Myocardial cell death in fibrillating and dilated human right atria.

OBJECTIVES: The aim of the present study was to determine if myocytes can die by apoptosis in fibrillating and dilated human atria. BACKGROUND: The cellular remodeling that occurs during atrial fibrillation (AF) may reflect a degree of dedifferentiation of the atrial myocardium, a process that may be reversible. METHODS: We examined human right atrial myocardium specimens (n = 50) for the presence of apoptotic myocytes. We used immunohistochemical and Western blotting analysis to examine the expression of a final effector of programmed cell death, caspase-3 (CASP-3) and of regulatory proteins from the BCL-2 family. RESULTS: Sections from atria in AF contained a high percentage of large myocytes with a disrupted sarcomeric apparatus replaced by glycogen granules (64.4 +/- 6.3% vs. 12.2 +/- 5.8%). These abnormal myocytes, which also predominated in atria from hearts with decreased left ventricular ejection fraction (42.3 +/- 10.1%), contained large nuclei, most of which were TUNEL positive, indicating a degree of DNA breakage. None of these abnormal myocytes expressed the proliferative antigen Ki-67. A small percentage of the enlarged nuclei (4.2 +/- 0.8%) contained condensed chromatin and were strongly TUNEL positive. Both the pro- and activated forms of CASP-3 were detected in diseased myocardial samples, which also showed stronger CASP-3 expression than controls. Expression of the antiapoptotic BCL-2 protein was decreased in diseased atria, whereas that of the proapoptotic BAX protein remained unchanged. CONCLUSIONS: In fibrillating and dilated atria, apoptotic death of myocytes with myolysis contributes to cellular remodeling, which may not be entirely reversible.     

Combined effects of a thymic peptide, thymopoietin and myasthenic patient sera in rat myotube culture.

We investigated in a rat myotube assay the combined effect of 26 myasthenic (MG) patient sera and a thymic peptide, thymopoietin (Tpo) which had previously been shown to bind Torpedo and human AChR and to compete with alpha-bungarotoxin (alpha-Bgt) binding. Cultures were first exposed to Tpo alone for 3 h (0.3, 7.5, 15 nM), then MG sera (5% final dilution) were added for an additional 18 h. Reduction in the amount of 125I-alpha-Bgt binding sites in the presence of various concentrations of Tpo were similar with control sera and in all the patients with low or undetectable anti-AChR Ab (11 cases). In cultures exposed to Tpo and sera with high anti-AChR Ab titre (15 cases), Tpo and anti-AChR Ab have an additive capacity to reduce the number of alpha-Bgt binding sites. The results are compatible with the hypothesis that anti-AChR Ab and Tpo could impair neuromuscular transmission by complementary mechanisms.     

Effect of Isoflurane Anesthesia on Antipyrine Pharmacokinetics in the Rat

Pharmaceutical Research -     

Differentiation of phyllodes breast tumors from fibroadenomas on MRI

OBJECTIVE: The purpose of our study was to evaluate the MRI appearance of phyllodes breast tumors and to differentiate them from fibroadenomas. MATERIALS AND METHODS: MR images were obtained on a 1.5-T imager. T1- and T2-weighted sequences and dynamic 2D fast-field echo T1-weighted sequences were performed. MR images of 23 patients with 24 phyllodes breast tumors (one malignant, 23 benign) were analyzed with respect to morphology and contrast enhancement. The tumors were compared with the MRI appearance of 81 fibroadenomas of 75 patients. RESULTS: Well-defined margins were seen in 87.5% of the phyllodes tumors and 70.4% of the fibroadenomas, and a round or lobulated shape in 100% and 90.1%, respectively. A heterogeneous internal structure was observed in 70.8% of phyllodes tumors and in 49.4% of fibroadenomas. Nonenhancing internal septations were found in 45.8% of phyllodes tumors and 27.2% of fibroadenomas. A significantly greater increase in signal was seen on T2-weighted images in the tissue surrounding phyllodes tumors (21%) compared with fibroadenomas (1.2%). Most of both lesions appeared with low signal intensity on T1- and T2-weighted images. After the administration of contrast material, 33.3% of phyllodes tumors and 22.2% of fibroadenomas showed a suspicious signal intensity-time course. CONCLUSION: Phyllodes breast tumors and other fibroadenomas cannot be precisely differentiated on breast MRI. Phyllodes tumors have benign morphologic features and contrast enhancement characteristics suggestive of malignancy in 33% of cases.     

