Predicting cancer risk from vinyl chloride exposure with a physiologically based pharmacokinetic model

A physiologically based pharmacokinetic (PBPK) model capable of describing the metabolism of vinyl chloride (VC) in rats, mice, and humans has been developed and validated by comparison with experimental data from experiments not used in model development. This PBPK model has been used to predict measures of delivered dose (reactive VC metabolites produced in the livers of the affected species) hypothesized to be involved in the induction of liver angiosarcoma in rats, mice, and human populations exposed to VC. Measures of delivered dose in rats were fit to an empirical dose-response model (the linearized multistage model of Crump et al.) and used to make predictions of liver angiosarcoma incidence in mice and human populations exposed to VC. This procedure gave a good prediction of angiosarcoma incidence in mice. Predictions of angiosarcoma incidence in humans were more than two orders of magnitude lower than risk estimations which did not utilize pharmacokinetic data, but were still almost an order of magnitude higher than actually observed in exposed human populations.     

Duodenal bicarbonate secretion: eradication of Helicobacter pylori and duodenal structure and function in humans

BACKGROUND & AIMS: Eradication of Helicobacter pylori expedites duodenal ulcer healing and prevents recurrences. Most patients with duodenal ulcers have impaired proximal duodenal mucosal bicarbonate secretion (DMBS). In patients with inactive, healed duodenal ulcers and normal subjects, the effect of H. pylori infection on DMBS and proximal duodenal secretory function and structure were examined. METHODS: DMBS was quantitated before and after eradication of H. pylori. Mucosal structure (duodenal bulb histopathology) and function (DMBS at rest and stimulated, effect of active vs. healed ulcer and of age) were determined in patients with duodenal ulcers and normal subjects. RESULTS: In patients with duodenal ulcers, H. pylori eradication normalized proximal DMBS. Histological examination of duodenal biopsy samples was comparable in patients with duodenal ulcers and normal subjects without apparent relationship between inflammation and DMBS. Significantly impaired DMBS occurred in response to all agonists tested (luminal acid, prostaglandin E2, and cephalic-vagal stimulation) in patients with duodenal ulcers, suggesting a generalized secretory defect. Neither the presence of active (vs.inactive) ulcer nor age significantly affected bicarbonate secretion. CONCLUSIONS: In patients with duodenal ulcers, eradication of H. pylori normalized proximal DMBS and may thereby reduce ulcer recurrences. Altered DMBS in patients with duodenal ulcers was unrelated to histopathologic abnormalities. Impaired bicarbonate secretion in patients with duodenal ulcers could be caused by a cellular and/or physiological regulatory transport defect possibly related to H. pylori.     

Segmentation of brain tissue from magnetic resonance images

Segmentation of medical imagery is a challenging problem due to the complexity of the images, as well as to the absence of models of the anatomy that fully capture the possible deformations in each structure. The brain is a particularly complex structure, and its segmentation is an important step for many problems, including studies in temporal change detection of morphology, and 3-D visualizations for surgical planning. We present a method for segmentation of brain tissue from magnetic resonance images that is a combination of three existing techniques from the computer vision literature: expectation/maximization segmentation, binary mathematical morphology, and active contour models. Each of these techniques has been customized for the problem of brain tissue segmentation such that the resultant method is more robust than its components. Finally, we present the results of a parallel implementation of this method on IBM's supercomputer Power Visualization System for a database of 20 brain scans each with 256 x 256 x 124 voxels and validate those results against segmentations generated by neuroanatomy experts.     

