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Intravenous diltiazem was administered to 10 pediatric patients with primary atrial tachyarrhythmias with rapid ventricular response. Rapid, consistent, and safe temporary ventricular rate control was obtained in all patients given this medication.
A simplified method was established for cryopreservation of peripheral blood stem cells (PBSCs) using hydroxyethyl starch (HES) and dimethylsulfoxide (DMSO) as a cryoprotective agent at -80 degrees C without rate-controlled freezing. The data indicate that a cryoprotective solution consisting of 6% HES and 5% DMSO produced the highest recovery rates for nucleated cells (92.0 +/- 3.5%), CFU-GM (73.8 +/- 4.1%) and BFU-E (82.2 +/- 6.9%), and the highest trypan blue viability (88.4 +/- 3.6%). For long-term cryopreservation of PBSCs, CFU-GM recovery rates remained almost unchanged during 5-18 months; the mean CFU-GM recovery rate after 18 months of cryopreservation was 70 +/- 11%. When large-scale samples of PBSCs in 100-ml freezing bags were cryopreserved for clinical use, cell and CFU-GM recoveries were similar. Using this method, 10 patients with hematological malignancy received PBSC transplants after marrow-ablative chemotherapy. All demonstrated early engraftment; seven are now alive in unmaintained complete remission for 3.5-15 months after PBSC transplant. This simple and inexpensive method will be useful for the wider application of PBSC transplant as a therapeutic alternative in the treatment of malignant diseases.
The rate of binding a fairly large ligand molecule to a protein is reduced below the usual diffusion-controlled rate by the requirement of a certain rotational orientation. A simple, approximate treatment of this effect is given for special cases of spherical and ellipsoidal ligands. As the center of an ellipsoidal ligand approaches a protein surface, there is an effective repulsive potential between ligand and surface owning to restricted rotation of the ligand. The frequency factor kT/h of the Eyring rate theory is replaced in these reactions involving diffusion in solution by D/Rlambda, where D = diffusion coefficient of ligand, lambda = thermal deBroglie wavelength of ligand, and R = "capture" distance around the binding site on the protein.
BACKGROUND: The need for new treatment strategies for cardiac arrhythmias has motivated our continuing development of gene therapeutic options. Previously, we reported a decreased heart rate in an acute model of atrial fibrillation after atrioventricular nodal gene transfer. Here, we expand those observations to persistent atrial fibrillation and severe heart failure. METHODS AND RESULTS: After 3 weeks of atrial fibrillation, domestic swine received atrioventricular nodal gene transfer with adenoviruses encoding beta-galactosidase (beta-gal), wild-type Galpha(i2) (wtGi), or constitutively active mutant (cGi). Heart rates in awake, alert animals were not altered by beta-gal or wtGi. cGi caused a sustained 15% to 25% decrease in heart rate. The wtGi effect became evident with sedation. A tachycardia-induced cardiomyopathy was present before gene transfer. In the beta-gal group, cardiomyopathy worsened over time. In the wtGi group, the condition improved slightly, and in the cGi group, ejection fraction was near normal at the end of the study. TUNEL staining results corroborated this finding. CONCLUSIONS: cGi overexpression in the porcine atrioventricular node causes physiologically relevant heart rate control in persistent atrial fibrillation. These data advance the development of gene therapy as a potential treatment for common cardiac arrhythmias.
The dromotropic pacemaker concept needs a rate responsive algorithm in which the pacing rate is controlled by the atrioventricular conduction time (AVCT). To develop basic concepts for such a rate responsive algorithm, the influence of the pacing rate on the AVCT was investigated. Seven patients (62 +/- 7.8 years) with sick sinus syndrome and intact atrioventricular conduction underwent two cardiopulmonary exercise tests (CPX) on a treadmill. According to the determination of the anaerobic threshold (AT) and the patients maximum capacity in the first incremental CPX the work rate for two exercise levels below and above the AT were chosen for the second constant workload CPX. The calculation of the optimal pacing rate (HRopt) was based on the oxygen uptake (VO2) during exercise after reaching steady-state conditions. According to the increase of the VO2 from 14.8 +/- 2.3 mL/min per kilogram during aerobic work (38.3 +/- 16.0 W) to 19.4 +/- 4.7 mL/min per kilogram during anaerobic work (80.6 +/- 32.3 W), the HRopt was calculated to be 98.6 +/- 6.9 beats/min and 116.4 +/- 4.7 beats/min. Starting from HRopt, the pacing rate was increased (overpacing) and decreased (underpacing) by about 5 beats/min every minute. At optimal pacing rate the AVCT decreased significantly from 233.0 +/- 30.5 ms during aerobic work and to 226.4 +/- 27.3 ms during anaerobic work (P < 0.05). Whereas overpacing induced a significant prolongation of the AVCT during aerobic work (4.17 +/- 1.78 ms per 10 beats/min) and anaerobic work (3.84 +/- 1.60 ms per 10 beats/min), underpacing yielded a significant shortening of the AVCT by about 4.49 +/- 2.64 ms per 10 beats/min during aerobic work and 4.75 +/- 1.87 ms per 10 beats/min during anaerobic work (P < 0.01). The slopes of the regression lines of the relationship between AVCT and pacing rate were not significantly. different. Based on the reciprocal relationship of heart rate (HR) and AVCT, basic concepts may be established for a dromotropic rate responsive algorithm.
