Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019829 (Hodgkin's disease)
 30,247 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. We have developed a comprehensive mathematical model of an afferent synaptic connection to the soma of a medial nucleus tractus solitarius (mNTS) neuron. Model development is based on numerical fits to quantitative data recorded in our laboratory. This work is part of a continuing collaborative effort aimed at identifying and characterizing the mechanisms responsible for the non-linear integrative properties of this first synapse in the baroreceptor reflex. 2. The complete model consists of three major parts: 1) a Hodgkin-Huxley (HH)-type membrane model of the prejunctional sensory terminal bouton; 2) a multistage model describing vesicular storage, adenosine 3',5'-cyclic monophosphate (cAMP)- and Ca(2+)-dependent mobilization, release and recycling; and 3) a HH-type membrane model of the postjunctional mNTS cell that includes descriptions for a desensitizing non-N-methyl-D-aspartate (NMDA) ionic current that is responsible for the fast excitatory postsynaptic potentials (EPSPs) observed in mNTS cells. The membrane models for both the terminal bouton and the mNTS neuron are coupled to separate lumped fluid compartment models describing intracellular Ca2+ ion concentration dynamics. 3. Our modeling strategy is twofold. The first is to validate model performance by reproducing a wide variety of experimental data both from our laboratory and from the literature. The second is to explore the functional aspects of the model in order to gain a greater appreciation for the balance between presynaptic mechanisms (e.g., terminal membrane properties and vesicular dynamics) and postsynaptic mechanisms (e.g., non-NMDA receptor kinetics and neuronal dynamics) that underlie the afferent synaptic drive of mNTS neurons. 4. The model accurately reproduces EPSP dynamics recorded with the use of a wide range of stimulus protocols. The model can also mirror the unique pattern of graded frequency- and use-dependent reduction in peak EPSP magnitude observed experimentally through 60 s of constant, suprathreshold synaptic activation. We demonstrate how vesicular mobilization, recycling, and receptor kinetics can function synergistically in establishing synaptic transfer. Furthermore, we show that by allowing the aggregate rate of vesicle mobilization to respond in a use-dependent manner, it is possible to compensate for the attenuating affects of desensitization at elevated rates of stimulation. 5. Our simulations indicate that the low-frequency characteristics of this synapse are dominated by vesicular dynamics, whereas the high-frequency properties arise from a combination of Ca(2+)-dependent vesicular mobilization and the kinetics of the non-NMDA receptor. Desensitization can influence the peak magnitude and decay time of the EPSP, thereby affecting synaptic throughput. However, we demonstrate that, as the time course of neurotransmitter in the synaptic cleft decreases, the influence of desensitization should be somewhat diminished. As a result, the effective bandwidth of the synapse increases and becomes limited by the gating characteristics of the non-NMDA channel. 6. The model also includes a neuromodulatory aspect in that the frequency response of the synapse can be modulated by an adenylate cyclase-mediated regulatory mechanism. Although our simulations indicate the behavior of a limited number of possible neuromodulatory agents, the results demonstrate the pivotal role such agents could play in modifying synaptic transfer characteristics presynaptically. 7. Both continuous and burst-mode tract stimulation evoke patterns of action potentials in spontaneously active mNTS neurons that are mimicked very well by our model. Our simulations demonstrate that, as the rate of stimulation increases beyond approximately 20-30 Hz, the inherent low-pass frequency-response characteristics of the synapse limit the overall dynamic range of the mNTS neuron, causing the postsynaptic cell to "entrain" at frequencies within its normal operating range.
 ...
PMID:Afferent synaptic drive of rat medial nucleus tractus solitarius neurons: dynamic simulation of graded vesicular mobilization, release, and non-NMDA receptor kinetics. 898 91

