Infarct Volume Predicts Hospitalization Costs in Anterior Circulation Large-Vessel Occlusion Stroke.

BACKGROUND AND PURPOSE: Anterior circulation large-vessel occlusion stroke, one of the most devastating stroke subtypes, is associated with substantial economic burden. We aimed to identify predictors of increased acute care hospitalization costs associated with anterior circulation large-vessel occlusion stroke. MATERIALS AND METHODS: Comprehensive cost-tracking software was used to calculate acute care hospitalization costs for patients with anterior circulation large-vessel occlusion stroke admitted July 2012 to October 2014. Patient demographics and stroke characteristics were analyzed, including final infarct volume on follow-up neuroimaging. Predictors of hospitalization costs were determined using multivariable linear regression including subgroup cost analyses by treatment technique (endovascular, IV tPA-only, and no reperfusion therapy) and sensitivity analyses incorporating patients initially excluded due to early withdrawal of care. RESULTS: Three hundred forty-one patients (median age, 69 years; interquartile range, 57-80 years; median NIHSS score, 16; interquartile range, 13-21) were included in our primary analysis. Final infarct volume, parenchymal hematoma, baseline NIHSS score, ipsilateral carotid stenosis, age, and obstructive sleep apnea were significant predictors of acute care hospitalization costs. Final infarct volume alone accounted for 20.87% of the total cost variance. Additionally, final infarct volume was consistently the strongest predictor of increased cost in primary, subgroup, and sensitivity analyses. CONCLUSIONS: Final infarct volume was the strongest predictor of increased hospitalization costs in anterior circulation large-vessel occlusion stroke. Acute stroke therapies that reduce final infarct volume may not only improve clinical outcomes but may also prove cost-effective.

Single-channel current/voltage relationships of two kinds of Na+ channel in vertebrate sensory neurons.

The electrical signals of nerve and muscle are fundamentally dependent on the voltage-gated Na+ channel, which is responsible for the rising phase of the action potential. At least two kinds of Na+ channel are expressed in the membrane of frog dorsal root ganglion (DRG) cells: Na+ channels with fast kinetics that are blocked by tetrodotoxin (TTX) at high affinity, and Na+ channels with slower kinetics that are insensitive to TTX. Recordings of single-channel currents from frog DRG cells, under conditions favoring Na+ as the charge carrier, reveal two distinct amplitudes of single-channel events. With 300 mM external Na+, single-channel events that can be measured in the presence of 1 microM TTX have a slope conductance 7.5 pS. In the absence of TTX, events with a slope conductance of 14.9 pS dominate. Ensemble averages of the smaller single-channel events display the slower kinetics characteristic of the macroscopic TTX-insensitive Na+ currents, and ensemble averages of the larger events display the faster kinetics characteristic of the TTX-sensitive currents. The results are consistent with the idea that the toxin-binding site is sufficiently close to the pore to influence ion permeation.

Large and small vertebrate sensory neurons express different Na and K channel subtypes.

Sensory neurons of frog dorsal root ganglia (DRG) express at least two subtypes of voltage-gated Na channel and at least two subtypes of voltage-gated K channel. The Na channel subtypes have different sensitivities to tetrodotoxin (TTX) and different kinetics. The TTX-sensitive (TTX-s) Na channel inactivates rapidly and is blocked by nanomolar TTX. The TTX-insensitive (TTX-i) Na channel resists blockage by up to 100 microM TTX (it is blocked by saxitoxin) and inactivates 2-6 times more slowly. The two subtypes of voltage-gated K channel differ in activation kinetics: the fast subtype activates 2-8 times faster than the slow subtype. These Na and K channel subtypes are distributed differentially by cell size, falling into three major groups: (i) small cells with slowly activating K channels and a mixture of TTX-s and TTX-i Na channels; (ii) small cells with slowly activating K channels and TTX-s Na channels; and (iii) large cells with rapidly activating K channels and TTX-s Na channels. The contributions of these channel subtypes to the electrical properties of sensory neurons were investigated under conditions that minimized the contribution of Ca current. Under these conditions, action potential duration is correlated with the channel subtypes expressed: cells with both TTX-i and TTX-s Na channels and slowly activating K channels exhibit long-duration action potentials, cells with TTX-s Na channels and slowly activating K channels exhibit intermediate-duration action potentials, and cells with TTX-s Na channels and rapidly activating K channels exhibit short-duration action potentials.

