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PubMed2006

Gestational exposure to methylmercury and selenium: effects on a spatial discrimination reversal in adulthood.

Selenium, a nutrient, and methylmercury, a developmental neurotoxicant, are both found in fish. There are reports that selenium sometimes ameliorates methylmercury's neurotoxicity, but little is known about the durability of this protection after low-level gestational exposure. Developmental methylmercury exposure disrupts behavioral plasticity, and these effects extend well into adulthood and aging. The present experiment was designed to examine interactions between developmental low-level methylmercury and nutritionally relevant dietary selenium on discrimination reversals in adulthood. Female rats were exposed, in utero, to 0, 0.5, or 5 ppm mercury as methylmercury via drinking water, approximating mercury exposures of 0, 40, and 400 microg/kg/day. They also received both prenatal and postnatal exposure to a diet containing selenium from casein only (0.06 ppm) or 0.6 ppm selenium, creating a 2 (chronic Se)x3 (gestational MeHg) full factorial design, with six to eight rats per cell. Behavior was evaluated with a spatial discrimination procedure using two levers and sucrose reinforcers. All groups acquired the original discrimination similarly. Rats exposed to low selenium (0.06 ppm), regardless of MeHg exposure, required more sessions to complete the first reversal and made more omissions during this reversal than high selenium (0.6 ppm) animals, but the two diet groups did not differ on subsequent reversals. Rats exposed to MeHg, regardless of selenium exposure, made more errors than controls on the first and third reversals, which was away from the original discrimination. MeHg-exposed animals also had shorter choice latencies than controls during the first session of a reversal. Low selenium increased the number of omissions during a reversal, whereas high MeHg exposure produced perseverative responding (errors) on the lever that was reinforced during the original discrimination. However, there was no interaction between selenium and MeHg exposure.

Age Factors↗

PubMed2006

Induction and activity-dependent reversal of persistent LTP and LTD in lateral perforant path synapses in vivo.

The reversibility of long-term potentiation (LTP) and heterosynaptic long-term depression (LTD) lasting weeks was examined in the lateral perforant path of freely moving adult Sprague-Dawley rats. LTP lasting weeks was rapidly reversed within minutes by high-frequency heterosynaptic stimulation of the medial perforant path, in an N-methyl-D-aspartate receptor-dependent manner. LTP reversal also occurred, albeit more slowly and to a lesser extent, when animals were given 1-3 weeks of overnight exposure to an enriched environment (EE). LTD likewise was reversed upon repeated EE exposure. A covert similarity between the degrees of LTP and LTD reversal was revealed when the small potentiation effect of EE treatment by itself on lateral path responses was taken into account. Despite its ability to reverse previously acquired synaptic plasticity, two weeks of EE treatment had no effect on animals' retention of the platform location in a spatial watermaze task, although it did facilitate new learning. These data are in agreement with the hypothesis that hippocampal synapses retain the capacity for rapid synaptic change even when otherwise relatively stable plasticity has previously been induced. Slow reversal of such plasticity did not correlate with a loss of memory retention, possibly because either slow changes permit reorganization of representations such that both old and new information can be accommodated, or else the new information is synaptically represented in orthogonal fashion to the old information.

Analysis of Variance↗

PubMed2005

Total reversibility testing as indicator of the clinical efficacy of formoterol in COPD.

RATIONALE: The Global Initiative for Chronic Obstructive Lung Disease guidelines recommend bronchodilator reversibility testing to guide treatment decisions. This study evaluated the relationship between the change in forced expiratory volume in 1 s (FEV1) with salbutamol or formoterol and the clinical effects of a 4-week formoterol (Foradil) treatment. METHODS: At Visit 1, patients (n = 448) with stable chronic obstructive pulmonary disease took an FEV1 reversibility test using 200 microg salbutamol via a metered dose inhaler. At Visit 2 (Day 0), an FEV1 reversibility test was performed using formoterol via a dry-powder inhaler (Aerolizer). Patients then received formoterol 12 microg twice daily until Visit 3 (Day 21-30), when a further formoterol FEV1 reversibility test was performed. Clinical parameters included FEV1, symptom questionnaires and rescue medication use. RESULTS: There was no significant relationship between the immediate change in FEV1 with salbutamol and the absolute change from baseline in FEV1, symptom scores or rescue medication use after a 4-week formoterol treatment. Relative immediate change in FEV1 with formoterol was correlated with change in rescue medication use (P = 0.02) and FEV1 at Visit 3 (P < 0.001). Total reversibility in FEV1 with formoterol (post-dose Visit 3-pre-dose Visit 2) was correlated with all treatment efficacy variables (P<0.01). CONCLUSIONS: Immediate salbutamol reversibility testing, as performed under these study conditions, failed to predict the clinical efficacy of formoterol. Total reversibility after 4 weeks of formoterol treatment may be a better predictor of clinical benefits of long-term bronchodilator therapy.

