Dopamine and beta-band oscillations differentially link to striatal value and motor control.

Parkinson's disease is characterized by decreased dopamine and increased beta-band oscillatory activity accompanying debilitating motor and mood impairments. Coordinate dopamine-beta opposition is considered a normative rule for basal ganglia function. We report a breakdown of this rule. We developed multimodal systems allowing the first simultaneous, chronic recordings of dopamine release and beta-band activity in the striatum of nonhuman primates during behavioral performance. Dopamine and beta signals were anticorrelated over seconds-long time frames, in agreement with the posited rule, but at finer time scales, we identified conditions in which these signals were modulated with the same polarity. These measurements demonstrated that task-elicited beta suppressions preceded dopamine peaks and that relative dopamine-beta timing and polarity depended on reward value, performance history, movement, and striatal domain. These findings establish a new view of coordinate dopamine and beta signaling operations, critical to guide novel strategies for diagnosing and treating Parkinson's disease and related neurodegenerative disorders.

Atrial signal variations and pacemaker malsensing during exercise: a study in the time and frequency domain.

To give some explanation for atrial malsensing in dual chamber pacing that occurs only during exercise, atrial electrograms from 33 patients were telemetrically recorded and analyzed in both the time and frequency domains. During exercise, an overall decrease from 6.4 +/- 1.9 to 5.6 +/- 1.9 mV (-11%) in the atrial signal amplitude was noted. Despite considerable variability among patients, marked changes occurred in 15 patients whose signals diminished by 11 to 49%. Slew rates showed a similar decrease from 1.35 +/- 0.45 to 1.18 +/- 0.45 V/s (-10.8%), with individual changes of as much as -51%. Signal attenuation in the time domain correlated well with frequency data, exhibiting a highly significant reduction of signal energy between 25 and 105 Hz. However, spectral distribution changed from rest to exercise, with a relative increase of signal energy in the range between 5 and 25 Hz and a decrease at higher frequencies. Individual changes differed widely when low (15 to 65 Hz) and high (65 to 115 Hz) frequencies were compared, but in a group of 11 patients signal attenuation in the high frequency band was more pronounced (-45%) than in the low frequency band (-23%). The clinical impact of the change in frequency distribution during ergometry was visualized by computer simulation of two different (low and high bandpass) filters. Although in individual patients, both characteristics may be favorable with respect to atrial sensing, it was observed in 11 patients that high pass filtering attenuates signal amplitudes by 10 to 24% in excess of the variation without filtering.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of right ventricular stimulation site on left ventricular function in atrial synchronous ventricular pacing.

OBJECTIVES: The study investigates the correlation between left ventricular function and QRS duration obtained by alternate right ventricular pacing sites. BACKGROUND: 1. Right ventricular apical pacing is associated with alterations of left ventricular contraction sequence. 2. A stimulation producing narrow QRS complexes is supposed to provide for better left ventricular contraction patterns. METHODS: Fourteen patients with third degree AV block received one ventricular pacing lead in apical position. The alternate lead was attached to that site on the septum that produced the smallest QRS complex as measured from the earliest to the last deflection in any of the orthogonal Frank leads (xyz). During atrial synchronous ventricular pacing, the AV delay was optimized individually and for each stimulation site using mitral valve doppler or impedance cardiography. By radionuclide ventriculography, the phase distribution histogram of left ventricular contraction was evaluated as area under the curve (AuC); systolic function was determined as ejection fraction (EF) and as absolute ejected counts (EC) in random order. The difference (delta) in QRS duration between apical and septal stimulation (deltaxyz) was correlated with the difference in phase distribution (deltaAuC) and ejection parameters (deltaEF, deltaEC). RESULTS: QRS duration was shorter with septal than with apical pacing in 9 out of 14 patients (64%); it was longer in 4 (29%), and no difference was seen in 1 patient. There was a significant positive correlation between the change in QRS duration (deltaxvz) and phase distribution (deltaAuC: r = 0.66393, p = 0.010) and a significant negative correlation to systolic function (deltaEF: r = 0.70931, p = 0.004; deltaEC: r = 0.74368, p = 0.002). CONCLUSIONS: In atrial synchronous right ventricular pacing, if the AV delay is adapted individually, decreased QRS duration obtained by alternate pacing sites is significantly correlated with homogenization of left ventricular contraction and with increased systolic function in acute tests.

Optimised function for determining time to peak creatine kinase and creatine kinase-MB as non-invasive reperfusion indicators after thrombolytic therapy in acute myocardial infarction.