Combined use of NMR, distance geometry and MD calculations for the conformational analysis of opioid peptides of the type [D(L)-Cys2, D(L)-Cys5]enkephalin

To understand the cellular processes involved in learning and memory, the cellular responses of neurons to calcium (Ca2+) signals, which can be evoked via synaptic activity, should be examined. A series of investigations in primary cultures of neurons revealed that the regulation of brain-derived neurotrophic factor (BDNF) mRNA expression is mediated by almost the same Ca2+ signaling pathways as that of c-fos mRNA expression. Such early co-activation of both genes in response to Ca2+ signals further suggests that sets of calcium-responsive genes (CaRGs) are concurrently activated by Ca2+ signals. The products encoded by CaRGs should then evoke a variety of physiological responses in neurons with the expression of another set of genes, the products of which are directly involved in the outcomes of neuronal functions. Thus, a cascade of gene expression can be induced by Ca2+ signals evoked via synaptic activity. It is of particular interest to identify the CaRGs and investigate the regulational mechanisms of their expression. A cellular approach using primary cultures of neurons would therefore lead to a better understanding of the intracellular processes involved in learning and memory.     

The University of Florida frameless high-precision stereotactic radiotherapy system

PURPOSE: To develop and test a system for high precision fractionated stereotactic radiotherapy that separates immobilization and localization devices. METHODS AND MATERIALS: Patient localization is achieved through detection and digital registration of an independent bite plate system. The bite plate is made and linked to a set of six infrared light emitting diodes (IRLEDs). These IRLEDs are detected by an infrared camera system that identifies the position of each IRLED within 0.1 to 0.15 mm. Calibration of the camera system defines isocenter and translational X, Y, and Z axes of the stereotactic radiosurgery subsystem and thereby digitally defines the virtual treatment room space in a computer linked to the camera system. Positions of the bite plate's IRLEDs are processed digitally using a computer algorithm so that positional differences between an actual bite plate position and a desired position can be resolved within 0.1 mm of translation (X, Y, and Z distance) and 0.1 degree of rotation. Furthermore, bite plate misalignment can be displayed digitally in real time with translational (x, y, and z) and rotational (roll, pitch, and yaw) parameters for an actual bite plate position. Immobilization is achieved by a custom head mold and thermal plastic mask linked by hook-and-loop fastener tape. The head holder system permits rotational and translational movements for daily treatment positioning based on the bite plate localization system. Initial testing of the localization system was performed on 20 patients treated with radiosurgery. The system was used to treat 11 patients with fractionated stereotactic radiotherapy. RESULTS: Assessment of bite plate localization in radiosurgery patients revealed that the patient's bite plate could be positioned and repositioned within 0.5 +/- 0.3 mm (standard deviation). After adjustments, the first 11 patients were treated with the bite plate repositioning error reduced to 0.2 +/- 0.1 mm. CONCLUSIONS: High precision stereotactic radiotherapy can be delivered using separate localization and immobilization systems. Treatment setup and delivery can be accomplished in 15 min or less. Advantages compared with standard systems require further study.     

'Health law 2000': the legal system and the changing health care market

The failure of national health reform confirmed in many ways the conservative nature of the American legal system. Legislatures, regulatory agencies, and courts usually find themselves in a reactive posture, responding to groups and individuals aggrieved by changing circumstances. The rapid transformation of the U.S. health care system through managed care presents an extreme example of this phenomenon, involving billions of dollars, millions of lives, and thousands of existing laws. Over the next few years the legal system will face a host of difficult issues deriving from the integration of health care financing and delivery, and the consolidation of fragmented providers into large corporations and contractual networks. What emerges may be neither logical nor consistent but no doubt will reflect the intricate interplay of societal and individual interests in health care.     

Self-report and observer measures of substance abuse among homeless mentally ill persons in the cross-section and over time

The comparability of self-report and observer measures of substance abuse among 118 homeless mentally ill persons was assessed using cross-sectional and longitudinal measures. Possible correlates of nondisclosure were identified from demographic variables and clinical indicators. Lifetime abuse reported at baseline was a sensitive predictor of subsequent abuse behavior in the project, but cross-sectional measures based only on self-report or observer ratings failed to identify many abusers. A total of 17% of the subjects never disclosed abuse that was observed during the project. The level of substance abuse is likely to be severely underestimated among homeless mentally ill persons when only one self-report measure is used at just one point in time. This problem can, however, largely be-overcome by incorporating information from observers and from multiple follow-ups or by focusing on lifetime rather than current abuse. We also conclude that underreporting may bias estimates of some correlates of substance abuse.     