Human herpesvirus 6 variant A (HHV-6A) and human herpesvirus 6 variant B (HHV-6B) are two closely related yet distinct viruses. These visuses belong to the Roseolovirus genus of the betaherpesvirus subfamily; they are most closely related to human herpesvirus 7 and then to human cytomegalovirus. Over 95% of people older than 2 years of age are seropositive for either or both HHV-6 variants, and current serologic methods are incapable of discriminating infection with one variant from infection with the other. HHV-6A has not been etiologically linked to any human disease, but such an association will probably be found soon. HHV-6B is the etiologic agent of the common childhood illness exanthem subitum (roseola infantum or sixth disease) and related febrile illnesses. These viruses are frequently active and associated with illness in immunocompromised patients and may play a role in the etiology of Hodgkin's disease and other malignancies. HHV-6 is a commensal inhabitant of brains; various neurologic manifestations, including convulsions and encephalitis, can occur during primary HHV-6 infection or in immunocompromised patients. HHV-6 and distribution in the central nervous system are altered in patients with multiple sclerosis; the significance of this is under investigation.
 ...
PMID:Human herpesvirus 6. 922 65

Growth rates of neoplasms could be calculated only on the basis of mitotic and apoptotic indices (MI and AI, respectively), assessed on tissue sections, if the duration of mitosis and apoptosis (Tm and Ta, respectively) in vivo were known. For humans, this is practically never the case. What use then can be made of MI and AI to arrive at a relative, crude estimate of the state of growth? As a model system to study this problem, we chose diffusely growing stage I + II non-Hodgkin's lymphomas (dNHL, n = 94). Cluster analysis revealed the existence of 3 highly distinct groups of dNHL (clusters I, II and III) in the MI vs. AI per case plot, with a roughly linear relation between both parameters. Most nosologic entities defined by the REAL classification comprise cases that were represented in more than one cluster. We adopted the simple formula GI (growth index) = XMI - AI, where X (= Ta/Tm) remains to be evaluated. Based on the assumption that spontaneous regressions of dNHL are rare but do occur, we estimated that X = 2 or, possibly, 3 are best fits for the pooled dNHLs studied. With the assumption of X = 2, (i) 2MI - AI gave relatively lower values for dNHL than proliferative indices such as %Ki-67+ cells; (ii) values for 2MI/AI per cluster showed a pattern inverse to that for %bcl-2+ cells; and (iii) a plot of 2MI - AI vs. 2MI/AI per case allowed the recognition, especially among NHLs with a low cell turnover, of cases where accumulation of presumably longer-lived cells is an important factor in determining growth.
 ...
PMID:Growth patterns of diffuse non-Hodgkin's lymphomas estimated from mitotic and apoptotic indices. 933 38

A 54-year-old man who had been irradiated in 1964 for cervical involvement by Hodgkin's disease was admitted in December 1994 to our clinic with strong complaints of dysphagia. The reason was a moderately differentiated squamous cell carcinoma of the proximal esophagus in the previously irradiated region. The patient had no risk factors (abuse of nicotine or alcohol) for the developement of esophageal carcinoma. A reirradiation was performed, but the disease progressed locally and two weeks after the beginning of the therapy the patient developed two tracheoesophagocutaneous fistulae. The radiation therapy was discontinued and the tumor stenosis was bridged by a tube closing the fistulae. A retrospective dose analysis to evaluate the applied doses will be performed. Furthermore, an overview of 66 cases of the literature with radiation-induced esophageal carcinoma analysed concerning applied dose and latent interval will be given. In conclusion the reported case fits the criteria for radiation-induced malignancies (Chudecki Br J Radiol 1972;45:303-4) known from literature: (1) a history of previous irradiation, (2) a cancer occurring within the irradiated area, (3) gross tissue damage due to an excessive dose of radiation, and (4) a long latent interval between irradiation and development of cancer. Esophageal carcinomas belong to the rare secondary malignancies after the therapeutic use of ionizing radiation. Nevertheless in patients with dysphagia they should be suspected as a differential diagnosis even many years after mediastinal irradiation. The treatment of these tumors is very difficult and is associated with a poor prognosis.
 ...
PMID:Radiation-induced esophageal carcinoma 30 years after mediastinal irradiation: case report and review of the literature. 1022 1

