Magnetic resonance imaging of the breast improves detection of invasive cancer, preinvasive cancer, and premalignant lesions during surveillance of women at high risk for breast cancer.

PURPOSE: To assess the diagnostic accuracy of mammography, ultrasound, and magnetic resonance imaging (MRI) of the breast in the surveillance of women at high risk for breast cancer. EXPERIMENTAL DESIGN: In this prospective comparison study, women at high risk for breast cancer were offered annual surveillance examinations, consisting of mammography, ultrasound, and MRI, at a single tertiary care breast center. The sensitivity and specificity of each modality was based on the histopathologic evaluation of suspicious findings from all modalities plus the detected interval cancers. RESULTS: Three hundred and twenty-seven women underwent 672 complete imaging rounds. Of a total of 28 detected cancers, 14 were detected by mammography, 12 by ultrasound, and 24 by MRI, which resulted in sensitivities of 50%, 42.9%, and 85.7%, respectively (P < 0.01). MRI detected not only significantly more invasive but also significantly more preinvasive cancers (ductal carcinoma in situ). Mammography, ultrasound, and MRI led to 25, 26, and 101 false-positive findings, which resulted in specificities of 98%, 98%, and 92%, respectively (P < 0.05). Thirty-five (35%) of these false-positive findings were atypical ductal hyperplasias, lesions considered to be of premalignant character. Nine (26%) of those were detected by mammography, 2 (6%) with ultrasound, and 32 (91%) with MRI (P < 0.01). CONCLUSION: Our results show that MRI of the breast improves the detection of invasive cancers, preinvasive cancers, and premalignant lesions in a high-risk population and should therefore become an integral part of breast cancer surveillance in these patients.     

Hemolytic uremic syndrome due to an altered factor H triggered by neonatal pertussis

We report on a previously healthy newborn suffering from severe Bordetella pertussis infection who developed hemolytic uremic syndrome (HUS) a few weeks after the onset of whooping cough, with a fatal outcome. A factor H protein with abnormal mobility was found in the serum of the patient as analyzed by Western blotting, indicating that B. pertussis infection might have triggered HUS in a genetically predisposed patient. Received: 13 July 2000 / Revised: 3 October 2001 / Accepted: 9 October 2001     

Structural requirements for inhibition of the neuronal nitric oxide synthase (NOS-I): 3D-QSAR analysis of 4-oxo- and 4-amino-pteridine-based inhibitors

The family of homodimeric nitric oxide synthases (NOS I-III) catalyzes the generation of the cellular messenger nitric oxide (NO) by oxidation of the substrate L-arginine. The rational design of specific NOS inhibitors is of therapeutic interest in regulating pathological NO levels associated with sepsis, inflammatory, and neurodegenerative diseases. The cofactor (6R)-5,6,7,8-tetrahydrobiopterin (H(4)Bip) maximally activates all NOSs and stabilizes enzyme quaternary structure by promoting and stabilizing dimerization. Here, we describe the synthesis and three-dimensional (3D) quantitative structure-activity relationship (QSAR) analysis of 65 novel 4-amino- and 4-oxo-pteridines (antipterins) as inhibitors targeting the H(4)Bip binding site of the neuronal NOS isoform (NOS-I). The experimental binding modes for two inhibitors complexed with the related endothelial NO synthase (NOS-III) reveal requirements of biological affinity and form the basis for ligand alignment. Different alignment rules were derived by building other compounds accordingly using manual superposition or a genetic algorithm for flexible superposition. Those alignments led to 3D-QSAR models (comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA)), which were validated using leave-one-out cross-validation, multiple analyses with two and five randomly chosen cross-validation groups, perturbation of biological activities by randomization or progressive scrambling, and external prediction. An iterative realignment procedure based on rigid field fit was used to improve the consistency of the resulting partial least squares models. This led to consistent and highly predictive 3D-QSAR models with good correlation coefficients for both CoMFA and CoMSIA, which correspond to experimentally determined NOS-II and -III H(4)Bip binding site topologies as well as to the NOS-I homology model binding site in terms of steric, electrostatic, and hydrophobic complementarity. These models provide clear guidelines and accurate activity predictions for novel NOS-I inhibitors.     

