Suramin and prostate cancer: where do we go from here?
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Drug Monitoring↗
Biomedical subjects
J W Clark
Publications and source records attributed to J W Clark.
Phase I trial of high-dose infused zidovudine combined with leucovorin plus fluorouracil.
This phase I trial evaluated a high-dose, short-term infusion of zidovudine (AZT) following oral leucovorin (LV) and bolus 5-fluorouracil (FUra). Thirteen patients with metastatic cancer received 30 cycles of therapy. Plasma monitoring demonstrated a dose-dependent increase in peak plasma levels of AZT through the range of dose levels, from 104.3 +/- 8.7 microM at the 1.5 g/m2 dose of AZT to 1312.6 +/- 165.9 microM at the 11.0 g/m2 dose. While AZT did not potentiate the usual clinical toxicities of LV plus FUra, an unexpected finding of symptomatic hypotension during the AZT infusion was the dose-limiting toxicity in this trial. One partial response was observed in a previously untreated patient with metastatic colorectal cancer. The maximal tolerated dose of AZT, 7.0 g/m2 over 2 hr, is recommended for future phase II evaluation of this novel combination.
Adult↗
Pancreatic cancer symposium: epidemiology, etiology, pathogenesis, and therapy.
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Allergy and Immunology↗
Changes in tyrosine-phosphorylated p190 and its association with p120 type I and p100 type II rasGAPs during myelomonocytic differentiation of human leukemic cells.
A M(r) 190,000 protein (p190) functions as a GTPase-activating protein (GAP) for Rho and Rac family proteins, which are involved in regulating cytoskeletal actin and membrane ruffling. Tyrosine-phosphorylated p190 also complexes with rasGAP, a regulator of Ras activity, thus possibly linking Ras and Rho pathways. Leukemic cells induced to differentiate along myelomonocytic lineages have increased filamentous actin (as evidenced by phalloidin staining) and extended pseudopodia, and become irregularly shaped and flattened, suggesting altered Rho and Rac function. We, therefore, hypothesized that changes in p190 and its association with rasGAP are an integral part of these shape changes. During phorbol 13-myristate 25-acetate-induced monocytic differentiation of HL60 promyelocytic and RWLeu4 chronic myelogenous leukemic cells, the total amount of p190 decreases rapidly but returns to initial levels by 12 h. In RWLeu4, this was accompanied by commensurate changes in p190 tyrosine phosphorylation and association with p120 type I rasGAP. Association of p190 and type I rasGAP was demonstrated by immunoprecipitation with antibodies to either protein. An additional band at M(r) 100,000 (p100) was detected in immunoprecipitates after 12 h of phorbol 13-myristate 25-acetate treatment. Reverse transcription-PCR and immunoblot analyses suggest that p100 is type II rasGAP, an alternatively spliced product of p120 type I rasGAP. p100 was expressed only in response to direct protein kinase C activators, but all classes of differentiation agents increased tyrosine-phosphorylated p190. Rho and Rac are known to be involved in regulating actin polymerization. The results presented here show that the association of p190 with type I rasGAP parallels increases in actin polymerization and cell adhesion. This suggests a role for p190-rasGAP interactions in phorbol 13-myristate 25-acetate-induced cytoskeletal reorganization.
Base Sequence↗
Intravascular membrane oxygenation and carbon dioxide removal with IVOX: can improved design and permissive hypercapnia achieve adequate respiratory support during severe respiratory failure?