This study compared variation in the quality of cryopreserved boar spermatozoa and the control and accuracy of cooling rates between three semen freezers (CryoLogic Freeze Control CL3000, Planer Products Kryo Save Compact KS1.7/Kryo 10 Control module and a controlled rate 'Watson' freezing machine developed within our laboratory). Five ejaculates were collected from each of 15 boars (five boars from each of three breeds). Semen was diluted into a commercial freezing buffer (700 mOsm/kg, 3% v/v glycerol) and placed into 0.5 ml straws. Three straws per treatment, from each ejaculate were cooled to -5 degrees C at 6 degrees C/min, held at -5 degrees C for 30s while ice crystal formation was induced, then further cooled from -5 to 80 degrees C at either 40 degrees C/min (Kryo Save Compact KS1.7 and Watson) or 6 degrees C/min (Freeze Control CL3000). Precise measurements of temperature fluctuations during the programmed cooling curves were made by inserting thermocouples into the semen filled straws. Semen was assessed for %motile cells, motility characteristics using computer-assisted semen analysis (CASA), plasma membrane integrity (%SYBR-14 positive stained spermatozoa) and acrosome integrity (%FITC-PNA positive stained spermatozoa). Spermatozoa cryopreserved using the Freeze Control CL3000 system (maximum rate of 6 degrees C/min) exhibited reduced post-thaw viability (14.2+/-2.8% mean plasma membrane intact spermatozoa) when compared to both the KS1.7 and Watson freezers (optimal rate of 40 degrees C/min) (18.4+/-3.2 and 25.7+/-3.7% mean plasma membrane intact spermatozoa, respectively). Differences in motility characteristics were observed between spermatozoa cryopreserved at 40 degrees C/min with the Watson apparatus preserving a larger proportion of sperm with progressive motility. Cooling curves in the CL3000 and KS1.7 were interrupted by a pronounced increase in temperature at -5 degrees C that corresponded with the latent heat of fusion released with ice crystal formation. This temperature change was significantly reduced in the cooling curves produced by the Watson freezer. These findings suggest that preserving spermatozoa using the Watson freezer improved post-thaw semen quality, with regard to sperm motility characteristics. Furthermore, that post-thaw semen viability was enhanced by minimising temperature fluctuations resulting from the release of the latent heat of fusion at ice crystal formation.
We propose herein an improved microfluidic system for continuous and precise particle separation. We have previously proposed a method for particle separation called "pinched flow fractionation." Using the previously reported method, particles can be continuously separated according to differences in their diameters, simply by introducing liquid flows with and without particles into a specific microchannel structure. In this study, we incorporated PDMS membrane microvalves for flow rate control into the microfluidic device to improve the separation accuracy. By adjusting the flow rates distributed to each outlet, target particles could be precisely collected from the desired outlet. We succeeded in separating micron and submicron-size polymer particles. This method can be used widely for continuous and precise separation of various kinds of particles, and can function as an important part of microfluidic systems.
Because of the relatively poor intestinal absorption of ampicillin sodium, efforts have been made to enhance ampicillin absorption by co-administration of absorption promoters. In the present study the enhancing effect of sodium decanoate on rate and extent of rectal ampicillin absorption in rats has been evaluated after rate-controlled and site-controlled delivery of aqueous solutions. Rectal absorption without enhancer was extremely low (8 +/- 7%), and the addition of 0.032 M sodium decanoate gave comparable values. However, administration in 0.16 M decanoate considerably increased ampicillin bioavailability, to 79 +/- 30%, whereas the absorption rate was not significantly affected.
