Effect of anisotropy on ventricular vulnerability to unidirectional block and reentry by single premature stimulation during normal sinus rhythm in rat heart.

Single high-intensity premature stimuli when applied to the ventricles during ventricular drive of an ectopic site, as in Winfree's "pinwheel experiment," usually induce reentry arrhythmias in the normal heart, while single low-intensity stimuli barely do. Yet ventricular arrhythmia vulnerability during normal sinus rhythm remains largely unexplored. With a view to define the role of anisotropy on ventricular vulnerability to unidirectional conduction block and reentry, we revisited the pinwheel experiment with reduced constraints in the in situ rat heart. New features included single premature stimulation during normal sinus rhythm, stimulation and unipolar potential mapping from the same high-resolution epicardial electrode array, and progressive increase in stimulation strength and prematurity from diastolic threshold until arrhythmia induction. Measurements were performed with 1-ms cathodal stimuli at multiple test sites (n = 26) in seven rats. Stimulus-induced virtual electrode polarization during sinus beat recovery phase influenced premature ventricular responses. Specifically, gradual increase in stimulus strength and prematurity progressively induced make, break, and graded-response stimulation mechanisms. Hence unidirectional conduction block occurred as follows: 1) along fiber direction, on right and left ventricular free walls (n = 23), initiating figure-eight reentry (n = 17) and tachycardia (n = 12), and 2) across fiber direction, on lower interventricular septum (n = 3), initiating spiral wave reentry (n = 2) and tachycardia (n = 1). Critical time window (55.1 ± 4.7 ms, 68.2 ± 6.0 ms) and stimulus strength lower limit (4.9 ± 0.6 mA) defined vulnerability to reentry. A novel finding of this study was that ventricular tachycardia evolves and is maintained by episodes of scroll-like wave and focal activation couplets. We also found that single low-intensity premature stimuli can induce repetitive ventricular response (n = 13) characterized by focal activations.NEW & NOTEWORTHY We performed ventricular cathodal point stimulation during sinus rhythm by progressively increasing stimulus strength and prematurity. Virtual electrode polarization and recovery gradient progressively induced make, break, and graded-response stimulation mechanisms. Unidirectional conduction block occurred along or across fiber direction, initiating figure-eight or spiral wave reentry, respectively, and tachycardia sustained by scroll wave and focal activations.

[Can Quality of Patient Identification be Influenced by Training? - Results of a Randomised Multicentre Study with Multimodal Intervention]. / Welchen Einfluss haben Schulungen auf die Qualität der Patientenidentifikation? ­ Ergebnisse aus einer randomisierten, multizentrischen und multimodalen Interventionsstudie.

Background: Attributing clinical care to patients unambiguously is a precondition for patient safety. The German Coalition for Patient Safety has published a recommendation on this topic. Issue: The here presented study examined whether and to what extent documentation quality as one determining factor of correct patient identification can be improved positively by inter-professional training. Method: In our randomised multi-centric study physicians and nurses from 8 units in 4 hospitals were trained. The control group consisted of untrained unit teams. Effects of the intervention were measured by investigating documentation errors in clinical records before and after the training. Results: As a result of our intervention the number of documents with documentation errors/patient charts could be reduced by 37.3% (p<0.001). Conclusion: The results of the study point to the training of recommendations on preventing errors as an effective instrument for the improvement of patient safety.

[Development, Application and Evaluation of a Concept for Safe Patient Identification in Hospital - How can Knowledge Transfer Succeed?] / Entwicklung, Anwendung und Evaluation eines Konzeptes zur sicheren Patientenidentifikation im Krankenhaus ­ Wie kann der Wissenstransfer gelingen?

Aim of the Study: In order to minimise the risk of patient misidentification in clinical settings, the German Coalition for Patient Safety published recommendations for safety patient identification in 2008. The aim of this study was to develop, implement and evaluate a theoretical framework of knowledge transfer. The purpose of the framework was to enhance hospital staff's ability to apply the recommendations for safe patient identification in the daily routine of patient care. Method: A data bank-based research and literature review have been conducted. Research topics were: knowledge transfer, change management and implementation science. Within the application of the concept group interviews were held with hospital staff and the interview material was evaluated using content analysis. On this basis a tailored multifaceted implementation strategy has been developed and applied in 8 hospital wards of 4 hospitals belonging to a communal hospital concern. The evaluation of the developed knowledge transfer concept was conducted 4 weeks after the concept application with a written questionnaire. Results: The developed framework concept of knowledge translation consisted of 4 phases built on top of each other: initiation phase; analysis phase; implementation phase; evaluation phase. The multifaceted implementation strategy included 3 interventions: a poster, a computer-based training and a guideline for team meetings. The survey yielded responses from 56 individuals: 96% declared that they know about the existence of the recommendations for safe patient identification; 86% said that they know about the content of the recommendations; 91% have striven to apply the recommendations in the daily routine of patient care; 71% stated that the recommendations for safe patient identification have become integral part in the daily routine of patient care. To become aware of the recommendations and its content the respondents have used on average 2.3 interventions, however the effect of the CBS was relatively small. Conclusion: The developed theoretical framework concept for knowledge transfer provides a way to integrate the recommendations for safe patient identification in the daily routine of patient care and to counteract risk factors promoting misidentification. Therefore a multifaceted implementation strategy is promising.

