Biphasic action of aldosterone on Akt signaling in cardiomyocytes.

Both aldosterone and Akt signaling play pivotal roles in the pathogenesis of heart failure. However, little is known about the correlation between them. We herein investigated whether aldosterone interacts with Akt signaling in a coordinated manner in cardiomyocytes. Neonatal rat cardiomyocytes were stimulated with aldosterone for either a short (10-min) or long (24-h) time. The phosphorylation of Akt and its downstream effector, GSK3ß, were transiently increased after short-term stimulation, which was blocked by either PI3K or Na(+)/H(+) exchanger inhibitors, but not by the mineralocorticoid receptor antagonist, eplerenone. Long-term stimulation also significantly increased Akt-GSK3ß phosphorylation and this effect was reduced by eplerenone. Thus, these results suggest that aldosterone activates Akt signaling via a biphasic reaction that occurs through different cascades. To understand the significance of the rapid action of aldosterone, cardiomyocytes were exposed to hydrogen peroxide for from 10 to 60 min. A short-term aldosterone stimulation (for up to 30 min) significantly protected cardiomyocytes from oxidative stress-induced cellular damage. Eplerenone did not abrogate this beneficial effect, while a PI3K inhibitor did. Therefore, during the early phase, aldosterone has favorable effects on cardiomyocytes, partly by acute activation of a mineralocorticoid receptor-independent cascade through the Na(+)/H(+) exchanger, PI3K, and Akt. In contrast, its persistent activity produces pathological effects partly by chronic Akt activation in a mineralocorticoid receptor-dependent manner.

[Relapse of small cell carcinoma of the lung with metastasis to iris].

We reported a case of small cell carcinoma of the lung with metastasis to the iris during a stage of complete remission obtained with chemotherapy and radiation therapy. The patient was a 55-year-old man hospitalized for hoarseness and abnormal chest radiographs in August 1996. Small cell carcinoma of the lung had been diagnosed, and the stage was limited disease. Treatment consisted of 3 cycles of chemotherapy with cisplatin and etoposide, together with radiation therapy. The patient achieved complete remission and was discharged. In mid-December, he visited an eye clinic with the complaints of blurred vision and congestion in the right eye. Metastatic tumor of the iris was diagnosed. At that time, neither local recurrence of the lung cancer nor metastasis to other organs were observed. The patient was treated with cisplatin and etoposide again, resulting in a reduction of the iris tumor's size. After chemotherapy, the right eye was treated with electron irradiation, and the iris tumor and other clinical signs almost entirely disappeared. The patient retained normal vision during the clinical course.

[Sarcoidosis differentially diagnosed from mediastinal tumor by thoracoscopic biopsy].

A 46-year-old man presented with swallowing difficulty and dyspnea when in the supine position. Chest X-ray and computed tomographic (CT) films disclosed left pleural effusion and a tumor shadow extending invasively from superior to anterior mediastinum around the heart and large arteries. These observations called for a differential diagnosis from malignant lymphoma, invasive thymoma, and small cell carcinoma. Bronchofiberscopy and percutaneous tumor biopsy were performed, but the findings were inconclusive. Thoracoscopic biopsy yielded a diagnosis of sarcoidosis. No extrathoracic lesions were detected. Corticosteroid therapy (30 mg/day of prednisolone) was started. After 6 months of treatment (7.5 mg/day of prednisolone), the tumor shadow was reduced in size and the patient's swallowing difficulty and dyspnea subsided. This was a rare case of sarcoidosis extending invasively around the heart and large arteries, and that needed to be differentiated from mediastinal tumor. Thoracoscopic biopsy should be actively enlisted as a diagnostic procedure in difficult cases of this kind.

[Idiopathic bronchiolitis obliterans organizing pneumonia complicated by transitory cystic lesion in the healing stage].

A 21-year-old man was admitted to our hospital because chest X-ray films disclosed infiltrative shadows indicative of Mycoplasma pneumonia. He experienced fever and dry cough for 2 weeks. Chest X-ray findings showed ground-glass shadows in the lower fields of both lungs. The patient was not responsive to antibiotic therapy (PAPM/BP 1 g/day and CLDM 1,200 mg/day); dyspnea advanced rapidly and spikes of fever persisted. On hospital day 5, chest computed tomographic (CT) films disclosed interstitial shadows in all lower lung fields with dense infiltration. A transbronchial lung biopsy (TBLB) was performed on day 7, and TBLB specimens demonstrated infiltration of mononuclear cells in alveolar septa and organizing exudate in alveolar ducts with polypoid granulation tissue. Bronchoalveolar lavage fluid findings revealed an increase in the total cell count and the percentage of lymphocytes. The CD 4/CD 8 ratio was normal. The findings of other laboratory tests ruled out drug-induced lung disease, infectious disease, and collagen disease. Idiopathic bronchiolitis obliterans with organizing pneumonia (BOOP) was diagnosed. Corticosteroid therapy (methyl prednisolone: 500 mg/day) was started. After 2 weeks of treatment (prednisolone: 30 mg/day), the dyspnea and fever disappeared. Chest CT films showed that the interstitial shadows had largely resolved, but that a large cystic lesion had formed rapidly in the right lower lung field (right S 6). To the best of our knowledge, no cases of BOOP complicated by cystic lesions in the healing stage have been reported to date. We speculated that polypoid granulation in a bronchiole had given rise to a check-valve mechanism. After 2 months of treatment (prednisolone: 15 mg/day), the cystic lesion disappeared. We concluded that the bronchiolar lesion of polypoid granulation had resolved in response to therapy, thus facilitating air-way communication and the release of air from the cyst.

A novel method of conjugation of daunomycin with antibody with a poly-L-glutamic acid derivative as intermediate drug carrier. An anti-alpha-fetoprotein antibody-daunomycin conjugate.

In studies on antitumor antibody-cytotoxic drug conjugates as potential antitumor agents with improved tumor specificity, daunomycin (DM) was first linked to a poly-L-glutamic acid (PLGA) derivative having a single masked thiol group. At the thiol group, DM-linked PLGA was bound to horse anti-rat alpha-fetoprotein (AFP) antibody. The anti-AFP antibody-PLGA-DM conjugate (anti-AFP conjugate, DM/PLGA/Ig molar binding ratio, 7.5/1.2/1.0) retained most of the antigen-binding activity of the parent antibody and was more potent than either unconjugated DM, a conjugate similarity prepared with normal horse immunoglobulin (normal conjugate), or an unconjugated mixture of anti-AFP antibody and DM in an in vitro cytotoxicity assay against the AFP-producing rat ascites hepatoma cell line AH66. Anti-AFP conjugate tended to be less cytotoxic than DM against the AFP-nonproducing rat ascites hepatoma AH272 cells, and in this case there was no difference between the cytotoxicities of anti-AFP conjugate and of normal conjugate.