On the influence of test speed and environment in the fatigue life of small diameter nitinol and stainless steel wire.

To better understand the complex interplay of speed and environment on metals commonly used in implants, rotary bend fatigue tests were conducted on stainless steel and nitinol wires. A range of alternating strains was tested to create ε-N curves at two speeds (physiologic and accelerated) and in three environments (deionized water at body temperature, phosphate buffered saline at body temperature, and laboratory air at ambient room temperature). Results indicate that speed and environment can affect the observed fatigue life in nuanced ways. An electropotential monitoring technique was demonstrated to characterize fatigue crack growth which may be useful in future investigations.

Rotary Bend Fatigue of Nitinol to One Billion Cycles.

Nitinol implants, especially those used in cardiovascular applications, are typically expected to remain durable beyond 108 cycles, yet literature on ultra-high cycle fatigue of nitinol remains relatively scarce and its mechanisms not well understood. To investigate nitinol fatigue behavior in this domain, we conducted a multifaceted evaluation of nitinol wire subjected to rotary bend fatigue that included detailed material characterization and finite element analysis as well as post hoc analyses of the resulting fatigue life data. Below approximately 105 cycles, cyclic phase transformation, as predicted by computational simulations, was associated with fatigue failure. Between 105 and 108 cycles, fractures were relatively infrequent. Beyond 108 cycles, fatigue fractures were relatively common depending on the load level and other factors including the size of non-metallic inclusions present and the number of loading cycles. Given observations of both low cycle and ultra-high cycle fatigue fractures, a two-failure model may be more appropriate than the standard Coffin-Manson equation for characterizing nitinol fatigue life beyond 108 cycles. This work provides the first documented fatigue study of medical grade nitinol to 109 cycles, and the observations and insights described will be of value as design engineers seek to improve durability for future nitinol implants.

Harmony search: Current studies and uses on healthcare systems.

One of the popular metaheuristic search algorithms is Harmony Search (HS). It has been verified that HS can find solutions to optimization problems due to its balanced exploratory and convergence behavior and its simple and flexible structure. This capability makes the algorithm preferable to be applied in several real-world applications in various fields, including healthcare systems, different engineering fields, and computer science. The popularity of HS urges us to provide a comprehensive survey of the literature on HS and its variants on health systems, analyze its strengths and weaknesses, and suggest future research directions. In this review paper, the current studies and uses of harmony search are studied in four main domains. (i) The variants of HS, including its modifications and hybridization. (ii) Summary of the previous review works. (iii) Applications of HS in healthcare systems. (iv) And finally, an operational framework is proposed for the applications of HS in healthcare systems. The main contribution of this review is intended to provide a thorough examination of HS in healthcare systems while also serving as a valuable resource for prospective scholars who want to investigate or implement this method.

Third-Generation Minimally Invasive Chevron Akin Osteotomy for Hallux Valgus.

BACKGROUND: Multiple operative techniques have been developed for hallux valgus with varying success. The most recent developments in minimally invasive surgery have evolved into the third-generation minimally invasive chevron Akin (MICA) osteotomy. Good results have been shown from originator centers, but this is one of the first series from a nonoriginator center, and the first to use a validated patient-reported outcome measure. METHODS: Forty consecutive patients undergoing third-generation MICA for hallux valgus were included. Primary outcome measures included Manchester-Oxford Foot Questionnaire (MOXFQ) and American Orthopaedic Foot & Ankle Society (AOFAS) scores and Coughlin satisfaction rates at 12 months. Secondary outcome measures included radiographic parameters, complications, and recurrence rates. RESULTS: At 12 months, the MOXFQ score improved from 58 to 10 and the AOFAS score improved from 48 to 93, with 70% of patients reporting excellent outcomes and 30% good ones. Two cases started as mild, 29 cases as moderate, and 9 cases as severe as defined by radiographic criteria. Hallux valgus angles improved from 32 degrees to 12 degrees, and intermetatarsal angles improved from 13 degrees to 7 degrees. There were 4 cases of Akin screw removal for soft tissue irritation. There were no other complications, including recurrence. CONCLUSION: The third-generation MICA technique was a safe and effective approach to treating hallux valgus. Further research should focus on long-term outcomes and comparative data with other commonly performed operative techniques. LEVEL OF EVIDENCE: Level IV, case series.

Characterizing fretting damage in different test media for cardiovascular device durability testing.