OBJECTIVES: We compared the effects of five pharmacologic regimens on the circadian rhythm and exercise-induced changes of ventricular rate (VR) in patients with chronic atrial fibrillation (CAF). BACKGROUND: Systematic comparison of standardized drug regimens on 24 h VR control in CAF have not been reported. METHODS: In 12 patients (11 male, 69+/-6 yr) with CAF, the effects on VR by 5 standardized daily regimens: 1) 0.25 mg digoxin, 2) 240 mg diltiazem-CD, 3) 50 mg atenolol, 4) 0.25 mg digoxin + 240 mg diltiazem-CD, and 5) 0.25 mg digoxin + 50 mg atenolol; were studied after 2 week treatment assigned in random order. The VR data were analyzed by ANOVA with repeated measures. The circadian phase differences were evaluated by cosinor analysis. RESULTS: The 24-h mean (+/-SD) values of VR (bpm) were - digoxin: 78.9 +/- 16.3, diltiazem: 80.0+/-15.5, atenolol: 75.9+/-11.7, digoxin + diltiazem: 67.3+/-14.1 and digoxin + atenolol: 65.0+/-9.4. Circadian patterns were significant in each treatment group (p < 0.001). The VR on digoxin + atenolol was significantly lower than that on digoxin (p < 0.0001), diltiazem (p < 0.0002) and atenolol (p < 0.001). The time of peak VR on Holter was significantly delayed with regimens 3 and 5 which included atenolol (p < 0.03). During exercise, digoxin and digoxin + atenolol treatments resulted in the highest and lowest mean VR respectively. The exercise Time-VR plots of all groups were nearly parallel (p = ns). The exercise duration was similar in all treatment groups (p = ns). CONCLUSIONS: This study indicates that digoxin and diltiazem, as single agents at the doses tested, are least effective for controlling ventricular rate in atrial fibrillation during daily activity. Digoxin + atenolol produced the most effective rate control reflecting a synergistic effect on the AV node. The data provides a basis for testing the effects of chronic suppression of diurnal fluctuations of VR on left atrial and ventricular function in CAF.
Human therapeutic levels of valproic acid (VPA) and phenobarbital (PB) could be maintained in the mouse for a period of one week by controlled rate application (CRA) via subcutaneously implanted osmotic minipumps. PB-levels dropped markedly during one week of application, possibly by autoinduction. The interaction of PB and VPA was investigated by CRA of a mixture of both drugs. PB-levels were increased by VPA, probably due to enzyme inhibition, while VPA-levels were decreased by PB, probably by enzyme induction. Our results indicate tha CRA of drugs such as VPA and PB via implantable osmotic minipumps may be a valuable procedure for drug interaction studies during steady-state conditions.
Radiofrequency catheter ablation or modification of the atrio-ventricular junction is an effective therapy of drug refractory supraventricular tachyarrhythmias (ST). Higher endothelin (ET) levels were observed during nonsustained STs. We aimed to examine the effect of sustained STs and the applied rate-control therapy on plasma ET levels. Twenty-two patients (12 men; mean age, 64.4 +/- 13.2 years; ejection fraction, 41.8 +/- 11.2%; New York Heart Association (NYHA) class I: 3 cases, NYHA II: 11 cases, and NYHA III: 8 cases) suffering of atrial fibrillation (n = 11), atrial flutter (n = 7), atrial paroxysmal tachycardia (n = 3), or sinus tachycardia (n = 1) were studied, having coronary artery disease (n = 8), dilative cardiomyopathy (n = 5), or no underlying diseases (n = 9). All groups went under catheter ablation (same protocol, duration: 35 +/- 10.3 mins; rate before ablation, 100-170/min in every case; after ablation, 70-80/min in Groups I and II and 70-90/min in Group III). A pacemaker (PM) was implanted 2 months before ablation in Group I (n = 9) and during ablation in Group II (n = 7). No PM was implanted in Group III (n = 6). A control group (n = 13; 7 men; mean age, 66.15 +/- 6.7 years) with sinus rhythm got a PM without ST and ablation. Blood samples were collected from the cubital vein immediately before (control), and 5 mins and 24 hrs after ablation. Plasma ET-1 and big ET-1 levels were measured after immunoprecipitation with Western blot analysis. There were no differences between plasma ET-1 levels in the ST groups and the control group (Groups I, II, and III vs. control group: 0.66 +/- 0.04 fmol/ml, 0.93 +/- 0.12 fmol/ml, and 0.68 +/- 0.05 fmol/ml vs. 0.50 +/- 0.05 fmol/ml, respectively; P < 0.05). Comparing the control, 5-min, and 24-hr samples, ET-1 levels decreased significantly after supraventricular tachycardia ablation in Groups I and III (control vs. Group I, 5 mins and 24 hrs: 0.66 +/- 0.04 fmol/ml vs. 0.50 +/- 0.04 fmol/ml and 0.29 +/- 0.05 fmol/ml; control vs. Group III, 24 hrs: 0.68 +/- 0.05 vs. 0.34 +/- 0.05 fmol/ml; P < 0.05). No plasma big ET-1 changes were measured in any of the groups. The rapid decrease of ET levels after catheter ablation suggests that a high ventricular rate can be a trigger of ET production. PM implantation procedure seems to interfere with the ET decrease in ST patients.