The intravenacaval oxygenator and carbon dioxide removal device (IVOX) conceived by Mortensen at CardioPulmonics is a diffusion-limited device capable of removing 30% of CO2 production of an adult at normocapnia with minimal reduction in ventilator requirements. Through mathematical modeling, an ex vivo venovenous bypass circuit to model the vena cava and animal models of severe smoke inhalation injury, the practice of permissive hypercapnia has been established to enhance CO2 removal by IVOX. By allowing the blood PCO2 to rise gradually, the CO2 excretion by IVOX can be linearly increased in a 1:1 relationship. Experimental and clinical studies have shown that CO2 removal by IVOX increased from 30-40 ml/min at normal blood PCO2 to 80-90 ml/min at PCO2 of 90 mm Hg. In addition, IVOX with permissive hypercapnia allowed a significant reduction in minute ventilation and peak airway pressure. Design changes could also improve the performance of IVOX. Increased surface area and mixing with more fibers and crimping in new prototypes of IVOX significantly increased CO2 removal and oxygen transfer. Active mixing in the blood to decrease the boundary layer resistance can further enhance gas exchange of IVOX. In conclusion, gas exchange by the current design of IVOX is limited, and improvements in design are needed for it to become a more clinically applicable device. Permissive hypercapnia can significantly enhance CO2 removal by IVOX as well as significantly reduce ventilator requirements.
Adult↗
Substance P: correlation of CSF and plasma levels.
OBJECTIVE: To determine the correlation between cerebrospinal fluid and plasma concentrations of substance P. PATIENTS: 37 patients undergoing lumbar puncture for various diagnostic purposes. MEASUREMENTS: Samples of cerebrospinal fluid and blood were obtained at the same visit. Substance P was measured by radioimmunoassay technique. At least 4 separate measurements were conducted on each sample to insure accuracy. RESULTS: The mean plasma SP level was 1.195 (+/- 1.1). The mean cerebrospinal fluid substance P level was 1.075 (+/- .07). There was a statistically significant positive correlation between substance P level in the plasma and cerebrospinal fluid. The Pearson correlation coefficient was 0.656 (P < .0001) and the Spearman correlation coefficient was 0.698 (P < .0001). CONCLUSIONS: Plasma substance P levels closely correlate with cerebrospinal fluid substance P levels. This will simplify the measurement of substance P in the evaluation of therapeutic agents for headache.
Adult↗
A mathematical model of a rabbit sinoatrial node cell.
A mathematical model for the electrophysiological responses of a rabbit sinoatrial node cell that is based on whole cell recordings from enzymatically isolated single pacemaker cells at 37 degrees C has been developed. The ion channels, Na(+)-K+ and Ca2+ pumps, and Na(+)-Ca2+ exchanger in the surface membrane (sarcolemma) are described using equations for these known currents in mammalian pacemaker cells. The extracellular environment is treated as a diffusion-limited space, and the myoplasm contains Ca(2+)-binding proteins (calmodulin and troponin). Original features of this model include 1) new equations for the hyperpolarization-activated inward current, 2) assessment of the role of the transient-type Ca2+ current during pacemaker depolarization, 3) inclusion of an Na+ current based on recent experimental data, and 4) demonstration of the possible influence of pump and exchanger currents and background currents on the pacemaker rate. This model provides acceptable fits to voltage-clamp and action potential data and can be used to seek biophysically based explanations of the electrophysiological activity in the rabbit sinoatrial node cell.
Animals↗
Analysis of factors affecting gas exchange in intravascular blood gas exchanger.
A mathematical model of an intravascular hollow-fiber gas-exchange device, called IVOX, has been developed using a Krogh cylinder-like approach with a repeating unit structure comprised of a single fiber with gas flowing through its lumen surrounded by a coaxial cylinder of blood flowing in the opposite direction. Species mass balances on O2 and CO2 result in a nonlinear coupled set of convective-diffusion parabolic partial differential equations that are solved numerically using an alternating-direction implicit finite-difference method. Computed results indicated the presence of a large resistance to gas transport on the external (blood) side of the hollow-fiber exchanger. Increasing gas flow through the device favored CO2 removal from but not O2 addition to blood. Increasing blood flow over the device favored both CO2 removal as well as O2 addition. The rate of CO2 removal increased linearly with the transmural PCO2 gradient imposed across the device. The effect of fiber crimping on blood phase mass transfer resistance was evaluated indirectly by varying species blood diffusivity. Computed results indicated that CO2 excretion by IVOX can be significantly enhanced with improved bulk mixing of vena caval blood around the IVOX fibers.