In vitro durability tests of cardiovascular devices are often used to evaluate the potential for fretting damage during clinical use. Evaluation of fretting damage is important because severe fretting can concentrate stress and lead to the loss of structural integrity. Most international standards call for the use of phosphate buffered saline (PBS) for such tests although there has been little evidence to date that the use of PBS is appropriate in terms of predicting the amount of fretting damage that would occur in vivo. In order to determine an appropriate test media for in vitro durability tests where fretting damage is being evaluated, we utilized an in vitro test that is relevant to cardiovascular devices both in terms of dimensions and materials (nitinol, cobalt-chromium, and stainless steel) to characterize fretting damage in PBS, deionized water (DIW), and heparinized porcine blood. Overall, tests conducted in blood were found to have increased levels of fretting damage over tests in DIW or PBS, although the magnitude of this difference was smaller than the variability for each test media. Tests conducted in DIW and PBS led to mostly similar amounts of fretting damage with the exception of one material combination where DIW had greatly reduced damage compared to PBS and blood. Differences in fretting damage among materials were also observed with nitinol having less fretting damage than stainless steel or cobalt-chromium. In general, evaluating fretting damage in PBS or DIW may be appropriate although caution should be used when selecting test media and interpreting results given some of the differences observed across different materials.

Sodium Hypochlorite Treatment and Nitinol Performance for Medical Devices.

Processing of nitinol medical devices has evolved over the years as manufacturers have identified methods of reducing surface defects such as inclusions. One recent method proposes to soak nitinol medical devices in a 6% sodium hypochlorite (NaClO) solution as a means of identifying surface inclusions. Devices with surface inclusions could in theory then be removed from production because inclusions would interact with NaClO to form a visible black material on the nitinol surface. To understand the effects of an NaClO soak on performance, we compared as-received and NaClO-soaked nitinol wires with two different surface finishes (black oxide and electropolished). Pitting corrosion susceptibility was equivalent between the as-received and NaClO-soaked groups for both surface finishes. Nickel ion release increased in the NaClO-soaked group for black oxide nitinol, but was equivalent for electropolished nitinol. Fatigue testing revealed a lower fatigue life for NaClO-soaked black oxide nitinol at all alternating strains. With the exception of 0.83% alternating strain, NaClO-soaked and as-received electropolished nitinol had similar average fatigue life, but the NaClO-soaked group showed higher variability. NaClO-soaked electropolished nitinol had specimens with the lowest number of cycles to fracture for all alternating strains tested with the exception of the highest alternating strain 1.2%. The NaClO treatment identified only one specimen with surface inclusions and caused readily identifiable surface damage to the black oxide nitinol. Damage from the NaClO soak to electropolished nitinol surface also appears to have occurred and is likely the cause of the increased variability of the fatigue results. Overall, the NaClO soak appears to not lead to an improvement in nitinol performance and seems to be damaging to the nitinol surface in ways that may not be detectable with a simple visual inspection for black material on the nitinol surface.

Integrating Multiple Receptor Conformation Docking and Multi Dimensional QSAR for Enhancing Accuracy of Binding Affinity Prediction.

BACKGROUND: The accuracy of molecular conformation for Quantitative Structure Activity Relationship (QSAR) studies is an important criteria, and the most favourable bioactive conformer selection is a tough task. Correct ligand alignment as input for 3D-QSAR is an important step that is prone to human biases. Multiple-dimensional QSAR (mQSAR) approach provides a promising alternative to classic 3D-QSAR for drug discovery purposes. OBJECTIVE: Obtaining ligand conformations from multiple receptor conformation docking (MRCD) will reduce the margin of error by incorporating the receptor based alignment of ligand conformations. To validate this assumption we performed 6D QSAR studies on reported HIV-1 protease inhibitors using Quasar 6.0. MATERIALS & METHOD: The ensemble of conformation was obtained by MRCD of ligands in thirteen crystal structures of HIV-1 protease. 6D QSAR model was built using 65 cyclic urea molecules reported as HIV-1 protease inhibitors. Predictive ability of the model was validated using 35 cyclic urea molecules as test set. External predictive ability of the model was evaluated using a set of 24 HIV-1 protease inhibitors having varied structural scaffold. RESULT: 6D QSAR model obtained showed a reliable cross-validated r2(q2) of 0.899, r2(classic) of 0.908 and yielded a predictive r2 (p2) of 0.527. The ratio of q2/r2 was 0.991 and p2/q2 was 0.586 for external test set. CONCLUSION: The QSAR results invariably suggest that our approach is suitable for the identification of molecules having HIV-1 protease inhibitory potency. The underlying philosophy combines flexible docking for the identification of the binding modes and 6D QSAR for their quantification.