1. We have developed a mathematical model of the L-type Ca2+ current, which is based on data from whole-cell voltage clamp experiments on rat ventricular myocytes. Ion substitution methods were employed to investigate the ionic selectivity of the channel. Experiments were configured with Na+, Ca2+ or Ba2+ as the majority current carrier. 2. The amplitude of current through the channel is attenuated in the presence of extracellular Ca2+ or Ba2+. Our model accounts for channel selectivity by using a modified Goldman-Hodgkin-Katz (GHK) configuration that employs voltage-dependent channel binding functions for external divalent ions. Stronger binding functions were used for Ca2+ than for Ba2+. 3. Decay of the ionic current during maintained depolarization was characterized by means of voltage- and Ca2+-dependent inactivation pathways embedded in a five-state dynamic channel model. Particularly, Ca2+ first binds to calmodulin and the Ca2+-calmodulin complex is the mediator of Ca2+ inactivation. Ba2+-dependent inactivation was characterized using the ttau same scheme, but with a decreased binding to calmodulin. 4. A reduced amount of steady-state inactivation, as evidenced by a U-shaped curve at higher depolarization levels (>40 mV) in the presence of [Ca2+]o, was observed in double-pulse protocols used to study channel inactivation. To characterize this phenomenon, a mechanism was incorporated into the model whereby Ca2+ or Ba2+ also inhibits the voltage-dependent inactivation pathway. 5. The five-state dynamic channel model was also used to simulate single channel activity. Calculations of the open probability of the channel model are generally consistent with experimental data. A sixth state can be used to simulate modal activity by way of introducing long silent intervals. 6. Our model has been tested extensively using experimental data from a wide variety of voltage clamp protocols and bathing solution manipulations. It provides: (a) biophysically based explanations of putative mechanisms underlying Ca2+- and voltage-dependent channel inactivation, and (b) close fits to voltage clamp data. We conclude that the model can serve as a predictive tool in generating testable hypotheses for further investigation of this complex ion channel.
 ...
PMID:A model of the L-type Ca2+ channel in rat ventricular myocytes: ion selectivity and inactivation mechanisms. 1108 Feb 58

The aim of the present study was to investigate the single-channel properties of different gating modes in the native human cardiac Na+ channel. Patch-clamp experiments were performed at low noise using ultrathick-walled pipettes. In 17 cell-attached patches containing only one channel, fast back and forth switching between five different Na+-channel gating modes (F-mode, M1-mode, M2-mode, S-mode, and P-mode) was identified, but no difference in the gating properties was found between normal and diseased cardiomyocytes from atrium or ventricle, respectively. Hodgkin-Huxley fits to the ensemble-averaged currents yielded the activation-time (tau(m)) and inactivation-time (tau(h)) constants. tau(m) was comparably fast in the F-mode, M1-mode, M2-mode, and S-mode (0.15 ms) and slow in the P-mode (0.3 ms). tau(h) ranged from 0.35 ms (F-mode) to 4.5 ms (S-mode and P-mode). The mean open-channel lifetime (tau(o)) was shortest in the F-mode and P-mode (0.15 ms) and longest in the S-mode (1.25 ms). The time before which half of the first channel openings occurred (t(0.5)) was comparably short in the F-mode, M1-mode, M2-mode, and S-mode (0.3 ms) and long in the P-mode (0.9 ms). It is concluded that (1) a single native human cardiac Na+ channel can be recorded at low noise, (2) this channel can change its gating properties at a time scale of milliseconds, (3) lifetimes of the observed gating modes are short ranging from milliseconds to seconds only, and (4) the gating modes are characterized by specific activation and inactivation kinetics and differ at least in their mean open time and first latency.
 ...
PMID:Identification of gating modes in single native Na+ channels from human atrium and ventricle. 1221 91