In studies to ascertain the basis of dynamic changes in the P wave, bipolar epicardial potentials were recorded from multiple atrial electrodes in dogs. One hundred to 120 activation times were displayed by a digital computer and used to construct atrial isotemporal activation sequence maps. Changes in heart rate or beat-to-beat cycle length were induced by vagal stimulation or infusion of autonomic mediating drugs. Changes in cycle length were associated with dynamic changes in the atrial activation sequence and surface P-wave. A conspicuous finding was that epicardial atrial depolarization began at three widely separated locations. These three points were consistently present in all animals and were generally located at the 12, 3, and 6 o'clock positions of the superior vena cava-right atrial junction. The dynamic changes in P waves and atrial activation sequence which accompanied the changes in cycle length were due to sudden shifts in the point of earliest activity between the three early sites. Asymmetric atrial depolarization with more rapid conduction along the crista terminalis, superior interatrial band, and pectinate muscles was present in all dogs. Although the anisotropic atrial geometry played an important role in the asymmetric conduction, the widely distributed onset of activity contributed significantly to the uneven spread. The multiple points of origin of the atrial wavefront might be explained by either a trifocal, distributed pacemaker or the epicardial exits of three specialized pathways conducting an impulse emanating from a single focus. These data explain the dynamic variation in P-wave morphology in normal hearts and also imply a relationship between the altered origin of atrial depolarization, atypical P waves, brady- or tachyarrhythmias, and heart rate control.
RATIONALE AND OBJECTIVES: Gross-total surgery under intraoperative magnetic resonance imaging (MRI) is a promising method of glioma removal. The purpose of this article is intraoperative measurement of resected tumor volume in MRI-guided glioma surgery using semiautomatic image segmentation to unbiased resection rate control. MATERIALS AND METHODS: A newly developed software program based on a fuzzy connectedness (FC) segmentation algorithm was used to achieve fast and semiautomatic tumor segmentation and tumor volume measurement. The program was validated by retrospective study of eight glioma cases and then applied to seven glioma cases. All clinical cases underwent actual MRI-guided surgery using 0.3-T open magnets. RESULTS: The volume of the tumor before resection ranged from 10.1 to 206.7 mL. A comparison of the results of manual segmentation with those of the semiautomatic FC-based segmentation gave an average dice similarity coefficient of 0.80 and an average match of 76%. Volume measurement combined with a developed software program enabled quantitative monitoring of tumor removal, which was critical in the near-total resection of glioma in MRI-guided surgery. CONCLUSION: The FC-based tumor segmentation method can be used for intraoperative tumor segmentation and volume measurement in MRI-guided glioma surgery using 0.3-T open magnets. This method is useful for objective resection rate monitoring, which may ultimately minimize the amount of residual tumor in glioma surgery.
True physiologic pacing is only feasible in patients with heart block and normal sinus rhythm using atrial synchronized pacing. In sick sinus syndrome (SSS) or atrial fibrillation no adequate sensing possibility is present. For these conditions something other than electrical signals must be found to guide rate control. In clinical experiments a thermistor integrated in a bipolar pacing lead was implanted in one of the authors as well as in a pacemaker patient. Treadmill tests at 3, 6, and 10 km per hour have shown no substantial increase of the central venous temperature (CVT) in the lower effort range; an increase of 0.6-0.75 degrees Celsius (degrees C) in the medium range; and an increase of 1.35 degrees C in the higher range, respectively. External pacing in the author, or rate variations by programming the VVI, M unit in the patient at rest do not influence CVT. CVT correlates well in the medium-range group, which mostly reflects the capabilities of the average pacemaker patient. In the higher effort range a delay between rate increase and increase of CVT is noticed. There is no increase in CVT beyond the physiologic variations in the lower effort range.
