Differential expression and origin of membrane-type 1 and 2 matrix metalloproteinases (MT-MMPs) in association with MMP2 activation in injured human livers

Matrix metalloproteinase-2 (MMP2) activation is associated with basement membrane remodeling that occurs in injured tissues and during tumor invasion. The newly described membrane-type MMPs (MT-MMPs) form a family of potential MMP2 activators. We investigated the localization and steady-state levels of MT1-MMP and MT2-MMP mRNA, compared with those of MMP2 and tissue inhibitor of MMP-2 in 22 hepatocellular carcinomas, 12 liver metastases from colonic adenocarcinomas, 13 nontumoral samples from livers with metastases, 10 benign tumors, and 6 normal livers. MMP2 activation was analyzed by zymography in the same series. The expression of MT1-MMP mRNA and the activation of MMP-2 were increased in hepatocellular carcinomas, metastases, and cholestatic nontumoral samples. MT2-MMP mRNA was rather stable in the different groups. MT1-MMP mRNA levels, but not MT2-MMP mRNA, correlated with MMP-2 and tissue inhibitor of MMP-2 mRNA levels and with MMP2 activation. In situ hybridization showed that MT1-MMP mRNA was expressed in stromal cells, and MT2-MMP mRNA was principally located in both hepatocytes and biliary epithelial cells. Consistently, freshly isolated hepatocytes expressed only MT2-MMP mRNA, and culture-activated hepatic stellate cells showed high levels of MT1-MMP mRNA. These results indicate that in injured livers, MMP2 activation is related to a coordinated high expression of MMP2, tissue inhibitor of MMP-2, and MT1-MMP. Furthermore, the finding of a preferential expression of MT2-MMP in hepatocytes, together with our previous demonstration that the activation of stellate cell-derived MMP2 in co-culture requires interactions with hepatocytes (Am J Pathol 1997, 150:51-58), suggests that parenchymal cells might play a pivotal role in the MMP2 activation process.     

Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins

BACKGROUND: Atrial fibrillation, the most common sustained cardiac arrhythmia and a major cause of stroke, results from simultaneous reentrant wavelets. Its spontaneous initiation has not been studied. METHODS: We studied 45 patients with frequent episodes of atrial fibrillation (mean [+/-SD] duration, 344+/-326 minutes per 24 hours) refractory to drug therapy. The spontaneous initiation of atrial fibrillation was mapped with the use of multielectrode catheters designed to record the earliest electrical activity preceding the onset of atrial fibrillation and associated atrial ectopic beats. The accuracy of the mapping was confirmed by the abrupt disappearance of triggering atrial ectopic beats after ablation with local radio-frequency energy. RESULTS: A single point of origin of atrial ectopic beats was identified in 29 patients, two points of origin were identified in 9 patients, and three or four points of origin were identified in 7 patients, for a total of 69 ectopic foci. Three foci were in the right atrium, 1 in the posterior left atrium, and 65 (94 percent) in the pulmonary veins (31 in the left superior, 17 in the right superior, 11 in the left inferior, and 6 in the right inferior pulmonary vein). The earliest activation was found to have occurred 2 to 4 cm inside the veins, marked by a local depolarization preceding the atrial ectopic beats on the surface electrocardiogram by 106+/-24 msec. Atrial fibrillation was initiated by a sudden burst of rapid depolarizations (340 per minute). A local depolarization could also be recognized during sinus rhythm and abolished by radiofrequency ablation. During a follow-up period of 8+/-6 months after ablation, 28 patients (62 percent) had no recurrence of atrial fibrillation. CONCLUSIONS: The pulmonary veins are an important source of ectopic beats, initiating frequent paroxysms of atrial fibrillation. These foci respond to treatment with radio-frequency ablation.     

Spherical particles of phenolic resin treated with iron oxide

This paper describes the preparation and characterization of phenolic resins’ thermospheres covered by a magnetic phase of iron oxide. The thermospheres were prepared by allowing phenol and formaldehyde to react under dispersion polymerization conditions and the iron oxide phase was incorporated in situ onto the phenolic resin particles by adding concentrated NH₃ to FeCl₂ in DMSO. This reaction was conducted at 70 °C under nitrogen atmosphere in a controlled temperature vessel, and the modified resin was isolated and dried in vacuo. Both pure and modified resins were characterized by DRX, TG-DTA, and MEV/EDX. The modified particles were attracted by a magnetic field, indicating the fixation of magnetic iron oxide. No diffraction peaks were observed in DRX analysis; thermal analysis (DTA) of both pure and modified resins presented exothermic events between 300 and 680 °C, and 300 and 570 °C, respectively, indicating the microstructure of the resin was modified after the treatment. Thermogravimetric analysis (TGA) of the pure resin registered a 2.0% residue, compared to 8.0% for the modified resin. These residues correspond to about 7.0% of fixed iron oxide. MEV/EDX analyses confirm the modification of the resins by the process of fixing iron oxide.     