Safety and efficacy of two sustained-release intrareticular selenium supplements and the associated placental and colostral transfer of selenium in beef cattle.

One hundred fifty Se-deficient, pregnant, crossbred beef cows were assigned to 1 of 4 treatment groups: group A, Se-deficient control; group B, 1 Se bolus at 0 and 119 days; group C, 1 Se bolus at 0 days; and group D, 2 Se pellets at 0 days. The Se bolus is an osmotic pump designed to release 3 mg of Se/d into the reticulorumen. The Se pellets weight approximately 30 g and contain 10% elemental Se, which is liberated in the reticulorumen. The Se bolus is designed to provide Se supplementation for 120 days and the Se pellets provide supplementation for up to 18 months. Cattle were maintained on Se-deficient pasture or forages prepared from these pastures for the duration of the experiment. Blood samples were collected from cows prior to treatment (time 0) and at 28, 52, 119, and 220 days thereafter and analyzed for blood Se (BSe) concentration. Body weights were recorded at each sampling time. Blood Se concentration of cows from all supplemented groups were significantly (P less than 0.01) higher than control values at all sample dates after treatments began. By the end of the 220-day study, treatment group-B cattle had significantly (P less than 0.01) higher BSe concentrations than any other group. Body weights of treatment groups fluctuated throughout the study, but did not differ (P greater than 0.05) between groups. One cow and 6 calves born to cows during the experimental period died. Necropsy of 5 calves provided no evidence linking these deaths to treatments.(ABSTRACT TRUNCATED AT 250 WORDS)

On the measurement of stability in over-time data.

In this article, autoregressive models and growth curve models are compared. Autoregressive models are useful because they allow for random change, permit scores to increase or decrease, and do not require strong assumptions about the level of measurement. Three previously presented designs for estimating stability are described: (a) time-series, (b) simplex, and (c) two-wave, one-factor methods. A two-wave, multiple-factor model also is presented, in which the variables are assumed to be caused by a set of latent variables. The factor structure does not change over time and so the synchronous relationships are temporally invariant. The factors do not cause each other and have the same stability. The parameters of the model are the factor loading structure, each variable's reliability, and the stability of the factors. We apply the model to two data sets. For eight cognitive skill variables measured at four times, the 2-year stability is estimated to be .92 and the 6-year stability is .83. For nine personality variables, the 3-year stability is .68. We speculate that for many variables there are two components: one component that changes very slowly (the trait component) and another that changes very rapidly (the state component); thus each variable is a mixture of trait and state. Circumstantial evidence supporting this view is presented.

Charge movements measured during transverse-tubular uncoupling in frog skeletal muscle.

Capacity transients and slow asymmetric charge-movements are measured in frog skeletal muscle using the Vaseline-gap voltage-clamp technique. Capacity transients show a rapid phase lasting 10-30 microseconds, due to the charging of the surface membrane capacitance, and a slower phase lasting several milliseconds, consistent with the charging of the transverse tubular system (T-system). Exposure to isotonic CsF caused the ratio of the slowly-charging capacitance (Cslow) to the fast-charging capacitance to decline by 88 +/- 9% (n = 16). Electron micrographs of four fibers treated with CsF show disruption and disorganization of the T-system and sarcoplasmic reticulum membranes and a greater than 90% decrease in the number of dyads and triads. The role of CsF was investigated: Fibers exposed to CsF internally or externally, exhibit slower and less complete loss of Cslow than fibers exposed both internally and externally. Little loss of Cslow occurs during the external exposure to CsF. The bulk of loss occurs only after the fiber is returned to Ca++-containing solution. Elevated external Ca++ causes more rapid and more complete loss of Cslow. The time-course of Cslow loss is gradual, occurring over a period of 10 min to 2 h. The progressive loss of Cslow is accompanied by a progressive decline in the peak of the slow asymmetric charge-movement and a progressive slowing of charge movement kinetics. These effects are qualitatively accounted for by including gradual tubular uncoupling in a distributed model of charge movement proposed by B. Simon and K. G. Beam (1985, J. Gen. Physiol., 85:21-42).

