Improving human-in-the-loop simulation to optimize soldier-systems integration.

OBJECTIVE: To identify requirements for human-in-the-loop simulation capabilities and improve their utility in predicting and optimizing soldier-systems integration. BACKGROUND: Technological development rates within the military are rapidly increasing. Emergent technologies often exclude in-depth consideration of human-system interactions until the physical prototyping phase. Human-in-the-loop simulation tools can allow for earlier consideration of humans in the development process; however, use remains limited. METHOD: Semi-structured interviews were conducted with key informants to yield perspectives on current human-in-the-loop simulation capabilities and utility specific to the military. An inductive approach to thematic analysis was used to extract critical themes from transcribed interview data. A scoping review was completed to supplement the data obtained from interviews and summarize knowledge regarding requirements for human-in-the-loop simulation and analysis capabilities targeted to the military. RESULTS: Interviews were conducted with five experts representing the sectors of Vehicle/Equipment Design, Simulation, and Army Research. A total of 2274 sources were identified, and 64 papers were retained for the scoping review. Thematic analysis of the combined data sources yielded six important themes to consider with respect to requirements for future human-in-the-loop simulation capabilities targeting soldier-systems integration. CONCLUSION: This study has identified eight key requirements to support the use of human-in-the-loop simulation tools to predict and optimize soldier-systems integration and performance. APPLICATION: Addressing key requirements will improve the ability of current human-in-the-loop simulation tools to accommodate the military's need for human consideration early in the design process.

Endoscopic ultrasonography-guided portal injection chemotherapy for hepatic metastases.

INTRODUCTION: We hypothesized that endoscopic ultrasonography-guided portal injection chemotherapy (EPIC) using irinotecan-loaded microbeads may achieve increased intrahepatic concentrations, while decreasing systemic exposure. This may achieve enhanced efficacy for the treatment of diffuse liver metastases, while decreasing systemic toxicities. MATERIALS AND METHODS: In eight anesthetized 35 kg pigs, EPIC was performed transgastrically using the linear-array echoendoscope and a 22 g fine-needle aspiration. In four animals, irinotecan (100 mg) loaded onto 75-150 micron liquid chromatography (LC) beads was injected. In four animals, saline was injected into the portal vein and unloaded irinotecan (100 mg) was injected into the jugular vein. Plasma (every 15 min), and at 1 h bone marrow, liver and skeletal muscle samples were obtained. Irinotecan and SN-38 (active metabolite) concentrations were assayed by LC/mass spectrometry. RESULTS: The procedure was performed safely in all eight animals. Compared with systemic administration, EPIC resulted in almost twice the hepatic concentration of irinotecan (6242 vs. 3692 ng/g) and half the systemic concentrations in plasma (1092 vs. 2762 ng/mL), bone marrow (815 vs. 1703 ng/mL) and skeletal muscle (521 vs. 1058 ng/g). SN-38 levels were lower with EPIC (liver: 166 vs. 681 ng/g; plasma: 1.8 vs. 2.4 ng/mL; bone marrow: 0.9 vs. 1.4 ng/mL; muscle 4.6 vs. 9.2 ng/g). Liver histology showed the beads within small portal venules. CONCLUSIONS: EPIC using irinotecan-loaded microbeads can enhance hepatic exposure to irinotecan, while decreasing systemic concentrations. SN-38 levels were lower with EPIC indicating that a substantial portion of the irinotecan was still loaded onto beads. The microbeads may act as a reservoir resulting in prolonged hepatic drug exposure.

Intraocular use of rituximab.

PURPOSE: To evaluate the toxicity of 1 mg of intraocular rituximab and to present a small case-series of patients treated with intravitreal rituximab. METHODS: Rituximab (1 mg/0.1 ml) was injected in the vitreous of one eye of three Dutch-belted rabbits. Two animals were injected with balanced salt solution as controls. At 1 month the rabbits were killed and the eyes examined by light microscopy. Three patients (five eyes) with intraocular lymphoma were also treated with a 1 mg injection of rituximab. RESULTS: The treated rabbit eyes and the control eyes showed no light microscopic evidence of ocular toxicity at 1 month following injection. The five human eyes of three patients have shown no evidence of intraocular toxicity with a median follow-up time of 3.6 months (range 2.0-6.4 months). One patient received a total of four injections in the right eye and three injections in the left eye. CONCLUSION: Intravitreal rituximab at a dose of 1 mg does not appear to cause toxicity in rabbit eyes and in the five eyes of three patients.

Mercury induces regional and cell-specific stress protein expression in rat kidney.