The effect of isoflurane on neutrophil selectin and beta(2)-integrin activation in vitro

Isoflurane is reported to reduce ischemia-reperfusion injury. Lower expression of CD11b may be responsible for attenuated postischemic neutrophil adhesion to vascular endothelium. However, neutrophil adhesion to vascular endothelium is a multistep process involving several selectins and beta(2)-integrins. Therefore, we assessed whether isoflurane affects the activation of the selectins P-selectin glycoprotein ligand-1 (PSGL-1) and L-selectin and the beta(2)-integrins CD11a and CD11b. Whole blood was incubated for 60 min with 0.5 or 1 minimum alveolar anesthetic concentration (MAC) isoflurane. After incubation, neutrophils were activated with N-formyl-methionyl-leucyl-phenylalanine (FMLP) or phorbol-12-myristate-13-acetate (PMA). Activation of adhesion molecules was evaluated via flow cytometry, and 1 MAC isoflurane reduced the expression of CD11a in the unstimulated samples. After stimulation with FMLP and PMA, shedding of L-selectin was lower in the presence of isoflurane. Furthermore, 1 MAC isoflurane reduced FMLP-induced activation of CD11a and CD11b compared with unexposed blood samples. These results demonstrate that isoflurane affects the activation of three adhesion molecules involved in the multistep process of neutrophil recruitment. First, isoflurane inhibits the activation of L-selectin, which mediates the neutrophil tethering and rolling on the vascular endothelium. Second, isoflurane attenuates the activation of both beta(2)-integrins-CD11a and CD11b-which mediate firm adhesion and transendothelial migration. IMPLICATIONS: Adhesion of neutrophils to endothelial cells in reperfusion injury is mediated by different adhesion molecules. This study indicates that the inhibiting effect of isoflurane on neutrophil recruitment may be mediated by a decreased activation of the L-selectin and by attenuation of the activation of the beta(2)-integrins CD11a and CD11b.     

Stereoscopic illusory contours--cortical neuron responses and human perception

In human perception, figure-ground segregation suggests that stereoscopic cues are grouped over wide areas of the visual field. For example, two abutting rectangles of equal luminance and size are seen as a uniform surface when presented at the same depth, but appear as two surfaces separated by an illusory contour and a step in depth when presented with different retinal disparities. Here, we describe neurons in the monkey visual cortex that signal such illusory contours and can be selective for certain figure-ground directions that human observers perceive at these contours. The results suggest that these neurons group stereoscopic cues over distances up to 8 degrees. In addition, we compare these results with human perception and show that the mean stimulus parameters required by these neurons also induce optimal percepts of illusory contours in human observers.     

N-myc oncogene overexpression down-regulates IL-6; evidence that IL-6 inhibits angiogenesis and suppresses neuroblastoma tumor growth

Angiogenesis is an indispensable prerequisite for the progression and metastasis of solid malignancies. Tumor angiogenesis appears to be governed by alterations of tumor suppressor or oncogenes operant in a broad range of tumors. We have addressed this issue in neuroblastoma, a malignancy characterized by the near-exclusive amplification and overexpression of the N-Myc oncogene. Here, we report that N-Myc overexpression results in down-regulation of interleukin-6 (IL-6) and that IL-6 is an inhibitor of endothelial cell proliferation and VEGF-induced rabbit corneal angiogenesis. STAT3 is instrumental for IL-6 activity as infection with adenoviruses expressing a phosphorylation deficient STAT3 mutant renders endothelial cells insensitive to the antiproliferative action of IL-6. Finally, though IL-6 does not influence neuroblastoma cell growth, IL-6-expressing xenograft tumors in mice exhibit reduced neovascularization and suppressed growth. Our data shed new light on the mechanisms by which N-myc oncogene amplification enhances the malignant phenotype in neuroblastomas.