Na channel distribution in vertebrate skeletal muscle.

The loose patch voltage clamp has been used to map Na current density along the length of snake and rat skeletal muscle fibers. Na currents have been recorded from (a) endplate membrane exposed by removal of the nerve terminal, (b) membrane near the endplate, (c) extrajunctional membrane far from both the endplate and the tendon, and (d) membrane near the tendon. Na current densities recorded directly on the endplate were extremely high, exceeding 400 mA/cm2 in some patches. The membrane adjacent to the endplate has a current density about fivefold lower than that of the endplate, but about fivefold higher than the membrane 100-200 micron from the endplate. Small local variations in Na current density are recorded in extrajunctional membrane. A sharp decrease in Na current density occurs over the last few hundred micrometers from the tendon. We tested the ability of tetrodotoxin to block Na current in regions close to and far from the endplate and found no evidence for toxin-resistant channels in either region. There was also no obvious difference in the kinetics of Na current in the two regions. On the basis of the Na current densities measured with the loose patch clamp, we conclude that Na channels are abundant in the endplate and near-endplate membrane and are sparse close to the tendon. The current density at the endplate is two to three orders of magnitude higher than at the tendon.

Risk factors for traumatic infant death in Oregon, 1973 to 1982.

A retrospective study of risk factors for traumatic infant deaths in Oregon occurring from 1973 through 1982 was performed using vital records and medical examiner records. A total of 146 such deaths occurred during this period. Relative risks were calculated for various risk factors in the study group compared with all Oregon births. Factors found to be significantly associated with all traumatic deaths were low maternal age, out-of-hospital birth, unwed mother, late or no prenatal care, low birth weight, and low maternal education. Race, sex, and birth order were not associated with traumatic infant death. The traumatic deaths were grouped into homicides and accidents. The same risk factor associations, with the exception of out-of-hospital birth, were found for each group.

Na channels in skeletal muscle concentrated near the neuromuscular junction.

Neuronal function depends crucially on the spatial segregation of specific membrane proteins, particularly the segregation associated with sites of synaptic contact. Understanding the factors governing this localization of proteins is a major goal of cellular neurobiology. A conspicuous example of synaptic specialization is the almost exclusive localization of vertebrate skeletal muscle acetylcholine (ACh) receptors to the subsynaptic membrane of the neuromuscular junction (for example, refs 1,2). The localization of other membrane proteins in skeletal muscle has been much less studied, but a knowledge of their distribution is crucial for understanding the factors governing regional specialization. We have explored the distribution in muscle of the voltage-gated Na channel responsible for the action potential using the loose patch-clamp technique, and have measured Na currents in 5-10 micron-diameter membrane patches as a function of distance from the end plate region of snake and rat muscle fibres. Here we report that the Na current density immediately adjacent to the endplate is 5-10-fold higher than at regions away from the endplate. The increased Na current density falls off rapidly with distance, reaching the background level 100-200 micron from the endplate. Although one might expect ACh receptors to be concentrated near the region of ACh release, such a concentration for Na channels, which propagate the impulse throughout the length of the cell, is surprising and suggests that factors similar to those responsible for concentrating ACh receptors at the endplate also operate to concentrate Na channels.

Altered sodium and gating current kinetics in frog skeletal muscle caused by low external pH.