Administration, Inhalation↗

PubMed2005

Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation.

We investigated optimal dose of prothrombin complex concentrate (PCC) for acute reversal of oral anticoagulation in patients with major hemorrhagic complications or who required invasive procedures. We also checked how rapidly international normalized ratio (INR) was reversed after PCC administration. INR was measured before and 10-60 min after administration of PCC with or without vitamin K in 42 patients (men 28, women 14, median age of 70 years old) who had received warfarin but required rapid reversal of INR because of a hemorrhagic complication or medical procedure. The amount of PCC administered was 200 IU in six patients, 500 IU in 30, 1000 IU in 3, and 1500 IU in the other 3. Additional administration of PCC was performed when the correction of INR was inadequate. In 10 of the 42 cases, INR was measured serially, before, 10 and 60 min and 12-24 h after the administration of PCC and vitamin K. In the six patients who received PCC of 200 IU, INR values of 3.34 median (range 2.06 to 5.08) decreased to 1.85 (range 1.23 to 2.43) significantly (Wilcoxon's rank sum test, p=0.028), but in three patients (50%), INR values were still above 2.0 after the administration. In 30 patients treated with PCC of 500 IU, values decreased from 2.49 median (range 1.54 to 10.00) to 1.19 (range 0.87 to 1.55) significantly (p<0.0001). The corrected INR values were below 1.5 in 25 of 26 patients (96%) who had initial INR values from 2.0 to 4.9. In four patients with initial INR of 5.0 or more, the reversed INR was below 1.5 in one (25%), between 1.5 and 2.0 in two (50%), and above 2.0 in one (25%) who had additional administration of 500 IU PCC lowering INR from 2.01 to 1.48. Values of INR in the six patients receiving 1000 IU or 1500 IU, INR decreased from 2.33 median (range 1.96 to 4.00) to 0.96 (range 0.87 to 1.24, p=0.028). In the 10 patients with serial measurement, INR changed from 2.67 median (range 2.05 to 10.00) to 1.17 (range 0.99 to 1.60) 10 min after the administration. The INR values remained stable 60 min and 12-24 h after the PCC administration. The 500 IU of PCC is likely to be optimal dose of PCC for emergent reversal of INR in patients requiring rapid correction of INR below 5.0, but to be inadequate dose in patients with INR of 5.0 or more. PCC administration with vitamin K may finish reversing INR rapidly within 10 min and keep the reversed INR values for 12-24 h.

Administration, Oral↗

PubMed2006

Alpha 1-acid glycoprotein reverses cocaine-induced sodium channel blockade in cardiac myocytes.

UNLABELLED: Alpha 1-acid glycoprotein (AAG) is an acute phase protein capable of binding basic drugs. This action explains its reversal of sodium channel blockade by drugs such as amitriptyline and quinidine. We report here the reversal of cocaine-induced sodium channel blockade by AAG. The sodium channel blocking property of cocaine is a major mechanism behind cocaine-induced sudden cardiac death, since sodium channels play a key role in the initiation and regulation of the heart beat. Voltage-gated sodium current (I(Na)) was recorded using whole-cell patch-clamp techniques. Guinea-pig cardiac ventricular myocytes were isolated and continuously perfused at room temperature with physiological solutions. At concentrations ranging from 5 to 320 microM cocaine showed a dose-dependent and reversible blockade of I(Na) with an IC50 of 45.9 microM. The addition of equimolar amounts of AAG to cocaine produced almost complete reversal of cocaine's effects, suggesting a single binding site for cocaine on the AAG molecule. With changes of peak I(Na) normalized against control as 1, cocaine at 20 and 40 microM reduced I(Na) to 0.62+/-0.042 (n = 6) and 0.57+/-0.052 (n = 9), respectively, and the addition of an equimolar concentration of AAG reversed I(Na) to 0.86+/-0.022 and 0.91+/-0.060, respectively. IN CONCLUSION: AAG reverses cocaine-induced sodium channel blockade in a dose-dependent manner, indicating a therapeutic potential to reverse acute cocaine cardiac toxicity.

