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Impaired parasympathetic heart rate control in mice with a reduction of functional G protein betagamma-subunits.

Acetylcholine released on parasympathetic stimulation slows heart rate through activation of muscarinic receptors on the sinus nodal cells and subsequent opening of the atrial muscarinic potassium channel (K(ACh)). K(ACh) is directly activated by G protein betagamma-subunits. To elucidate the physiological role of Gbetagamma for the regulation of heart rate and electrophysiological function in vivo, we created transgenic mice with a reduced amount of membrane-bound Gbeta protein by overexpressing nonprenylated Ggamma(2)-subunits in their hearts using the alpha-myosin heavy chain promoter. At baseline and after muscarinic stimulation with carbachol, heart rate and heart rate variability were determined with electrocardiogram telemetry in conscious mice and in vivo intracardiac electrophysiological studies in anesthetized mice. Reduction of the amount of functional Gbetagamma protein by >50% caused a pronounced blunting of the carbachol-induced bradycardia as well as the increases in time- and frequency-domain indexes of heart rate variability and baroreflex sensitivity that were observed in wild types. In addition, sinus node recovery time and inducibility of atrial arrhythmias were reduced in transgenic mice. Our data demonstrate in vivo that Gbetagamma plays a crucial role for parasympathetic heart rate control, sinus node automaticity, and atrial arrhythmia vulnerability.

Animals↗

Growth rate control of adherent bacterial populations.

We report a novel in vitro method which, through application of appropriate nutrient limitations, enables growth rate control of adherent bacterial populations. Exponentially growing cells are collected by pressure filtration onto cellulose acetate membranes. Following inversion into the bases of modified fermentors, membranes and bacteria are perfused with fresh medium. Newly formed and loosely attached cells are eluted with spent medium. Steady-state conditions (dependent upon the medium flow rate) at which the adherent bacterial biomass is constant and proportional to the limiting nutrient concentrations are rapidly achieved, and within limits, the growth rate is proportional to the medium flow rate. Scanning electron microscopic studies showed that such populations consist of individual cells embedded within an extracellular polymer matrix.

Bacterial Adhesion↗

Lip-jaw and tongue-jaw coordination during rate-controlled syllable repetitions.

The present study investigated the relationship between functionally relevant compound gestures and single-articulator component movements of the jaw and the constrictors lower lip and tongue tip during rate-controlled syllable repetitions. In nine healthy speakers, the effects of speaking rate (3 vs 5 Hz), place of articulation, and vowel type during stop consonant-vowel repetitions (/pa/, /pi/, /ta/, /ti/) on the amplitude and peak velocity of differential jaw and constrictor opening-closing movements were measured by means of electromagnetic articulography. Rather than homogeneously scaled compound gestures, the results suggest distinct control mechanisms for the jaw and the constrictors. In particular, jaw amplitude was closely linked to vowel height during bilabial articulation, whereas the lower lip component amplitude turned out to be predominantly rate sensitive. However, the observed variability across subjects and conditions does not support the assumption that single-articulator gestures directly correspond to basic phonological units. The nonhomogeneous effects of speech rate on articulatory subsystem parameters indicate that single structures are differentially rate sensitive. On average, an increase in speech rate resulted in a more or less proportional increase of the steepness of peak velocity/amplitude scaling for jaw movements, whereas the constrictors were less rate sensitive in this respect. Negative covariation across repetitions between jaw and constrictor amplitudes has been considered an indicator of motor equivalence. Although significant in some cases, such a relationship was not consistently observed across subjects. Considering systematic sources of variability such as vowel height, speech rate, and subjects, jaw-constrictor amplitude correlations showed a nonhomogeneous pattern strongly depending on place of articulation.

Analysis of Variance↗

Evolution of heart rate control after transplantation: conduction versus autonomic innervation.