Blood Gas Analysis↗
A- and C-type rat nodose sensory neurons: model interpretations of dynamic discharge characteristics.
1. Neurons of the nodose ganglia provide the sole connection between many types of visceral sensory inputs and the central nervous system. Electrophysiological studies of isolated nodose neurons provide a practical means of measuring individual cell membrane currents and assessing their putative contributions to the overall response properties of the neuron and its terminations. Here, we present a comprehensive mathematical model of an isolated nodose sensory neuron that is based upon numerical fits to quantitative voltage- and current-clamp data recorded in our laboratory. Model development was accomplished using an iterative process of electrophysiological recordings, nonlinear parameter estimation, and computer simulation. This work is part of an integrative effort aimed at identifying and characterizing the fundamental ionic mechanisms participating in the afferent neuronal limb of the baroreceptor reflex. 2. The neuronal model consists of two parts: a Hodgkin-Huxley-type membrane model coupled to a lumped fluid compartment model that describes Ca2+ ion concentration dynamics within the intracellular and external perineuronal media. Calcium buffering via a calmodulin-type buffer is provided within the intracellular compartment. 3. The complete model accurately reproduces whole-cell voltage-clamp recordings of the major ion channel currents observed in enzymatically dispersed nodose sensory neurons. Specifically, two Na+ currents exhibiting fast (INaf) and slow tetrodotoxin (TTX)-insensitive (INas) kinetics; low- and high-threshold Ca2+ currents exhibiting transient (ICa,t) and long-lasting (ICa,n) dynamics, respectively; and outward K+ currents consisting of a delayed-rectifier current (IK), a transient outward current (I(t)) and a Ca(2+)-activated K+ current (IK,Ca). 4. Whole-cell current-clamp recordings of somatic action-potential dynamics were performed on enzymatically dispersed nodose neurons using the perforated patch-clamp technique. Stimulus protocols consisted of both short (< or = 2.0 ms) and long (> or = 200 ms) duration current pulses over a wide range of membrane holding potentials. These studies clearly revealed two populations of nodose neurons, often termed A- and C-type cells, which exhibit markedly different action-potential signatures and stimulus response properties. 5. Using a single set of equations, the model accurately reproduces the electrical behavior of both A- and C-type nodose neurons in response to a wide variety of stimulus conditions and membrane holding potentials. The structure of the model, as well as the majority of its parameters are the same for both A- and C-type implementations.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Multiple modes of activity in a model neuron suggest a novel mechanism for the effects of neuromodulators.
1. Previous examination of the phase space of a mathematical model of a bursting molluscan neuron has demonstrated the existence of multiple stable oscillatory modes. The present study examined the extent to which multistability could be regulated by known modulatory agents, the consequences of that regulation on the response of the neuron to synaptic inputs, the effects of noise, and the potential of multistability to enrich the repertoire of neuromodulatory effects. 2. Coexisting stable attractors may appear when a change is made in a voltage-dependent conductance in a manner that simulates the application of a neuromodulator. A small transient perturbation can shift the model neuron between stable modes, greatly amplifying the original perturbation. Thus the model becomes more sensitive to conventional synaptic inputs. These mode shifts are robust in the presence of low-amplitude synaptic noise. 3. In response to random high-amplitude synaptic noise, a model neuron rendered multistable by a simulated application of a neuromodulator produces apparently random activity, whereas in response to the same synaptic noise, a monostable model neuron produces barely perturbed regular activity. Thus an increase in the number of attractors enhances sensitivity to both conventional synaptic inputs and noise. Conversely, a decrease is associated with a reduction in sensitivity. 4. The response of a neuron to a subsequent transient perturbation in the level of neuromodulator depends on the steady-state level of the neuromodulator. For example, if the steady-state level is associated with a multistable neuron, a mode shift produced by such a transient change in the level of neuromodulator (manifested in our model as a conductance change) can persist after the conductance is returned gradually to its original value. Thus multistable dynamic activity permits the effects of a neuromodulator to persist when the neuromodulator is no longer present. 5. The mechanism of mode shifting between coexisting stable oscillatory modes introduces a number of novel possibilities with potentially profound implications for information processing and storage in a single neuron.
