Noninvasive Electrocardiographic Imaging (ECGI): Application of the Generalized Minimal Residual (GMRes) Method

Electrocardiographic imaging (ECGI) is a developing imaging modality for cardiac electrophysiology and arrhythmias. It reconstructs epicardial potentials, electrograms, and isochrones from electrocardiographic body-surface potentials noninvasively. Current ECGI methodology employs Tikhonov regularization, which imposes constraints on the reconstructed potentials or their derivatives. This approach can sometimes reduce spatial resolution by smoothing the solution. Accuracy depends on a priori knowledge of solution characteristics and determination of an optimal regularization parameter. These properties led us to implement an independent, iterative approach for ECGI—the generalized minimal residual (GMRes) method—which does not apply constraints. GMRes was applied to experimental data during activation/repolarization of normal and infarcted hearts. GMRes reconstructions were compared to Tikhonov reconstructions and to measured gold standards in isolated hearts. Overall, the accuracy of GMRes solutions was similar to Tikhonov regularization. However, in certain cases GMRes recovered localized potential features (e.g., multiple potential minima), which were lost in the Tikhonov solution. Simultaneous use of these two complementary methods in clinical ECGI will ensure reliability and maximal extraction of diagnostic information in the absence of a priori information about a patient's condition.© 2003 Biomedical Engineering Society. PAC2003: 8719Hh, 8757Gg     

Epstein-Barr virus association and ALK gene expression in anaplastic large-cell lymphoma

Anaplastic large cell lymphoma of T/null-cell type (ALCL) is associated with a characteristic genetic abnormality t(2;5) that results in the NPM-ALK chimeric gene and the protein product derived thereof. In 10% to 20% of ALCLs, the translocation partners of the ALK gene are genes other than NPM (variant translocations). ALK gene expression limited to the cytoplasm implies a variant translocation. In this study, we have investigated 46 cases of ALCL for expression and localization of ALK protein and its association with Epstein-Barr virus (EBV) (by hybridization to EBV-encoded nuclear RNA-1 [EBER-1] and immunostaining for LMP-1). ALCL patients with a null cell phenotype were significantly younger as compared with those of T-cell phenotype (mean age: 28 years v 42 years; P =.018). Sixteen of 46 ALCL cases (34%) were ALK positive. ALK-positive patients were significantly younger (mean age: 25 years for those with both cytoplasmic and nuclear staining; 22 years for those with exclusive cytoplasmic staining; and 41 years for those negative for the ALK gene; P =.023). EBER-1 was detected in 9 of 46 cases (20%), and LMP-1 expression was noted in 5 of them. By polymerase chain reaction analysis, all EBV-associated cases that were investigated showed type I EBV. Whereas 2 of 23 T-cell ALCLs (9%) were EBER-1+, and 7 of 23 null-cell ALCLs (30%) showed EBV association (P =.057). EBV association was seen in 20% of ALK-negative cases, in 0% of cases with ALK gene expression in both nucleus and cytoplasm, and in 60% of cases with ALK gene expression exclusively in the cytoplasm (P =.02). Further, although ALK-positive-EBER-1+ cases were LMP-1 negative, ALK-negative-EBER-1+ cases were LMP-1 positive. Our study raises the question whether EBV might have an etiological role in the evolution of ALCLs that lack classical t(2;5).     

Demineralization and ion binding action of polycarboxylate cement liquid on human dental enamel

The demineralization and ion binding effects on dental tissues due to poly(acrylic) acid attack under different dilution conditions of the latter are studied by scanning electron microscope (SEM) and infrared (IR) spectroscopy. The results indicate that in addition to the general demineralization effects such as preferential prism core attack, prism periphery attack, and protruding prism rods, competing ion binding effects also occur. Using optimum dilution conditions, the microstructural effects of demineralization and ion binding are shown and the effects are related to IR spectral observations.     

A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer.