Animals↗

PubMed2003

Display-control arrangement correspondence and logical recoding in the Hedge and Marsh reversal of the Simon effect.

When left and right keypresses are made to stimuli in left and right locations, and stimulus location is irrelevant to the task, responses are typically faster when stimulus location corresponds with response location than when it does not (the Simon effect). This effect reverses when the relevant stimulus-response mapping is incompatible, with responses being slower when stimulus and response locations correspond (the Hedge and Marsh reversal). Simon et al. (Acta Psychol. 47 (1981) 63) reported an exception to the Hedge and Marsh reversal for a situation in which the relevant stimulus dimension was the color of a centered visual stimulus and the irrelevant location information was left or right tone location. In contrast, similar experiments have found a reversal of the Simon effect for tone location when relevant visual locations were mapped incompatibly to responses. We conducted four experiments to investigate this discrepancy. Both results were replicated. With an incompatible mapping, irrelevant tone location showed a small reverse Simon effect when the relevant visual dimension was physical location but not when the color of a centered stimulus or the direction in which an arrow pointed conveyed the visual location information. The reversal occurred in a more standard Hedge and Marsh task in which the irrelevant dimension was location of the colored stimulus, but only when the response keys were visibly labeled. Several of the results suggest that display-control arrangement correspondence is the primary cause of the Hedge and Marsh reversal, with logical recoding playing only a secondary role.

Color Perception↗

PubMed1999

Determinants of pulmonary venous flow reversal in mitral regurgitation and its usefulness in determining the severity of regurgitation.

Pulmonary venous flow (PVF) reversal is observed in mitral regurgitation (MR) and can be detected by Doppler echocardiography. However, the determinants of PVF alterations in MR have not been analyzed with simultaneous quantitative methods, and the diagnostic accuracy of flow reversal is uncertain. Prospectively, in 128 patients with isolated MR of various degrees (regurgitant fraction 4% to 81%), Doppler echocardiography was used to measure PVF velocity simultaneously to quantify MR by 2 methods and to perform a comprehensive hemodynamic assessment. Systolic PVF velocity was 4 +/- 56 cm/s (systolic flow reversal in 39 patients) and showed the strongest correlations with mitral effective regurgitant orifice (r = -0.56, p <0.0001). In multivariate analysis, larger effective regurgitant orifice (p <0.0001), eccentric jets (p = 0.0023), longer jets (p = 0.0033), and lower mitral regurgitant velocity (p = 0.0015) were independent determinants of decreased systolic PVF velocity. In organic MR, increased filling pressures were associated with systolic PVF reversal. Blunted systolic flow was associated with shorter mitral deceleration time (p <0.0001) and enlarged left atrium (p = 0.0007). For the diagnosis of severe MR (regurgitant orifice > or = 35 mm2, regurgitant fraction > or = 50%), systolic flow reversal sensitivity was 61% and 60%, and specificity was 92% and 85%, respectively. Among 29 patients in whom surgery demonstrated severe mitral lesions, 12 (41%) had no systolic flow reversal preoperatively. In patients with MR, the determinants of systolic PVF are complex and, in addition to the degree of MR, include the hemodynamic consequences of MR, jet characteristics, left ventricular filling, and left atrial volume alterations. Consequently, systolic PVF reversal is a useful sign of severe MR but of relatively low sensitivity, emphasizing the importance of quantifying MR.

Aged↗

PubMed1997

Pattern-reversal visual evoked potentials in patients with epiretinal membrane.

