Astrocytic induction of matrix metalloproteinase-9 and edema in brain hemorrhage.

We tested the hypothesis that astrocytic matrix metalloproteinase-9 (MMP-9) mediates hemorrhagic brain edema. In a clinical case of hemorrhagic stroke, MMP-9 co-localized with astrocytes and neurons in peri-hematoma areas. In a mouse model where blood was injected into striatum, MMP-9 was colocalized with astrocytes surrounding the hemorrhagic lesion. Because MMP-9 is present in blood as well as brain, we compared four groups of wild type (WT) and MMP-9 knockout (KO) mice: WT blood injected into WT brain, KO blood into KO brain, WT blood into KO brain, and KO blood into WT brain. Gel zymography showed that MMP-9 was elevated in WT hemorrhagic brain tissue but absent from KO hemorrhagic brain tissue. Edematous water content was elevated when WT blood was injected into WT brain. However, edema was ameliorated when MMP-9 was absent in either blood or brain or both. To further assess the mechanisms involved in astrocytic induction of MMP-9, we next examined primary mouse astrocyte cultures. Exposure to hemoglobin rapidly upregulated MMP-9 in conditioned media within 1 to 24 h. Hemoglobin-induced MMP-9 was reduced by the free radical scavenger U83836E. Taken together, these data suggest that although there are large amounts of MMP-9 in blood, hemoglobin-induced oxidative stress can trigger MMP-9 in astrocytes and these parenchymal sources of matrix degradation may also be an important factor in the pathogenesis of hemorrhagic brain edema.     

Clinical Effectiveness of Tolvaptan in Patients with Acute Decompensated Heart Failure and Renal Failure: Design and Rationale of the AQUAMARINE Study

Purpose

Over half of all admitted acute decompensated heart failure (ADHF) patients have renal failure. Although diuretics represent the mainstay of treatment strategy even in this population, there are unmet needs for safer and more effective treatment. Tolvaptan is a vasopressin-2 receptor antagonist, and we hypothesized that adding tolvaptan to standard diuretic therapy would be more effective in ADHF patients with renal function impairment.

Methods

The Answering question on tolvaptan’s efficacy for patients with acute decompensated heart failure and renal failure (AQUAMARINE) is a multicenter, randomized controlled clinical trial, which will enroll 220 patients from 17 hospitals in Japan. ADHF patients whose estimated glomerular filtration rate is above 15 and below 60 mL/min/1.72 m² will be randomly assigned within 6 h after admission to usual care with furosemide or tolvaptan add-on therapy. Primary endpoint is achieved urine output within 48 h. Secondary endpoints include dyspnea relief measured by 7-points Likert scale, incidence of worsening renal function, dose of furosemide used within 48 h, and changes of brain natriuretic peptide.

Conclusion

This study is the first multicenter study in Japan to evaluate clinical effectiveness of tolvaptan add-on therapy in ADHF patients with renal failure. The results of this study address the treatment strategy of this high-risk population (UMIN Clinical Trial Registry Number: UMIN000007109).     

Both plasma lysophosphatidic acid and serum autotaxin levels are increased in chronic hepatitis C

OBJECTIVES: Recent accumulating evidence indicates that lysophosphatidic acid (LPA) is a lipid mediator, abundantly present in blood, with a wide range of biologic actions including the regulation of proliferation and contraction in liver cells. Although it is speculated that LPA might play a role in pathophysiologic processes in vivo, not only its role but also even a possible alteration in its blood concentration under specific diseases is essentially unknown. Autotaxin (ATX), originally purified as an autocrine motility factor for melanoma cells, was revealed to be a key enzyme in LPA synthesis. We determined LPA and ATX levels in the blood of patients with liver disease. METHODS: ATX activity was measured by determining choline with the substrate of lysophosphatidylcholine, and the LPA level by an enzymatic cycling method in 41 patients with chronic hepatitis C. RESULTS: The serum ATX activity and plasma LPA level were significantly increased in patients, and were correlated positively with serum hyaluronic acid, and negatively with platelets, albumin, and prothrombin time. The plasma LPA level was strongly correlated with serum ATX activity. There were significant correlations between the histologic stage of fibrosis and both the serum ATX activity and plasma LPA level. CONCLUSIONS: The serum ATX activity and plasma LPA level are increased in chronic hepatitis C in association with liver fibrosis. Our study may provide the first evidence showing a significant increase of both ATX and LPA in the blood under a specific disease.     

The analysis of leukemic relapse after allogeneic bone marrow transplantation]

This report presents the analysis of leukemic relapse of 52 patients who received allogeneic bone marrow transplantation between July 1984 and May 1990. Conditioning regimen consisted of TBI + CY and GVHD prophylaxis consisted of cyclosporin-A and methotrexate. The relapse ratios of chronic myelogenous leukemia (CML) (21 in chronic phase, 1 in accelerated phase, 1 in blastic crisis), acute nonlymphocytic leukemia (ANLL) (all 17 in 1st CR), acute lymphocytic leukemia (ALL) (all 12 in 1st CR) were 13%, 18%, 25%, respectively, and 3 year disease free survival (DFS) was as follows, CML 68%, ANLL 72%, ALL 49%. Regarding acute GVHD grading and chronic GVHD presence, 3 year DFS was as follows, acute GVHD 0 degree: 59%, I degree: 78%, II degree-IV degree: 53%, chronic GVHD (+): 82% GVHD (-): 77%. In our center leukemic relapse has been the major cause of death after BMT since 1984. Among 9 relapsed cases, one recurred more than 3 years after BMT, and another one got recurrent leukemia of donor origin.     

Comparison between 5-fluorocytosine, amphotericin B and the combined administration of these agents in the therapeutic effectiveness for cryptococcal meningitis.

Therapeutic effectiveness of 5-fluorocytosine (5-FC), amphotericin B (Am B) and both in combined administration were retrospectively assessed and compared with one another in 28 patients with cryptococcal meningitis. Combined administration was significantly superior to Am B alone and to 5-FC alone, and these agents were suggested to afford a synergetic effect in combined administration. Adverse reactions associated with combined administration did not essentially differ from those with Am B or 5-FC alone. Combined administration was able to decrease the incidence and severity of adverse reactions by employing lower doses of Am B, and this combined administration reduced the duration of treatment. An appropriate dose for each agent in combined administration was deemed to be about 0.350 mg/kg/day Am B i.v. and 150 mg/kg/day 5-FC p. o. based on the results of this study.