PURPOSE: Three agents with differing mechanisms of action are available for treatment of advanced colorectal cancer: fluorouracil, irinotecan, and oxaliplatin. In this study, we compared the activity and toxicity of three different two-drug combinations in patients with metastatic colorectal cancer who had not been treated previously for advanced disease. PATIENTS AND METHODS: Patients were concurrently randomly assigned to receive irinotecan and bolus fluorouracil plus leucovorin (IFL, control combination), oxaliplatin and infused fluorouracil plus leucovorin (FOLFOX), or irinotecan and oxaliplatin (IROX). The primary end point was time to progression, with secondary end points of response rate, survival time, and toxicity. RESULTS: A total of 795 patients were randomly assigned between May 1999 and April 2001. A median time to progression of 8.7 months, response rate of 45%, and median survival time of 19.5 months were observed for FOLFOX. These results were significantly superior to those observed for IFL for all end points (6.9 months, 31%, and 15.0 months, respectively) or for IROX (6.5 months, 35%, and 17.4 months, respectively) for time to progression and response. The FOLFOX regimen had significantly lower rates of severe nausea, vomiting, diarrhea, febrile neutropenia, and dehydration. Sensory neuropathy and neutropenia were more common with the regimens containing oxaliplatin. CONCLUSION: The FOLFOX regimen of oxaliplatin and infused fluorouracil plus leucovorin was active and comparatively safe. It should be considered as a standard therapy for patients with advanced colorectal cancer.     

Incomplete hypospadiac urethral duplication with posterior urethral valves

Urethral duplication (UD) is an uncommon malformation. Obstruction rarely occurs in hypospadiac UD. We describe two children with incomplete hypospadiac UD in association with posterior urethral valves, a combination not previously recognised. The embryonic significance of this anomaly is discussed. Accepted: 30 September 1997     

Introduction of macromolecules into synaptosomes using electroporation

Synaptic terminals are sites of high metabolic activity and thus are particularly vulnerable to oxidative stress. Oxidative damage to proteins can be toxic to neurons and may cause irreversible cell damage and neurodegeneration. A neuroprotective mechanism used by cells to combat oxidative damage is to selectively degrade damaged proteins. Therefore, it is of interest to study the mechanism of degradation of oxidatively damaged proteins in synaptosomes. One way of oxidizing synaptosomal proteins in vitro is by incubating intact synaptosomes in the presence of an oxidizing agent. A problem with this approach is that it may also cause oxidative damage to the machinery required to recognize and degrade oxidized proteins. We have, therefore, introduced a fluorescent macromolecule into synaptosomes to assess the feasibility of using this technique to study how oxidized proteins are degraded and removed from synaptic terminals. Synaptosomes were subjected to electroporation in the presence of FITC labelled-dextran with an average molecular weight of 70000 (FD-70) and non-specific binding was determined by running parallel experiments in lysed synaptosomes. Following extensive washing, synaptosomes were assayed for the presence of intra-synaptosomal FD-70 by measuring fluorescence in a microplate fluorescence reader. Significant differences in fluorescence were found between intact and lysed synaptosomes with maximal uptake at 100 V/ 1500 microF (approx. 36 pmol/mg protein). To determine if membrane transport was compromised by electroporation, uptake of 3H-arginine was compared in control and electroporated synaptosomes. While untreated electroporated synaptosomes showed a loss of 22% in the ability to transport arginine, preincubation in the presence of 1 mM ATP resulted in a complete restoration of arginine transport. These results show that electroporation is a potentially useful technique for introducing a specific oxidized protein, into synaptic terminals so its metabolic fate can be examined.     

Randomized phase II trial of the clinical and biological effects of two dose levels of gefitinib in patients with recurrent colorectal adenocarcinoma.