Diurnal fluid expression and activity of intervertebral disc cells.

The intervertebral discs are large cartilaginous structures situated between the vertebral bodies, occupying around one third of the length of the spinal column. They act as the joints of the spine and carry mechanical load arising from body weight and muscle activity. Loads change with every alteration of posture and activity and the discs thus undergo a diurnal loading pattern with high loads on the discs during the day's activity and low loads on it at night during rest. As the disc is an osmotic system, around 25% of the disc's fluid is expressed and re-imbibed during each diurnal cycle with consequent changes in the osmotic environment of the disc cells. Here, present information on the effect of osmotic changes in disc cell metabolism is reviewed; results indicate that prevailing osmolarity is a powerful regulator of disc cell activity.

A biochemical logic gate using an enzyme and its inhibitor. 1. The inhibitor as switching element.

Molecular-scale logic systems will allow for further miniaturization of information processing assemblies and contribute to a better understanding of brain function. Of much interest are the pertinent biological systems, some of the basic components of which are biomolecular switching elements and enzyme-based logic gates. In this series of accounts, results of investigations are presented on the implementation of an enzyme/inhibitor logic gate operating under the rules of Boolean algebra. In this report (part 1 of the series), consideration is given to the experimental conditions-particularly the irradiation mode-that affect the performance of proflavine as inhibitor of alpha-chymotrypsin. Also, assessments are made on the reversibility of the process involved and the long-term stability of the system. Moreover, using a theoretical conformational analysis of proflavine and its reduction products, detailed features were established regarding their three-dimensional structure, partial charge distribution, and hydrophobicity. Accordingly, an understanding was reached as to the factors affecting the interaction between these compounds and the enzyme. In part 2 of this series, the actual implementation of an AND logic gate will be presented. This gate involves proflavine and a chemically derivatized alpha-chymotrypsin, and its operation relies on the conclusions reached in this report regarding the optimal mode for controlling the inhibitory activity of proflavine.

A simulation of the SA node by a phase response curve-based model of a two-dimensional pacemaker cells array.

This paper presents a simulation of the sino-atrial (SA) node by a two-dimensional pacemaker cells array model, based on phase response curve (PRC) interaction. This simple model of the cardiac pacemaker cells, involves only the most basic functional properties, which play a direct role in the determination of the SA node rhythm. The two most relevant functional properties of the pacemaker cells are: The intrinsic cycle length, an "internal" feature of each pacemaker cell, and the PRC, an "overall collective" function. The PRC contains the "information" about the type of interactions of each pacemaker cell with the outside world (i.e., interaction with neighboring cells, external stimulus, etc.), and "strength" of the interaction (strong, weak, etc.). We studied the spatial interaction among a large number of pacemaker cells (15 x 15), as a function of the regional variation of cells properties, the "electrical" coupling between cells (the PRC), and the appearance of regions with abnormal cycle lengths. We investigated the influence of those parameters on the mutual interaction between the pacemaker cells, on the activation pattern and conduction time of the array, and on a pseudo-electrocardioigram (ECG) signal. This study demonstrates that by representing the pacemaker cells in the SA node by only two fundamental features, and by applying a simple physical-mathematical model, we can create a global picture of the SA node system. This enables us to explore physiological phenomena related to the genesis and maintenance of the SA node activity, and to gain insight into the conditions which predispose the SA node instability, and conduction disturbances.

Phase response curve based model of the SA node: simulation by two-dimensional array of pacemaker cells with randomly distributed cycle lengths.

A simulation of the SA node is presented, based on a 2D array (15 x 15) model of randomly distributed pacemaker cells, interacting via a phase response curve (PRC). The model involves only the basic properties that play a direct role in the determination of the SA node rhythm: intrinsic cycle length and PRC. The PRC reflects the 'type' of interaction of each pacemaker cell with the outside world (neighbouring cells, external stimulus, etc.). A major outcome of this study is the demonstration that global dynamics and the degree of 'disorder' of the SA node are strongly affected by the cycle length distribution of the model, as well as spatial inhomogeneity in the cell-to-cell 'electrical' coupling (PRC). Those factors also determine the conduction velocity throughout the SA node and may therefore be responsible for anisotropic conduction. For example, lowering the PRC parameters (d and a) by 25% increases the array activation time from 46 to 126 ms. The model also responds appropriately to a perturbation such as a vagal pulse. This pulse produces a shift of the dominant pacemaker to another site in the array and a transient lengthening of the array cycle length, for example from 312 to 355 ms.

