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Guinea-pig cardiac myocytes loaded intracellularly with Na+ show spontaneous contractile activity and transient membrane depolarizations or inward currents. We have investigated whether both phenomena can be attributed to release of Ca2+ from overloaded cellular stores causing contractile activation and at the same time generating an inward current due to Ca2+ efflux by the electrogenic Na+/Ca2+ exchange. Variations in membrane potential by voltage clamp or in ionic composition of the superfusion medium changed the amplitude and frequency of spontaneous inward currents in the direction expected from computations of the Na+/Ca2+ exchange. Caffeine in concentrations that activate the Ca2+ release channel of the sarcoplasmic reticulum produced a vigorous contraction accompanied by a large current transient. After exposure to ryanodine both Isp and spontaneous contractions were abolished. Spontaneous inward currents were depressed by inhibitors of the Na+/Ca2+ exchange. The results with caffeine and ryanodine demonstrate that unimpaired sarcoplasmic reticular function is a prerequisite for both the contractile and the electrical event. From the characteristics of Isp it is proposed that this current is due to electrogenic Na+/Ca2+ exchange.

Scientific research on empowerment so far is nearly exclusively focused on the adult population. Nevertheless, it is possible to show a link between empowerment and a) the developmental psychology concepts of resilience, b) autogenetic concepts and c) concepts of risks and resources. This paper aims to study the role of personal, familial and other social resources as well as personal autonomy for subjective health-ratings.A secondary analysis of the health data of 7,000 children and adolescents aged 10-17 years of the German health behaviour in school-aged children (HBSC) study as well as 1,700 children aged 11-17 years of the mental health module (BELLA Study) within the German health interview and examination survey for children and adolescents (KiGGS) was performed. Statistical analyses encompassed analyses of variance and linear regression.Analyses of the HBSC study showed a protective effect for school-class climate as well as parental support, whereby school was associated with fewer self-reported health complaints. Analyses of the BELLA/KiGGS study showed personal, familial and other social resources as well as personal autonomy as unique predictors for a better health-related quality of life (KINDL-R). This was true even if psychological problems were observed.The results confirm the importance of strengthening personal, familial and other social resources as well as the principal importance of personal autonomy for coping with health risks and health impairments. Future research explicitly focussed on empowerment could relate to the role of personal resources within children's and adolescents' contact with the medical and health care system. It can be expected that strengthening personal resources benefits and improves the communication and active participation of children and adolescents within treatment-decision and -evaluation.

The human cardiac transient outward potassium current (Ito) is believed to be composed of the pore-forming Kv4.3 alpha-subunit, coassembled with modulatory beta-subunits as KChIP2, MiRP1 and DPP6 proteins. beta-Subunits can alter the pharmacological response of Ito; therefore, we analysed the effects of flecainide on Kv4.3/KChIP2 channels coassembled with MiRP1 and/or DPP6 beta-subunits.Currents were recorded in Chinese hamster ovary cells stably expressing K(V)4.3/KChIP2 channels, and transiently transfected with either MiRP1, DPP6 or both, using the whole-cell patch-clamp technique.In control conditions, Kv4.3/KChIP2/MiRP1 channels exhibited the slowest activation and inactivation kinetics and showed an 'overshoot' in the time course of recovery from inactivation. The midpoint values (Vh) of the activation and inactivation curves for Kv4.3/KChIP2/DPP6 and Kv4.3/KChIP2/MiRP1/DPP6 channels were approximately 10 mV more negative than Vh values for Kv4.3/KChIP2 and Kv4.3/KChIP2/MiRP1 channels. Flecainide (0.1-100 microM) produced a similar concentration-dependent blockade of total integrated current flow (IC50 approximately 10 microM) in all the channel complexes. However, the IC50 values for peak current amplitude and inactivated channel block were significantly different. Flecainide shifted the Vh values of both the activation and inactivation curves to more negative potentials and apparently accelerated inactivation kinetics in all channels. Moreover, flecainide slowed recovery from inactivation in all the channel complexes and suppressed the 'overshoot' in Kv4.3/KChIP2/MiRP1 channels.Flecainide directly binds to the Kv4.3 alpha-subunit when the channels are in the open and inactivated state and the presence of the beta-subunits modulates the blockade by altering the gating function.