In cardiac transplantation, the donor organ is not initially innervated and demonstrates decreased heart rate variability (HRV). However, HRV may improve after several months. The mechanism for HRV improvement has not been elucidated; autonomic "reinnervation" of the donor heart has been proposed. The role of atrioatrial conduction from recipient to donor organ has not been evaluated. We prospectively evaluated cardiac transplant patients with a limited electrophysiology study at the time of their surveillance biopsies. Recordings were made of recipient and donor signals, observing conduction properties between recipient and donor atria. Holter recordings were analyzed and HRV was determined using spectral analysis techniques, recording mean RR interval, low-frequency power (LF), high-frequency power (HF), and the LF/HF ratio. These were compared to published norms. From November 1999 to May 2000, 21 patients (6 female) who underwent cardiac transplantation participated at a median age of 101 months (range, 4.1-217 months). Time posttransplant ranged from 26 days to 71 months. Holter data were available for 20 patients and demonstrated dissociated P waves in 13 (65%). The mean heart rate on Holter was 111 beats per minute (bpm) (range, 85-161 bpm). We were able to record distinct recipient atrial signals in 16 of 21 (76%) patients. The average recipient tissue heart rate was 55% that of the donor heart rate. We documented atrioatrial association in only 1 patient. HRV did not reach normal values for most patients and did not increase with time posttransplantation. The LF values were in the normal range for most patients, whereas 3 patients had normal HF values and 2 patients had values just below normal. Recipients of heart transplantation have a predominantly sympathetic influence of HRV. These preliminary data suggest that atrioatrial conduction does not play a role in reestablishing normal heart rate control following pediatric cardiac transplantation.

Adolescent↗

Update on Atrial Fibrillation: Restoration of Sinus Rhythm or Ventricular Rate Control?

In patients with persistent atrial fibrillation, two therapeutic alternatives exist, namely restoration and maintenance of sinus rhythm versus ventricular rate control combined with anticoagulation. Currently, the selection of the best therapeutic strategy in an individual patient relies for the most part on clinical judgement and personal experience. At present, there are no prospective scientific data to support the superiority of one treatment over the other with respect to overall survival or quality of life. This review summarizes the present knowledge on this important clinical problem with particular emphasis on issues such as efficacy of antiarrhythmic drugs to prevent recurrent atrial fibrillation, proarrhythmic hazards of these compounds, or efficacy and safety of anticoagulation in nonrheumatic atrial fibrillation. These data serve as the basis of ongoing clinical trials prospectively comparing the merits and demerits of the two therapeutic strategies in the most common arrhythmia encountered in clinical practice.

Journal Article↗

Atrial fibrillation: maintaining stability of sinus rhythm or ventricular rate control? The need for prospective data: the PIAF trial.

Atrial fibrillation is one of the most commonly encountered clinical arrhythmias. Different treatment options for this rhythm disorder exist with the electrical and/or pharmacological cardioversion to sinus rhythm with subsequent antiarrhythmic drug therapy to prevent recurrences being one of the primary therapeutic goals. Another alternative, however, is represented by the control of the ventricular rate in patients with persistent atrial fibrillation. The question of which these two strategies should be preferred in the majority of patients with atrial fibrillation has not been studied in a prospective way. Given the background of conflicting data with respect to the prognostic impact of atrial fibrillation and of the increasing evidence concerning the risks of antiarrhythmic drug treatment in atrial fibrillation, a prospective multicenter trial has been initiated to compare these two therapeutic alternatives prospectively. Patients will be randomly assigned to cardioversion with subsequent antiarrhythmic drug therapy to prevent recurrent atrial fibrillation or to a therapy aiming exclusively at control of the ventricular rate during persistent atrial fibrillation. All patients will receive anticoagulation by means of warfarin (target INR 2.5-3.5) to prevent thromboembolic complications. The rationale and the design of the PIAF trial (Pharmacological intervention in Atrial Fibrillation) are discussed below. The pilot phase of this study has begun patient enrollment in the spring of 1995.

Adolescent↗

Long-term hematologic reconstitution after autologous peripheral blood progenitor cell transplantation: a comparison between controlled-rate freezing and uncontrolled-rate freezing at 80 degrees C.

BACKGROUND: The most widely used system for peripheral blood progenitor cell (PBPC) cryopreservation is controlled-rate freezing (CRF). Uncontrolled-rate freezing (URF) at -80 degrees C has also been used, but its clinical impact has not been studied sufficiently yet. STUDY DESIGN AND METHODS: Two groups of patients were compared: Group A consisted of 69 patients autotransplanted with PBPCs cryopreserved with CRF; Group B consisted of 192 patients autotransplanted with PBPCs cryopreserved with URF at -80 degrees C. The same cryoprotectant solution and storage system were used. RESULTS: A significant delay of hematologic reconstitution (HR) in the URF group was observed for neutrophils greater than 0.5 x 10(9) per L and for platelets greater than 20 x 10(9) per L and greater than 50 x 10(9) per L; we did not observe any differences in the clinical course. The long-term HR was comparable in the two groups, all patients showed stable engraftment, and no late graft failures were observed. CONCLUSION: Our study confirms that URF is safe and allows sustained long-term engraftment without increasing the risks of transplantation, even though the early engraftment after URF is slower.

Adolescent↗

[Value of electrocardiographic treadmill test for rate control strategy in permanent atrial fibrillation].

