Comparison of the resistance of C57BL/6 and C3H/He mice to infection with Mycobacterium paratuberculosis

Susceptibility of C57BL/6 (Bcgs) and C3H/HeN (Bcgr) mice to an intraperitoneal infection with Mycobacterium paratuberculosis strain 19698 was compared (by histopathology and the number of mycobacteria isolated from the spleen). Mycobacterial counts from the spleen of Bcgr mice progressively decreased over the course of infection but remained unchanged in Bcgs mice. Granulomatous lesions and acid-fast bacteria were consistently present in the liver and lymph nodes of Bcgs mice, whereas lesions were transient or absent in Bcgr mice. These results indicate that Bcgr mice are inherently resistant to M. paratuberculosis, whereas Bcgs mice are inherently susceptible. These differences may prove useful in elucidating the mechanisms of resistance and susceptibility to paratuberculosis and other mycobacterial infections.     

Phase I trial of weekly scheduling and pharmacokinetics of titanocene dichloride in patients with advanced cancer

PURPOSE: To determine the maximum-tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of a weekly schedule of titanocene dichloride (TD) and to define the pharmacokinetics of titanium in plasma and urine. PATIENTS AND METHODS: Twenty patients with a median age of 58 years received 83 courses of TD. TD was given as 1-hour infusion at escalating doses from 70 to 185 mg/m2/wk. Pharmacokinetic analysis was performed in eight patients for total plasma titanium (TPTi) and in three patients for ultrafiltrable titanium (UFTi). RESULTS: At the fifth dose level (185 mg/m2/wk), a variety of DLTs were seen in five patients: fatigue in three, bilirubinemia in one, and hypokalemia in two. A further six patients were treated at 140 mg/m2; only one had dose-limiting creatinine elevation and this dose was therefore defined as the MTD. No myelosuppression or alopecia were observed. One patient with adenocarcinoma of unknown primary had a minor response. Pharmacokinetic analysis showed that TPTi maximum concentration (Cmax) values were linear with dose and elimination of TPTi was triphasic with a long terminal half-life (t1/2; median, 165 hours; range, 89 to 592). Between 7% and 24.3% of the total of administered titanium was eliminated in urine over the first 24 hours. In contrast, UFTi elimination was described by a one-compartment model with a t1/2 of 0.41 hours; peak levels of UFTi were 5.2% +/- 2.5% those of TPTi. CONCLUSION: The MTD of TD given on a weekly schedule is 140 mg/m2, with cumulative, but reversible creatinine and bilirubin elevation being the DLTs.     

Comparative evaluation of FUNGITEST and broth microdilution methods for antifungal drug susceptibility testing of Candida species and Cryptococcus neoformans

The FUNGITEST method (Sanofi Diagnostics Pasteur, Paris, France) is a microplate-based procedure for the breakpoint testing of six antifungal agents (amphotericin B, flucytosine, fluconazole, itraconazole, ketoconazole, and miconazole). We compared the FUNGITEST method with a broth microdilution test, performed according to National Committee for Clinical Laboratory Standards document M27-A guidelines, for determining the in vitro susceptibilities of 180 isolates of Candida spp. (50 C. albicans, 50 C. glabrata, 10 C. kefyr, 20 C. krusei, 10 C. lusitaniae, 20 C. parapsilosis, and 20 C. tropicalis isolates) and 20 isolates of Cryptococcus neoformans. Overall, there was 100% agreement between the methods for amphotericin B, 95% agreement for flucytosine, 84% agreement for miconazole, 83% agreement for itraconazole, 77% agreement for ketoconazole, and 76% agreement for fluconazole. The overall agreement between the methods exceeded 80% for all species tested with the exception of C. glabrata (71% agreement). The poorest agreement between the results for individual agents was seen with C. glabrata (38% for fluconazole, 44% for ketoconazole, and 56% for itraconazole) and C. tropicalis (50% for miconazole). The FUNGITEST method misclassified as susceptible 2 of 12 (16.6%) fluconazole-resistant isolates, 2 of 10 (20%) itraconazole-resistant isolates, and 4 of 8 (50%) ketoconazole-resistant isolates of several Candida spp. Further development of the FUNGITEST procedure will be required before it can be recommended as an alternative method for the susceptibility testing of Candida spp. or C. neoformans.     

Microstructural evidence for short-circuit oxygen diffusion paths in the oxidation of a dilute Ni-Cr alloy

A comparative study of high-temperature oxidation of Ni containing 1 at.% Cr and pure Ni was carried out. Instead of the conventional kinetics study using thermogravimetry, a microlithographic marker experiment was designed. Observation of the markers using cross-sectional TEM and SEM has revealed striking differences in the scale morphology, microstructures, and oxidation mechanisms between pure Ni and the Cr-doped Ni substrates. In particular, the results suggest that a small addition of Cr promotes significant inward transport of oxygen. Marker experiments revealed that NiO grown on pure Ni is wholly attributable to outward-cation diffusion. In contrast, NiO grown on Ni–1 at.% Cr exhibited formation of a substantial inner layer having a submicron grain size, established by the markers to have formed from oxygen ingress. For pure Ni, voids were observed to be distributed only within oxide grains. In contrast, for Ni containing 1 at.% Cr, elongated pores formed extensively along oxide-grain boundaries. Formation of new fine-grain oxide in these pores was observed to have sometimes completely resealed the void. It is, therefore, proposed that the transport of oxygen in the case of oxide scale grown on Ni–1 at.% Cr occurs via voids (pores) formed by vacancy coalescence at the grain boundaries.     