PURPOSE: To determine the extent of pattern-reversal visual evoked potential parameter alteration by epiretinal membranes and to investigate the use of pattern-reversal visual evoked potential in the estimation of macular function in eyes with epiretinal membrane and in the fellow eyes. METHODS: In both eyes of 162 patients with epiretinal membrane, 92 of primary and 70 of secondary origin, pattern-reversal visual evoked potentials were recorded. Check sizes of 17', 10', and 7' (minutes of arc) were used. Parameters investigated were N80 and P100 latencies and P100 amplitude. RESULTS: No significant difference was detected between eyes with epiretinal membrane of primary and secondary origin regarding visual acuity and the pattern-reversal visual evoked potential parameters for the different check sizes. Compared with the fellow eyes, the eyes with epiretinal membrane had a significantly reduced visual acuity, prolonged N80 and P100 latencies, and a reduced P100 amplitude for the different check sizes. Compared with a separate control group (N = 20) with patients 50 to 59 years old, eyes with epiretinal membrane (N = 9) showed the same features as in the total group, but only for the 17' and 10' check sizes. The fellow eyes (N = 9) showed a significant reduction of the P100 amplitude (P < .05) for the pattern sizes of 17' and 10', but no difference in visual acuity or pattern-reversal visual evoked potential latency was found. CONCLUSIONS: In eyes with epiretinal membrane, pattern-reversal visual evoked potential latencies are prolonged, and amplitude is reduced. Relationships between clinical parameters and pattern-reversal visual evoked potential parameters require further study.

Evoked Potentials, Visual↗

PubMed1998

Physiologic comparison of forward and reverse wheelchair propulsion.

OBJECTIVES: Conventional wheelchair propulsion is physiologically demanding because of the small muscle mass that is used and the low mechanical efficiency of the movement. Previous research has suggested that a reverse wheeling technique might be more economical than conventional forward wheeling. The present study sought to compare the physiologic demands of forward and reverse wheeling techniques. DESIGN: A repeated measures design was used to compare the dependent variables between forward and reverse wheeling techniques in the same subjects. SETTING: Human exercise research laboratory. PARTICIPANTS: Ten able-bodied men. INTERVENTION: Subjects completed graded, discontinuous exercise tests on a wheelchair ergometer, using both forward and reverse wheeling techniques. MAIN OUTCOME MEASURES: Oxygen uptake (VO2), ventilation (VE), and heart rate were measured during the last 30 seconds of each 3-minute exercise stage. Blood lactate concentration ([La]) and rating of perceived exertion (RPE) were determined immediately after each stage. RESULTS: Repeated measures analysis of variance demonstrated that VO2, VE, heart rate, [La], and RPE were all significantly greater (p < .05) with reverse wheeling compared with forward wheeling. VO2, values with reverse wheeling averaged 9% higher than forward wheeling at identical power outputs. CONCLUSIONS: Reverse wheelchair propulsion is physiologically more demanding than conventional forward wheelchair propulsion and does not appear to offer potential for improving the economy of wheelchair propulsion.

Adult↗

PubMed1994

Testing for microscopic reversibility in the gating of maxi K+ channels using two-dimensional dwell-time distributions.

An assumption usually made when developing kinetic models for the gating of ion channels is that the transitions among the various states involved in the gating obey microscopic reversibility. If this assumption is incorrect, then the models and estimated rate constants made with the assumption would be in error. This paper examines whether the gating of a large conductance Ca-activated K+ channel in skeletal muscle is consistent with microscopic reversibility. If microscopic reversibility is obeyed, then the number of forward and backward transitions per unit time for each individual reaction step will, on average, be identical and, consequently, the gating must show time reversibility. To look for time reversibility, two-dimensional dwell-time distributions of the durations of open and closed intervals were obtained from single-channel current records analyzed in the forward and in the backward directions. Two-dimensional dwell-time distributions of pairs of open intervals and of pairs of closed intervals were also analyzed to extend the resolution of the method to special circumstances in which intervals from different closed (or open) states might have similar durations. No significant differences were observed between the forward and backward analysis of the two-dimensional dwell-time distributions, suggesting time reversibility. Thus, we find no evidence to indicate that the gating of the maxi K+ channel violates microscopic reversibility.

Animals↗

PubMed1996

Simulations of reversible protein aggregate and crystal structure.

