Dysregulated expression of fatty acid oxidation enzymes and iron‐regulatory genes in livers of Nrf2‐null mice

Background and Aim: Hepatic excessive iron may play a role in the pathogenesis of non‐alcoholic steatohepatitis (NASH). Nrf2 is a master regulator of antioxidative responses. However, the role of Nrf2 in lipid and iron homeostasis remains unclear. Accordingly, it was examined how Nrf2 regulates lipid‐related and iron‐regulatory genes after feeding a high‐fat diet (HFD) with iron. Methods: Wild‐type and Nrf2‐null mice were fed the following diets: (i) control diet (4% soybean oil) for 12 weeks, (ii) control diet for 8 weeks followed by control diet containing 0.5% carbonyl iron for 4 weeks, (iii) HFD (4% soybean oil and 16% lard) for 12 weeks, (iv) HFD for 8 weeks followed by HFD containing 0.5% carbonyl iron for 4 weeks. Blood and livers were removed after 12 weeks. Results: Nrf2‐null control mice exhibited a tendency towards higher hepatic triglycerides compared to wild‐type control mice. Hepatic malondialdehyde was higher and hepatic iron levels tended to be higher in Nrf2‐null mice than wild‐type counterparts while on a HFD. The HFD with iron synergistically induced mRNA expression of Pparα targets, including Acox and Cpt1 in wild‐type mice, yet the induction was diminished in Nrf2‐null mice. Hepatic hepcidin and ferroportin 1 mRNA expression were increased in wild‐type mice after feeding a HFD with iron, but were unchanged in any group of Nrf2‐null mice. Conclusions: Nrf2 deletion dysregulates hepatic mRNA expression of β‐oxidation enzymes and iron‐related genes, possibly causing a trend for increased hepatic triglyceride and iron concentrations. Nrf2 may have roles in the progression of NASH.     

Education to promote verbal communication by caregivers in geriatric care facilities

Aim: Our previous study divided the verbal communication between caregivers and elderly residents at geriatric care facilities into Type I communication (to elicit activities of daily living) and Type II communication (conversation that occurs in normal social life) and found that Type II communication promotes utterances by elderly residents. This study conducted an education intervention to promote Type II talking by caregivers and evaluated the results. Methods: At three geriatric care facilities, 243 caregivers who might care for 36 elderly residents experienced training involving lectures and group discussion to understand the importance of Type II talking and how to apply it to their daily work. A statistical comparison was applied to the changes in Type II talking duration from before the intervention, 1 week after the intervention, and 3 months after the intervention to evaluate the effect of the educational intervention. Results: At two facilities, the Type II talking duration increased significantly from before the educational intervention to 1 week after the intervention and remained higher after 3 months. However, the educational intervention's effect was not clear at one facility. There was no significant difference in the elderly persons' total utterance duration, but it increased from before the intervention to 1 week after the intervention. Conclusion: After the educational intervention, the amount of Type II talking by the caregivers increased significantly 1 week after the intervention for two facilities, but although the amount of Type II talking was higher at 3 months than before the intervention, it was not as high as 1 week after the intervention.     

Positive association of circulating levels of advanced glycation end products (AGEs) with pigment epithelium-derived factor (PEDF) in a general population

We have recently found that serum levels of pigment epithelium-derived factor (PEDF), a glycoprotein with anti-oxidative and anti-inflammatory properties, are elevated in proportion to the accumulation of the number of the components of the metabolic syndrome. Since formation and accumulation of advanced glycation end products (AGEs) progress under the metabolic syndrome and that PEDF could inhibit the AGE-elicited tissue damage, it is conceivable that PEDF levels may be increased as a counter-system against AGEs in patients with the metabolic syndrome. However, correlation between circulating levels of AGEs and PEDF in humans remains to be elucidated. In this study, we investigated the relationship between serum AGE and PEDF levels in a general population and examined the effects of AGEs on PEDF gene expression in vitro. One hundred ninety-six Japanese subjects in a general population underwent a complete history and physical examination, determination of blood chemistries, including serum levels of AGEs and PEDF. In multiple regression analyses, creatinine, body mass index, triglycerides, AGEs and insulin were independently correlated with serum PEDF levels. AGEs dose-dependently increased PEDF gene expression in cultured adipocytes and liver cells. Our present study demonstrated first that circulating AGEs were one of the independent correlates of serum levels of PEDF. Adipose tissue and liver may be target organs for the AGE-induced PEDF overexpression in humans. Serum PEDF levels may be elevated in response to circulating AGEs as a counter-system against the AGE-elicited tissue damage.     

