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Biomedical subjects

M B Wagner

Publications and source records attributed to M B Wagner.

At least 19 recordsLinked to original sources
PubMed2000

cGMP-dependent protein kinase mediates stimulation of L-type calcium current by cGMP in rabbit atrial cells.

OBJECTIVES: cGMP has been shown to exert both stimulatory and inhibitory effects on cardiac L-type calcium current (I(Ca)). The physiological role of cGMP in regulation of cardiac activity is still controversial. cGMP may be of importance in regulation of I(Ca) in atrial cells. The present study was focused on the role of cGMP in the modulation of I(Ca) in rabbit atrial cells. METHODS: Enzymatically isolated adult rabbit atrial cells were used to measure I(Ca) using whole cell voltage clamp. Expressed levels of cGMP-dependent protein kinase (PKG) were determined by Western blotting using PKG specific antibody in homogenates from atrial and ventricular cells. RESULTS: Nitrosoglutathione (GSNO), a nitric oxide donor that stimulates soluble guanylyl-cyclase to elevate cGMP levels increased I(Ca) while soluble G-cyclase inhibitors, ODQ or methylene blue inhibited I(Ca). Intracellular application of 8BrcGMP increased I(Ca) and blocked the inhibitory effect of methylene blue. KT-5823, an inhibitor of PKG inhibited I(Ca) and the stimulatory effect of GSNO was completely blocked ODQ or KT-5823. Inhibition of cAMP dependent protein kinase (PKA) by the 6-22 peptide completely blocked the stimulation of I(Ca) by the beta-agonist isoproterenol but not by GSNO. The potency of isoproterenol to stimulate I(Ca) was very high for atrial cells (EC(50) 2.4+/-0.6 nM) and only 100 nM isoproterenol was required to stimulate I(Ca) maximally (21.4+/-0.7 pA/pF) to a level (23.8+/-1.6 pA/pF) achieved with the inclusion of 100 microM cAMP in the pipette solution. GSNO produced an additive effect on I(Ca) already stimulated by either 10 microM isobutylmethylxanthine (phosphodiesterase inhibitor) or a low concentration (1 nM) isoproterenol but failed to produce any effect on I(Ca) maximally stimulated by 100 nM isoproterenol. Inhibition of PKG by KT-5823 significantly decreased the efficacy of isoproterenol and the maximal I(Ca) achieved with 100 nM isoproterenol was decreased to 8.2+/-0.6 pA/pF in the presence of KT-5823. Western blot analysis showed much higher expression of PKG in atrial cells compared to ventricular cells. CONCLUSIONS: These findings suggest that stimulatory effects of cGMP on I(Ca) in rabbit atrial cells are likely to be mediated via PKG dependent phosphorylation of calcium channels or associated proteins and that the effects of cGMP are not antagonistic to cAMP. PKG is highly expressed in atrial cells and PKG dependent phosphorylation may be necessary for maintaining basal I(Ca) and fully stimulating I(Ca) by beta-adrenergic activation in atrial cells.

1-Methyl-3-isobutylxanthine↗
PubMed2000

Measurements of calcium transients in ventricular cells during discontinuous action potential conduction.

The L-type calcium current (I(Ca)) is important in sustaining propagation during discontinuous conduction. In addition, I(Ca) is altered during discontinuous conduction, which may result in changes in the intracellular calcium transient. To study this, we have combined the ability to monitor intracellular calcium concentration ([Ca(2+)](i)) in an isolated cardiac cell using confocal scanning laser fluorescence microscopy with our "coupling clamp" technique, which allows action potential propagation from the real cell to a real-time simulation of a model cell. Coupling a real cell to a model cell with a value of coupling conductance (G(C) = 8 nS) just above the critical value for action potential propagation results in both an increased amplitude and an increased rate of rise of the calcium transient. Similar but smaller changes in the calcium transient are caused by increasing G(C) to 20 nS. The increase of [Ca(2+)](i) by discontinuous conduction is less than the increase of I(Ca), which may indicate that much of [Ca(2+)](i) is the result of calcium released from the sarcoplasmic reticulum rather than the integration of I(Ca).