STUDY OBJECTIVE: The aim of the study was to investigate the use of an optimised function to approximate and interpolate the time course of serum creatine kinase and creatine kinase-MB values after thrombolytic therapy in acute myocardial infarction. DESIGN: A three parameter interpolating function was developed which approximates the time course of serum enzyme levels. In the proposed function, time to peak creatine kinase and maximum of creatine kinase determined from raw data were used as starting parameters of the non-linear interpolation routine, thus providing ideal starting conditions for the iteration. The efficacy of the function was compared with that of three other functions cited in published reports (log-normal distribution function, modified gamma density function, three compartment function). SUBJECTS: Serum enzyme data from 20 patients with acute myocardial infarction were used in the comparisons. The patients have all been treated with anisoylated plasminogen streptokinase activator complex. RESULTS: In comparison with the other models, deviations of the experimental model function from the raw data were minimal. The fit remained stable for time intervals between blood samples of up to 6 h. CONCLUSIONS - Due to its numerical stability, the function outlined in this study is suitable for large clinical reperfusion trials. In the case of uncomplicated infarctions without thrombolytic therapy, the area under the creatine kinase activity curve could be directly calculated in terms of maximum activity and time to peak.

Factor VIII: C (FVIII: C) recovery and half-life after infusion of steam-treated high purity factor VIII concentrate in severe hemophilia A--comparison of one-stage assay, two-stage assay and a chromogenic substrate assay.

Factor VIII:C recovery and half-life was measured in 16 hemophilia A patients under comprehensively standardized conditions. Each patient received the same lot of a steam-treated high purity FVIII concentrate at a dose of 19-33 U/kg body weight. A comparison was made between the one-stage assay, the two-stage assay and a chromogenic substrate test for FVIII:C determination using a FXa-sensitive chromogenic substrate. Factor VIII:C potency of the administered FVIII concentrate was measured using calibration curves derived from a concentrate standard and FVIII:C plasma levels were read from calibration curves derived from a plasma standard. The chromogenic assay showed a good reproducibility at FVIII:C levels between 0.015 and 0.50 U/ml. The FVIII:C recoveries calculated from the results of the one-stage assay, the two-stage assay and the chromogenic substrate test were 109 +/- 20, 92 +/- 14 and 81 +/- 11% (mean +/- SD), respectively. The elimination half-lives of FVIII:C were calculated by non-linear least square analysis using a modified computerized Gauss-Newton algorithm. The half-lives calculated from the FVIII:C plasma levels measured by the one-stage assay, the two-stage assay and the chromogenic test were 23.8 +/- 6.4, 22.2 +/- 5.7 and 17.1 +/- 4.8 h (mean +/- SD), respectively. No previous study has reported such long half-life values. Our findings indicate that measurements of recoveries and half-lives by the chromogenic FVIII:C assay and by computerized non-linear least square analysis allow the possibility of individualized FVIII replacement therapy.

Neutrophil adhesion and activation during systemic thrombolysis in acute myocardial infarction.

In a pilot study, alterations of polymorphonuclear neutrophil function during systemic thrombolysis in acute myocardial infarction have been investigated in humans. The following parameters of neutrophil function were measured before and at 15 and 45 minutes after initiation of systemic thrombolysis with a recombinant tissue-type plasminogen activator in 20 patients with acute myocardial infarction: (1) neutrophil adhesion and (2) neutrophil activation. During systemic thrombolysis a significant decrease was observed in neutrophil adhesion (5.5+/-6.4 to 3.2+/-3.3; p<0.05), in phagocyting neutrophil activation (39+/-18 to 25+/-14%; p<0.05), and in resting neutrophil activation (9+/-7 to 3+/-4%; p<0.05). Successful reperfusion coincided with a significantly higher reduction of phagocyting neutrophil activation (40+/-14 to 20+/-12% vs. 39+/-24 to 26+/-19% in unsuccessful reperfusion; p<0.05), and of neutrophil adhesion (6.2+/-5.7 to 2.7+/-3.0 vs. 4.1+/-3.8 to 3.5+/-4.0 in unsuccessful reperfusion; p<0.05) during thrombolysis. Systemic thrombolysis in acute myocardial infarction is accompanied by a reduction in neutrophil adhesion and activation dependent on thrombolytic success.

Modern strategies for treatment of acute myocardial infarction: significance of haemostaseological and rheological findings.

In spite of equivalent clinical efficacy of various thrombolytic agents for the treatment of acute myocardial infarction there is evidence of different drug-depending influences on the haemostatic and fibrinolytic system. In the present study 40 patients with acute myocardial infarction have been investigated. 20 patients received 750,000 and 1.5 mio U streptokinase (SK), respectively, 10 patients 30 mg anisoylated plasminogen streptokinase activator complex (BRL 26921) and 10 patients a combination of 200,000 U urokinase (UK) and 4.5 mio U pro-urokinase (PUK) as a short-term intravenous treatment. Reperfusion of coronary arteries has been achieved in 70 to 100 percent. Major not fatal bleedings occurred in 2 patients. One patient died within 72 hours after beginning of the myocardial infarction. The longest duration of fibrinolytic activity was observed in the BRL 26921 group (half-disappearance time close to 2 h). It was significantly shorter in the SK groups showing a dose-dependency. Plasma concentration of fibrinogen dropped beyond normal levels following SK and BRL 26921, but not under UK/PUK. Plasma viscosity correlated with fibrinogen decrease and displayed a dose-depending relationship with the presence of SK. Haemorheological effects are suggested to be important for the clinical efficacy of thrombolytic therapy in myocardial infarction.