Mental health problems in children and adolescents constitute health impairments with major implications regarding individual wellbeing as well as daily and social functioning. In addition, these problems often burden the social partners of the individual. Within the German Health Interview and Examination Survey for Children and Adolescents (KiGGS), the parents of 14478 children and adolescents aged 3-17 answered the Strengths and Difficulties Questionnaire (SDQ) which assesses behavioral problems and strengths in the areas emotional problems, hyperactivity, behavioral problems, peer problems and prosocial behavior. According to the results of the Total Difficulties Score (SDQ) 11,5 % girls (G) and 17,8 % boys (B) are classified borderline or abnormal, respectively. 92,5 % (G) and 86,3 % (B) display an adequate pro social behavior. Most prevalent problem areas are behavioral problems (G = 11,9 %, B = 17,9 %), emotional problems (G = 9,7 %, B = 8,6 %) and hyperactivity problems (G = 4,8 %, B = 10,8 %). The test-data of approximately 8,1 % of the respondents with high socio-economic status (SES), 13,4 % of those with middle SES and 23,2 % of those with low SES hinted at mental health problems. Migrants are more frequently affected than non-migrants. Results point at the need for early detection and prevention of commencing mental health problems. Especially the noneasily accessible groups like those with low socioeconomic status or migrants have to be considered.

This study investigates the health-related quality of life of children and adolescents in Germany, using the internationally employed KINDL-R questionnaire for measuring the health-related quality of life of children and adolescents. In the National Health Interview and Examination Survey for Children and Adolescents (KiGGS) the parents of 14,836 children and adolescents aged 3-17 years completed the KINDL-R, as well as 6,813 children and adolescents (11-17 years old). The reliability (Cronbach's alpha = 0.85) and validity of the measurements using the KINDL-R were confirmed. The differences in health-related quality of life of children and adolescents from different social backgrounds and with different health statuses, which were to be expected on theoretical grounds, were demonstrated by the KINDL-R scores (size of effect "d" up to 1.52). The means and percentiles were calculated for the total sample as well as stratified by age group, sex, geographical region (East/West), migratory status and socio-economic status. The results of this study can be used as representative, normative data for the population of children and adolescents in Germany in general, as well as stratified for sociodemographic and socio-economic subpopulations, in order to interpret test scores on health-related quality of life (KINDL-R).

There have long been reservations about measuring quality of life of children and adolescents, but those have been largely overcome by the development of validated methods such as the KINDL(R) Life Quality Questionnaire. There is a consensus nowadays about the most important dimensions of children's quality of life. Reliable data can be obtained also in dimensions other than those known in adults (self-esteem, satisfaction of relations with those of similar age, school performance). Quality of life can now be examined in relation to age and developmental stage. As judgments made by parents and children differ, opinions given by others may provide additional information, but can replace self-assessment to only a small extent. In therapeutic decisions involving older children or adolescents their own pronouncements are used in preference. Examples are given to show that also in paediatrics investigations of quality of life can contribute to assessing needs, decision-making and quality control in medical care. Paying attention to aspects concerning quality of life represents a changed attitude within medicine. Subjective estimates of their health given by young persons may in future provide a yardstick for medical action.

During the last ten years we have made substantial progress in our understanding of the underlying mechanisms of atrial fibrillation. The high rate associated alterations in electrical and structural properties of the atria, referred to as atrial remodeling, promote the progression of atrial fibrillation. The development of new therapeutic approaches addresses three different directions: (i) prevention of atrial remodeling, especially of structural remodeling; (ii) increase of long-term efficacy of currently used drugs and improvement of their side-effect profile; and (iii) design of atria- and pathology-specific antiarrhythmic drugs without concomitant proarrhythmic effects in the ventricles. The current review outlines the pathophysiology of atrial fibrillation and focuses on electrical remodeling. The properties of new antiarrhythmic drugs for atrial fibrillation are discussed in detail.

The SF-8, a relatively new instrument for measuring health-related quality of life, was used in the German National Telephone Health Survey 2003. The SF-8 provides results which are comparable to those of the SF-36, the instrument most commonly used internationally. The German National Telephone Health Survey provides nationally representative data for the residential population in Germany aged 18 and older. In addition to the measurement of health-related quality of life, comprehensive information on chronic illnesses and complaints, health care needs, utilisation of health care, risk factors, risk behaviour and social status is also collected, making differentiated analyses possible. According to the data collected, men rate their quality of life in all dimensions higher than women. With increasing age, quality of life for both men and women decreases in the physical dimensions, while increasing in the mental health dimensions. Apart from chronic disease and pain having a negative impact on health-related quality of life, social differences are also observable, in that worse health-related quality of life is reported by respondents with lower socioeconomic status.

