Factor XI deficiency caused by a mutation of Gly400Val

The patient described herein is a 69-year-old Japanese woman with a history of excessive bleeding after left heminephrectomy for a malignant renal tumor at 31 years of age. Her parents, who do not have abnormal bleeding, are first cousins. Her factor XI activity was less than 1% of normal with an prolonged activated partial thromboplastin time (APTT) of 74.3 seconds. Analysis of the patient's factor XI genes revealed homozygosity for a valine substituting for the wild-type glycine at amino acid 400 (Gly400Val). The patient has two children, neither of whom has abnormal bleeding and whose factor XI activities are 62% and 57% of normal, with APTT levels within normal limits in both cases. We herein report on a Japanese family with factor XI deficiency caused by Gly400Val mutation.     

A case report of hemodialysis intolerance with eosinophilia

We report the case of a patient who developed eosinophilia during hemodialysis and became intolerant to dialysis therapy. The patient, a 40-year-old woman, was initiated on hemodialysis for end-stage renal failure caused by chronic glomerulonephritis. After starting on dialysis, her eosinophil count gradually increased. During the ninth session, she developed abdominal pain of an unknown cause after approximately 1 h of dialysis. The symptom, which persisted in the following sessions, was considered to be a dialysis-related complication. We attempted different dialyzers and anticoagulants, but without improvement. The dialysis therapy was discontinued and steroid treatment was given. The hypereosinophilic condition improved rapidly and dialysis therapy was restarted successfully without causing abdominal pain. To investigate the cause of this problem, we measured the leukocyte count and anaphylatoxin C3a level in peripheral blood during dialysis, and compared the results before and after steroid treatment. The results showed that the significant decrease in the leukocyte count observed before steroid treatment was reduced to a mild decrease after steroid treatment. In contrast, C3a did not show a significant difference between the values obtained before and after steroid treatment. These findings suggest that eosinophilia played an important role in the etiology of dialysis intolerance and that C3a was not involved in the decrease in leukocytes under the conditions experienced by the present patient.     

Stanford type A aortic dissection with Child B liver cirrhosis

Cardiac surgery using cardiopulmonary bypass in patients with advanced liver cirrhosis has been infrequently performed, and reported to be too risky. Aortic dissection accompanied with liver cirrhosis is extremely rare. A 61-year-old woman who had aortic dissection and Child B liver cirrhosis underwent ascending aorta replacement. Liver protection during cardiopulmonary bypass was successfully accomplished by moderate hypothermia and use of an aortic occlusion balloon to maintain sufficient hepatic blood flow.     

Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet

Recently, nonalcoholic steatohepatitis (NASH) was found to be correlated with cardiovascular disease events independently of the metabolic syndrome. The aim of this study was to investigate whether an atherogenic (Ath) diet induces the pathology of steatohepatitis necessary for the diagnosis of human NASH and how cholesterol and triglyceride alter the hepatic gene expression profiles responsible for oxidative stress. We investigated the liver pathology and plasma and hepatic lipids of mice fed the Ath diet. The hepatic gene expression profile was examined with microarrays and real-time polymerase chain reactions. The Ath diet induced dyslipidemia, lipid peroxidation, and stellate cell activation in the liver and finally caused precirrhotic steatohepatitis after 24 weeks. Cellular ballooning, a necessary histological feature defining human NASH, was observed in contrast to existing animal models. The addition of a high-fat component to the Ath diet caused hepatic insulin resistance and further accelerated the pathology of steatohepatitis. A global gene expression analysis revealed that the Ath diet up-regulated the hepatic expression levels of genes for fatty acid synthesis, oxidative stress, inflammation, and fibrogenesis, which were further accelerated by the addition of a high-fat component. Conversely, the high-fat component down-regulated the hepatic gene expression of antioxidant enzymes and might have increased oxidative stress. CONCLUSION: The Ath diet induces oxidative stress and steatohepatitis with cellular ballooning. The high-fat component induces insulin resistance, down-regulates genes for antioxidant enzymes, and further aggravates the steatohepatitis. This model suggests the critical role of lipids in causing oxidative stress and insulin resistance leading to steatohepatitis.     