Collagen fiber architecture of a cultured dermal tissue

Advances in tissue engineering have led to the development of artificially grown dermal tissues for use in burn and ulcer treatments. An example of such an engineered tissue is Dermagraft, which is grown using human neonatal fibroblasts on rectangular sheets of biodegradable mesh. Using small angle light scattering (SALS), we quantified the collagen fiber architecture of Dermagraft with the mesh scaffold contributions removed through the use of a structurally based optical model. Dermagraft collagen fibers were found to have a preferred direction nearly parallel to the long dimension of the kite-shaped mesh opening with small spatial variations over the mesh. This study demonstrated the utility of SALS as a rapid and inexpensive technique for the evaluation of gross collagen fiber architecture in engineered tissues.     

Binding of the aflatoxin-glutathione conjugate to mouse glutathione S-transferase A3-3 is saturated at only one ligand per dimer

The binding of two different reaction products (p-nitrobenzyl glutathione and the aflatoxin-glutathione conjugate) to mouse glutathione S-transferase A3-3 (mGSTA3-3) has been measured using equilibrium dialysis and a direct fluorescence quenching technique. As expected, p-nitrobenzyl glutathione was found to bind with a stoichiometry of 2.24 +/- 0.17 mol/mol of dimeric enzyme. However, the much larger aflatoxin-glutathione conjugate, 8, 9-dihydro-8-(S-glutathionyl)-9-hydroxyl-aflatoxin B1 (AFB-GSH), was found to bind with a stoichiometry of 1.12 +/- 0.08 mol/mol of dimeric enzyme. p-Nitrobenzyl glutathione bound mGSTA3-3 with a dissociation constant (Kd) of 59 +/- 17 microM while the aflatoxin-glutathione conjugate bound the enzyme with a Kd of 0.86 +/- 0.19 microM. Glutathione competitively inhibited binding of AFB-GSH to mGSTA3-3 with a Ki of 1.5 mM, suggesting that AFB-GSH was binding to the enzyme active site. Although AFB-GSH bound to mGSTA3-3 with a stoichiometry of 1 mol/mol of dimeric enzyme, AFB-GSH completely inhibited activity toward 1-chloro-2, 4-dinitrobenzene, indicating that AFB-GSH binding to one active site alters affinity for 1-chloro-2,4-dinitrobenzene in the active site of the other subunit. To our knowledge, this is the first report of a glutathione S-transferase reaction product which binds to the enzyme with a stoichiometry of 1 mol/mol of dimer.     

Effect of some parasitic infection on neurotransmitters in the brain of experimentally infected mice before and after treatment

The effects of some parasitic infection (bilharziasis, toxocariasis and trichinosis) on the brain of experimentally infected mice were investigated. Eighty animals were classified into four groups, group I contained five non infected animals as a control group. The other groups each contained twenty-five mice infected with Schistosoma mansoni (group II), Toxocara canis (group III) and Trichinella spiralis (group IV). Each infected group was divided into two subgroups (a,b). Subgroup (a) left untreated and subgroups (b) treated by praziquantel (in group II) and mebendazole (in group III and IV). Histopathological and immunological examination using peroxidase antiperoxidase (PAP) technique and neurotransmitters estimation (nor-epinephrine, dopamine and serotonine) were carried. In the untreated animals, there were mild histopathological changes and mild antigenic deposition in subgroups (IIa and IIIa) and marked changes in subgroup (IVa). There were significant decrease in dopamine in subgroup (IIIa), not improved after treatment (subgroup IIIb) and significant decrease in nor-epinephrine and serotonine in subgroup (IVa) improved after treatment in subgroup (IVb). The neurotransmitters changes may explain the motor, behavioural and emotional changes that occurred with these parasites.