Action Potentials↗
PubMed2000

Electrical interactions between a real ventricular cell and an anisotropic two-dimensional sheet of model cells.

We have extended our "coupling clamp" technique, in which we couple a real cell to a real-time simulation of a model cell, to now incorporate a real cardiac cell as the central element of a two-dimensional sheet of model cells, in which the coupling conductances may be different in the x and y directions and a specific region of lack of coupling conductance may serve as a resistive barrier. We stimulated the real cell in the central location and determined the critical size of the real cell for successful activation of the entire sheet. We found that this critical size was decreased when anisotropy was present compared with the isotropic case and was further decreased when the central site of stimulation was close to the resistive barrier. The heart normally has some degree of anisotropy, and it has been shown that the remodeling that occurs in peri-infarction zones produces a particular loss of lateral connections compared with end-to-end connections among heart cells. We propose that the normal existence of anisotropy and enhancement of the degree of anisotropy both by loss of lateral gap junctions and the development of resistive barriers may play a facilitating role in the development of ectopic foci that may lead to cardiac arrhythmias.

Animals↗
PubMed2000

A spontaneously active focus drives a model atrial sheet more easily than a model ventricular sheet.

Tachycardias can be produced when focal activity at ectopic locations in either the atria or the ventricles propagates into the surrounding quiescent myocardium. Isolated rabbit atrioventricular nodal cells were coupled by an electronic circuit to a real-time simulation of an array of cell models. We investigated the critical size of an automatic focus for the activation of two-dimensional arrays made up of either ventricular or atrial model cells. Over a range of coupling conductances for the arrays, the critical size of the focus cell group for successful propagation was smaller for activation of an atrial versus a ventricular array. Failure of activation of the arrays at smaller focus sizes was due to the inhibition of pacing of the nodal cells. At low levels of coupling conductance, the ventricular arrays required larger sizes of the focus due to failure of propagation even when the focus was spontaneously active. The major differences between activation of the atrial and ventricular arrays is due to the higher membrane resistance (lower inward rectifier current) of the atrial cells.

Animals↗
PubMed2000

Fast pacing facilitates discontinuous action potential propagation between rabbit atrial cells.

We examined the critical coupling conductance (G(C)) for propagation at different pacing cycle lengths (CLs) (1,000 and 400 ms). As G(C) was progressively reduced, propagation failed at a CL of 1,000 ms, whereas propagation succeeded at a CL of 400 ms over a range of G(C) values before failing at a CL of 400 ms at a lower G(C), showing facilitation of propagation at the shorter CL. Critical G(C) was (means +/- SE) 0.8 +/- 0.1 nS for a CL of 400 ms and 1.3 +/- 0.1 nS for a CL of 1,000 ms (a 63% increase, P < 0.002, n = 9 cell pairs). In 14 uncoupled cells, action potential duration at 30% repolarization (APD(30)) increased from 19.9 +/- 2.5 to 41.8 +/- 2.6 ms (P < 0.001) as CL decreased from 1,000 to 400 ms. In five cell pairs, critical G(C) with 4-aminopyridine (4-AP) was reduced to 0.4 +/- 0.1 nS at a CL of 1,000 ms (P < 0.05 compared with control solution), and critical G(C) in 4-AP was unchanged by decreasing CL to 400 ms. It is possible that the "remodeling" of atrial cells due to atrial fibrillation or tachycardia, which has been shown to produce a decrease in the transient outward current, may result in an enhanced ability to propagate, possibly facilitating further development of fibrillation under conditions of decreased cellular coupling.

Action Potentials↗
PubMed2000

Assessing the antimicrobial prescription request process in a teaching hospital in Brazil: regulations and training.