Long-term phlebotomy with low-iron diet therapy lowers risk of development of hepatocellular carcinoma from chronic hepatitis C

Background We have previously demonstrated that in patients with chronic hepatitis C (CHC), iron depletion improves serum alanine aminotransferase (ALT) levels as well as hepatic oxidative DNA damage. However, it has not been determined whether continuation of iron depletion therapy for CHC favorably influences its progression to hepatocellular carcinoma (HCC). Methods We conducted a cohort study on biopsy-proven CHC patients with moderate or severe liver fibrosis who failed to respond to previous interferon (IFN) therapy or had conditions for which IFN is contradicted. Patients were divided into two groups: subjects in group A (n = 35) underwent weekly phlebotomy (200 g) until they reached a state of mild iron deficiency, followed by monthly maintenance phlebotomy for 44–144 months (median, 107 months), and they were advised to consume a low-iron diet (5–7 mg iron/day); group B (n = 40) comprised CHC patients who declined to receive iron depletion therapy. Results In group A, during the maintenance phase, serum ALT levels decreased to less than 60 IU/l in all patients and normalized (<40 IU/l) in 24 patients (69%), whereas in group B no spontaneous decrease in serum ALT occurred. Hepatocarcinogenesis rates in groups A and B were 5.7% and 17.5% at the end of the fifth year, and 8.6% and 39% in the tenth year, respectively. Multivariate analysis revealed that iron depletion therapy significantly lowered the risk of HCC (odds ratio, 0.57) compared with that of untreated patients (P = 0.0337). Conclusions Long-term iron depletion for CHC patients is a promising modality for lowering the risk of progression to HCC.     

Enhanced cell-to-cell contacts between activated microglia and pyramidal cell dendrites following kainic acid-induced neurotoxicity in the hippocampus

Microglia participate in immune responses in the brain. However, little is known about the contact-mediated interaction between microglia and neurons. We report here that the cell-to-cell contacts between microglial processes and dendrites of hippocampal CA1 neurons were dramatically increased in density and area following local injection of kainic acid (KA). A similar KA-induced increase in the degree of intercellular contacts was observed in mice lacking telencephalin (TLCN), a neuronal dendritic adhesion molecule of ICAM family. The results suggest that adhesive contacts independent of TLCN and contact-mediated interactions between microglia and dendrites were promoted by excitotoxic brain injury.     

Decreased serum levels of hepatocyte growth factor in male adults with high-functioning autism

BACKGROUND: The mechanisms underlying the pathophysiology of autism are currently unknown. Given the role of hepatocyte growth factor (HGF) in brain development, we hypothesized that HGF plays a role in the pathophysiology of autism. In this study, we studied whether serum HGF levels are altered in subjects with high-functioning autism. METHODS: Using an enzyme-linked immunosorbent assay (ELISA), we measured serum levels of HGF in 17 male adults with high-functioning autism and age-matched 18 male healthy subjects. RESULTS: The serum levels (503.5+/-160.5 pg/mL (mean+/-SD)) of HGF in the subjects with high-functioning autism were significantly (Mann-Whitney U=34.0, p<0.001) lower than those (817.6+/-232.4 pg/mL (mean+/-SD)) of control subjects. However, there were no correlations between serum HGF levels and clinical variables in the patients. CONCLUSIONS: This study suggests that reduced HGF levels may play a role in the pathophysiology of high-functioning autism.     

Short-chain aldehyde-derived ligands for RAGE and their actions on endothelial cells

The formation and accumulation of advanced glycation endproducts (AGE) have been implicated in the development of diabetic vascular complications. Their biological responses are known to be mediated by the receptor for AGE (RAGE). Recently, AGE have been proposed to be derived not only from the classical Maillard reaction but also from other pathways of sugar autoxidation and metabolism. Here, we report the identification of glyceraldehydes (Gcer)- and glycolaldehyde (Gcol)-derived AGE as RAGE ligands and their presence in vivo. The apparent dissociation constants assessed by surface-plasmon resonance (SPR) analysis with purified human RAGE proteins were 360 nM for Gcer-AGE and 1.35 microM for Gcol-AGE. The radiolabeled-ligand binding assay with RAGE-expressing COS-7 cells revealed similar association kinetics. Competitive SPR assay with antibodies specific to the respective AGE fractions demonstrated abundant existence of both Gcer- and Gcol-AGE in RAGE affinity-purified proteins from human sera. The serum contents of Gcer- and Gcol-AGE in a diabetic patient were about twice as high as those in a healthy control. Functionally, Gcer- and Gcol-AGE upregulated the endothelial cell levels of mRNA for vascular endothelial growth factor (VEGF) and the secretion of its protein product into the culture media and DNA synthesis in a dose-dependent manner. Further, these endothelial responses were augmented by RAGE overexpression. The results suggest that RAGE engagement of Gcer- and Gcol-AGE may elicit angiogenesis through the induction of autocrine VEGF, thereby contributing to the development and progression of diabetic angiopathies.