Search

Resurgent tail [Na.sup.+] currents were first discovered in cerebellar Purkinje neurons. A recent study showed that a 14-mer fragment of a mouse [beta]4 subunit, [[beta]4.sub.154-167], acts as an intracellular open-channel blocker and elicits resurgent currents in Purkinje neurons (Grieco, T.M., J.D. Malhotra, C. Chen, L.L. Isom, and I.M. Raman. 2005. Neuron. 45:233-244). To explore these phenotypes in vitro, we characterized [[beta]4.sub.154-167] actions in inactivation-deficient cardiac hNav1.5 [Na.sup.+] channels expressed in human embryonic kidney 293t cells. Intracellular [[beta]4.sub.154-167] from 25-250 [micro]M elicited a conspicuous time-dependent block of inactivation-deficient [Na.sup.+] currents at 50 mV in a concentration-dependent manner. On and off rates for [[beta]4.sub.154-167] binding were estimated at 10.1 [[micro]M.sup.-1][s.sup.-1] and 49.1 [s.sup.-1], respectively. Upon repolarization, large tail currents emerged with a slight delay at -140 mV, probably as a result of the rapid unblocking of [[beta]4.sub.154-167]. Near the activation threshold (approximately -70 mV), resurgent tail currents were robust and long lasting. Likewise, [[beta]4.sub.154-167] induces resurgent currents in wild-type hNav1.5 [Na.sup.+] channels, although to a lesser extent. The inactivation peptide acetyl-KIFMK-amide not only restored the fast inactivation phenotype in hNav1.5 inactivation-deficient [Na.sup.+] channels but also elicited robust resurgent currents. When modified by batrachotoxin (BTX), wild-type hNav1.5 [Na.sup.+] channels opened persistently but became resistant to [[beta]4.sub.154-167] and acetyl-KIFMK-amide block. Finally, a lysine substitution of a phenylalanine residue at D4S6, F1760, which forms a part of receptors for local anesthetics and BTX, rendered cardiac [Na.sup.+] channels resistant to [[beta]4.sub.154- 167]. Together, our in vitro studies identify a putative S6-binding site for [[beta]4.sub.154-167] within the inner cavity of hNav1.5 [Na.sup.+] channels. Such an S6 receptor readily explains (1) why [[beta]4.sub.154-167] gains access to its receptor as an open-channel blocker, (2), why bound [[beta]4.sub.154-167] briefly prevents the activation gate from closing by a 'foot-in-the-door' mechanism during deactivation, (3) why BTX inhibits [[beta]4.sub.154-167] binding by physical exclusion, and (4) why a lysine substitution of residue F1760 eliminates [[beta]4.sub.154-167] binding.

In the functional electrical stimulation of the lower extremity of paraplegics to achieve standing and walking, a mathematical model describing the passive elastic joint moments is essential in order to implement model-based control algorithms. In a previous investigation of ten normal persons we had found significant coupling of passive, elastic joint moments between neighboring joints due to muscle groups that span both joints (biarticular muscles). Thus, we now investigated the biarticular coupling in six paraplegic patients. A comparison to the averaged results of the ten normal persons showed that while the biarticular joint moment coupling due to the gastrocnemius muscle was well preserved in all patients, the coupling due to the rectus femoris was greatly reduced and the coupling due to the hamstring muscle group was negligible. We offer pathophysiologically based explanations for these characteristic differences including the speculation that the predominantly extensor-type spasticity in our patients exercises mainly the anti-gravity muscles such as the gastrocnemius and the rectus femoris, while permitting greater atrophy of the hamstring muscle group. A previously presented double-exponential equation that predicts the joint moments under consideration of the neighboring joint angles could be fitted well to the experimental data. Index Terms--Joint coupling, model, paraplegics, passive elastic joint moment.

Artifacts may occur in many in vitro models of pulse oximetry due to the optical effects of synchronously oriented and/or deformed erythrocytes. Although these artifacts are most likely negligible in living superficial tissues, they are demonstrated to have considerable influence on the calibration curve obtainable from the in vitro simulation of pulse oximetry in such models, especially at low oxygen saturations. Therefore, we have developed a modified in vitro model which reduces the effect of these artifacts. This is achieved by excluding data obtained during pressure transients and by raising the blood flow velocity. As a result, the model more closely approximates in vivo pulse oximetry, particularly under clinically important conditions of low blood oxygen saturation levels. Index Terms--Artifacts, in vitro model, pulse oximetry.

Purpose: Dabigatran (D) is increasingly used for chronic anticoagulation in place of warfarin (W). These patients may present for catheter-based procedures requiring full anticoagulation with heparin. This study compares the heparin sensitivity of patients previously on dabigatran, on warfarin, or on no chronic anticoagulant during ablation of atrial fibrillation. Patients and methods: In a retrospective study of patients treated with D, W, or neither drug (N) undergoing atrial ablation, the timing of heparin doses and resulting activated clotting times were collected. First, the initial activated clotting time response to the first heparin bolus was compared. Then, a non-linear mixed effects modelling (NONMEM) analysis was performed, fitting a pharmacokinetic and -dynamic model to the entire anticoagulation course of each patient. Resulting model coefficients were used to compare the different patient groups. Results: Data for 66 patients on dabigatran, 95 patients on warfarin, and 27 patients on no anticoagulation were retrieved. The last dose of dabigatran or warfarin had occurred 27 hours and 15 hours before the procedure. Groups D and N both responded significantly less (P,0.05) to the initial heparin bolus than Group W (approximately 50%). Likewise, the model coefficients resulting from the fit to each group reflected a significantly lower heparin sensitivity in groups D and N compared to W. Clearances of the heparin effect in the model did not differ significantly among groups. Conclusion: Patients on warfarin with an average INR of 1.5 or higher are more sensitive to heparin than patients not previously anticoagulated or patients who discontinued dabigatran 27 hours earlier (approximately two half-lives) warfarin. [ABSTRACT FROM AUTHOR]