Animals↗
Biological response modifiers.
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Animals↗
Simulations of passive properties and action potential conduction in an idealized bullfrog atrial trabeculum.
This study investigates the properties of a distributed parameter model of an idealized trabeculum of cardiac muscle surrounded by a resistive-capacitive trabecular sheath. A mathematical approach is developed that permits the direct solution for the absolute potential in each medium [i.e., the intracellular (Vi), interstitial (Ve), and external (Vo) potentials), as opposed to obtaining solutions for the transmembrane potential V (where V identical to Vi-Ve). The mathematical description of the underlying individual cell is based upon quantitative whole-cell voltage-clamp measurements in bullfrog atrial myocytes. "Reduced" or "simplified" cell membrane models that lack the complete complement of transmembrane currents are compared with regard to their accuracy in representing the root, upstroke, and plateau regions of the propagated action potential in the complete model. The results show that a reduced cell membrane model must contain the sodium current INa, calcium current ICa, and background-rectifying K+ current IK1. A cell membrane model that contains a linear background K+ current IL instead of IK1 results in much poorer approximation to the upstroke, plateau, and conduction velocities of an action potential. The effects of varying the resistive-capacitive parameters of the trabecular sheath on both the passive properties (the time and space constants and the input resistance) and conduction parameters (time and space constants of the foot and conduction velocity of the action potential) of the trabeculum are also investigated. These simulations show that electrical activity within the trabeculum is much more sensitive to variations in the resistive component than in the capacitive component of the sheath. The trabecular sheath reduces the extracellular resistance seen by the cell by shunting current away from highly resistive interstitial medium into the volume conductor medium, which is of low resistance, and thereby increases conduction velocity. Finally, the addition of the cholinergic neurotransmitter acetylcholine to the extracellular medium reduces both the space constant of the trabeculum and the conduction velocity of propagated electrical activity.
Action Potentials↗
The influence of nodal constriction on conduction velocity in myelinated nerve fibers.
Myelinated nerve fibers exhibit a complex anatomy in the nodal region which includes a marked nodal-paranodal constriction and an intricate paranodal structure where the myelin sheath is separated from the axon by a narrow periaxonal space. In this study, a recently developed computational model of the mammalian myelinated nerve fiber based on electron microscopic data was employed to examine the effect of the nodal-paranodal axonal radius and periaxonal space width on the conduction of action potentials. These findings indicate that the nodal-paranodal constriction promotes higher conduction velocities by minimizing the component of the nodal capacity contributed by the paranodal axolemma. Model prediction of optimal nodal-paranodal radii is correlated with radii determined in experimental anatomical studies.
Action Potentials↗
An ionic current model for neurons in the rat medial nucleus tractus solitarii receiving sensory afferent input.
1. Neurons from a horizontal slice of adult rat brainstem were examined using intracellular recording techniques. Investigations were restricted to a region within the nucleus tractus solitarii, medial to the solitary tract and centred on the obex (mNTS). Previous work has shown this restricted area of the NTS to contain the greatest concentration of aortic afferent baroreceptor terminal fields. Electrical stimulation of the tract elicited short-latency excitatory postsynaptic potentials in all neurons. 2. mNTS neurons were spontaneously active with firing frequencies ranging between 1 and 10 Hz, at resting potentials of -65 to -45 mV. These neurons did not exhibit spontaneous bursting activity. 3. Depolarizing current injection immediately evoked a finite, high-frequency spike discharge which rapidly declined to a lower steady-state level (i.e. spike frequency adaptation, SFA). Increasing depolarizations produced a marked increase in the peak instantaneous frequency but a much smaller increase in the steady-state firing level. 4. Conditioning with a hyperpolarizing prepulse resulted in a prolonged delay of up to 600 ms before the first action potential (i.e. delayed excitation, DE) with an attendant decrease in peak discharge rates. DE was modulated by both the magnitude and duration of the prestimulus hyperpolarization, as well as the magnitude of the depolarizing stimulus. Tetrodotoxin (TTX) eliminated spike discharge but had little effect on the ramp-like membrane depolarization characteristic of DE. 5. We have developed a mathematical model for mNTS neurons to facilitate our understanding of the interplay between the underlying ionic currents. It consists of a comprehensive membrane model of the Hodgkin-Huxley type coupled with a fluid compartment model describing cytoplasmic [Ca2+]i homeostasis. 6. The model suggests that (a) SFA is caused by an increase in [Ca2+]i which activates the outward K+ current, IK,Ca, and (b) DE results from the competitive interaction between the injected depolarizing current and the hyperpolarization-activated transient outward K+ currents, IA and ID. 7. We conclude that our ionic current model is capable of providing biophysical explanations for a number of phenomena associated with brainstem neurons, either during spontaneous activity or in response to patterned injections of current. This model is a potentially useful adjunct for on-going research into the central mechanisms involved in the regulation of both blood pressure and ventilation.