Cells respond to physiologic stress by enhancing the expression of specific stress proteins. Heat-shock proteins (hsps) and glucose-regulated proteins (grps) are members of a large superfamily of proteins collectively referred to as stress proteins. This particular stress-protein response has evolved as a cellular strategy to protect, repair, and chaperone other essential cellular proteins. The objective of this study was to evaluate the differential expression of four hsps in the renal cortex and medulla during experimental nephrotoxic injury using HgCl2. Male Sprague-Dawley rats received single injections of HgCl2 (0.25, 0.5, or 1 mg Hg/kg, i.v.). At 4, 8, 16, or 24 h after exposure, kidneys were removed and processed for histopathologic, immunoblot, and immunohistochemical analyses. Nephrosis was characterized as minimal or mild (cytoplasmic condensation, tubular epithelial degeneration, single cell necrosis) at the lower exposures, and progressed to moderate or severe (nuclear pyknosis, necrotic foci, sloughing of the epithelial casts into tubular lumens) at the highest exposures. Western blots of renal proteins were probed with monoclonal antibodies specific for 4 hsps. In whole kidney, Hg(II) induced a time- and dose-related accumulation of hsp72 and grp94. Accumulation of hsp72 was predominantly localized in the cortex and not medulla, while grp94 accumulated primarily in the medulla but not cortex. The high, constitutive expression of hsp73 did not change as a result of Hg(II) exposure, and it was equally localized in cortex and medulla. Hsp90 was not detected in kidneys of control or Hg-treated rats. Since hsp72 has been shown involved in cellular repair and recovery, and since Hg(II) damage occurs primarily in cortex, we investigated the cell-specific expression of this hsp. Hsp72 accumulated primarily in undamaged distal convoluted tubule epithelia, with less accumulation in undamaged proximal convoluted-tubule epithelia. These results demonstrate that expression of specific stress proteins in rat kidney exhibits regional heterogeneity in response to Hg(II) exposure, and a positive correlation exists between accumulation of some stress proteins and acute renal cell injury. While the role of accumulation of hsps and other stress proteins in vivo prior to or concurrent with nephrotoxicity remains to be completely understood, these stress proteins may be part of a cellular defense response to nephrotoxicants. Conversely, renal tubular epithelial cells that do not or are unable to express stress proteins, such as hsp72, may be more susceptible to nephrotoxicity.

Sequential neuropathology of dogs treated with vigabatrin, a GABA-transaminase inhibitor.

Vigabatrin (Sabril) is a gamma-aminobutyric acid-transaminase (GABA-T) inhibitor that is effective in the treatment of certain types of drug-resistant or uncontrolled epilepsy but is known to cause microscopic vacuolation (intramyelinic edema) in the brains of treated rats, mice, and dogs. The effects of high oral doses (300 mg/kg/day) of vigabatrin administered orally to Beagle dogs were studied during treatment weeks 1-12 and recovery weeks 13, 14, 16, 20, 24, and 28. Emesis, loose stools, and anorexia and 3 drug-related deaths were observed during the first 4 wk of treatment but were virtually nonexistent thereafter because of adaptation to the drug aided by food supplementation. In more sensitive areas of the brain (columns of the fornix, thalamus, and hypothalamus), microscopic quantitative differences between background vacuolation in controls and drug-related vacuolation in treated dogs could be delineated after 4 wk, generally reached highest levels of severity between 8 and 12 wk, and were reversible upon cessation of dosing. Inhibition of brain GABA-T and elevation of brain GABA were noted after 1 wk of treatment. During the course of treatment vigabatrin ranged between 4-17 nmol/ml (plasma) and 42-1,570 nmol/ml [cerebrospinal fluid (CSF)] while CSF GABA concentrations were 4-32 nmol/ml (treated dogs) and 0.1-0.6 nmol/ml (control dogs). Although the cause of vigabatrin-induced microvacuolation is unknown, the results of the study demonstrated that GABA-T inhibition with subsequent GABA elevation occurred within the first week of treatment and was followed by the onset of detectable microvacuolation several weeks later.

Serologic survey for leptospirosis in coyotes in northcentral Kansas.

During 1975 to 1977, serum samples were collected from 101 adult coyotes (Canis latrans) captured in northcentral Kansas. Ten samples were seropositive by microagglutination testing and six of those samples were seropositive for multiple serovars. Titers for Leptospira interrogans serovars grippotyphosa, pyrogenes, djasiman, butembo, and pomona were demonstrated.

Experimentally induced leptospirosis in coyotes (Canis latrans).

Infection of coyotes (Canis latrans) with Leptospira interrogans serovars pomona, canicola, and copenhageni was accomplished by percutaneous inoculation. Bacteriologic, serologic, histopathologic, and fluorescent antibody techniques were used to investigate the infections. Leptospiremia was established with pomona. Leptospiruria was demonstrated with the three serovars. Serovar canicola was recovered from one coyote 134 days after it was inoculated.

Some hematologic and blood chemistry values in two herds of American bison in Kansas.

The data presented are compiled from two herds of American bison (Bison bison) in Kansas. In this study there were differences in the mean values of white blood cell count, neutrophil percentage, lymphocyte percentage and cholestrol, alkaline phosphatase, specific glutamic-oxalacetic transaminase concentrations between the age groups of animals under 2 years of age and bison over 2 year old. Differences in the two age groups paralleled those found in Jersey and Hereford cattle. Packed cell volume and hemoglobin concentrations was considerably higher than found in domestic Bovidae. More data is needed from other bison herds in this country to better describe the range of normal variation in individuals, population and age groups of B. bison.