We simulated the structure of reversible protein aggregates as a function of protein surface characteristics, protein-protein interaction energies, and the entropic penalty accompanying the immobilization of protein in a solid phase. These simulations represent an extension of our previous work on kinetically irreversible protein aggregate structure and are based on an explicit accounting of the specific protein-protein interactions that occur within reversible aggregates and crystals. We considered protein monomers with a mixture of hydrophobic and hydrophilic surface regions suspended in a polar solvent; the energetic driving force for aggregation is provided by the burial of solvent-exposed hydrophobic surface area. We analyzed the physical properties of the generated aggregates, including density, protein-protein contact distributions, solvent accessible surface area, porosity, and order, and compared our results with the protein crystallization literature as well as with the kinetically irreversible case. The physical properties of reversible aggregates were consonant with those observed for the irreversible aggregates, although in general, reversible aggregates were more stable energetically and were more crystal-like in their order content than their irreversible counterparts. The reversible aggregates were less dense than the irreversible aggregates, indicating that the increased energetic stability is derived primarily from the optimality rather than the density of the packing in the solid phase. The extent of hydrophobic protein-protein contacts and solvent-exposed surface area within the aggregate phase depended on the aggregation pathway: reversible aggregates tended to have a greater proportion of hydrophobic-hydrophobic contacts and a smaller fraction of hydrophobic solvent-exposed surface area. Furthermore, the arrangement of hydrophobic patches on the protein surface played a major role in the distribution of protein contacts and solvent content. This was readily reflected in the order of the aggregates: the greater the contiguity of the hydrophobic patches on the monomer surface, the less ordered the aggregates became, despite the opportunities for rearrangement offered by a reversible pathway. These simulations have enhanced our understanding of the impact of protein structural motifs on aggregate properties and on the demarcation between aggregation and crystallization.

Biophysical Phenomena↗

PubMed2002

Vasectomy reversal performed 15 years or more after vasectomy: correlation of pregnancy outcome with partner age and with pregnancy results of in vitro fertilization with intracytoplasmic sperm injection.

OBJECTIVE: To document a contemporary series of vasectomy reversals performed in men 15 years or more after vasectomy and to correlate the results with spousal age and results of ICSI for obstructive azoospermia. SETTING: University referral center for male infertility. DESIGN: Retrospective analysis of a single surgeon's experience compared with reported ICSI results. PARTICIPANT(S): One hundred seventy-three men who had vasectomy reversal 15 years or more after vasectomy. INTERVENTION(S): Reversal of vasectomy by vasovasostomy or epididymovasostomy. MAIN OUTCOME MEASURE(S): Correlation of pregnancy results after vasectomy reversal with spousal age and published ICSI results. RESULT(S): Pregnancy rates for the intervals of 15-19 years, 20-25 years, and >25 years after vasectomy were 49%, 39%, and 25%, respectively. For spousal age <30 years, 30--35 years, 36-40 years, and >40 years, pregnancy rates were 64%, 49%, 32%, and 28%, respectively. The overall pregnancy rate was 43%, which is similar to the pregnancy rate of 40% for ICSI in obstructive azoospermia. Sixty-two percent of the men required a unilateral or bilateral epididymovasostomy. CONCLUSION(S): Spousal age is an important predictive factor after vasectomy reversal among men who have reversal 15 years or more after vasectomy. Pregnancy rates after vasectomy reversal compare favorably with those obtained with ICSI.

Adult↗

PubMed2000

High-performance liquid chromatographic resolution of reverse isomers of 1,2-diacyl-rac-glycerols as 3,5-dinitrophenylurethanes.

The resolution of reverse isomers remains a major unsolved problem in glycerolipid chromatography. We have investigated the separation of the reverse isomers of 1,2-diacyl-rac-glycerols under a variety of high-performance liquid chromatography (HPLC) conditions. The reverse isomers of diacylglycerols having various pairs of acyl groups including short and highly unsaturated chains, which were prepared by partial Grignard degradation of the corresponding triacylglycerols, were chromatographed as 3,5-dinitrophenylurethanes. Excellent resolution was achieved for the reverse isomers of very different pairs of acyl groups, such as acetate-palmitate and docosahexaenoate-palmitate, by chiral-phase HPLC on columns containing (R)- and (S)-1-(1-naphthyl)ethylamine polymeric phases, reversed-phase HPLC on a highly efficient C18 column (4 microm particle size) and silver ion HPLC on a silver loaded cation-exchange column. The chiral-phase HPLC also permitted complete enantiomer resolution for all the reverse isomers examined. No satisfactory resolution by any of the HPLC methods, however, was obtained for the reverse isomers possessing minor differences in chain lengths and degree of unsaturation, such as laurate-palmitate and oleate-linoleate. The limitations of resolution and characteristics of elution are described.

Chromatography, High Pressure Liquid↗

PubMed2000

Amplitude degradation of time-reversed pulses in nonlinear absorbing thermoviscous fluids.