The Oxidation Behavior of Y2O3-Dispersed β-NiAl

Y₂O₃-dispersed NiAl was produced by a powder-metallurgy process. By adding Y as an oxide dispersion (OD), problems with NiY_x formation and internal oxidation were avoided. Short-term isothermal and cyclic-oxidation performance at 1200°–1500° C was compared to cast NiAl alloys with and without Zr. Results indicate that the Y₂O₃ addition was beneficial to scale adhesion and significantly modified the α-Al₂O₃ scale microstructure, similar to a Zr alloy addition. However, at 1400 and 1500° C, neither the Y₂O₃ or Zr additions changed the scale-growth rate, eliminated the formation of voids at the metal-scale interface or prevented scale spallation. These similarities in performance suggest that similar mechanisms occur when the reactive element is added as either an OD or an alloy addition.     

Hypermedia Support for Software Development: A Retrospective Assessment

Hypermedia technologies have been available for about a decade. Beginning with Douglas Engelbart, researchers have become interested in applying hypermedia concepts and technologies to software development. This paper assesses this symbiosis between hypermedia and software development as described by research contributions; by our count, more than one hundred articles. To date, no collection of, or guide to, this literature has been published. A number of significant contributions are classified, described, and appraised — providing a guide into what has been a rich but perhaps under-reported research area. Hypermedia has made significant contributions to software development in three primary areas: coping with massive amounts of information associated with software development projects; establishing and maintaining linkages between various types of software engineering documents; and enabling development engineers to record, document, and preserve knowledge about development thoughts, processes and rationale. These contributions may help direct the focus of future research towards building on, combining and assessing the resulting contributions. A research agenda is proposed along these lines.     

Cracking the walnut: Using a computer game to impact cognition,emotion, and behavior of highly aggressive fifth grade students

Three fifth grade highly aggressive students participated in a study examining effects of an aggression intervention game. Using single-subject multiple baseline research design, the effect of the game was measured across three domains: attribution of peer intent (cognitive), emotional response (affective) and behavior response (behavioral). The results indicate that, while there were observable individual differences, the game had an immediate impact on attribution of peer behavior across all participants, had a less predictable impact on reported behavioral reactions, and had no discernable impact on reported emotional response. Theoretical and practical implications of the study are discussed.     

Mycobacterial infection in guinea pigs

We described published reports of the chaos which exists in research concerning laboratory animal models for assay of tuberculosis (TB) vaccines and proposed a "rational animal model" as a solution to the problem. This animal model, an aerosol challenge model in guinea pigs, was recently applied to the problem of differences in growth characteristics of sputum isolates of low and high virulence. The same model was used to investigate the protective effect of high dose BCG given aerogenically. Based on studies in the guinea pig model of experimental airborne TB, and a review of the literature on pathogenesis of human TB, we described an "integrated model" for the pathogenesis of TB, a model which includes a role for both the endogenous reactivation and the exogenous reinfection pathways. Our hypothesis is that tubercle bacilli must be able to gain access to the "vulnerable region" in the lung apex in order to survive the effects of the CMI response. In endogenous reactivation TB (virulent tubercle bacilli), this access occurs via the bloodstream. Whereas in exogenous reinfection TB, access to the vulnerable region occurs via multiple exposures via the respiratory tract. Central to our perspective is the acceptance of the evidence that during first infection with virulent organisms, tubercle bacilli enter the bloodstream via the efferent lymphatics. We believe the hypotheses we have proposed have the potential to lead to a further increase in our knowledge of these mechanisms and are a prerequisite to studies aimed at the development of new vaccines.     

Evolution of the cranial computed tomography scan in child abuse

Computed tomography (CT) scans obtained at the time of clinical presentation have occasionally been reported to be normal in children with history and findings of significant abusive head injury. We have retrospectively observed abnormalities in "normal" scans of some similar children. We have also seen abnormalities develop on serial scanning. To determine how frequently these situations occur, we reviewed charts of 34 children with a final diagnosis of child abuse who also had cranial CT scans performed. Their CT scans were retrospectively reviewed by a pediatric radiologist. Eleven (11/34) CT scans had initially been interpreted as normal. Four (4/11) of these had been reinterpreted during the hospitalization as abnormal, affecting medical (1) and legal (3) outcome. Repeat scanning in three of the remaining seven resulted in surgical drainage of a subdural effusion (1) and affected legal outcome (2). Four of the seven initial scans felt normal throughout the hospitalizations were judged abnormal on retrospective review. This evaluation was confirmed in the two rescanned. Initial CT interpretation most often failed to appreciate changes in parenchymal density and small amounts of falcine or cortical subdural blood. Subsequent scans also showed evolving effusions and infarcts. Changes were noted in 1 1/2 to 5 days. The CT scan frequently shows subtle changes in the immediate posttrauma period. If the child does not recover promptly, subsequent scans frequently result in significant changes in clinical and legal management.