[Improvement of medication safety by identification of genetically predisposed subjects. Personalized clinical strategies and regulatory advices]. / Erhöhung der Arzneimitteltherapiesicherheit durch Identifizierung genetisch prädisponierter Personen. Personalisierte klinische Ansätze und regulatorische Maßnahmen.

BACKGROUND: Because adverse drug events (ADEs) have a high socio-economic impact there is an urgent need for effective prevention. In addition to process-related avoidable errors personalised approaches for the prevention of ADEs should also focus on genetic polymorphisms as potential causative agents. AIM: Using five case reports as examples therapeutic modalities are described to illustrate the clinical impact of prospective testing aimed at estimating the individual risk of susceptible subjects. MATERIAL AND METHODS: The role of the HLA system, the cytochrome P450 family, other metabolic enzymes and transport proteins are described to illustrate the broad range of genetic susceptibility. It is shown, why, when and for whom pretherapeutic tests on genetic polymorphisms are recommended to reduce the risk of ADEs. RESULTS: The determination of genetic susceptibility is already implemented in clinical practice prior to (1) carbamazepine therapy in south-east Asians and (2) treatment with abacavir independent of ethnicity. Before prescribing carbamazepine or abacavir, it is recommended that therapeutic decisions be based on these test results. CONCLUSION: The broad application of personalised medicine used as an effective tool for minimizing ADE risks is limited by the evidence-based benefit for the patient on the one hand and the costs of the test on the other hand.

[Patient safety indicators for medication safety (AMTS-PSI): international status, transferability and validation]. / Patientensicherheitsindikatoren zur Arzneimitteltherapiesicherheit (AMTS-PSI): Internationaler Status, Übertragbarkeit und Validierung*

BACKGROUND: The aim of this project was to identify international patient safety indicators used for medication safety (AMTS-PSI), to evaluate the validity by a panel of experts, and to examine the transfer of the international AMTS-PSI to the pharmacotherapy care of the German Health Care System. It was part of the "Agenda for the Improvement of Medication Safety 2008/2009 in Germany" of the German Ministry of Health. METHOD: National and international AMTS-PSI were identified by a systematic review (Set 1). To define patient safety indicators as a subdivision of quality indicators, the indicators were categorised by patient's risk of adverse drug events and the degree of prevention (Set 2). Duplicates of AMTS-PSI were excluded (Set 3). The content validity was determined by the "qualify-instrument" on categories "relevance", "evidence" and "feasibility". This process was based on a double-stage Delphi method. The transferability to the pharmacotherapy care of the German Health Care System of the AMTS-PSI was evaluated (Set 4). RESULTS: 385 AMTS-indicators were identified. The categorisation resulted in a set of 40 AMTS-PSI, 20 AMTS-PSI were excluded. The evaluation of the validity by the "qualify-instrument" and the transferability resulted in a set of 14 for the stationary, ambulant sector. They also were valid for both sectors. CONCLUSION: An AMTS-PSI-set was identified by a systematic review and recognised as valid for transferring it to the pharmacotherapy care of the German Health Care System by the "qualify-instrument". These 14 AMTS-PSI are mainly characterised by their relevance. Before using these indicators in practice, their further operationalisation seems necessary.

Porphyromonas gingivalis Impairs Oral Epithelial Barrier through Targeting GRHL2.

Oral mucosa provides the first line of defense against a diverse array of environmental and microbial irritants by forming the barrier of epithelial cells interconnected by multiprotein tight junctions (TJ), adherens junctions, desmosomes, and gap junction complexes. Grainyhead-like 2 (GRHL2), an epithelial-specific transcription factor, may play a role in the formation of the mucosal epithelial barrier, as it regulates the expression of the junction proteins. The current study investigated the role of GRHL2 in the Porphyromonas gingivalis (Pg)-induced impairment of epithelial barrier functions. Exposure of human oral keratinocytes (HOK-16B and OKF6 cells) to Pg or Pg-derived lipopolysaccharides (Pg LPSs) led to rapid loss of endogenous GRHL2 and the junction proteins (e.g., zonula occludens, E-cadherin, claudins, and occludin). GRHL2 directly regulated the expression levels of the junction proteins and the epithelial permeability for small molecules (e.g., dextrans and Pg bacteria). To explore the functional role of GRHL2 in oral mucosal barrier, we used a Grhl2 conditional knockout (KO) mouse model, which allows for epithelial tissue-specific Grhl2 KO in an inducible manner. Grhl2 KO impaired the expression of the junction proteins at the junctional epithelium and increased the alveolar bone loss in the ligature-induced periodontitis model. Fluorescence in situ hybridization revealed increased epithelial penetration of oral bacteria in Grhl2 KO mice compared with the wild-type mice. Also, blood loadings of oral bacteria (e.g., Bacteroides, Bacillus, Firmicutes, ß-proteobacteria, and Spirochetes) were significantly elevated in Grhl2 KO mice compared to the wild-type littermates. These data indicate that Pg bacteria may enhance paracellular penetration through oral mucosa in part by targeting the expression of GRHL2 in the oral epithelial cells, which then impairs the epithelial barrier by inhibition of junction protein expression, resulting in increased alveolar tissue destruction and systemic bacteremia.