The effect of low pH on the kinetics of Na channel ionic and gating currents was studied in frog skeletal muscle fibers. Lowering external pH from 7.4 to 5.0 slows the time course of Na current consistent with about a +25-mV shift in the voltage dependence of activation and inactivation time constants. Similar shifts in voltage dependence adequately describe the effects of low pH on the tail current time constant (+23.3 mV) and the gating charge vs. voltage relationship (+22.1 mV). A significantly smaller shift of +13.3 mV described the effect of pH 5.0 solution on the voltage dependence of steady state inactivation. Changes in the time course of gating current at low pH were complex and could not be described as a shift in voltage dependence. tau g, the time constant that describes the time course of the major component of gating charge movement, was slowed in pH 5.0 solution by a factor of approximately 3.5 for potentials from -60 to +45 mV. We conclude that the effects of low pH on Na channel gating cannot be attributed simply to a change in surface potential. Therefore, although it may be appropriate to describe the effect of low pH on some Na channel kinetic properties as a "shift" in voltage dependence, it is not appropriate to interpret such shifts as a measure of changes in surface potential. The maximum gating charge elicited from a holding potential of -150 mV was little affected by low pH.(ABSTRACT TRUNCATED AT 250 WORDS)

Simple shifts in the voltage dependence of sodium channel gating caused by divalent cations.

The effect of elevated divalent cation concentration on the kinetics of sodium ionic and gating currents was studied in voltage-clamped frog skeletal muscle fibers. Raising the Ca concentration from 2 to 40 mM resulted in nearly identical 30-mV shifts in the time courses of activation, inactivation, tail current decay, and ON and OFF gating currents, and in the steady state levels of inactivation, charge immobilization, and charge vs. voltage. Adding 38 mM Mg to the 2 mM Ca bathing a fiber produced a smaller shift of approximately 20 mV in gating current kinetics and the charge vs. voltage relationship. The results with both Ca and Mg are consistent with the hypothesis that elevated concentrations of these alkali earth cations alter Na channel gating by changing the membrane surface potential. The different shifts produced by Ca and Mg are consistent with the hypothesis that the two ions bind to fixed membrane surface charges with different affinities, in addition to possible screening.

Sodium channel gating currents in frog skeletal muscle.

Charge movements similar to those attributed to the sodium channel gating mechanism in nerve have been measured in frog skeletal muscle using the vaseline-gap voltage-clamp technique. The time course of gating currents elicited by moderate to strong depolarizations could be well fitted by the sum of two exponentials. The gating charge exhibits immobilization: at a holding potential of -90 mV the proportion of charge that returns after a depolarizing prepulse (OFF charge) decreases with the duration of the prepulse with a time course similar to inactivation of sodium currents measured in the same fiber at the same potential. OFF charge movements elicited by a return to more negative holding potentials of -120 or -150 mV show distinct fast and slow phases. At these holding potentials the total charge moved during both phases of the gating current is equal to the ON charge moved during the preceding prepulse. It is suggested that the slow component of OFF charge movement represents the slower return of charge "immobilized" during the prepulse. A slow mechanism of charge immobilization is also evident: the maximum charge moved for a strong depolarization is approximately doubled by changing the holding potential from -90 to -150 mV. Although they are larger in magnitude for a -150-mV holding potential, the gating currents elicited by steps to a given potential have similar kinetics whether the holding potential is -90 or -150 mV.

Modified kinetics and selectivity of sodium channels in frog skeletal muscle fibers treated with aconitine.

The effect of the plant alkaloid aconitine on sodium channel kinetics, ionic selectivity, and blockage by protons and tetrodotoxin (TTX) has been studied in frog skeletal muscle. Treatment with 0.25 or 0.3 mM aconitine alters sodium channels so that the threshold of activation is shifted 40-50 mV in the hyperpolarized direction. In contrast to previous results in frog nerve, inactivation is complete for depolarizations beyond about -60 mV. After aconitine treatment, the steady state level of inactivation is shifted approximately 20 mV in the hyperpolarizing direction. Concomitant with changes in channel kinetics, the relative permeability of the sodium channel to NH4,K, and Cs is increased. This altered selectivity is not accompanied by altered block by protons or TTX. The results suggest that sites other than those involved in channel block by protons and TTX are important in determining sodium channel selectivity.