The formation of an anti-restenotic/anti-thrombotic surface by immobilization of nitric oxide synthase on a metallic carrier.

Coronary stenosis due to atherosclerosis, the primary cause of coronary artery disease, is generally treated by balloon dilatation and stent implantation, which can result in damage to the endothelial lining of blood vessels. This leads to the restenosis of the lumen as a consequence of migration and proliferation of smooth muscle cells (SMCs). Nitric oxide (NO), which is produced and secreted by vascular endothelial cells (ECs), is a central anti-inflammatory and anti-atherogenic player in the vasculature. The goal of the present study was to develop an enzymatically active surface capable of converting the prodrug l-arginine, to the active drug, NO, thus providing a targeted drug delivery interface. NO synthase (NOS) was chemically immobilized on the surface of a stainless steel carrier with preservation of its activity. The ability of this functionalized NO-producing surface to prevent or delay processes involved in restenosis and thrombus formation was tested. This surface was found to significantly promote EC adhesion and proliferation while inhibiting that of SMCs. Furthermore, platelet adherence to this surface was markedly inhibited. Beyond the application considered here, this approach can be implemented for the local conversion of any systemically administered prodrug to the active drug, using catalysts attached to the surface of the implant.

Injectable hydrogels with high fixed charge density and swelling pressure for nucleus pulposus repair: biomimetic glycosaminoglycan analogues.

The load-bearing biomechanical role of the intervertebral disc is governed by the composition and organization of its major macromolecular components, collagen and aggrecan. The major function of aggrecan is to maintain tissue hydration, and hence disc height, under the high loads imposed by muscle activity and body weight. Key to this role is the high negative fixed charge of its glycosaminoglycan side chains, which impart a high osmotic pressure to the tissue, thus regulating and maintaining tissue hydration and hence disc height under load. In degenerate discs, aggrecan degrades and is lost from the disc, particularly centrally from the nucleus pulposus. This loss of fixed charge results in reduced hydration and loss of disc height; such changes are closely associated with low back pain. The present authors developed biomimetic glycosaminoglycan analogues based on sulphonate-containing polymers. These biomimetics are deliverable via injection into the disc where they polymerize in situ, forming a non-degradable, nuclear "implant" aimed at restoring disc height to degenerate discs, thereby relieving back pain. In vitro, these glycosaminoglycan analogues possess appropriate fixed charge density, hydration and osmotic responsiveness, thereby displaying the capacity to restore disc height and function. Preliminary biomechanical tests using a degenerate explant model showed that the implant adapts to the space into which it is injected and restores stiffness. These hydrogels mimic the role taken by glycosaminoglycans in vivo and, unlike other hydrogels, provide an intrinsic swelling pressure, which can maintain disc hydration and height under the high and variable compressive loads encountered in vivo.

Improving dosing of gentamicin in the obese patient: a 3-cycle drug chart and case note audit.

OBJECTIVES: To assess the use of an electronic dose calculator to improve accuracy in the use of a complex Gentamicin prescription policy and assess turnaround time of blood sampling to dose delivery in an NHS hospital. DESIGN: Retrospective review of drug chart, case notes and hospital antibiotic database. SETTING: University Hospitals Bristol, UK PARTICIPANTS: Patients receiving once daily intravenous gentamicin using the trust protocol, during the same time window for 3 consecutive years. MAIN OUTCOME MEASURES: i) Accuracy of dose and frequency prescription of Gentamicin. ii) Time frame for measurement of serum Gentamicin levels. RESULTS: Following the introduction of the online calculator, prescribing errors in obese patients dropped from 43% to 20%, a similar level as in non-obese patients. Errors in frequency calculations dropped from 12.8% to 4%. On average, drug doses could be administered within 2.5 hours of a blood sample being taken. CONCLUSIONS: Online tools can be used to improve prescribing for the complex dosing policies that will increasingly been required to tailor prescribing in obese patients. Serum gentamicin levels can be measured within a 2.5 hour time frame in the environment of an NHS hospital.