Influence of neutrophil separation on the expression of adhesion molecules.

In many assays of polymorphonuclear neutrophil (PMN) function the first step is separation of PMN from whole blood. In the present investigation it was examined if PMN separation leads to an altered expression of neutrophil surface membrane adhesion molecules. Samples have been taken from 20 healthy volunteers (10 male, 10 female; 39.7 +/- 11.8 years of age). PMN activation was measured cytometrically using the following antibodies against PMN surface membrane receptors: L-selectin (CD 62 L), beta-2-integrin Mac-1 (CD 11b) and Intercellular Adhesion Molecule 1 (CD54). PMN activation was determined in whole blood and after separation of PMN using density gradients. After PMN separation all three adhesion molecules appeared increased but the effect was only statistically significant for CD 54 (Wilcoxon test). Data (mean fluorescence intensity in arbitrary units) were: CD 62 L: 62 +/- 37 in whole blood, 82 +/- 28 after separation; p = 0.0674, CD 11b: 94 +/- 55 in whole blood, 111 +/- 47 after separation; p = 0.1454, CD 54; 13 +/- 12 in whole blood, 81 +/- 35 after separation; p < 0.0001. With the present data available it can be assumed that separation of PMN from whole blood can influence the results of flow cytometric assays.

Threshold and polarization properties of modern active fixation atrial leads.

The purpose of the study was to compare the stimulation characteristics of two modern active fixation leads (Ela 583F, vitreous carbon tip [ELA] and Intermedics 82-0008-1601, iridium oxide tip [IROX]) with a standard lead (Osypka KY 67 VC, carbon-covered elgiloy tip [OSY]). In three groups of ten patients each, minimum charge threshold delta Qmin and polarization properties were determined via charge telemetry of the pacemaker (Intermedics Cosmos II and Relay) 0, 2, 5, 10, 28, 90, and 180 days after implant (dai). The polarization parameters global capacitance Cg, global resistance Rg, polarization voltage U(p), and a time constant t* (t* = Cg.Rg) were obtained by nonlinear regression. U(p) was always significantly (sig) lower in ELA and IROX (0.04-0.10 V) compared to OSY (0.54-0.76 V). Rg was sig lower in ELA (330-437 omega) compared to OSY and IROX (414-588 omega) from 0 to 28 dai. From 2 to 10 dai, Cg was sig higher in ELA and IROX (3.8-4.2 microF) compared to OSY (3.3-3.4 microF). In the three groups, delta Qmin reached a comparable maximum (1-1.2 microC) at 5 dai. Therefore, vitreous carbon and iridium oxide atrial fixation leads exhibit low chronic polarization effects compared to a standard elgiloy lead, but do not show a sig reduction in charge threshold.

Atrial sensing performance of AV universal pacemakers during exercise.

To investigate the atrial sensing function of dual chamber pacemakers during exercise, we studied 57 patients aged 12 to 81 years (m = 65). They were paced for sinoatrial disorders (n = 15), second or third degree AV block (n = 37), or binodal disease (n = 11). The examination was performed 3-24 months (m = 11) after pacemaker implantation. Individual sensing thresholds were determined at rest in the supine position, and proper detection of atrial signals at the programmed sensitivity level was verified during a period of 5-9 minutes (m = 5.8). Without a change in the program of the unit, symptom-limited bicycle ergometry was performed at a maximum load of 25-200 Watts (m = 95) and 6-channel chest wall electrocardiograms were continuously recorded throughout the test, including recovery. During exercise, 25/57 patients (44%) exhibited poor atrial sensing of the pulse generator; after termination of exercise in 16 of the 25 patients, proper atrial sensing resumed within 1 to 7 minutes of recovery. In the remaining nine cases, ergometry was continued after lowering the sensitivity threshold to half the initial setting or, depending on the pacemaker model, by a value of 0.4 mV. This resulted in normal function of the pulse generator in all patients but one, who needed a sensitivity adjustment of another 0.4 mV. In a subgroup of 25 patients, telemetric atrial electrogram recordings were monitored during ergometry, 19 of which could be evaluated quantitatively. Besides random atrial signal variations, presumably due to ectopic beats or runs, a systematic decrease of the peak-to-peak amplitude by 0.1 to 1.6 mV (3-30%) was observed in 16/19 patients during exercise. Mean signal reduction amounted to 11.8% and was statistically significant at the 0.1% level. It is concluded from these findings that, besides testing of atrial sensing at rest, the follow-up of dual chamber pacemakers should include an exercise test.