Factors modifying the prognosis of Wilson's disease in childhood

The prognosis of Wilson's disease was investigated in 96 patients, in whom the disease had presented before 15 years of age and had begun between 1965 and 1983 (when D-penicillamine was widely available in Japan). In the activities of daily living, the prognosis was poor in those patients presenting with neurological symptoms. Interruption of D-penicillamine treatment was seen in one third of the patients, and it worsened the prognosis. Toxic side effects were seen in about half of the patients, being more frequent in the patients with initial neurological symptoms. A disappointing 17% of patients with slight or no side effects discontinued the drug. Death occurred in eight patients of whom seven had had initial hepatic symptoms. Not only early diagnosis and treatment before the appearance of hepatic failure or neurological symptoms, but also treatment throughout life without interruption is important for improving the prognosis of Wilson's disease.     

Recent advances in understanding how interleukin 13 signals are involved in the pathogenesis of bronchial asthma

The prevalence of allergic disease has dramatically increased in recent decades, especially in urban and industrialized areas. Allergic diseases are disorders of the immune system, the results of complex interactions among various genetic and environmental factors. Among them, the important role of interleukin 13 (IL-13), a Th2-type cytokine, has recently emerged in the pathogenesis of bronchial asthma. Based on studies using mice, great attention has been paid to the direct effects of IL-13 on bronchial tissues. In this review, we describe recent advances in understanding the signal transduction mechanism of IL-13, the involvement of IL-13 signal-related genes as genetic factors in the pathogenesis of bronchial asthma, and the expression of IL-13 receptor on bronchial tissues. We describe potential strategies for targeting IL-13 signals to improve allergic states.     

Increased bcl-2 expression in lymphocytes and its association with hepatocellular damage in patients with autoimmune hepatitis

The proto-oncogene product bcl-2 is known to inhibit apoptotic cell death, and its dysregulation might play a critical role in the development of autoimmune disease. To elucidate the role of bcl-2 in autoimmune hepatitis (AIH), its expression in peripheral blood mononuclear cells (PBMC) and in liver-infiltrating lymphocytes (LIL) was investigated. Increased bcl-2 expression in PBMC was found in AIH patients compared with that in chronic hepatitis C (CHC) patients and in healthy controls. The level of bcl-2 expression significantly correlated with serum ALT level. Further analysis showed that CD4+ T cells are enriched in bcl-2-expressing PBMC. To characterize the Th1/Th2 profile of bcl-2-expressing CD4+ T cells, intracellular interferon-gamma (IFN-gamma) and IL-4 were analysed. The results revealed that most of the bcl-2-expressing cells were found to be IFN-gamma-secreting Th1 cells. In three patients for whom their clinical courses could be followed, bcl-2 expression was decreased after the initiation of immunosuppressive therapy with corticosteroids. However, the level of IFN-gamma + cells was not altered. Immunohistochemical analysis also showed that large amounts of bcl-2+ cells were observed in periportal area in the liver. In conclusion, bcl-2-expressing cells were shown to be increased in peripheral blood and liver in AIH and the bcl-2 product was expressed mainly in CD4+ Th1-type cells, suggesting that these cells might promote the cellular immune response and contribute to the development of hepatitis and hepatocellular damage in AIH.     

Evaluation of the clinical pathway for laparoscopic cholecystectomy and simulation of short-term hospitalization.

The effectiveness of the clinical pathway for laparoscopic cholecystectomy was evaluated, and the efficiency of medical care was analyzed. The duration of hospitalization and the number of National Health Insurance (NHI) points for medical service fees were compared between 86 patients treated after introduction of the clinical pathway (pathway group) and 56 patients treated before introduction of the clinical pathway (pre-pathway group). In the pathway group, variance from the pathway occurred in 24 patients (27.9%) due to postponement of discharge in 7 patients, to earlier discharge in 5 patients, and to insertion of a bile duct catheter in 5 patients. Total and postoperative hospitalization times were significantly shorter in the pathway group than in the pre-pathway group (8.0 +/- 1.6 vs 13.7 +/- 9.0 days, p<0.0001, 5.4 +/- 1.1 vs 6.5 +/- 2.2 days, p<0.0001, respectively). In the pathway group, the total number of NHI points was lower and the number of points per day was higher. By simulation, the total number of NHI points for the 5-day pathway (discharge on postoperative day 3 or earlier) was significantly lower than that for the current 7-day pathway. Moreover, the weekly profit per bed with the 3-day pathway (discharge on postoperative day 1) was more than twice that with the current pathway. The results suggest that the clinical pathway for laparoscopic cholecystectomy is beneficial for patients and useful for the introduction of diagnosis procedure combination in our hospital.     