I introduce publicly available software for accurate fitting of Hodgkin-Huxley models to voltage-clamp data. I describe the model and non-linear fitting procedure employed by the software and compare its results with the usual method of fitting such models using potassium A-current data from a pyloric dilator cell of the lobster Panulirus interruptus and sodium current data from an electrocyte cell of the electric fish Sternopygus macrurus. The set of parameter values for the model determined by this software yield current traces that are substantially closer to the observed data than those determined from the usual fitting method. This improvement is due to the fact that the software fits all of the parameters simultaneously utilizing all of the data rather than fitting steady-state and time constant parameters disjointly using peak currents and portions of the rising and falling phases. I analyze the convergence properties of the software's fitting algorithm using simulated data showing that accurate parameter values are obtained for most of the parameters using any reasonable initial values. The software also incorporates a linear pre-estimation procedure to help in determining reasonable initial values for the full non-linear algorithm. I illustrate and discuss some of the inadequacies of voltage-clamp data.
 ...
PMID:NEUROFIT: software for fitting Hodgkin-Huxley models to voltage-clamp data. 1246 4

Phase-sensitive neurons in the electrosensory lateral line lobe in the electrosensory pathway of the wave-type electric fish, Gymnarchus niloticus, are specialized for sensing the time disparity between sensory inputs at different parts of the body surface that is necessary for an electrical behavior, jamming avoidance response. These neurons are sensitive to time disparity in the microsecond range between synaptic inputs that represent occurrence times of electrosensory signals at different areas on the body surface. We showed that an ideal Hodgkin-Huxley equation may serve as a time disparity detector that fits physiological precision, and the precision for the time disparity detection is largely regulated by the maximal g(K) conductance in the Hodgkin-Huxley equations.
 ...
PMID:Modeling of time disparity detection by the Hodgkin-Huxley equations. 1274 30

Significant error is made by using a point voltage clamp to measure active ionic current properties in poorly space-clamped cells. This can even occur when there are no obvious signs of poor spatial control. We evaluated this error for experiments that employ an isochronal I(V) approach to analyzing clamp currents. Simulated voltage clamp experiments were run on a model neuron having a uniform distribution of a single voltage-gated inactivating ionic current channel along an elongate, but electrotonically compact, process. Isochronal Boltzmann I(V) and kinetic parameter values obtained by fitting the Hodgkin-Huxley equations to the clamp currents were compared with the values originally set in the model. Good fits were obtained for both inward and outward currents for moderate channel densities. Most parameter errors increased with conductance density. The activation rate parameters were more sensitive to poor space clamp than the I(V) parameters. Large errors can occur despite "normal"-looking clamp curves.
 ...
PMID:Simulations of voltage clamping poorly space-clamped voltage-dependent conductances in a uniform cylindrical neurite. 1276 27

A reparameterized Hodgkin-Huxley-type model is developed that improves the 1952 model's fit to the biological action potential. In addition to altering Na(+) inactivation and K(+) activation kinetics, a voltage-dependent gating-current mechanism has been added to the model. The resulting improved model fits the experimental trace nearly exactly over the rising phase, and it has a propagation velocity that is within 3% of the experimentally measured value of 21.2 m/s (at 18.5 degrees C). Having eliminated most inaccuracies associated with the velocity-dependent rising phase of the action potential, the model is used to test Hodgkin's maximum velocity hypothesis, which asserts that channel density has evolved to maximize conduction velocity. In fact the predicted optimal channel density is more than twice as high as the actual squid channel density. When the available capacitance is reduced to approximate more modern serial Na(+)-channel models, the optimal channel density is 4 times the actual value. We suggest that, although Hodgkin's maximum velocity hypothesis is acceptable as a first approximation, the microscopic optimization perspective of natural selection will not explain the channel density of the squid unless other constraints are taken into account, for example, the metabolic costs of velocity.
 ...
PMID:Analysis of the optimal channel density of the squid giant axon using a reparameterized Hodgkin-Huxley model. 1683 67


<< Previous 1 2 3 4 5 Next >>