Successful treatment of stage III neuroblastoma based on prospective biologic staging: a Children's Cancer Group study

PURPOSE: To identify a biologically favorable and unfavorable subset of patients with Evans stage III neuroblastoma and to determine whether treatment stratification would improve the event-free survival (EFS) for high-risk patients and maintain excellent EFS for the lower-risk patients. PATIENTS AND METHODS: Risk stratification was performed by age, MYCN gene copy number, Shimada histopathologic classification, and serum ferritin level. Lower-risk patients were treated on the less intensive Children's Cancer Group (CCG)-3881, whereas high-risk patients were treated on CCG-3891, which included more intensive multimodality therapy and, in some cases, autologous bone marrow transplantation (ABMT). RESULTS: Of 228 Evans stage III patients entered onto the study, 92% also met the definition of International Neuroblastoma Staging System (INSS) stage 3. One hundred forty-three patients met the lower-risk criteria, which included 89 patients less than 1 year of age and 54 patients 1 year of age or greater, and favorable biology, whereas 85 patients were 1 year of age or greater and biologically unfavorable. Biologically unfavorable patients 1 year of age or greater who underwent gross surgical resection had improved survival, whereas the outcome of infants or biologically favorable older patients did not change according to resection. The EFS rate at 4 years was 100% for the patients with favorable biology of any age, 90% for those less than 1 year of age but with at least one unfavorable characteristic, and 54% for Evans stage III patients 1 year of age or greater with unfavorable biology. Age, ferritin level, MYCN copy number, Shimada histopathology, primary site, and intraspinal extension were significant univariate prognostic factors for all patients, but only MYCN copy number and age were independent factors in multivariate analyses. CONCLUSION: The excellent survival of the biologically favorable group and the historically improved EFS of the biologically unfavorable group suggest that biologic staging should be used to define the prognosis and treatment of stage III neuroblastoma.     

Cloning, sequencing and functional expression of a guinea pig lung bradykinin B2 receptor

Kinin receptors are classified as B1 and B2 based upon agonist and antagonist potencies and cloning and expression studies. Using sequences from human and rat bradykinin B2 receptors, polymerase chain reaction (PCR) was utilized to isolate cDNA from guinea pig lung. The receptor obtained is predicted to have 372 amino acids and shares > 80% sequence homology with human, rat, rabbit and mouse B2 receptors. In competition binding experiments in Chinese hamster ovary (CHO-K1) cells in which the guinea pig cDNA was expressed, [3H]bradykinin was displaced by kinin receptor ligands with an order of potency consistent with a B2 subtype. In CHO cells expressing the guinea pig receptor, bradykinin caused a concentration 45Ca2+ efflux. A B1 receptor agonist, desArg9-bradykinin, also caused 45Ca2+ efflux but with a potency several orders of magnitude lower than bradykinin. Curiously, several B1 and B2 receptor antagonists induced 45Ca2+ efflux, indicating that this receptor may be coupled differently in CHO cells than in native tissues.     