Laparoscopic Pancreatic Biopsy in Autoimmune Pancreatitis—Report of TWO Cases

Two cases of autoimmune pancreatitis that were diagnosed by laparoscopic pancreatic biopsy are reported. Patient 1 was a 71–year-old woman with obstructive jaundice and dry eyes. Endoscopic retrograde cholangiopancreatography (ERCP) revealed stenosis of the distal common bile duct and proximal main pancreatic duct. Only the head of the pancreas was enlarged. The patient had associated Sjogren's syndrome and sclerosing cholangitis. Patient 2 was a 65–year-old man with obstructive jaundice that occurred after laparoscopic cholecystectomy. ERCP revealed a diffusely irregular and narrowed pancreatic duct and stenosis of the distal common bile duct. The whole pancreas was enlarged. Both patients underwent laparoscopic pancreatic biopsy to rule out pancreatic cancer. The definitive diagnosis in each case was autoimmune pancreatitis. The postoperative course in both cases was uneventful. Both patients recovered quickly with steroid therapy undertaken soon after the biopsy. In summary, a laparoscopic approach for the pancreatic biopsy in autoimmune pancreatitis appears to be feasible and useful in determining the therapeutic strategy. (Dig Endosc 1999; 11: 250–254)     

Noninvasive Risk Stratification of Subjects with a Brugada‐Type Electrocardiogram and No History of Cardiac Arrest

Background: Recent studies suggest that the Brugada‐type electrocardiogram (ECG) is much more prevalent than the manifest Brugada syndrome. Although invasive electrophysiologic investigations have been proposed as a risk stratifier, their value is controversial, and alternative noninvasive techniques may be preferred. We sought a noninvasive strategy to detect a high‐risk group in a long‐term follow‐up study of subjects with a Brugada‐type ECG, and no history of cardiac arrest. Methods: This study enrolled 124 consecutive subjects with a Brugada‐type ECG. Prognostic indices included: age, sex, a family history of sudden death, syncopal episodes, a spontaneous coved‐type ST‐segment elevation, maximal magnitude of ST‐segment elevation, a spontaneous change in ST segment, a mean QRS duration, maximal QT interval, QT dispersion, late potentials (LP) by signal‐averaged ECG, and microvolt T‐wave alternans. Results: Of the 124 subjects, 20 consenting subjects had an implantable defibrillator before follow‐up. During a 40 ± 19‐month follow‐up, 12 subjects (9.7%) reached one of the endpoints (sudden death or ventricular tachyarrhythmia). Of the 12 risk indices, a family history of sudden death, syncopal episodes, a spontaneous coved‐type ST‐segment elevation, a spontaneous change in ST segment, and LP had significant values. In multivariate analysis, a spontaneous change in ST segment had the most significance (a relative hazard, 9.2; P = 0.036). Combined assessment of this index and other significant indices obtained higher positive predictive values (43–71%). Conclusions: A spontaneous change in ST segment is associated with the highest risk for subsequent events in subjects with a Brugada‐type ECG. The presence of syncopal episodes, a history of familial sudden death, and/or LP may increase its value.     

Pulmonary cryptococcosis combined with pulmonary tuberculosis]

We report a rare combination of pulmonary cryptococcosis and pulmonary tuberculosis in a diabetic patient. A 63-year-old man was admitted to our hospital in January 2002 for evaluation of an abnormal chest radiograph. In 1999, the abnormality had first been detected by mass screening radiography. In 2000, an abnormality in a chest radiograph was again detected in a mass screening, and he visited another hospital. A chest CT scan revealed a cavitating lesion and several nodules in the left lower lobe. Fiberoptic bronchoscopy was performed, but was not diagnostic. The patient was referred to our hospital. He had a history of diabetes mellitus starting in 1984. The chest CT scan revealed solid nodules in the left lower lobe and several micronodules in both upper lobes. Video-assisted thoracoscopic surgery was performed and specimens were obtained from the left S8 and left S1 + 2. Histologically, cryptococci were detected in the resected left S8. In addition, mycobacterium tuberculosis was cultured from the resected left S1 + 2. A diagnosis of combined pulmonary cryptococcal and tuberculous infections was made and treatment with itraconazole, isoniazid sodium methansulfonate, rifampicin, and ethambutol hydrochloride was given.     

Clinical application of human CD4+ CD25+ regulatory T cells for the treatment of inflammatory bowel diseases

As our understanding of the immunological and genetic basis of inflammatory bowel disease (IBD) grows, potential therapeutic options are being developed at a rapid pace. Nevertheless, new drugs for IBD are needed because about half of all patients with severe ulcerative colitis (UC) eventually undergo colectomy, and a significant part of Crohn's disease (CD) patients do not respond to standard medical therapies, including immunosuppressants and TNF-alpha neutralising antibodies, or suffer from significant side effects. Finally, recurrence of disease activity following remission is frequent in both UC and CD, and there is an unmet need for effective maintenance strategies. It is well-known that immune responses in the intestine remain in a state of controlled inflammation, suggesting that not only does active suppression by regulatory T (TR) cells play an important role in the normal intestinal homeostasis, but also its dysregulation might lead to the development of IBD. TR cells are functional subsets of T cells that downregulate adaptive immune responses by interfering with the activation of dendritic cells and proliferation of T cells. From experimental work it is now clear that TR cells play a critical role in maintaining immune homeostasis, and several therapeutic approaches have been targeted at the induction of TR cells in order to control mucosal inflammation. Before using TR cells clinically as living immunosuppressants for the treatment of IBD, however, we have to pass many critical checkpoints, such as the in vitro expansion of TR cells and the confirmation of their safety. This paper will discuss recently gained knowledge of human TR cells and the possibility of their clinical usages as a new strategy for the treatment of IBD.