Characterization of IL-4 and IL-13 signals dependent on the human IL-13 receptor alpha chain 1: redundancy of requirement of tyrosine residue for STAT3 activation

IL-4 and IL-13 are pleiotropic cytokines whose biological activities overlap with each other. IL-13 receptor alpha chain 1 (IL-13R alpha 1) is necessary for binding to IL-13, and the heterodimer composed of IL-13R alpha 1 and IL-4R alpha chain transduces IL-13 and IL-4 signals; however, the functional mapping of the intracellular domain of IL-13R alpha 1 is not fully understood. In this study, we constructed wild and mutated types of human IL-13R alpha 1, and analyzed IL-4 and IL-13 signals using an IL-13R alpha 1-transfected human B cell line. Expression of IL-13R alpha 1 evoked STAT3 activation by IL-4 and IL-13, and in stimulated human B cells, on which IL-13R alpha 1 was highly expressed, IL-4 and IL-13 induced STAT3 activation. Replacement of the two tyrosine residues completely abolished STAT3 activation, although replacing either tyrosine residue alone retained it. Furthermore, we found that the Box1 region and the C-terminal tail of IL-13R alpha 1 were critical for binding to Tyk2, and activation of Jak1, Tyk2, the insulin receptor substrate-1 and STAT6 respectively. These results suggest that STAT3 activation is involved with IL-4 and IL-13 signals in human B cells along with the activation of STAT6, and that there is a unique sequence in IL-13R alpha 1 to activate STAT3.     

Cytoskeletal organization in the supporting cell of the guinea pig organ of Corti

The rapid-freeze, deep-etch method was used to visualize the three-dimensional organization of cytoskeletons in the supporting cells of the guinea pig organ of Corti. Deep-etched replicas showed that both the head and basal portions of the pillar cell were composed of a filamentous network consisting of several kinds of fibrous elements, into which numerous microtubules and actin filaments were tightly inserted. Myosin S1-decoration showed that the main constituent element in such filamentous networks in the basal portion of the pillar cell was the actin and tiny cross-bridges interconnected the randomly oriented adjacent actin filaments.     

Clinical Implication of CXCL12 Expression in Gastric Cancer

PURPOSE: Recent research has revealed that tumor cells expressing chemokine receptors have a crucial impact on patient survival. However, there is no information regarding chemokine expression in gastro-intestinal cancer. This study immunohistochemically investigated CXCL12 expression in gastric cancer and evaluated its association with clinical factors, including patient prognosis. METHOD: A total of 185 gastric cancer patients receiving curative gastrectomy were assessed. CXCL12 expression was evaluated by immunohistochemical analysis. Tumors with CXCL12-positive cancer cells were regarded as CXCL12 positive, and according to the degree of CXCL12 expression, patients were divided into three groups (weak, 31 cases; moderate, 27 cases; strong, 20 cases). Correlations between CXCL12 expression and clinical factors in gastric cancer were then determined. RESULTS: CXCL12 was found in the cellular membrane of cancer cells. Seventy-four of 185 patients were classified into the CXCL12-positive group. Patients were divided into three groups according to the positivity of CXCL12 expression. Significant associations between CXCL12 and lymph node metastases (p < 0.05), depth of invasion (p < 0.01), lymphatic invasion (p < 0.01), tumor diameter (p < 0.05), and clinical stage (p < 0.01) were seen. Univariate analysis revealed that the CXCL12-positive group had significantly poorer surgical outcome than the CXCL12-negative group (p < 0.01). Multivariate analysis revealed CXCL12 to be an independent prognostic factor in gastric cancer (p = 0.02). CONCLUSION: Cancerous CXCL12 positivity was determined to be an independent prognostic factor in gastric cancer, with CXCL12-positive gastric cancer showing more-aggressive behavior. Autocrine CXCL12 secretion from tumor cells may activate CXCR-4 on the tumor cells, which may be related to of the viability of distant metastases.     

Chronic kidney disease, cardiovascular events, and the effects of perindopril-based blood pressure lowering: data from the PROGRESS study

Chronic kidney disease (CKD) is associated with a high risk of cardiovascular disease, but evidence regarding the effectiveness of interventions to reduce that risk is lacking. The Perindopril Protection against Recurrent Stroke Study (PROGRESS) study enrolled 6105 participants with cerebrovascular disease and randomly allocated them to perindopril-based blood pressure-lowering therapy or placebo. Individuals with CKD were at approximately 1.5-fold greater risk of major vascular events, stroke, and coronary heart disease, and were more than twice as likely to die (all P< or =0.002). Perindopril-based treatment reduced the risk of major vascular events by 30% and stroke by 35% among subjects with CKD, and the absolute effects of treatment were 1.7-fold greater for those with CKD than for those without. Considering patients with CKD and a history of cerebrovascular disease, perindopril prevented one stroke or other cardiovascular event among every 11 patients treated over five years. In conclusion, kidney function should be considered when determining the need for blood pressure lowering therapy in patients with cerebrovascular disease.