Acute tendon injuries in the hand and their management.

Acute tendon injuries to the hand are common. In the UK, there are approximately 12000 inpatient admissions annually for injuries to the tendons and muscles of the hand and wrist (Dew, 2009). Hand injuries involving the dominant hand can cause long-term disability if not appropriately managed. Diagnosis of tendon injuries in the hand relies on careful clinical assessment, particularly if flexor and extensor tendon injuries are not to be missed. This article describes the tendon structure, explains the causes of tendon injury and discusses their assessment and management for a foundation level doctor who will face these injuries regularly whether in primary care or the emergency department.

Replication forks of Escherichia coli are not the preferred sites for lysogenic integration of bacteriophage Mu.

The question of whether bacteriophage Mu prefers replication forks for lysogenic integration into Escherichia coli chromosomes was tested by using two different systems. In the first, inactivation of genes was scored in synchronized cultures infected by Mu at various times. No increase in the mutation frequency of a gene was found after infection at the time of its replication. In the second, the composition of colonies formed by bacteria lysogenized by Mu was determined; the newly formed lysogens should give rise to mixed colonies (containing lysogenized as well as nonlysogenized bacteria), uniform colonies, or both, depending on the mode of integration. Both types of colonies were found, and the fraction of uniform colonies was proportional to the relative length of the unreplicated segment of an average chromosome in the culture. The results in both systems clearly preclude the possibility that a lysogenizing Mu integrates with high preference at the chromosome replication forks.

Simulation of atrial activity by a phase response curve based model of a two-dimensional pacemaker cells array: the transition from a normal activation pattern to atrial fibrillation.

In this paper, we present an original model of the atria, based on our hypothesis that atrial cells have features of pacemaker cells, characterized by their normally longer intrinsic cycle lengths and different type of connection (stronger) than the, sino-atrial (SA) node pacemaker cells. The atrium is simulated by a two-dimensional array of pacemaker cells (25 x 25), composed of a region of SA node pacemaker cells (11 x 11) surrounded by atrial pacemaker cells. All pacemakers cells are characterized by only the most relevant functional properties, those which play the most direct role in the determination of the cardiac rate and in the mechanism of arrhythmias. These properties are: the intrinsic cycle length, tau, an 'internal' feature of each pacemaker cell, and the phase-response curve (PRC), an 'overall collective' function. The PRC embodies the interactions of each pacemaker cell with its neighboring cells, and thus represents the type of connection (strong, weak, etc.) of the pacemaker cell with its surroundings. In our model, the SA node region differs from the atrial region by cycle length distribution and PRCs. We studied the spatial interaction between SA node pacemaker cells and atrial pacemaker cells as a function of the regional variation of cells properties and as a function of the "electrical" coupling between cells (the PRC), in the SA node region, in the atrial region, and in a border zone between them. We investigated the influence of those parameters on the activation pattern, on the conduction time of the array, and on a pseudo-ECG signal. This study demonstrates that by representing the atrial cells as a population of 'pacemaker-like' cells, similar to the SA node pacemaker cells, but differing markedly in their cycle lengths and cell-to-cell interaction (PRC), we can create a global picture of the atrial system by applying a simple physical-mathematical model. This approach enables us to explore physiological phenomena related to the genesis and maintenance of atrial activity. It also reveals the conditions which predispose to atrial arrhythmias and conduction disturbances (e.g. tachycardia, pacemaker shift, re-entry, fibrillation). In particular, it yields insight into the mechanism of transition from normal atrial activity to the disordered state of atrial fibrillation. Therefore, this study suggests a new way of looking at the development of cardiac arrhythmias of atrial origin.

A PRC based model of a pacemaker cell: effect of vagal activity and investigation of the respiratory sinus arrhythmia.