It is known that antimicrobials are often prescribed inappropriately. One method used to deal with this problem is to regulate antimicrobial use by monitoring prescriptions. We report a study of physician compliance with the request for antibiotic process which was prepared and reviewed by a special infection control committee in our hospital the Nosocomial Infection Prevention Service (SCIH). The objective of this study was to identify the profile of inappropriate requests for restricted therapeutic antimicrobials used at Nossa Senhora da Conceição Hospital (HNSC), in Porto Alegre, Brazil. All 3,389 requests for therapeutic antimicrobials made between May 20, and October 31, 1996, were assessed and classified as appropriate and inappropriate. We determined that 17. 8% of the requests were inappropriate (a total of 720 errors). These were categorized according to 12 reasons for inappropriateness. Of these, the 3 most frequent inappropriate requests were deviation from standard use (26.73%), inappropriate length of treatment (23. 19%), and unfounded justification (13.61%). The reasons for inappropriateness were also arranged in three categories considering the following aspects: I. technical (59%); II. compatibility with the institutional program (32.36%), and III. administrative (8.61%). The 720 requests that were initially rejected were evaluated to see how antibiotic use was affected. In approximately 400 (55%), the forms could be appropriately modified after discussion with the physician. We conclude from this study that most of the inappropriate requests for antimicrobials in our hospital can be remedied by educating the staff since the errors were largely technical in nature. Thus, the SCIH should focus more on its role as an educational rather than as a regulatory body. By expanding this educational role, we anticipate improved physician compliance with our guidelines, and more appropriate antimicrobial prescribing and usage.

Anti-Bacterial Agents↗
PubMed1999

Electrical interactions among real cardiac cells and cell models in a linear strand.

Previous work with model systems for action potential conduction have been restricted to conduction between two real cells or conduction between a model cell and a real cell. The inclusion of additional elements to make a linear strand has allowed us to investigate the interactions between cells at a higher level of complexity. When, in the simplest case of a linear strand of three elements, the conductance between elements 2 and 3 (GC2) is varied, this affects the success or failure of propagation between elements 1 and 2 (coupled by GC1) as well as the success or failure of propagation between elements 2 and 3. Several major features were illustrated. 1) When GC1 was only slightly greater than the coupling conductance required for successful propagation between a model cell and a real cell, addition of a third element of the strand either prevented conduction from element 1 to element 2 (when GC2 was high) or allowed conduction from element 1 to element 2 but not conduction from element 2 to element 3 (when GC2 was low). 2) For higher levels of GC1, there was an allowable "window" of values of GC2 for successful conduction from element 1 through to element 3. The size of this allowable window of GC2 values increased with increasing values of GC1, and this increase was produced by increases in the upper bound of GC2 values. 3) When the size of the central element of the strand was reduced, this facilitated conduction through the strand, increasing the range of the allowable window of GC2 values. The overall success or failure of conduction through a structure of cells that has a spatially inhomogeneous distribution of coupling conductances cannot be predicted simply by the average or the minimum value of coupling conductance but may depend on the actual spatial distribution of these conductances.

Animals↗
PubMed1997

Risk factors for bleeding in major abdominal surgery using heparin thromboprophylaxis.

BACKGROUND: Patients undergoing major abdominal surgery are at risk of both bleeding and thrombotic complications and usually receive heparin thromboprophylaxis. PATIENTS AND METHODS: Risk factors for perioperative bleeding were examined in 3,809 patients in a double-blind, randomized trial investigating heparin thromboprophylaxis. The risk factors were modeled by logistic regression, and a risk score was calculated using the significant factors in the model. RESULTS: Bleeding was associated with the following factors in the model, given as adjusted odds ratios (ORa [95% confidence interval]): male sex (ORa 1.68 [1.21 to 2.34] P = 0.003), malignancy (ORa 1.69 [1.21 to 2.34] P = 0.008), gynecological surgery (ORa 1.62 [1.12 to 2.35] P = 0.011), and complex surgery (ORa 2.7 [2.02 to 3.62] P < 0.001). The risk of excessive bleeding for 0, 1, 2, and 3 risk factors was 2%, 6%, 11%, and 21%, respectively. CONCLUSIONS: The recognition of patients with these risk factors associated with perioperative bleeding should result in increased vigilance and may lead to modification of surgical and medical therapy.

