Systemic aluminum toxicity: effects on bone, hematopoietic tissue, and kidney

Although the full mechanisms are not yet elucidated, research into the mechanism of toxicity of aluminum (Al) on bone formation and remodeling and on hematopoietic tissue is ongoing. In contrast little information exists on the interactive effects of systemic Al and the kidney. In bone, both clinically and experimentally, high doses of Al inhibit remodeling, slowing both osteoblast and osteoclast activities and producing osteomalacia and adynamic bone disease. In contrast, while very low levels of Al are mitogenic in bones of experimental animals, the effect of low levels of Al in humans is unknown. Aluminum has been shown to have its mitogenic action at the osteoblast, but whether the effect on resorption is viz osteoblast-directed changes in osteoclast activity has not yet been determined. Parathyroid hormone (PTH) levels are disrupted by Al in humans and animals. Whether altered PTH levels play a major or even a minor role in Al-dependent osteotoxicity requires clarification. In hematopoietic tissue, Al causes a microcytic anemia, not reversible by iron. Friend leukemia cells treated with Al have been reported to accumulate excess iron, without incorporating it into ferritin or heme. It is not yet known which steps in iron metabolism are disrupted by Al, if they involve a single mechanism of action, or even if this disruption in iron metabolism accounts for the anemia seen in Al toxicosis. In kidney, research is needed to evaluate Al nephrotoxicity; there are almost no studies in this area. Furthermore, research is needed to evaluate mechanisms of renal Al excretion, presently shown by one study to occur at the distal tubule. Such studies might well throw light on whether Al plays a role in aggravating renal insufficiency, or whether the role of the kidney in Al toxicosis is limited to the causative effect of renal compromise on Al accumulation. In summary, while a number of mechanisms have been proposed for the toxic action of Al, no single mechanism emerges to explain these diverse effects of systemic Al. Recommendations for future research are presented and summarized in Table 1.     

ALCHEMIST: A General Purpose Transformation Generator

ALCHEMIST is a general purpose transformation generating environment, which supports specification, generation and execution of data transformations. ALCHEMIST allows an abstract specification of the transformation through a window-based interface and supports the generation and compilation of transformation program code from these specifications. Unlike compiler-compilers, ALCHEMIST is intended to automate building transformations between two complex representation formats and is thus especially suitable for constructing transformations between database tools, CASE tools, graphical editors or text formatters. In this paper we describe the design principles and the structure of ALCHEMIST, and demonstrate its use. We also discuss our experiences with several example transformations and present a real-life case study of using ALCHEMIST for interfacing two software development environments.     

A multiscale dynamic programming procedure for boundary detection in ultrasonic artery images

Ultrasonic measurements of human carotid and femoral artery walls are conventionally obtained by manually tracing interfaces between tissue layers. The drawbacks of this method are the interobserver variability and inefficiency. In this paper, we present a new automated method which reduces these problems. By applying a multiscale dynamic programming (DP) algorithm, approximate vessel wall positions are first estimated in a coarse-scale image, which then guide the detection of the boundaries in a fine-scale image. In both cases, DP is used for finding a global optimum for a cost function. The cost function is a weighted sum of terms, in fuzzy expression forms, representing image features and geometrical characteristics of the vessel interfaces. The weights are adjusted by a training procedure using human expert tracings. Operator interventions, if needed, also take effect under the framework of global optimality. This reduces the amount of human intervention and, hence, variability due to subjectiveness. By incorporating human knowledge and experience, the algorithm becomes more robust. A thorough evaluation of the method in the clinical environment shows that interobserver variability is evidently decreased and so is the overall analysis time. We conclude that the automated procedure can replace the manual procedure and leads to an improved performance.     

Improved targeting of an anti-epidermal growth factor receptor variant III monoclonal antibody in tumor xenografts after labeling using N-succinimidyl 5-iodo-3-pyridinecarboxylate

The crystal structure is reported of a complex between the dodecanucleotide sequence d(CGCGAATTCGCG)2and an analogue of the DNA binding drug Hoechst 33258, in which the piperazine ring has been replaced by an amidinium group and the phenol ring by a phenylamidinium group. The structure has been refined to an R factor of 19.5% at 2.2 A resolution. The drug is held in the minor groove by five strong hydrogen bonds, together with bridging water molecules at both ends. There are few other contacts with the floor of the groove, indicating a lack of isohelicity with the groove and suggesting (i) that the observed high DNA affinity of this drug is primarily due to the array of hydrogen bonds and (ii) that these more than compensate for its poor isohelicity.     

Iodine-131-labeled antitenascin monoclonal antibody 81C6 treatment of patients with recurrent malignant gliomas: phase I trial results

PURPOSE: To determine the maximum-tolerated dose (MTD) of iodine 131 (131I)-labeled 81C6 monoclonal antibody (mAb) in brain tumor patients with surgically created resection cavities (SCRCs) and to identify any objective responses to this treatment. METHODS: In this phase I trial, eligible patients were treated with a single injection of 131I-labeled 81C6. Cohorts of three to six patients were treated with escalating dosages of 131I (starting dose of 20 mCi with a 20-mCi escalation in subsequent cohorts) administered through an Ommaya reservoir in the SCRC. Patients were followed up for toxicity and response until death or for a minimum of 1 year after treatment. The SCRC patients, who were previously irradiated, were followed up without additional treatment unless progressive disease was identified. RESULTS: We administered 36 treatments of 131I doses up to 120 mCi to 34 previously irradiated patients with recurrent or metastatic brain tumors. Dose-limiting toxicity was reached at 120 mCi and was limited to neurologic or hematologic toxicity. None of the patients treated with less than 120 mCi developed significant neurologic toxicity; one patient developed major hematologic toxicity (MHT). The estimated median survival for patients with glioblastoma multiforme (GBM) and for all patients was 56 and 60 weeks, respectively. CONCLUSION: The MTD for administration of 131I-labeled 81C6 into the SCRCs of previously irradiated patients with recurrent primary or metastatic brain tumors was 100 mCi. The dose-limiting toxicity was neurologic toxicity. We are encouraged by the minimal toxicity and survival in this phase I trial. Radiolabeled mAbs may improve the current therapy for brain tumor patients.     

