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Cyclic AMP-response element-binding protein (CREB) is a transcription factor implicated in growth factor-dependent cell proliferation and survival, glucose homeostasis, spermatogenesis, circadian rhythms, and synaptic plasticity associated with memory. To study the phenotype of CREB overexpression in vivo, we generated CREB transgenic (TG) mice in which a myeloid specific hMRP8 promoter drives CREB expression. CREB TG mice developed spontaneous skin abscesses more frequently than wild type (WT) mice. To understand the role of CREB in myeloid function and innate immunity, chemokine expression in bone marrow derived macrophages (BMDMs) from CREB TG mice were compared with BMDMs from WT mice. Our results demonstrated decreased Keratinocyte-derived cytokine (KC) in CREB TG BMDMs but not TNFα protein production in response to lipid A (LPA). In addition, mRNA expression of KC and IL-1β (Interleukin)-1β was decreased in CREB TG BMDMs; however, there was no difference in the mRNA expression of TNFα, MCP-1, IL-6 and IL-12p40. The mRNA expression of IL-1RA and IL-10 was decreased in response to LPA. Nuclear factor kappa B (NFκB) expression and a subset of its target genes were upregulated in CREB TG mouse BMDMs. Although neutrophil migration was the same in both CREB TG and WT mice, Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity was significantly increased in neutrophils from CREB TG mice. Taken together, CREB overexpression in myeloid cells results in increased abscess formation in vivo and aberrant cytokine and chemokine response, and neutrophil function in vitro.

Osteosarcoma is the most common primary malignancy of bone in children, adolescents, and adults. Despite extensive surgery and adjuvant aggressive high-dose systemic chemotherapy with potentially severe bystander side effects, cure is attainable in about 70% of patients with localized disease and only 20%-30% of those patients with metastatic disease. Targeted therapies clearly are warranted in improving our treatment of this adolescent killer. However, a lack of osteosarcoma-associated/specific markers has hindered development of targeted therapeutics. We describe a novel osteosarcoma-associated cell surface antigen, ALCAM. We, then, create an engineered anti-ALCAM-hybrid polymerized liposomal nanoparticle immunoconjugate (α-AL-HPLN) to specifically target osteosarcoma cells and deliver a cytotoxic chemotherapeutic agent, doxorubicin. We have demonstrated that α-AL-HPLNs have significantly enhanced cytotoxicity over untargeted HPLNs and over a conventional liposomal doxorubicin formulation. In this way, α-AL-HPLNs are a promising new strategy to specifically deliver cytotoxic agents in osteosarcoma.

We previously described bicarbonate exchange dynamics in humans at rest and during exercise using a three-compartment model. In the present study we tested the effect of certain assumptions of this model on the prediction of the change in exchangeable bicarbonate with the increased metabolic rate of exercise. We compared this prediction with a measurement of CO2 retention after exercise onset determined from gas exchange data. The change in tissue bicarbonate stores was estimated from differences in the kinetics of adjustment of VO2 and VCO2, and this was added to an estimate of the changes in venous blood gas stores to estimate the total change in bicarbonate. When the commonly held assumption that endogenous CO2 production, thought to occur in a rapidly equilibrating peripheral compartment at rest, was also applied to the exercise condition, the three-compartment bicarbonate model predicted an unphysiologically large increase in bicarbonate stores (700 mmol, or over 15 L). In contrast, the 'gas exchange' approach predicted a relatively small increase in bicarbonate (26 mmol), consistent with other reports. The incompatibility of these findings with the assumption about the source of endogenous CO2 production in the bicarbonate model requires that the underlying physiological correlates of the three compartments change from rest to exercise.