Age alters the cardiovascular response to direct passive heating

During direct passive heating in young men, a dramatic increase in skin blood flow is achieved by a rise in cardiac output (Qc) and redistribution of flow from the splanchnic and renal vascular beds. To examine the effect of age on these responses, seven young (Y; 23 +/- 1 yr) and seven older (O; 70 +/- 3 yr) men were passively heated with water-perfused suits to their individual limit of thermal tolerance. Measurements included heart rate (HR), Qc (by acetylene rebreathing), central venous pressure (via peripherally inserted central catheter), blood pressures (by brachial auscultation), skin blood flow (from increases in forearm blood flow by venous occlusion plethysmography), splanchnic blood flow (by indocyanine green clearance), renal blood flow (by p-aminohippurate clearance), and esophageal and mean skin temperatures. Qc was significantly lower in the older than in the young men (11.1 +/- 0.7 and 7.4 +/- 0.2 l/min in Y and O, respectively, at the limit of thermal tolerance; P < 0. 05), despite similar increases in esophageal and mean skin temperatures and time to reach the limit of thermal tolerance. A lower stroke volume (99 +/- 7 and 68 +/- 4 ml/beat in Y and O, respectively, P < 0.05), most likely due to an attenuated increase in inotropic function during heating, was the primary factor for the lower Qc observed in the older men. Increases in HR were similar in the young and older men; however, when expressed as a percentage of maximal HR, the older men relied on a greater proportion of their chronotropic reserve to obtain the same HR response (62 +/- 3 and 75 +/- 4% maximal HR in Y and O, respectively, P < 0.05). Furthermore, the older men redistributed less blood flow from the combined splanchnic and renal circulations at the limit of thermal tolerance (960 +/- 80 and 720 +/- 100 ml/min in Y and O, respectively, P < 0. 05). As a result of these combined attenuated responses, the older men had a significantly lower increase in total blood flow directed to the skin.     

IMPS: An interactive mathematical proof system

IMPS is an interactive mathematical proof system intended as a general-purpose tool for formulating and applying mathematics in a familiar fashion. The logic of IMPS is based on a version of simple type theory with partial functions and subtypes. Mathematical specification and inference are performed relative to axiomatic theories, which can be related to one another via inclusion and theory interpretation. IMPS provides relatively large primitive inference steps to facilitate human control of the deductive process and human comprehension of the resulting proofs. An initial theory library containing over a thousand repeatable proofs covers significant portions of logic, algebra, and analysis and provides some support for modeling applications in computer science.Supported by the MITRE-Sponsored Research program.     

An angle-based design approach for rectangular electrostatictorsion actuators

In this paper, we develop a fast, angle-based design approach for rectangular electrostatic torsion actuators based on several simple equations. This approach is significantly more straightforward than the usual full calculation or simulation methods. The main results of the simplified approach are verified by comparing them with analytical calculations and MEMCAD simulations with fractional difference smaller than 3% for torsion mode dominant actuators. Also, good agreement is found by comparison with the measured behavior of a microfabricated full-plate device     

Immune response to recombinant mycobacterial proteins in patients with tuberculosis infection and disease

The capacity of four Mycobacterium tuberculosis recombinant antigens to elicit proliferation and cytokine production by human T cells was evaluated. Proliferative responses of peripheral blood mononuclear cells (PBMC) to all antigens were greater in healthy tuberculin reactors than in pulmonary tuberculosis patients, and proliferative responses of pleural fluid cells were greater than those of PBMC from patients with tuberculous pleuritis. The proliferative responses to the four recombinant antigens were similar in all patient groups, and there was no selective unresponsiveness to any antigen in pulmonary tuberculosis patients. The 38-kDa antigen induced less interferon-gamma than did the 10-, 30-, and 65-kDa antigens, and all four antigens induced similar amounts of interleukin-10. These results suggest that none of the four recombinant antigens are immunodominant, and that the 10-, 30-, and 65-kDa antigens are similar in their capacity to induce a potentially protective Th1-like response.     

Electrophysiologic characteristics and anatomical complexities of accessory atrioventricular pathways with successful ablation of anterograde and retrograde conduction at different sites