Kinetic and pharmacological properties of the sodium channel of frog skeletal muscle.

Na channels of frog skeletal muscle are studied under voltage clamp and their properties compared with those of frog myelinated nerve. A standard mathematical model is fitted to the sodium currents measured in nerve and in muscle to obtain a quantitative description of the gating kinetics. At 5 degrees C the kinetics in frog nerve and skeletal muscle are similar except that activation proceeds five times faster in nerve. Block of Na channels by saxitoxin is measured in nerve and in muscle. The apparent dissociation constants for the inhibitory complex are about 1 nM and not significantly different in nerve and muscle. Block of Na channels by external protons in muscle is found to have an apparent pKalpha of 5.33 and a voltage dependence corresponding to action of 27% of the membrane potential drop. Both values are like those for nerve. Shift of the peak sodium permeability-membrane potential curve with changes of external pH and Ca++ are found to be the same in nerve and muscle. It is concluded that Na channels of nerve and muscle are nearly the same.

An improved vaseline gap voltage clamp for skeletal muscle fibers.

A Vaseline gap potentiometric recording and voltage clamp method is developed for frog skeletal muscle fibers. The method is based on the Frankenhaeuser-Dodge voltage clamp for myelinated nerve with modifications to improve the frequency response, to compensate for external series resistance, and to compensate for the complex impedance of the current-passing pathway. Fragments of single muscle fibers are plucked from the semitendinosus muscle and mounted while depolarized by a solution like CsF. After Vaseline seals are formed between fluid pools, the fiber ends are cut once again, the central region is rinsed with Ringer solution, and the feedback amplifiers are turned on. Errors in the potential and current records are assessed by direct measurements with microelectrodes. The passive properties of the preparation are simulated by the "disk" equivalent circuit for the transverse tubular system and the derived parameters are similar to previous measurements with microelectrodes. Action potentials at 5 degrees C are long because of the absence of delayed rectification. Their shape is approximately simulated by solving the disk model with sodium permeability in the surface and tubular membranes. Voltage clamp currents consist primarily of capacity currents and sodium currents. The peak inward sodium current density at 5 degrees C is 3.7 mA/cm2. At 5 degrees C the sodium currents are smoothly graded with increasing depolarization and free of notches suggesting good control of the surface membrane. At higher temperatures a small, late extra inward current appears for small depolarizations that has the properties expected for excitation in the transverse tubular system. Comparison of recorded currents with simulations shows that while the transverse tubular system has regenerative sodium currents, they are too small to make important errors in the total current recorded at the surface under voltage clamp at low temperature. The tubules are definitely not under voltage clamp control.

Ionic selectivity of the sodium channel of frog skeletal muscle.

The ionic selectivity of the Na channel to a variety of metal and organic cations is studied in frog semitendinosus muscle. Na channel currents are measured under voltage clamp conditions in fibers bathed in solutions with all Na+ replaced by a test ion. Permeability ratios are calculated from measured reversal potentials using the Goldman-Hodgkin-Katz equation. The permeability sequence was Na+ approximately Li+ approximately hydroxylammonium greater than hydrazinium greater than ammonium greater than guanidinium greater than K+ greater than aminoguanidinium in the ratios 1:0.96:0.94:0.31:0.11:0.093:0.048:0.031. No inward currents were observed for Ca++, methylammonium, methylguanidinium, tetraethylammonium, and tetramethylammonium. The results are consistent with the Hille model of the Na channel selectivity filter of the node of Ranvier and suggest that the selectivity filter of the two channels is the same.