Abdomen↗
PubMed1997

Hospital-acquired infections among surgical patients in a Brazilian hospital.

A historical cohort study was conducted among surgical patients in a large general hospital in Porto Alegre, Brazil between March 1992 and May 1993. Data were collected by means of a retrospective chart review, which followed a standardized method based on the systematic review of all clinical and laboratory information available in the hospital records. The criteria for diagnosis of all hospital-acquired infections (HAIs) were based on those from the Centers for Disease Control, Atlanta. In total, 890 HAIs were detected among the 4199 patients included in the cohort. The incidence rate of HAIs for all sites combined was 21.20%. Incidence rates ranged from 2.95% for bloodstream infections to 8.65% for surgical wound infections. The overall incidence density was 16.32 HAIs per 1000 patient-days. Incidence densities ranged from 2.03 for bloodstream infections to 7.46 per 1000 patient-days for surgical wound infections. The median incubation period for surgical wound infections was seven days, and 29.4% of these infections were detected at post-discharge. Gram-negative bacteria were the most common organisms implicated in HAIs.

Adolescent↗
PubMed1997

Modulation of propagation from an ectopic focus by electrical load and by extracellular potassium.

We previously developed a technique (R. Kumar, R. Wilders, R. W. Joyner, H. J. Jongsma, E. E. Verheijck, D. A. Golod, A. C. G. van Ginneken, and W. N. Goolsby. Circulation 94: 833-841, 1996) for study of a mathematical model cell with spontaneous activity, viz. a "real-time" simulation of a rabbit sinoatrial node cell (SAN model cell; R. Wilders, H. J. Jongsma, and A. C. van Ginneken. Biophys. J. 60: 1202-1216, 1991) simultaneously being electrically coupled via our "coupling clamp" [H. Sugiura and R. W. Joyner. Am. J. Physiol. 263 (Heart Circ. Physiol. 32): H1591-H1604, 1992] circuit to a real, isolated ventricular myocyte. We now apply this technique to investigate effects of coupling conductance (Gc), cell size, and the modulation of membrane potential by elevated extracellular potassium concentration on the ability of an ectopic focus, represented by the SAN model cell, to successfully drive a ventricular cell. Values of Gc and the relative sizes of the two cells define three possible outcomes: 1) spontaneous pacing of the SAN model cell but not driving of the ventricular cell, 2) cessation of spontaneous pacing, or 3) pacing of the SAN model cell and driving of the ventricular cell. Below a critical size of the SAN model cell only the first two of these outcomes is possible. Above this critical size there is a range of Gc that allows successful operation of the system as an ectopic focus. Elevation of extracellular potassium concentration from 4 to 8 mM increases both the lower bound and upper bound of Gc for this range. Elevation of extracellular potassium concentration, as commonly observed in myocardial ischemia, may have effects on either inhibiting or releasing from inhibition an ectopic focus.

Animals↗
PubMed1996

Modeling triggered cardiac activity: an analysis of the interactions between potassium blockade, rhythm pauses, and cellular coupling.