A randomized trial between two neoadjuvant chemotherapy protocols: CDDP + 5-FU versus CDDP + VP16 in advanced cancer of the head and neck

We investigated a phase III randomized trial to compare efficacy and tolerance of CDDP + 5-FU to CDDP + VP16, both given intravenously in patients with unresectable advanced head and neck cancer. The 197 eligible patients were paired off successively on the basis of tumor sites and UICC stage. Comparisons were made through sequential closed plans. In 179 patients, tumor beds and cervical lymph nodes were irradiated, and 20 patients underwent salvage surgical procedures. Cisplatin plus 5-fluorouracil showed a response (CR + PR) rate of 15% greater than that observed with cisplatin plus etoposide (alpha=0.05, power 70%). Complete responses played a major role in the CDDP + 5-FU regimen. Furthermore, we noted a higher cervical node regression with this chemotherapy combination. Because radiotherapy was administered after chemotherapy, we could not analyze the mean duration response for each protocol. No significant difference in survival existed between the two groups. Myelosuppression was the most frequent sign of toxicity observed, especially with the CDDP + VP16 regimen. Mucositis was rare with allopurinol protection. In the CDDP + 5-FU group, one patient had grade 4 cardiac dysfunction, and 3 patients exhibited unconsciousness that may be related to cerebral vascular damage. Thirteen patients died, with 8 cases related to septic shock (5 CPPP + VP16 and 3 CDDP + 5-FU). Cisplatin plus 5-FU chemotherapy showed a satisfactory efficacy and acceptable toxicity profile compared with CDDP + VP16, with caution to patients with a cardiac or vascular history. Although we could not show a benefit in survival with the CDDP + 5-FU protocol, this trial supports literature data and confirms that this regimen may be proposed as a first-line therapy in advanced cancer of the head and neck.     

Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients

Administration of specific drugs may occasionally induce acquired long QT syndrome (aLQTS), a disorder that predisposes to ventricular arrhythmias, typically of the torsade de pointes (TdP) type, and sudden cardiac death. Forme fruste mutations in congenital LQTS (cLQTS) genes have been reported repeatedly as the underlying cause of aLQTS, and are therefore considered as an important risk factor. We evaluated the impact of genetic susceptibility for aLQTS through mutations in cLQTS genes. Five cLQTS genes (KCNH2, KCNQ1, SCN5A, KCNE1, KCNE2) were thoroughly screened for genetic variations in 32 drug-induced aLQTS patients with confirmed TdP and 32 healthy individuals. Missense forme frust mutations were identified in four aLQTS patients: D85N in KCNE1 (two cases), T8A in KCNE2, and P347S in KCNH2. Three other missense variations were found both in patients and controls, and are thus unlikely to significantly influence aLQTS susceptibility. In addition, 13 silent and six intronic variations were detected, four of which were found in a single aLQTS patient but not in the controls. We conclude that missense mutations in the examined cLQTS genes explain only a minority of aLQTS cases.Abbreviations cLQTS Congenital long QT syndrome - aLQTS Acquired long QT syndrome - TdP Torsade de pointes - ECG Electrocardiogram - QTc Corrected QT - PCR Polymerase chain reaction - LD Linkage disequilibrium     

An unusual familial cardiomyopathy characterized by aberrant accumulations of desmin-type intermediate filaments

Summary Immunofluorescence microscopy using antibodies specific for different intermediate filament types has been used to study a rare familial cardiomyopathy characterized electron microscopically by massive accumulations of unordered intermediate filaments. The results show that the inclusions in cardiac muscle cells are composed of the desmin type of intermediate filament characteristic of muscle tissues, and draw attention to the importance of these filaments in maintaining normal cardiac ultrastructure and function.