Action Potentials↗
Nonlinear dynamics in a model neuron provide a novel mechanism for transient synaptic inputs to produce long-term alterations of postsynaptic activity.
1. A mathematical model of a bursting molluscan neuron has been found to possess multiple modes of electrical activity, such as periodic beating (tonic firing), periodic bursting (bursts of action potentials separated by quiescent periods), and potentially chaotic bursting, all at a single set of parameters. The multiple modes correspond to multiple stable attractors, whose existence is an emergent property of the nonlinear dynamics of the system. 2. Transient synaptic inputs can switch the activity of the neuron between different modes. These mode transitions, which do not require any changes in the biochemical or biophysical parameters of the neuron, provide an enduring response to a transient input, as well as a mechanism for phasic sensitivity (i.e., temporal specificity). 3. These results provide new insights into the role of nonlinear dynamics in information processing and storage at the level of the single neuron.
Animals↗
Tyrosine phosphorylated proteins in chronic myelogenous leukemia.
An aberrantly expressed and highly active abl tyrosine kinase (p210bcr-abl) appears critical for the development and pathogenesis of chronic myelogenous-leukemia (CML). CML cells and cell lines each displayed a similar spectrum of phosphotyrosyl proteins. Analysis of these proteins by glycerol-gradient ultracentrifugation showed that many apparently existed as multimeric complexes. Confirming this, several of these proteins co-immunoprecipitated, along with the p210bcr-abl, with antibody to abl. Included were co-precipitating proteins identified as the p120 ras GTPase-activating protein (GAP) and the p62 protein that binds both to GAP and to a number of other tyrosine-phosphorylated proteins having peptide regions homologous to the second domain of src. Because p62, ras GAP and ras are involved in growth-factor and oncogene activation of cells, this pathway may also play an important role in CML.
Fusion Proteins, bcr-abl↗
Platelet-derived growth factor indirectly stimulates angiogenesis in vitro.
We evaluated the effect of platelet-derived growth factor (PDGF) on capillary formation using an in vitro angiogenesis model system in which microvascular fragments and myofibroblasts (Mfs) isolated from rat epididymal lipid tissues were grown in co-culture. In this system Mfs induce capillary formation by producing an endothelial cell growth factor and by secreting extracellular matrix components that cause endothelial cells to form cordlike structures. Addition of PDGF enhances in vitro capillary growth. Although some recently described microvascular endothelial cells display PDGF receptors and respond to PDGF, we found no evidence for direct PDGF action on the rat epididymal microvascular endothelial cells. Rather, we found that PDGF increased the proliferation of Mfs, as well as the production of Mf-derived endothelial cell growth factor and matrix collagen type I. Our results suggest that even in cases where the microvasculature lacks PDGF receptors, PDGF may accelerate capillary formation by activating connective tissue cells in the vicinity of endothelial cells.
Animals↗
Biological response modifiers.
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Antineoplastic Combined Chemotherapy Protocols↗