It is known that under certain conditions, a combination of potassium channel blockade, sympathetic nervous activity, and pauses in sinus rhythm can increase the occurrence of cardiac arrhythmias. Although the arrhythmogenic interactions of these three factors are not completely understood, it is believed that the associated arrhythmias may be initiated by afterpotentials via a process that we refer to as propagated triggered activity. Using a two-cell computational model of ventricular action potential kinetics, we simulate nonuniform potassium blockade, sympathetic nervous activity, and pauses in sinus rhythm under conditions of hypokalemia. Under these conditions, the two-cell model suggests that (1) the arrhythmogenic interactions of potassium blockade and sympathetic nervous activity are highly dependent on heart rate; (2) triggered activity induced by potassium blockade would most likely occur during a pause in sinus rhythm; (3) during a sufficiently large pause in sinus rhythm, potassium blockade can induce triggered activity at normal levels of sympathetic activity; and (4) potassium blockade can increase the probability of triggered activity only if heart rate falls within a critical range. We also show that during pauses in sinus rhythm, two-cell triggering interactions between potassium blockade and sympathetic activity closely parallel the parametric displacement of the dynamic instability underlying the afterpotentials. Our results indicate that the behavior of the triggering mechanism studied here is consistent with that of pause-induced arrhythmias.

Action Potentials↗
PubMed1996

Ambulatory visits to hospital emergency departments. Patterns and reasons for use. 24 Hours in the ED Study Group.

OBJECTIVES: To characterize the reasons ambulatory patients use hospital emergency departments (EDs) for outpatient care and to determine the proportion of ED patients who initially are assessed as having nonurgent conditions, but subsequently are hospitalized. DESIGN: Cross-sectional survey during a single 24-hour period of time. SETTING: Fifty-six hospital EDs nationwide. PATIENTS OR OTHER PARTICIPANTS: Consecutive ambulatory patients presenting for care. Patents who arrived by ambulance were excluded. RESULTS: Of 6441 ambulatory patients (79 percent of all ED visits) who were eligible for study, interviews were obtained from 6187 (96 percent). A total of 5323 patients (86 percent) had clinical reasons or preferences for seeking care at an ED, including 2799 (45 percent) who thought they had an emergency or an urgent condition or were too sick to go elsewhere. Nineteen percent (n=1199) reported that they were sent to the ED by a health care professional. Patients with a regular clinician or with insurance cited similar reasons for seeking care at an ED. A total of 3062 patients (50 percent) cited 1 or more nonfinancial barriers to care as an important reason for coming to the ED, and 949 (15 percent) cited financial considerations. A total of 3045 patents (49 percent of ambulatory patients and 37 percent of total ED visits) were assessed at triage as having a nonurgent condition; 166 of them (5.5 percent; 95 percent confidence interval, 4.7 percent-6.3 percent) were admitted to the hospital. CONCLUSIONS: Most ambulatory patients seek care in an ED because of worrisome symptoms or nonfinancial barriers to care. Although many ambulatory patients appear to have nonurgent conditions based on triage classification, a small but disturbing percentage of nonurgent patients are hospitalized.

Adolescent↗
PubMed1996

Modulating L-type calcium current affects discontinuous cardiac action potential conduction.

We have used pairs of cardiac cells (i.e., one real guinea pig ventricular cell and a real-time simulation of a numerical model of a guinea pig ventricular cell) to evaluate the effects on action potential conduction of a variable coupling conductance in combination with agents that either increase or decrease the magnitude of the L-type calcium current. For the cell pairs studied, we applied a direct repetitive stimulation to the real cell, making it the "leader" cell of the cell pair. We have demonstrated that significant delays in action potential conduction for a cell pair can occur either with a decreased value of coupling conductance or with an asymmetry in size such that the follower cell is larger than the leader cell. In both conditions we have shown that isoproterenol, applied to the real cell at very low concentrations, can reversibly decrease the critical coupling conductance (below which action potential conduction fails) for a cell pair with fixed cell sizes, or, for a fixed value of coupling conductance, increase the maximum allowable asymmetry in cell size for successful conduction. For either of these effects, we were able to show that treatment of the real cell with BayK 8644, which more specifically increases the magnitude of the L-type calcium current, was able to mimic the actions of isoproterenol. Treatment of the leader cell of the cell pair (the real cell) with nifedipine, which selectively lowers the magnitude of the L-type calcium current, had effects opposite those of isoproterenol or BayK 8644. The actions of nifedipine, isoproterenol, and BayK 8644 are all limited to conditions in which the conduction delay is on the order of 5 ms or more, whether this delay is caused by limited coupling conductance or by asymmetry in size of the cells. This limitation is consistent with the time course of the L-type calcium current and suggests that the effects of calcium channel blockers or beta-adrenergic blocking drugs, in addition to being selective for regions of the heart that depend on the L-type calcium current for the upstroke of the action potential, would also be somewhat selective for regions of the heart that have discontinuous conduction, either normally or because of some pathological condition.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1996