Presynaptic neural projections are thought to participate in the maturation of postsynaptic sensitivity to neurotransmitters. In the current study, we have examined the effects of sympathectomy with 6-hydroxydopamine on the ontogeny of the linkage of beta-adrenergic receptors to cardiac growth and heart rate control in the rat. Destruction of sympathetic projections at birth compromised the ability of beta-receptor stimulation to evoke cardiac hypertrophy, a defect which persisted into young adulthood. The chronotropic response to beta-receptor activation, assessed by acute challenge with a submaximally-effective dose of isoproterenol, also exhibited a slowed development, but did eventually achieve normal sensitivity. In contrast, neonatal sympathectomy had only minor effects on resting heart rate, basal heart rate (the intrinsic rate in the absence of autonomic input) or maximal heart rate; these animals also showed beta-receptor desensitization of chronotropic action in response to chronic isoproterenol treatment. Chronic isoproterenol treatment itself lowered the basal heart rate, regardless of whether animals were normal or sympathectomized. Thus, during critical developmental periods, sympathetic input to beta-receptors selectively programmes the linkage between postsynaptic receptors, tissue growth and heart rate.
The feasibility of transdermal controlled delivery system of 17beta-estradiol was investigated by conducting in vitro release studies. Several new 17beta-estradiol unilaminate adhesive devices capable of releasing 17beta-estradiol in a controlled fashion over a 24-h, 36-h, 96-h, 104-h, 168-h, and 216-h period have been developed using acrylic resins (Eudragits E100, RSPO, and RLPO) as adhesive and rate-controlling polymers. The in vitro release profiles of 17beta-estradiol from various TDS unilaminate devices were characterized in a new developed dissolution tester vessel (total volume 200 ml), using a new paddle. The release of drug from different formulations was measured by a sensitive high-performance liquid chromatographic (HPLC) method. The release of drug from all prepared adhesive devices seems to obey zero-order kinetics (r > 0.98). The effect of two different plasticizers (acetyltriburyl citrate [ATBC] and triethyl citrate [TEC]) on the release patterns of 17beta-estradiol from TDS formulations was studied, and they were almost identical. The effect of two different release modifiers, propylene glycol (PG) and myristic acid (MA), on the release pattern of 17beta-estradiol from prepared unilaminate devices was evaluated. It was shown that the use of these release modifiers significantly increased the release of 17beta-estradiol from a TDS unilaminate patch. Furthermore, these data clearly demonstrated that the acrylic resins are suitable polymers for the preparation of 17beta-estradiol TDS adhesive devices.
Prazosin (PRZ) in conventional tablet form (P-CT) has the disadvantages of a relatively short terminal half-life, a slight solubility in water and the well-recognized adverse effect of symptomatic orthostatic hypotension. The pharmacokinetic study of a new rate-controlled formulation of prazosin (Prazosin-Gastrointestinal System: P-GS) was performed in 9 pregnant women during the third trimester of pregnancy. Patients had persistent elevation of blood pressure. The subjects gave their informed consent for oral administration of 1 daily dose of 5 mg P-GS at 8 a.m. A first analysis period on day 1 enabled definition of the initial pharmacokinetic behavior of the drug, while the aim of a second was to evaluate its fate at plateau. The clinical course of both mother and fetus was subsequently monitored. This was an open, non-randomized study, each patient serving as her own control. For 3 patients, we aimed to determine the possible transplacental passage of PRZ at delivery. PRZ levels were measured by HPLC and data were analysed by noncompartmental linear pharmacokinetic methods. The data show: (i) P-GS was well tolerated by all patients and there were no significant changes in fetal heart rate during the study. (ii) A significant decrease in diastolic blood pressure was observed after the 36th hour following the first dose of P-GS while a reduction in systolic blood pressure was observed on day 4. (iii) An approximated relative bioavailability (f'P-GS) of 36.5% was calculated. P-GS appears to have a lower bioavailability than P-CT in women of similar gestational age. (iv) Both Cmax and AUC0-->infinity are significantly increased at plateau. Further, terminal half-life is increased with regard to the value determined with P-CT. No accumulation of PRZ was noted at steady-state. (v) P-GS is an example of an oral zero-order absorption product that offers one approach to control and improve the outcome of hypertensive therapy during pregnancy. This treatment could represent an alternative to methyldopa as a first treatment of pregnancy-associated hypertension. (vi) There is a slight transplacental passage of the drug (of the order of 10-20%).
In chronic obstructive lung disease (asthma, chronic bronchitis, obstructive emphysema) there is a segmental reduction in the caliber of the airways, which always results in obstruction to air-flow. Increased airway resistance is a physiological expression of airway obstruction.The addition of inspiratory flow rate control to an intermittent positive pressure breathing device permits slow filling of a lung with obstructed airways, and is presented as a simple means of reducing the high pulmonary flow resistance and increasing the tidal volume.