AIM: of our study was to determine the correlation between physical activity tolerance assesed by exercise tolerance test (ETT) and dynamics of change of echocardiographic parameters of left atrium (LA) and left ventricle (LV) in standard transtoracic echocardiography (TTE) in long-term follow up of patients with persistent nonvalvular atrial fibrillation (AF). MATERIALS AND METHODS: We studied 67 patients (W/M: 23/44; mean age 63.2 +/- 7.1 years) with persistent AF lasting longer than 1 month. Rate control strategy targeted resting heart rate 70-90/min. All study subject underwent ETT in order to assess their exercise capacity. Before ETT we performed TTE in all patients and calculated the area of LA (LAar), longitudinal and saggital diameter of LA (LAlax, LAsax), LV end-diastolic diameter (LVEDD) and LV shortening fraction (FS). TTE was performed again in 2 and 12 months after beginning of observation. RESULTS: Using variation analysis we established the correlation between time of ETT in patients with persistent AF and dynamics of change of specific echocardiographic parameters in 12 months follow-up. In patients with ETT time <60 sec we observed statistically significant rise of LAar from 26.5 +/- 6.1 to 29.6 +/- 4.9 cm2 (p < 0.05; ANOVA) and deterioration of LV function assessed with FS from 35.6 +/- 5.3% on the beginning to 31.7 +/- 7.4% at the end of study (p < 0.02; ANOVA). There was no correlation between time of ETT and dynamics of change of other echocardiographic parameters in patients with time of ETT >60 sec. CONCLUSIONS: Time of exercise tolerance test limited with heart failure symptoms is an independent factor predicting dynamics of change of chosen echocardiographic parameters of left heart in long-term observation of patients with persistent atrial fibrillation.

Aged↗

Effect of conventional controlled-rate freezing and vitrification on morphology and metabolism of bovine blastocysts produced in vitro.

This study compares the effects of conventional controlled-rate freezing and vitrification on the morphology and metabolism of in vitro-produced bovine blastocysts. Day 7 expanded blastocysts cultured in synthetic oviduct fluid with 5% fetal calf serum were frozen in 1.36 M glycerol, 0.25 M sucrose or vitrified in 25% glycerol, 25% ethylene glycol. Cell alterations and in vitro development were evaluated immediately after thawing or after 72 h. The effect of cryopreservation on inner cell mass and trophectoderm (TE) cell number as well as glucose, pyruvate, and oxygen uptakes, and lactate release by blastocysts were evaluated. Immediately after thawing, blastocysts showed equivalent cell membrane permeabilization after both cryopreservation procedures, while alterations in nuclear staining were more frequent in vitrified embryos. After culture, similar survival and hatching rates were observed. Both procedures decreased cell number immediately after thawing and after 72 h. However, the number of TE cells was lower in frozen embryos than in vitrified ones. In relation to this, frozen blastocysts showed a decrease in glucose, pyruvate, and oxygen uptake, although those parameters were not altered in vitrified embryos. An increased glycolytic activity was also observed in frozen embryos, indicating a stress response to this procedure.

Animals↗

Learned heart-rate control by a patient with a ventricular parasystolic rhythm.

A 31-year-old woman with a ventricular parasystolic rhythm is described. The arrhythmia was always absent below a rate of 72 per minute, and always present over a rate of 106 per minute. Voluntary heart-rate control was learned using a biofeedback techinque, as a result of which she could increase her rate by 25 per minute and decrease it by 1-2 per minute. Both voluntary speeding and exercise brought on the arrhythmia, but later in the training she could reach a higher heart-rate before the arrhythmia appeared. Propranolol inhibited the arrhythmia only to the extent that is slowed the heart.

Adult↗

Disease-control rates following intensity-modulated radiation therapy for small primary oropharyngeal carcinoma.

BACKGROUND: The purpose of this study was to assess the ability of intensity-modulated radiation therapy (IMRT) to achieve favorable disease-control rates while minimizing parotid gland doses in patients treated for small primary tumors of the oropharynx. METHODS AND MATERIALS: We retrospectively identified all patients who received IMRT as treatment for a small (<4 cm) primary tumor of the oropharynx between October 2000 and June 2002. Tumor characteristics, IMRT parameters, and patient outcomes were assessed. RESULTS: Fifty-one patients met the criteria for our study. All patients had treatment to gross disease with margin (CTV1), and all but 1 had treatment to the bilateral necks. The most common treatment schedule (39 patients) was a once-daily fractionation of prescribed doses of 63-66 Gy to the CTV1 and 54 Gy to subclinical sites, delivered in 30 fractions. Twenty-one patients (40%) had gastrostomy tubes placed during therapy; in 4 patients, the tube remained in place for more than 6 months after completion of IMRT. The median follow-up was 45 months. The 2-year actuarial locoregional control, recurrence-free, and overall survival rates were 94%, 88%, and 94%, respectively. CONCLUSIONS: These preliminary data suggest that treatment with IMRT results in favorable locoregional control of small primary oropharynx tumors. IMRT did not appear to have a more favorable acute toxicity profile in this group with respect to the use of a feeding tube; however, the mean dose of radiation delivered to the parotid gland by IMRT was decreased, because 95% of patients had a mean dose of <30 Gy to at least one gland.