PURPOSE: The clinical objective of this trial was to evaluate gefitinib in patients with metastatic colorectal cancer that had progressed despite prior treatment. Serial tumor biopsies were performed when possible and analyzed for activation of the epidermal growth factor receptor (EGFR) signaling pathway. Serial serum samples were measured for amphiregulin and transforming growth factor-alpha (TGFalpha). PATIENTS AND METHODS: One hundred fifteen patients were randomly assigned to receive gefitinib 250 or 500 mg orally once a day. One hundred ten patients were assessable for clinical efficacy. Biologic evaluation was performed on paired tumor samples from 28 patients and correlated with clinical outcome. RESULTS: Median progression-free survival was 1.9 months (95% CI, 1.8 to 2.1 months) and 4-month progression-free survival rate was 13% +/- 5%. One patient achieved a radiographic partial response (RR = 1%; 95% CI, 0.01% to 5%). Median survival was 6.3 months (95% CI, 5.1 to 8.2 months). The most common adverse events were skin rash, diarrhea, and fatigue. In the biopsy cohort, expression of total or activated EGFR, activated Akt, activated MAP-kinase, or Ki67 did not decrease following 1 week of gefitinib. However, a trend toward decreased post-treatment levels of activated Akt and Ki67 was observed in patients with a PFS higher than the median, although these did not reach the .05 level of significance. CONCLUSION: Gefitinib is inactive as a single agent in patients with previously treated colorectal cancer. In tumor samples, gefitinib did not inhibit activation of its proximal target, EGFR. Trends were observed for inhibition of downstream regulators of cellular survival and proliferation in patients achieving longer progression-free survival.     

Antitumor activity and antioxidant role of Bauhinia racemosa against Ehrlich ascites carcinoma in Swiss albino mice [corrected]

AIM: To study the antitumor effect and antioxidant role of Bauhinia racemosa. METHODS: Antitumor activity and antioxidant status of methanol extract (50, 100, and 200 mg/kg) of Bauhinia racemosa stem bark was evaluated against Ehrlich ascites carcinoma (EAC) tumor in mice. Acute and short-term toxicity studies were performed initially in order to ascertain the safety of methanol extract of Bauhinia racemosa (MEBR). After 24 h of tumor inoculation, the extract was administered daily for 14 d. After administration of the last dose followed by 18 h fasting, mice were then sacrificed for observation of antitumor activity. The effect of MEBR on the growth of transplantable murine tumor, life span of EAC bearing hosts and simultaneous alterations in the hematological profile and liver biochemical parameters (lipid peroxidation, antioxidant enzymes) were estimated. RESULTS: The MEBR showed decrease in tumor volume, packed cell volume and viable cell count, and increased the nonviable cell count and mean survival time thereby increasing life span of EAC tumor bearing mice. Hematological profile reverted to more or less normal levels in extract treated mice. Treatment with MEBR decreased the levels of lipid peroxidation and increased the levels of glutathione, superoxide dismutase and catalase. CONCLUSION: The methanol extract of Bauhinia racemosa stem bark exhibited antitumor effect by modulating lipid peroxidation and augmenting antioxidant defense system in EAC bearing mice.     

Induction of natural IgE by glucocorticoids

IgE mediates allergic responses by coating mast cell or basophil surfaces and inducing degranulation upon binding a specific allergen. IgE can also be spontaneously produced in the absence of foreign allergens; yet the origin, regulation, and functions of such “natural” IgE still remain largely unknown. Here, we find that glucocorticoids enhance the production of IgE in B cells both in vivo and ex vivo without antigenic challenge. Such IgE production is promoted by B cell–intrinsic glucocorticoid receptor signaling that reinforces CD40 signaling and synergizes with the IL-4/STAT6 pathway. In addition, we found that rare B cells in the mesenteric lymph nodes are responsible for the production of glucocorticoid-inducible IgE. Furthermore, locally produced glucocorticoids in the gut may induce natural IgE during perturbations of gut homeostasis, such as dysbiosis. Notably, mice preemptively treated with glucocorticoids were protected from subsequent pathogenic anaphylaxis. Together, our results suggest that glucocorticoids, classically considered to be broadly immunosuppressive, have a selective immunostimulatory role in B cells.