The linear wave equation in a lossless medium is time reversible, i.e., every solution p(x, t) has a temporal mirror solution p(x, -t). Analysis shows that time reversal also holds for the lossless nonlinear wave equation. In both cases, time-reversal invariance is violated when losses are present. For nonlinear propagation loses cannot normally be ignored; they are necessary to prevent the occurrence of multivalued waveforms. Further analysis of the nonlinear wave equation shows that amplification of a time-reversed pulse at the array elements also leads to a violation of time reversal even for lossless nonlinear acoustics. Numerical simulations are used to illustrate the effect of nonlinearity on the ability of a time-reversal system to effectively focus on a target in an absorbing fluid medium. We consider both the amplitude and arrival time of retrodirected pulses. The numerical results confirm that both shock generation (with the accompanying absorption) and amplification at the array, adversely affect the ability of a time-reversal system to form strong retrodirective sound fields.

Acoustics↗

PubMed1998

Electrooptic analysis of macromolecule dipole moments using asymmetric reversing electric pulses.

The use of symmetric reversing electric field pulses in electrooptic studies of rigid macromolecules in order to determine the ratio between the permanent and the induced dipole moments is well established. Application of this method to studies of small macromolecules requires a field reversal time of only a few nanoseconds. No high current pulse generator capable of producing symmetric kV pulses with such a short reversal time is available for studies of small macromolecules in physiological salt solutions, but it has long been known how to make such reversing pulses that are asymmetric. In order to take advantage of the opportunity offered by the latter fact, we here present a theoretical analysis in the thermal domain of the electrooptic properties of solutions containing rigid macromolecules with axial symmetry when exposed to asymmetric reversing electric field pulses. The analytical expressions needed for quantitative determination of the ratio between the permanent and the induced electric dipole moments of rigid macromolecules using electrooptic data obtained employing reversing electric pulses with given asymmetry are presented. The feasibility of this new approach is demonstrated by including experimental electric birefringence data for a 12 kDa protein (segment 14 of alpha-spectrin from Drosophila brains) in near physiological salt solutions obtained using a coaxial cable pulser producing 2 microseconds long pulses with a reversal time of about 15 ns.

Algorithms↗

PubMed1998

Effects of Cd2+, Pb2+ and CH3Hg+ on high voltage-activated calcium currents in pheochromocytoma (PC12) cells: potency, reversibility, interactions with extracellular Ca2+ and mechanisms of block.

Effects of the neurotoxic heavy metals Cd2+, Pb2+ and CH3Hg+ on current carried by Ca2+ ions (I(Ca)) through high-voltage activated Ca2+ channels in nerve growth factor (NGF)-differentiated pheochromocytoma (PC12) cells were examined to characterize possible differences in the mechanism of action of these metals on Ca2+ channel function. Specifically, the potency and reversibility of effect on I(Ca) by each metal was examined, as well as the relationship between extracellular [Ca2+] and potency of block of I(Ca) by Cd2+ and Pb2+. In addition, the effect of each of these metals on Ca2+ channels when applied to the intracellular side of the membrane was also examined. When extracellular solution contained 20, 10 or 5 mM Ca2+, the estimated IC50 values (total metal concentration) for block of I(Ca) were 15, 10, and 6.5 microM for Cd2+ and 7.5, 2.0 and 1.1 microM for Pb2+, respectively. CH3Hg+ (1-10 microM) blocked I(Ca) (20 mM Ca2+) in a time- and concentration-dependent manner. When cells were washed with metal-free solutions, block of I(Ca) by Cd2+ was reversed rapidly, whereas block by Pb2+ was reversed only partially, and block of I(Ca) by CH3Hg+ was not reversed. When Pb2+ and CH3Hg+ treated cells were washed in metal-free solutions containing 50 microM D-penicillamine (DPEN), block of I(Ca) by 10 microM Pb2+ was rapidly and completely reversed, whereas, block of I(Ca) by 5 microM CH3Hg+ was not reversed. Higher concentrations (500 microM) of 2,3-dimercapto-1-propane sulfonic acid (DMPS) did reverse partially the block of I(Ca) by 5 and 10 microM CH3Hg+. When Cd2+, Pb2+ or CH3Hg+ was present in the intracellular solution, Ca2+ channel currents were significantly reduced. These results characterize effects of Cd2+ on Ca2+ channels and demonstrate that Cd2+, Pb2+ and CH3Hg+ differ in their actions on Ca2+ channels.