A Low-Power Integrated Circuit for a Wireless 100-Electrode Neural Recording System

Recent work in field of neuroprosthetics has demonstrated that by observing the simultaneous activity of many neurons in specific regions of the brain, it is possible to produce control signals that allow animals or humans to drive cursors or prosthetic limbs directly through thoughts. As neuroprosthetic devices transition from experimental to clinical use, there is a need for fully-implantable amplification and telemetry electronics in close proximity to the recording sites. To address these needs, we developed a prototype integrated circuit for wireless neural recording from a 100-channel microelectrode array. The design of both the system-level architecture and the individual circuits were driven by severe power constraints for small implantable devices; chronically heating tissue by only a few degrees Celsius leads to cell death. Due to the high data rate produced by 100 neural signals, the system must perform data reduction as well. We use a combination of a low-power ADC and an array of "spike detectors" to reduce the transmitted data rate while preserving critical information. The complete system receives power and commands (at 6.5 kb/s) wirelessly over a 2.64-MHz inductive link and transmits neural data back at a data rate of 330 kb/s using a fully-integrated 433-MHz FSK transmitter. The 4.7times5.9 mm² chip was fabricated in a 0.5-mum 3M2P CMOS process and consumes 13.5 mW of power. While cross-chip interference limits performance in single-chip operation, a two-chip system was used to record neural signals from a Utah Electrode Array in cat cortex and transmit the digitized signals wirelessly to a receiver     

Simultaneous measurements of cytosolic and mitochondrial Ca2+ transients in HT29 cells

Loading of HT29 cells with the Ca2+ dye fura-2/AM resulted in an nonhomogeneous intracellular distribution of the dye. Cellular compartments with high fura-2 concentrations were identified by correlation with mitochondrial markers, cellular autofluorescence induced by UV, and dynamic measurement of autofluorescence after inhibition of oxidative phosphorylation. Stimulation with carbachol (10(-4) mol/liter) increased cytosolic, nuclear, and mitochondrial Ca2+ activity ([Ca2+]c, [Ca2+]n, and [Ca2+]m, respectively) measured by UV confocal and conventional imaging. Similar results were obtained with a prototype two-photon microscope (Zeiss, Jena, Germany) allowing for fura-2 excitation. The increase of [Ca2+]m lagged behind that of [Ca2+]c and [Ca2+]n by 10-20 s, and after removing the agonist, [Ca2+]m also decreased with a delay. A strong increase of [Ca2+]m occurred only when a certain threshold of [Ca2+]c (around 1 micromol/liter) was exceeded. In a very similar way, ATP, neurotensin, and thapsigargin increased [Ca2+]c and [Ca2+]m. Carbonyl cyanide p-trifluoromethoxyphenylhyrdrazone reversibly reduced the increase of [Ca2+]m. The source of the mitochondrial Ca2+ increase had intra- and extracellular components, as revealed by experiments in low extracellular Ca2+. We conclude that agonist-induced Ca2+ signals are transduced into mitochondria. 1) Mitochondria could serve as a Ca2+ sink, 2) mitochondria could allow the modulation of [Ca2+]c and [Ca2+]n signals, and 3) [Ca2+]m may serve as a stimulatory metabolic signal when a cell is highly stimulated.     

Specific blockade of slowly activating I(sK) channels by chromanols -- impact on the role of I(sK) channels in epithelia

Chromanols, which were recently shown to inhibit cAMP-mediated Cl- secretion in colon crypts via a blockade of a cAMP-activated K+ conductance, were analyzed for their effects on distinct cloned K+ channels expressed in Xenopus oocytes. The lead chromanol 293B specifically inhibited I(sK) channels with an IC50 of 7 micromol/l without affecting the delayed rectifier Kv1.1 or the inward rectifier Kir2.1. Moreover, several other chromanols displayed the same rank order of potency for I(sK) inhibition as demonstrated in colon crypts. Finally, we tested the effects of the previously described I(sK) blocker azimilide on cAMP mediated Cl- secretion in rat colon crypts. Similar to 293B azimilide inhibited the forskolin induced Cl- secretion. These data suggest that I(sK) protein induced K+ conductances are the targets for the chromanol 293B and its analogues, and azimilide.     

Investigation of a synthetic peptide as immunogen for a variant epidermal growth factor receptor associated with gliomas

We have previously demonstrated antibody production to a glioma-associated variant form of the human epidermal growth factor receptor in rabbits that had received a synthetic peptide mimicking the unique primary structure of the variant protein as immunogen. We report here the response of mice, rabbits, goats, and macaques immunized by various protocols to this peptide. Titers to both peptide- and cell-elaborated variant receptor were measured, and the capacity to recognize the variant receptor in human tumor samples was determined. Within the range of species and strains investigated, we demonstrated a variable species-associated response to the peptide (rabbits > mice > goats > rats > macaques). Rabbits and a single goat produced specific, high titer antibody activity to the variant receptor protein following immunization with peptide alone. Murine titers to the parent protein were not appreciable following peptide immunization alone; additional immunization with variant receptor as expressed on cell membranes was used to boost this response.