examine the role of thyroid hormones in the seasonal breeding cycle in Japanese monkeys (Macaca fuscata fuscata), sexually mature females were thyroidectomized (n=6) in early December, during the midbreeding season, or they received sham operations (n=4). They were housed indoors individually, and blood samples were collected two to three times a week to monitor gonadotropin and gonadal steroid hormone secretions. Control monkeys exhibited ovulatory cycles during the breeding season. The mean dates of onset and end of the ovulatory cycles were October 22±13 d and February 25±14 d, respectively. These dates coincided well with those of our colonies under captivity. By contrast, three of the six thyroidectomized monkeys terminated ovulatory cycles immediately after operations; the remaining three monkeys ovulated only once or twice after thyroid removal. The mean dates of onset and end of the ovulatory cycles of thyroidectomized monkeys were October 18±4 d and December 31±4 d, respectively. This was a significantly earlier termination of the ovulatory cycles than in controls. Mean concentrations of plasma thyroxine of control monkeys were maintained throughout the experimental period, whereas plasma thyroxine concentrations of thyroidectomized monkeys decreased abruptly to undetectable levels. Thyroidectomized monkeys exhibited significantly higher levels of plasma prolactin (PRL) than controls. Moreover, even in control monkeys, plasma PRL increased during the transition out of the breeding season. These results suggest that thyroid hormones play an important role in the regulation of ovulatory cycles in Japanese monkeys, directory or indirectly, possibly by mediating the changes of PRL secretion.