Within a comprehensive comparison of telephone and postal survey methods the SF-8 was applied to assess adult's health-related quality of life. The 1690 subjects were randomly assigned to a telephone survey and a postal survey. Comparisons across the different modes of administration addressed the response rates, central tendency, deviation, ceiling and floor effects observed in the SF-8 scores as well as the inter-item correlation. The importance of age and gender as moderating factors was investigated. Results indicate no or small statistically significant differences in the responses to the SF-8 depending on the actual mode of administration and the health aspect questioned. It was concluded that further investigations should focus on the exact nature of these deviations and try to generate correction factors.

To obtain a Spanish version of the Kindl semantically and culturally equivalent to the original German version and to test its psychometric properties.The methodology used in the adaptation process was based on the forward-backward translation method. To assess the psychometric properties of the Spanish Kindl, the pilot test of the project "Screening for and promotion of HRQL in children and adolescents: a European Public Health perspective (Kidscreen)" it was include in. A classroom was selected for each educational level (8-16 years old) from three schools in Gerona and Barcelona. The Spanish Kindl was administered twice, one week apart. Internal consistency was assessed by computing Cronbach alpha and test-retest stability was assessed using intraclass correlation coefficients (ICC). Analysis of variance was performed according to age, sex, type of school, and self-perceived health status.Half of the items (12/24) required minor changes during the adaptation process. The response rate was 91 % (n = 447). Internal consistency was acceptable for most domains (alpha range = 0.40-0.88), as was test-retest stability (ICC range = 0.52-0.80). Girls and older teenagers scored worse in most domains (p0.01). No differences were found by type of school.The Spanish version of the Kindl showed adequate reliability and validity coefficients and represents a new HRQL instrument that can be applied in pediatric clinical practice and public health.

The National Health Survey for Children and Adolescents plans to collect data on the health status of children and adolescents in the 0-17 years age bracket which can be used for the generalisation and implementation of measures. In this context, assessment of mental and subjective health, in addition to collection of data concerning somatic health, is of great importance in a survey on the health status of children and adolescents in Germany. The proportion of children and adolescents afflicted by--in part long lasting--mental health problems and disorders is considerable. Subjective impairment due to somatic, psychological or social factors result in a reduced quality of life. Last but not least, personal, familial, and social assets of children and adolescents are relevant as protective factors for their mental and subjective health. Experiences and results from the pilot test of the survey demonstrate that the instruments selected for assessing mental health problems (SDQ), health related quality of life (KINDL), and assets (a combination of various scales) are appropriate for epidemiological purposes. They may supply valuable data to estimate the prevalence of mental health problems and psychiatric disorders, to identify risk groups needing intervention, and to describe the subjective health of children and adolescents in Germany.

Few instruments have been developed to screen emotional and behavioural problems and mental disorders using questionnaire methods in a broad study, as will be done in the Health Survey for Children and Adolescents. In the context of this survey's pretest, two questionnaires--the Child Behavior Checklist (CBCL) and the Strengths and Difficulties Questionnaire (SDQ)--were compared regarding their psychometric properties, their diagnostic power, and the study participants' acceptance of the instruments. With this comparison, the question was addressed concerning which of the two questionnaires mentioned above is more reliable, valid and acceptable to the participants in describing mental health problems and psychiatric disorders in a population-based survey intended for a target age group of 6 to 17-year olds. The results of this methodical comparison show that both instruments are comparably useful for screening purposes. Both instruments detected mental disorders that were established in a clinical interview with equal probability. In this regard, the self-report tends to be superior to the parents' report in the age group from 11 to 17 years. The SDQ displays a slightly higher acceptance and--in comparison to the CBCL--a considerably lower number of items. It can therefore be recommended for use in the survey.

Children's and adolescents' mental health is an epidemiological outcome of considerable public health relevance. This is based on a comparably high prevalence of mental health problems and disorders in children and adolescents. The supplementary study 'Mental Health', which is a modular part of the Health Survey for Children and Adolescents conducted by the Robert Koch Institute, aims at assessing the prevalence of specific mental health problems and disorders in a representative sample of children and adolescents in Germany. Furthermore, determinants of mental health will be studied in a developmental context. Screening to assess mental health problems will be performed in a representative sub-sample of the National Health Survey for Children and Adolescents. The sub-sample will comprise approximately 4,000 children and adolescents aged 7 to 17 years. Participants are interviewed once to assess the occurrence of risk factors and available assets (protective factors) for mental health, thus providing valuable data for health monitoring and planning (cross-sectional part of the study). A sub-group of this cross-sectional sample as well as an additional clinical sample are repeatedly studied in a longitudinal design. This part of the study is carried out to estimate the effect size of risk and protective factors on mental health, and to analyse their combined effects on the developmental process. From the findings, clues to effective prevention and intervention strategies can be derived.