Adult↗

The use of a liquid-phase controlled rate freezing system for the successful cryopreservation of mouse pre-embryos.

OBJECTIVES: To investigate the ability of a liquid-phase, controlled-rate freezing machine to generate reproducible freezing gradients with a constant rate of change; temperature fluctuations and heat dissipation during seeding; to assess the viability of mouse pre-embryos exposed to the silicone liquid cooling phase and the rates of survival and viability of mouse pre-embryos cryopreserved using this system. DESIGN: Freezing gradients were generated from the bath or a sample and compared for reproducibility and slope. Temperature fluctuations and gradients around the freezing chamber and the temperature rises and dissipation during seeding were measured. The toxicity of the silicone polymer freezing-phase was tested with mouse pronuclear pre-embryos. Different developmental stages of mouse pre-embryos were frozen and thawed and survival recorded in vitro and in vivo. SETTING: Research Laboratories, Sinai Hospital of Baltimore, Baltimore, Maryland. MAIN OUTCOME MEASURES: The reproducibility of freezing gradients; temperature fluctuations during seeding; and the in vitro and in vivo viability of mouse pre-embryos exposed to the silicone polymer or frozen and thawed. RESULTS: The freezing gradients generated were constant and reproducible with a constant rate of change; no temperature differences were recorded around the freezing chamber; temperature changes at seeding are minimal and rapidly dispersed. The silicone polymer was nontoxic to mouse pre-embryos and mouse pre-embryos frozen with the system and subsequently thawed are viable both in vitro and in vivo. CONCLUSIONS: This liquid-phase cryopreservation system is an attractive option for assisted reproductive technologies laboratories because liquid nitrogen is not required for operation, it is reliable, there are small temperature fluctuations during seeding, and it can be kept constantly running.

Animals↗

Clinical review: clinical management of atrial fibrillation - rate control versus rhythm control.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in the critically ill and is associated with adverse outcomes. Although there are plausible benefits from conversion and maintenance of sinus rhythm (the so-called 'rhythm-control' strategy), recent randomized trials have failed to demonstrate the superiority of this approach over the rate-control strategy. Regardless of approach, continuous therapeutic anticoagulation is crucial for stroke prevention. This review addresses the findings of these studies and their implications for clinical management of patients with atrial fibrillation.

Anti-Arrhythmia Agents↗

Central venous blood temperature for rate control of physiological pacemakers.

In 17 pacemaker patients and 14 volunteers we studied the behaviour of central venous blood temperature and heart rate under different kinds of exercise. Data were recorded by means of 5F catheter placed at the right ventricle. Temperature was measured with a thermistor incorporated in the lead. We found the increase in central venous blood temperature to be dependent on the individual exercise capacity and work load performed. The maximum temperature increase seen was 1.7 degrees Celsius. Subjects with lower physical fitness showed a more pronounced increase in temperature and heart rate compared to more physically fit subjects at the same work load. Due to its close relationship to metabolic and circulatory parameters, central venous blood temperature represents an appropriate signal to control the rate of physiological pacemaker systems. A special algorithm also using the initial dip for rate control has been incorporated into a pacemaker system, that is currently under clinical investigation (Intermedics NOVA MR).

Adult↗

Characterization of emulsified chitosan-PLGA matrices formed using controlled-rate freezing and lyophilization technique.