Acute upregulation of blood-brain barrier glucose transporter activity in seizures. Am J Physiol Heart Circ Physiol 279: H1346-H1354, 2000.--Brain extraction of [sup.18]F-labeled 2-fluoro-2-deoxy-D-glucose (FDG) was significantly higher in pentylene tetrazole (PTZ)-treated rats (32 [+ or -] 4%) than controls (25 [+ or -] 4%). The FDG permeability- surface area product (PS) was also significantly higher with PTZ treatment (0.36 [+ or -] 0.05 ml[multiplied by][min.sup.- 1][multiplied by] [g.sup.-1]) than in controls (0.20 [+ or -] 0.06 ml[multiplied by][min.sup.-1][multiplied by][g.sup.-1]). Cerebral blood flow rates were also elevated by 50% in seizures. The internal carotid artery perfusion technique indicated mean [[sup.14]C] glucose clearance (and extraction) was increased with PTZ treatment, and seizures increased the PS by 37 [+ or -] 16% (P [is less than] 0.05) in cortical regions. Because kinetic analyses suggested the glucose transporter half-saturation constant ([K.sub.m]) was unchanged by PTZ, we derived estimates of 1) treated and 2) control maximal transporter velocities ([V.sub.max]) and 3) a single [K.sub.m]. In cortex, the glucose transporter [V.sub.max], was 42 [+ or -] 11% higher (P [is less than] 0.05) in PTZ-treated animals (2.46 [+ or -] 0.34 [micro]mol[multiplied by][min.sup.-1] [multiplied by][g.sup.-1]) than in control animals (1.74 [+ or -] 0.26 [micro]mol[multiplied by][min.sup.-1] [multiplied by][g.sup.-1]), and the [K.sub.m] = 9.5 [+ or -] 1.6 mM. Blood-brain barrier (BBB) [V.sub.max] was 31 [+ or -] 10% greater (P [is less than] 0.05) in PTZ-treated (2.36 [+ or -] 0.30 [micro]mol[multiplied by][min.sup.-1][multiplied by][g.sup-1]) than control subcortex (1.80 [+ or -] 0.25 [micro]mol[multiplied by] [min.sup.-1][multiplied by][g.sup.1]). We conclude acute upregulation of BBB glucose transport occurs within 3 min of an initial seizure. Transporter [V.sub.max] and BBB glucose permeability increase by 30-40%. blood-brain barrier glucose transporter; maximal velocity; half-saturation constant; pentylene tetrazole seizures; unsaturated permeability-surface area products; transporter recruitment; intrinsic activity

Co-exposure to methyl ethyl ketone (MEK) potentiates the neurotoxicity of n-hexane in humans as well as in animals. This effect is associated with increased persistence of 2,5-hexanedione (2,5-HD) in blood, probably due to inhibition of 2,5-HD phase II biotransformation by MEK. There is no previous quantitative toxicokinetic model to describe this interaction. In this study we constructed a toxicokinetic model to depict the inhibition of 2,5-HD metabolism and elimination by MEK. Experimental data on 2,5-HD blood concentrations in rats from a published study were used to estimate model parameters. Three different inhibition mechanisms were evaluated: competitive, uncompetitive, and noncompetitive inhibition. Extrapolation from high to low doses was made to assess the interactive effects of MEK on 2,5-HD beyond experimental conditions. The models developed successfully described the toxicokinetic behavior of 2,5-HD when inhibited by MEK. The competitive inhibition model yielded a much lower estimate for the constant (65.5 mg/l) of 2,5-HD inhibition by MEK than did the uncompetitive and noncompetitive models (403 and 440 mg/l, respectively). The apparent half-life of 2,5-HD appeared to be a linear function of the Michaelis-Menten constant, and 2,5-HD and MEK concentrations in rats. The area under the curve of 2,5-HD in blood of rats was a nonlinear function of 2,5-HD and MEK concentrations in the blood. This study highlights the importance of the interactive effect of MEK on deactivation and elimination of 2,5-HD, and further illustrates the advantage of toxicokinetic modeling to investigate chemical interactions associated with exposure to multiple chemical agents. [ABSTRACT FROM AUTHOR]

ABSTRACT. The clinical course of 65 children with hyperthyrodism in whom antithyroid medication was initiated has been reviewed retrospectively. Fifty-five patients received only this projected medical therapy with propylthiouracil or methimazole. Sustained remission in excess of one year following cessation of drugs occurred in 31 patients (56%). All but two achieved that remission within 4.5 years. Of the 31 patients, 24 have been followed-up for more than two years off medication with only one relapse. Twenty-four patients are still under medical therapy, 14 for longer than 4.5 years. By methods of life-table analysis, the data on all 65 patients gave an estimate of 25% remitting within the first two years and a median remission time of 4 to 4.5 years. These results suggest a continuing remission rate of 25% every two years for up to six years of follow-up. Analysis of presenting variables (assessment of age at onset of disease, sex, family history, initial laboratory data, gland size, and degree of exophthalmos) that might have distinguished which patients were likely to undergo remission was attempted. There were no clearly significant differences with any of these variables although several suggestive differences emerged. These included a tendency toward earlier remission in patients older than 13 years, in boys of any age, and in patients of any age or sex in whom initial triiodothyronine (T[sub 3] RIA) was < 645 ng/100 ml. An approach to long-term medical management is proposed. Pediatrics 65:550-556, 1980; hyperthyroidism, antithyroid drugs, disease remission, Graves' disease. [ABSTRACT FROM AUTHOR]