Efficacy of two different ProMACE-CytaBOM derived regimens in advanced aggressive non-Hodgkin's lymphoma. Final report of a multicenter trial conducted by GISL

BACKGROUND AND OBJECTIVE: To compare the efficacy of ProME(Epidoxorubicin)CE-CytaBOM (PE-C) and ProMI(Idarubicin)CE-CytaBOM (PI-C) in the treatment of adult patients with aggressive non Hodgkin's lymphoma in a multicenter randomized controlled trial performed by 18 centers of the Italian Lymphoma Study Group (GISL). DESIGN AND METHODS: One hundred and twenty-eight and 122 patients were randomly assigned to receive either 6 courses of PE-C or PI-C, respectively. Some patients achieving complete remission with induction therapy participated in another randomized study comparing no further therapy versus maintenance therapy consisting of four blocks of two drugs. RESULTS: The rate of CRs was 62% and 64% for patients treated with PE-C and PI-C, respectively (p = 0.51). The 5-year relapse-free survival was 60% for PE-C and 53% for PI-C (p = 0.29). The estimated relapse-free disease survival rates at 4 years were 75% for patients in the consolidation group and 57% for those in the observation group (p = 0.11). Patients alive in first complete remission 4 years after study entry were estimated to be 39% in the PE-C arm and 38% in the PI-C arm (p = 0.90). The 3-year and 5-year estimated survival rates were 61% and 55% for the PE-C group and 56% and 47% for the PI-C group (p = 0.26). Fatal toxicities occurred in 7 patients (2.9%) with active disease and in 4 patients (1.7%) in complete remission. Stage (p = 0.04), bulky disease (p = 0.02), serum LDH (p = 0.0006), serum albumin (p = 0.0051), hemoglobin (p = 0.0011), performance status (p = 0.0001), International prognostic index (p < 0.0001) and the index proposed by the French group G.E.L.A. (p < 0.0001) were of prognostic value. In a multivariate analysis (Cox regression model) alternatively IPI alone or G.E.L.A. index plus performance status emerged as independent prognostic factors. INTERPRETATION AND CONCLUSIONS: The present study indicates that epirubicin and idarubicin in a combined chemotherapy regimen, have similar activities. The toxic profile also indicates the safety of both anthracyclines at the dosages employed, suggesting their possible dose escalation in a combined chemotherapy setting. PE-C and PI-C were both effective and feasible regimens in an outpatient setting, with acceptable cardiovascular toxicity. The trend toward a better outcome in patients undergoing consolidation therapy after the achievement of a complete remission, warrants further investigation.     

Successful irrigated-tip catheter ablation of atrial flutter resistant to conventional radiofrequency ablation

BACKGROUND: Catheter ablation of typical right atrial flutter is now widely performed. The best end point has been demonstrated to be bidirectional isthmus block. We investigated the use of irrigated-tip catheters in a small subset of patients who failed isthmus ablation with conventional radiofrequency (RF) ablation. METHODS AND RESULTS: Of 170 patients referred for ablation of common atrial flutter, conventional ablation of the cavotricuspid isthmus with >21 applications failed to create a bidirectional block in 13 (7.6%). An irrigated-tip catheter ablation was performed on identified gaps in the ablation line according to a protocol found to be safe in animals: a moderate flow rate of 17 mL/min and temperature-controlled (target, 50 degrees C) RF delivery with a power limit of 50 W. Bidirectional isthmus block was achieved in 12 patients by use of a mean delivered power of 40+/-6 W with a single application in 6 patients and 2 to 6 applications in the other 6. No side effects occurred during or after the procedure. CONCLUSIONS: Irrigated-tip catheter ablation is safe and effective for achieving cavotricuspid isthmus block when conventional RF energy has failed.     

Dissolution behaviour of calcium phosphate coatings obtained by laser ablation

Pulsed laser deposited calcium phosphate coatings on titanium alloy have been tested under simulated physiological conditions in order to evaluate the changes in morphology, composition and structure. The coatings were deposited under different conditions to obtain different crystalline structures, ranging from amorphous and mixed crystalline phases to pure crystalline hydroxyapatite (HA). The coated samples were immersed in a Ca-free Hank's balanced salt solution for up to 5 days. Characterization of the coatings was performed by X-ray diffraction, scanning electron microscopy and Fourier-transform Raman spectroscopy before and after immersion. Their dissolution behaviour was also monitored through their mass loss and calcium release. Coatings of pure HA preserve their morphology and structure during the exposure time in solution. In multiphasic coatings, consisting of HA with tetracalcium phosphate (TetraCP) or beta-tricalcium phosphate (beta-TCP) with a-tricalcium phosphate (alpha-TCP), microporosity is induced by the complete dissolution of TetraCP or gamma-TCP. Amorphous calcium phosphate coatings totally dissolve.     

Heat flow parameters affecting dendrite spacings during unsteady-state solidification of Sn-Pb and Al-Cu alloys

Solidification thermal parameters and dendrite arm spacings have been measured in hypoeutectic Sn-Pb and Al-Cu alloys solidified under unsteady-state heat flow conditions. It was observed that both primary and secondary spacings decreased with increased solute content for Sn-Pb alloys. For Al-Cu alloys, the primary spacing was found to be independent of composition, and secondary spacings decrease as the solute content is increased. The predictive theoretical models for primary spacings existing in the literature did not generate the experimental observations concerning the Sn-Pb and Al-Cu alloys examined in the present study. The theoretical Bouchard-Kirkaldy’s (BK’s) equation relating secondary spacings with tip growth rate has generated adequately the experimental results for both metallic systems. The insertion of analytical expressions for tip growth rate and cooling rate into the predictive model, or into the resulting experimental equations in order to establish empirical formulas permitting primary and secondary dendritic spacings to be determined as functions of unsteady-state solidification parameters such as melt superheat, type of mold, and transient metal/mold heattransfer coefficient is proposed.