This study evaluated the formation of chitosan-50:50 poly-lactic-co-glycolic acid (PLGA) blend matrices using controlled-rate freezing and lyophilization technique (CRFLT). An emulsion system was used in the presence of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), a cellular component, as a stabilizer. Blended scaffolds showed an open pore morphology and homogenous interdispersion of PLGA and chitosan. Forming emulsions after dissolving PLGA in chloroform, benzene, or methylene chloride indicated better emulsion stability with benzene and chloroform. Scaffolds formed by freezing at -20, -78, and -196 degrees C from these emulsions showed significant influence of the solvent and freezing temperature on the microarchitecture of the scaffold. By controlling the concentration of chitosan, scaffolds with greater than 90% porosity were attained. Since the two polymers degrade by different mechanisms, formed scaffolds were analyzed for degradation characteristics for 4 weeks in presence of 10 mg/L lysozyme. These results showed no significant difference in the weight loss and dimension changes, as all scaffolds showed significant (a) weight loss and (b) nearly 60% reduction in volume. Further, pH of the incubation media decreased in all the samples. When cellular activity of green fluorescence protein-transfected smooth muscle cells was analyzed, no apparent cytotoxicity was observed. However, the cell spreading area decreased. In summary, these results show promising potential in tissue engineering and drug delivery applications.

Biocompatible Materials↗

The signal for growth rate control and stringent sensitivity in E. coli is not restricted to a particular sequence motif within the promoter region.

Hybrid promoter constructs were used to determine the DNA sequence requirements for stringent and growth rate control within a promoter region. The promoters were obtained by fusing complementing sequence regions located upstream and downstream from the GCGC discriminator motif of the growth rate regulated rRNA P1 promoter and a non-regulated tac promoter variant. The activities and the regulatory response of the hybrid promoters were determined in vivo using a promoter test vector system with the chloramphenicol acetyltransferase (CAT) reporter gene. Measurements were made at different growth rates and after starvation for isoleucine to induce the stringent response. Neither the upstream nor the downstream sequence of P1 relative to the GCGC discriminator motif conferred comparable regulatory features when fused to the complementing sequences of the non-regulated mutant tac promoter. A minor response to amino acid deprivation or changes in the growth rate was noted for the hybrid promoter with the rrnB P1 upstream segment and the tac downstream element, pointing to a slightly different importance of the two sequence elements for regulation. The parallel effects for stringent as well as growth rate regulation of the hybrid promoters supports the view of a common mechanism for both types of control. However, none of the promoter sequence elements on its own was able to restore the complete regulatory behaviour of their 'parent' promoters.

Base Sequence↗

Carotid baroreflex heart rate control during the active and the assisted breathing cycle in man.

The interaction between the phase of the breathing cycle and the carotid baroreflex heart rate control was studied in fifteen healthy subjects with special reference to respiratory sinus arrhythmia (RSA). Carotid baroreceptors were stimulated by neck suction. With a standardized breathing pattern, two types of experiment were performed. (a) Neck suction applied in counter phase with the respiratory arterial pressure variations; this reduced the amplitude and shifted the phase of the transmural carotid arterial pressure oscillations but did not influence the RSA. (B) During active as well as ventilator assisted breathing, brief periods of neck suction were applied during either inspiration (insufflation) or expiration. Neck suction during active inspiration did not change the amplitude of the RSA but when applied during expiration, increased it by 6.8 beats X min-1 (P less than 0.001). In the ventilator experiments, neck suction during insufflation and expiration augmented the RSA equally, by 5.3 beats X min-1 (P less than 0.05). The results indicate a decreased sensitivity of the carotid arterial baroreflex during active inspiration, with no equivalent during assisted breathing, and suggest that the change in baroreflex sensibility is a prerequisite for the rise of the RSA.

Adult↗

Electrically-assisted skin permeation of two synthetic capsaicin derivatives, sodium nonivamide acetate and sodium nonivamide propionate, via rate-controlling polyethylene membranes.

The objective of this study was to examine the transdermal delivery of sodium nonivamide acetate (SNA) using iontophoresis and electroporation with ultra high molecular weight polyethylene membranes (Solupor) to achieve controlled transdermal drug delivery. A derivative of SNA, sodium nonivamide propionate (SNP), was also used as a model drug in this investigation. Iontophoresis increased the transdermal permeation of SNA as compared to passive diffusion. Most Solupor membranes were rate-limiting for the iontophoretic permeation of SNA except for Solupor 8P07, which showed negligible resistance to SNA delivery. The tortuosity (Gurley number), pore size, and the current density-induced attachments on the surface of the Solupor membranes may have been important for their rate-controlling effect. The trends for inhibiting or controlling SNA permeation were similar for both iontophoretic and electroporation applications. The higher molecular size and lower hydrophilicity of SNP compared to SNA resulted in lower permeation of SNP using electrically-assisted methods. Moreover, the various types of Solupor membranes showed similar trends for both SNA and SNP. This present study indicates that Solupor membranes act as rate-limiting membranes for controlling the release and skin permeation of both SNA and SNP by electrically-assisted methods.

Administration, Cutaneous↗