Animals↗

PubMed1995

Effective and less toxic reversal of low-molecular weight heparin anticoagulation by a designer variant of protamine.

PURPOSE: This investigation assessed protamine reversal of heparin anticoagulation by formation of a protamine-heparin alpha-helix by use of a new designer-variant protamine [+18BE] that was made from an existing protamine variant [+18B] whose non-alpha-helix-forming amino acid proline (P) was replaced by an alpha-helix-forming glutamic acid (E). The rate of administration of the new [+18BE] variant protamine on efficacy and toxicity in comparison to that of [+21] standard protamine and [+18B] was also studied. METHODS: Acetyl-EAA(K2A2K2A)4K2-Amide [+18BE] was administered intravenously in a 1:1 dose to low-molecular-weight heparin (LMWH)-anticoagulated (intravenous 150 IU antifactor Xa/kg) dogs over 10 seconds or 3 minutes (n = 7, each group). Reversal efficacy was documented by measuring activated clotting time, thrombin clotting time, antifactor Xa, and antifactor IIa. Toxicity was defined by measuring systemic blood pressure, heart rate, cardiac output, pulmonary artery pressure, and oxygen consumption. Measurements were made at baseline, after administration of LMWH, before its reversal, and for 30 minutes thereafter. Results were compared with those after LMWH reversal with [+21] standard protamine and the [+18B] variant. A total toxicity score (TTS) was calculated for each compound from maximal declines in blood pressure, heart rate, cardiac output, and oxygen consumption. RESULTS: LMWH anticoagulation reversal was significantly (p < 0.01) less toxic over 10 seconds and 3 minutes with the [+18BE] designer variant (TTS -2.3, -2.2) compared with the [+21] standard protamine (TTS -6.4, -7.2). Percent LMWH reversal at 3 minutes revealed [+18BE] to have antifactor Xa activity as high as 91%, compared with 68% for protamine [+21], when given over 3 minutes (p < 0.05). CONCLUSIONS: This investigation documents that a new designer variant of protamine [+18BE] has superior efficacy compared with [+21] standard protamine for reversal of LMWH anticoagulation and that this occurs with a highly favorable toxicity profile.

Amino Acid Sequence↗

PubMed1998

Neural network classifications and correlation analysis of EEG and MEG activity accompanying spontaneous reversals of the Necker cube.

It has recently been suggested that reentrant connections are essential in systems that process complex information [A. Damasio, H. Damasio, Cortical systems for the retrieval of concrete knowledge: the convergence zone framework, in: C. Koch, J.L. Davis (Eds.), Large Scale Neuronal Theories of the Brain, The MIT Press, Cambridge, 1995, pp. 61-74; G. Edelman, The Remembered Present, Basic Books, New York, 1989; M.I. Posner, M. Rothbart, Constructing neuronal theories of mind, in: C. Koch, J.L. Davis (Eds.), Large Scale Neuronal Theories of the Brain, The MIT Press, Cambridge, 1995, pp. 183-199; C. von der Malsburg, W. Schneider, A neuronal cocktail party processor, Biol. Cybem., 54 (1986) 29-40]. Reentry is not feedback, but parallel signalling in the time domain between spatially distributed maps, similar to a process of correlation between distributed systems. Accordingly, it was expected that during spontaneous reversals of the Necker cube, complex patterns of correlations between distributed systems would be present in the cortex. The present study included EEG (n=4) and MEG recordings (n=5). Two experimental questions were posed: (1) Can distributed cortical patterns present during perceptual reversals be classified differently using a generalised regression neural network (GRNN) compared to processing of a two-dimensional figure? (2) Does correlated cortical activity increase significantly during perception of a Necker cube reversal? One-second duration single trials of EEG and MEG data were analysed using the GRNN. Electrode/sensor pairings based on cortico-cortical connections were selected to assess correlated activity in each condition. The GRNN significantly classified single trials recorded during Necker cube reversals as different from single trials recorded during perception of a two-dimensional figure for both EEG and MEG. In addition, correlated cortical activity increased significantly in the Necker cube reversal condition for EEG and MEG compared to the perception of a non-reversing stimulus. Coherent MEG activity observed over occipital, parietal and temporal regions is believed to represent neural systems related to the perception of Necker cube reversals.

Adolescent↗