Effect of glucose on Treponema denticola cell behavior.

INTRODUCTION: Treponema denticola inhabits the oral subgingival environment and is part of a proteolytic benzoyl-dl-arginine-naphthylamide-positive 'red complex' associated with active periodontal disease. Spirochetes have a unique form of chemotactic motility that may contribute to their virulence. Chemotaxis is essential for efficient nutrient-directed translocation. METHODS: We examined the effect of glucose on T. denticola cell velocity, expression of periplasmic flagella proteins, and chemotaxis, e.g. translocation into capillary tubes. RESULTS: The presence of glucose did not significantly effect T. denticola cell velocity in high viscosity conditions nor did it alter periplasmic flagella protein expression. The addition of glucose to capillary tubes resulted in greater numbers of T. denticola cells in tubes containing glucose. A non-motile mutant did not migrate into capillary tubes containing glucose. CONCLUSION: These results are consistent with a chemotactic response to glucose that is motility dependent.

Myocardial electrical propagation in patients with idiopathic dilated cardiomyopathy.

Myocardial propagation may contribute to fatal arrhythmias in patients with idiopathic dilated cardiomyopathy (IDC). We examined this property in 15 patients with IDC undergoing cardiac transplantation and in 14 control subjects. An 8 x 8 array with electrodes 2 mm apart was used to determine the electrical activation sequence over a small region of the left ventricular surface. Tissue from the area beneath the electrode array was examined in the patients with IDC. The patients with IDC could be divided into three groups. Group I (n = 7) had activation patterns and estimates of longitudinal (theta L = 0.84 +/- 0.09 m/s) and transverse (theta T = 0.23 +/- 0.05 m/s) conduction velocities that were no different from controls (theta L = 0.80 +/- 0.08 m/s, theta T = 0.23 +/- 0.03 m/s). Group II (n = 4) had fractionated electrograms and disturbed transverse conduction with normal longitudinal activation, features characteristic of nonuniform anisotropic properties. Two of the control patients also had this pattern. Group III (n = 4) had fractionated potentials and severely disturbed transverse and longitudinal propagation. The amount of myocardial fibrosis correlated with the severity of abnormal propagation. We conclude that (a) severe contractile dysfunction is not necessarily accompanied by changes in propagation, and (b) nonuniform anisotropic propagation is present in a large proportion of patients with IDC and could underlie ventricular arrhythmias in this disorder.

Elucidation of a PTS-carbohydrate chemotactic signal pathway in Escherichia coli using a time-resolved behavioral assay.

Chemotaxis of Escherichia coli toward phosphotransferase systems (PTSs)-carbohydrates requires phosphoenolpyruvate-dependent PTSs as well as the chemotaxis response regulator CheY and its kinase, CheA. Responses initiated by flash photorelease of a PTS substrates D-glucose and its nonmetabolizable analog methyl alpha-D-glucopyranoside were measured with 33-ms time resolution using computer-assisted motion analysis. This, together with chemotactic mutants, has allowed us to map out and characterize the PTS chemotactic signal pathway. The responses were absent in mutants lacking the general PTS enzymes EI or HPr, elevated in PTS transport mutants, retarded in mutants lacking CheZ, a catalyst of CheY autodephosphorylation, and severely reduced in mutants with impaired methyl-accepting chemotaxis protein (MCP) signaling activity. Response kinetics were comparable to those triggered by MCP attractant ligands over most of the response range, the most rapid being 11.7 +/- 3.1 s-1. The response threshold was <10 nM for glucose. Responses to methyl alpha-D-glucopyranoside had a higher threshold, commensurate with a lower PTS affinity, but were otherwise kinetically indistinguishable. These facts provide evidence for a single pathway in which the PTS chemotactic signal is relayed rapidly to MCP-CheW-CheA signaling complexes that effect subsequent amplification and slower CheY dephosphorylation. The high sensitivity indicates that this signal is generated by transport-induced dephosphorylation of the PTS rather than phosphoenolpyruvate consumption.