Bivalirudin, used in patients with heparin-induced thrombocytopenia, is a direct thrombin inhibitor. Since it is a rarely used drug, clinical experience with its dosing is sparse. We develop two approaches to predict the Partial Thromboplastin Time (PTT) based on bivalirudin infusion rates. The first approach is model free and utilizes regularized regression. It is flexible enough to be used as predictors bivalirudin infusion rates measured over several time instances before the time at which a PTT prediction is sought. The second approach is model based and proposes a specific model for obtaining PTT which uses a shorter history of the past measurements. We learn population-wide model parameters by solving a nonlinear optimization problem. We also devise an adaptive algorithm based on the extended Kalman filter that can adapt model parameters to individual patients. The latter adaptive model emerges as the most promising as it yields reduced mean error compared to the model-free approach. The model accuracy we demonstrate on actual patient measurements is sufficient to be useful in guiding the optimal therapy. [ABSTRACT FROM PUBLISHER]

Resurgent tail Na+ currents were first discovered in cerebellar Purkinje neurons. A recent study showed that a 14-mer fragment of a mouse β4 subunit, β4154-167, acts as an intracellular open-channel blocker and elicits resurgent currents in Purkinje neurons (Grieco, T.M., J.D. Malhotra, C. Chen, L.L. Isom, and I.M. Raman. 2005. Neuron. 45:233-244). To explore these phenotypes in vitro, we characterized β4154-167 actions in inactivation-deficient cardiac hNav1.5 Na+ channels expressed in human embryonic kidney 293t cells. Intracellular β4154-167 from 25-250 µM elicited a conspicuous time-dependent block of inactivation-deficient Na+ currents at 50 mV in a concentration-dependent manner. On and off rates for β4154-167 binding were estimated at 10.1 µM-1s-1 and 49.1 s-1 respectively. Upon repolarization, large tail currents emerged with a slight delay at -140 rnV, probably as a result of the rapid unblocking of β4154-167. Near the activation threshold (approximately -70 mV), resurgent tail currents were robust and long lasting. Likewise, β4154-167 induces resurgent currents in wild-type hNav1.5 Na+ channels, although to a lesser extent. The inactivation peptide acetyl-KIFMK-amide not only restored the fast inactivation phenotype in hNav1.5 inactivation-deficient Na+ channels but also elicited robust resurgent currents. When modified by batrachotoxin (BTX), wild-type hNav1.5 Na+ channels opened persistently but became resistant to β4154-157 and acetyl-KIFMK-amide block. Finally, a lysine substitution of a phenylalanine residue at D4S6, F1760, which forms a part of receptors for local anesthetics and BTX, rendered cardiac Na+ channels resistant to β4154-167. Together, our in vitro studies identify a putative S6-binding site for β4154-167 within the inner cavity of hNav1.5 Na+ channels. Such an S6 receptor readily explains (1) why β4154-167 gains access to its receptor as an open-channel blocker, (2), why bound β4154-167 briefly prevents the activation gate from closing by a "foot-in-the-door" mechanism during deactivation, (3) why BTX inhibits β4154-167 binding by physical exclusion, and (4) why a lysine substitution of residue F1760 eliminates β4154-167 binding. [ABSTRACT FROM AUTHOR]

Bivalirudin is used in patients with heparin-induced thrombocytopenia and is a direct thrombin inhibitor. Since it is a rarely used drug, clinical experience with its dosing is sparse. We develop a model that predicts the effect of bivalirudin, measured by the Partial Thromboplastin Time (PTT) , based on its past fusion rates. We learn population-wide model parameters by solving a nonlinear optimization problem that uses a training set of patient data. More interestingly, we devise an adaptive algorithm based on the extended Kalman filter that can adapt model parameters to individual patients. The latter adaptive model emerges as the most promising as it reduces both the mean error and, drastically, the per-patient error variance. The model accuracy we demonstrate on actual patient measurements is sufficient to be useful in guiding optimal therapy.

Bivalirudin is direct thrombin inhibitor used in patients with heparin-induced thrombocytopenia. A pharmacokinetic and--dynamic model that predicts the partial thromboplastin time (PTT) based on the past infusion rates of bivalirudin following dose adjustment would be useful to guide optimal therapy. In this retrospective study we randomized 132 patients to a derivation and a validation cohort, and tested two models. The first model is a single-state linear model; the other incorporates a non-linear element to account for renal elimination of bivalirudin. Both models predicted PTT changes equally well with root-mean squared errors of 15 to 16 seconds (Pearson correlation coefficients for both were 0.67). Intra- and inter-individual variability of response to bivalirudin was significant. Although a high percentage of patients had moderate to severe renal dysfunction at one point during the bivalirudin infusion, the non-linear model that incorporates variable renal clearance of drug did not perform better than the linear model. This finding persisted even in the subgroup analysis of patients with moderate and low estimated glomerular filtration rates.