INTRODUCTION: Catheter ablation may eliminate anterograde and retrograde accessory pathway conduction at closely adjacent but anatomically discrete sites. However, the mechanisms of this discrepancy, the electrophysiologic and anatomical characteristics, and information about systematic study from a large patient population are not available. The purpose of this study was to investigate the electrophysiologic characteristics and anatomical complexities of the accessory pathway in which anterograde and retrograde conduction was successfully ablated at different sites. METHODS AND RESULTS: Thirty-eight (10.9%) patients (19 men and 19 women; mean age 37 +/- 2.4 years) fulfilling the criteria of having separate ablation sites for anterograde and retrograde conduction were designated as group I, and the other 310 patients (215 men and 95 women; mean age 47 +/- 0.6 years) were designated as group II. The patients with right-sided free-wall pathways had the highest incidence (18.6%) of separate ablation sites. The anatomical distance between anterograde and retrograde directions (left anterior oblique view, 13 +/- 0.6 vs 8 +/- 0.9 mm, P < 0.01; right anterior oblique view, 17 +/- 0.6 vs 5 +/- 0.7 mm, P < 0.01), and incidence of conduction impairment in one direction after successful ablation of another direction (15% vs 78%, P < 0.05) differed significantly between left and right free-wall pathways. The mean distances obtained from left (7 +/- 0.4 vs 14 +/- 0.4 mm, P < 0.05) and right (7 +/- 1.1 vs 15 +/- 0.9 mm, P < 0.05) anterior oblique views were shorter in patients who had impairment of conduction properties than those in patients without impaired conduction after successful ablation of one direction. CONCLUSIONS: This study showed that anatomical and functional dissociation of the accessory pathway into anterograde and retrograde components was possible. Further study on the relation between electrophysiologic and pathologic characteristics would be helpful to confirm these findings.     

Acute phase proteins in male Chinese schizophrenic patients in Singapore

The effects of orientating pairs of synergistic monoclonal antibodies (mAb) on binding of human chorionic gonadotropin (hCG) was studied by radioimmunoassay (RIA), enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance (SPR). Antibody synergy towards hCG required two functionally intact antibodies located adjacent to each other and with different epitope specificities. We investigated whether immobilization procedures avoiding protein denaturation, increasing proper orientation and promoting higher molecular flexibility of the synergistic mAb resulted in significantly enhanced antigen, binding. Synergistic mAb pairs captured through their Fc-region by protein G or a polyclonal serum against the Fc-part of mouse IgG could be used at 10-fold lower coating concentrations to achieve maximal binding of the analyte as compared with the same mAb pairs coated directly onto polystyrene. The synergistic effect observed with protein A used as capture varied greatly with the subclasses of the two synergistic antibodies employed. Scatchard analysis revealed that the number of functionally synergistic antibody sites participating in the binding of hCG for one mAb pair was about 10 times higher for the protein G-captured as compared with the directly coated synergistic pair. Biotinylated synergistic mAb pairs, coated directly or captured by streptavidin, did not display any enhanced antigen binding when tested in SPR or ELISA. With SPR, synergy was only observed when the synergistic mAb had been captured through their Fc-region. Using protein G or a polyclonal rabbit anti-IgG1 serum as capture reagents in SPR, synergistic triple mAb combinations against hCG were demonstrated.     

Cellular localization of antiviral polyoxometalates in J774 macrophages

The main objective of the present study was to examine the relationship between regular benzodiazepine (BZD) use and drinking patterns in 55-year-old female residents of Malm?, Sweden. All women born in 1935 (a total of 1223 subjects) were invited to a health screening at the Preventive Medicine Section, Malm? General Hospital; 69% agreed to participate. The screening included an extensive health questionnaire, and the responses to 33 items assessing social background, including immigrant status, use of BZD and analgesics, alcohol consumption (the revised Malm?-MAST), smoking and morbidity were analysed. A psychiatric symptoms scale including five of these items was constructed, yielding a Cronbach's alpha of 0.57. Present use of BZD hypnotics and/or tranquillizers was acknowledged by 6% of the women. BZD use at any time in the past or present was endorsed by 23%. Endorsement of > or = 3 revised Malm?-MAST items, indicating problem drinking, occurred in 3% of the participants; 16% were teetotallers and about 25% were regular weekend drinkers. BZD use was significantly more likely to occur in women with the following characteristics: early retirement, pain symptoms, longstanding use of analgesics, multiple psychiatric symptoms. Drinking patterns in relation to BZD use indicated that regular weekend drinkers were significantly less likely to be current and/or previous BZD users than problem drinkers and teetotallers. Logistic regression analyses indicated that use of BZDs was mainly predicted by endorsement of multiple psychiatric symptoms.