Exercise participation in a frail elderly population.

A low-intensity exercise demonstration project was developed jointly by researchers, social service practitioners, and program participants to actively involve frail older people in their own health maintenance. This article describes this collaborative process and its impact on the success of the health promotion program, which was conducted at three senior centers serving a low-income, urban elderly population. Participants were predominantly sedentary women over age 70 with multiple chronic conditions. The program was conducted with peer leaders to facilitate its continuation after the research demonstration phase. In addition to positive health outcomes related to functional mobility, blood pressure maintenance, and overall well-being, this intervention was successful in sustaining active participation in regular physical activity through the use of peer leaders selected by the program participants. The planning, implementation, and outcomes of this project illustrate the benefits and challenges of combining research and practice perspectives in conducting health promotion interventions with older populations.

Black or African American↗
PubMed1996

Evaluation of a program for long-term treatment of Duchenne muscular dystrophy. Experience at the University Hospitals of Cleveland.

One hundred and forty-four boys who had Duchenne muscular dystrophy were managed at a single center between 1953 and 1994 and were followed for a mean of 8.9 years. The long duration of follow-up provided an opportunity to examine the effects of physical therapy and orthopaedic treatment on contractures of the lower extremities and on the duration of the ability to walk. Contractures of the lower extremities were controlled best when patients were managed with a combination of daily passive stretching exercises, prescribed periods of standing and walking, tenotomy of the Achilles tendon, posterior tibial-tendon transfer, and application of knee-ankle-foot orthoses. Approximately two years after bracing, the severity of the contracture of the heel cords was similar in the patients who had had an operation and those who had not. By the fourth year after bracing, however, the patients who had had an operation had less severe contractures than those who had had bracing alone. Five to seven years after the operation and bracing, control of contractures was still good, especially for the patients who had had posterior tibial-tendon transfer. Contracture of the knee was well controlled five to seven years after bracing in all patients who had had bracing, with or without an operation. The program enabled the patients who had been managed with bracing to walk until a mean age of 13.6 years. After loss of the ability to walk with bracing, the ability to stand continued for an additional two years with use of orthoses. The findings of the present study demonstrate the value of traditional methods of operative treatment and bracing for controlling contractures of the lower extremities in patients who have Duchenne muscular dystrophy and for prolonging their ability to walk.

Adolescent↗
PubMed1995

A model study of propagation of early afterdepolarizations.

Early afterdepolarizations (EAD's) are irregularities of the cardiac action potential that interrupt or retard repolarization. EAD's have been linked to the development of specific types of cardiac arrhythmias, however, the mechanism underlying the development of these arrhythmias remains unclear. We implemented a two-element kinetic model of the ventricular action potential to investigate a potentially arrhythmogenic form of triggered activity. By approximating EAD's by a sinusoidal driving force, we were able to study the effects of interelement coupling resistivity and sinusoidal frequency and amplitude on the triggering of action potentials. We demonstrated EAD's in a ventricular action potential model by altering the potassium and calcium channels to simulate experimental conditions under which EAD's occur. We also found that triggered activity depends critically on the frequency and amplitude of the driving force and also on the degree of cellular uncoupling between the elements. Our results suggest that triggered activity (due to EAD's) may be suppressed by drugs that improve coupling in unhealthy tissue, or ones that prevent EAD formation by inhibiting calcium channels.

Action Potentials↗