In this study we present a computer model of a pacemaker cell subjected to vagal stimulation. This model allows us to investigate the entrainment phenomena of the pacemaker cell resulting from its dynamic interaction with a periodic train of vagal bursts. The possibility of entrainment depends mainly on the fact that a vagal stimulation discharge can "correct" the pacemaker rhythm by an amount that depends on its instantaneous relationship to the pacemaker cycle length. This very simple model, is based on the two most important functional properties of the cardiac pacemaker cells. The first property is the intrinsic pacemaker cycle length, which is an "internal" parameter of the cell, describing the most basic feature of a pacemaker cell. The second one is the phase response curve (PRC), which is an "overall collective" function, containing all the "information" about the possible interactions between the pacemaker cell and the outside world (i.e. its interaction with surrounding cells, external stimulus, etc.). A "collective" PRC was reconstructed from the resulting effects of all the pulses composing a burst. It appears that the PRC parameters as well as the vagal burst parameters are important factors in predicting the entrainment phenomena. Specifically, we found that the tendency of the pacemaker cell to become synchronized with bursts of vagal activity is greater, the larger the number of pulses per burst. However, increasing the number of pulses may also increase the tendency of the pacemaker towards instability, which was unveiled as changes in the configuration of the "collective" PRC. We applied the periodic train of vagal bursts so as to simulate the respiratory sinus arrhythmia (RSA) modulation on the pacemaker cell. We included also a modulation of sympathetic origin, represented as periodic changes in the intrinsic pacemaker cycle length. The frequency response of the pacemaker to "autonomic" modulations allowed us to demonstrate that the RSA dynamics can be interpreted in terms of the entrainment of the pacemaker cell by the respiratory modulation of vagal activity.

A phase response curve based model: effect of vagal and sympathetic stimulation and interaction on a pacemaker cell.

This study introduces a simple mathematical model for a pacemaker cell affected by an external parasympathetic and/or sympathetic input. The model presented is based on the two most important functional properties of the cardiac pacemaker cells. The first property is the intrinsic pacemaker cycle length, an "internal" parameter of the cell. The second basic property is the phase response curve (PRC), a function which reflects the various interactions of the pacemaker cell with the outside world (i.e. interaction with surrounding cells, external stimulus). The vagal stimulus is simulated as affecting the pacemaker cycle length via a PRC, while the sympathetic input is expressed in the model as a continuous reduction in the pacemaker cycle length. When combined vagal and sympathetic activation is allowed, our model shows that autonomic systems are also capable of interacting. First, we studied the entrainment phenomena resulting from a repetitively applied vagal stimulus. Various complex patterns of dynamic interaction between the pacemaker cell and the vagal input were simulated. The PRC parameters appear to be an important factor in the prediction of the entrainment phenomena. Specifically, they permit a quantitative description of the limits of a 1:1 synchronization zone. Next, we apply this model to qualitatively investigate the phenomenon of "accentuated antagonism" between parasympathetic and sympathetic autonomic branches. We examined the various options for this interaction in regulating the pacemaker periodicity. Although this model is a simplified reflection of the biological system, we conclude that it can mimic many aspects of the dynamic autonomic control and of the possible interactions between vagal and sympathetic stimulation of a pacemaker cell.

A single pacemaker cell model based on the phase response curve.

A single pacemaker cell model and its response to repetitive external depolarization stimulations is described in this paper. This model is a simple model based on the two most important functional properties of the cardiac pacemaker cells. The first property is the intrinsic pacemaker cycle length, which is an 'internal' parameter of the cell, describing the most important feature of a pacemaker cell. The second functional property is the phase response curve (PRC), which is an 'overall collective' function: it contains all the 'information' about the possible interactions of the pacemaker cell with the outside world (external stimulus, interaction with surrounding cells, etc.). This study demonstrates that by representing the pacemaker cell only by two fundamental features, and by applying a simple physical-mathematical model, a global picture of the system can be achieved, allowing us to explore qualitatively various physiological phenomena related to the pacemaker function. For example, we demonstrated that the PRC is a crucial parameter in the prediction of the entrainment phenomena of a single pacemaker cell in response to a periodic train of depolarization pulses. Specifically, the PRC permits a quantitative determination of the 1:1 synchronization range for a single pacemaker cell and an external depolarization pulse. Moreover, we show that the PRC can be used to represent the type of external stimulus applied to the pacemaker (e.g. depolarization pulse) and its intensity. Therefore, the PRC emerges as an important determinant and a useful 'tool' for the understanding of the dynamic interaction of pacemaker cells with the outside world. As a result of our simulations, we unveil a new important parameter: the 'degree of influence', which determines the range of 1:1 synchronization between an external depolarization pulse and a pacemaker cell. This interaction parameter is a direct function of the PRC parameters. It appears to be a helpful 'tool' for the understanding of synchronization and mutual entrainment mechanisms between the pacemaker cell and an external stimulus, and therefore it supports the basic importance of the PRC in the description and determination of these mechanisms.