In Public Health, an outlook developed emphasising the importance of assets and protective factors in addition to stress and risk factors. The study aimed at the development of a brief, multidimensional questionnaire to assess protective factors for the mental health of children and adolescents. This questionnaire was to be tested as a self-report survey instrument. In a random sample consisting of 883 children and adolescents aged 11 to 17 years scales already validated in empirical research as well as questions newly developed from aspects of protective factors identified in the literature were applied in a written questionnaire. Three dimensions, covering social, personal and family assets, could be identified from the items by factor analysis. The resulting scales for the assessment of protective factors were analysed for their psychometric characteristics. Mental health and health-related quality of life served as validation criteria. The protective factors proved to significantly influence these outcomes in regression analyses, showing a proportion of explained variance of up to 53 %. The child and adolescent self-report measure presented is apt to give a picture of protective factors for mental health representing the three dimensions of social, personal, and family assets.

Background: Peginterferon α-2b plus ribavirin therapy in previously untreated patients with chronic hepatitis C yields the highest sustained virological response rates of any treatment strategy but is expensive. Aims: To estimate the cost effectiveness of treatment with peginterferon α-2b plus ribavirin compared with interferon α-2b plus ribavirin for initial treatment of patients with chronic hepatitis C. Methods: Individual patient level data from a randomised clinical trial with peginterferon plus ribavirin were applied to a previously published and validated Markov model to project lifelong clinical outcomes. Quality of life and economic estimates were based on German patient data. We used a societal perspective and applied a 3% annual discount rate. Results: Compared with no antiviral therapy, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 4.2 and 4.7 years, respectively. Compared with standard interferon α-2b plus ribavirin, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 0.5 and by 1.0 years with incremental cost effectiveness ratios of €11 800 and €6600 per quality adjusted life year (QALY), respectively. Subgroup analyses by genotype, viral load, sex, and histology showed that peginterferon plus weight based ribavirin remained cost effective compared with other well accepted medical treatments. Conclusions: Peginterferon α-2b plus ribavirin should reduce the incidence of liver complications, prolong life, improve quality of life, and be cost effective for the initial treatment of chronic hepatitis C.

The European Society of Cardiology has convened a Task Force on Sudden Cardiac Death in order to provide a comprehensive, educational document on this important topic. The main document has been published in the European Heart Journal in August 2001. The Task Force has now summarized the most important clinical issues on sudden cardiac death and provided tables with recommendations for risk stratification and for prophylaxis of sudden cardiac death. The present recommendations are specifically intended to encourage the development and revision of national guidelines on prevention of sudden cardiac death. The common challenge for cardiologists, physicians of other medical specialties and health professionals throughout Europe is to realize the potential for sudden cardiac death prevention and to contribute to public health efforts to reduce its burden.

In most macrovascular endothelial cell (EC) preparations, resting membrane potential is determined by the inwardly rectifying K+ current (I(K1)), whereas in microvascular EC the presence of I(K1) varies markedly. Cultured microvascular EC from small vessels of human omentum were examined by means of the voltage-clamp technique to elucidate the putative role of I(K1) in maintaining resting membrane potential. Macrovascular EC from human iliac artery and bovine aorta served as reference. Human omentum EC showed an outwardly rectifying current-voltage relation. Inward current was hardly sensitive to variations of extracellular [K+] and Ba2+ block suggesting lack of I(K1). However, substitution of extracellular [Na+] and/or [Cl-] affected the current-voltage relation indicating that Na+ and Cl- contribute to basal current. Furthermore, outward current was reduced by tetraethylammonium (10 mM), and cell-attached recordings suggested the presence of a Ca2+-activated K+ current. In contrast to human omentum EC, EC from human iliac artery and bovine aorta possessed inwardly rectifying currents which were sensitive to variations of extracellular [K+] and blocked by Ba2+. Thus, the lack of I(K1) in human omentum EC suggests that resting membrane potential is determined by Na+ and Cl- currents in addition to K+ outward currents.

Clinical and experimental evidence suggest that the parasympathetic nervous system is involved in the pathogenesis of atrial fibrillation (AF). However, it is unclear whether changes in G-protein-coupled inward rectifying K(+) current (I(K,ACh)) contribute to chronic AF.In the present study, we used electrophysiological recordings and competitive reverse-transcription polymerase chain reaction to study changes in I(K,ACh) and the level of the I(K,ACh) GIRK4 subunit in isolated human atrial myocytes and the atrial tissue of 39 patients with sinus rhythm and 24 patients with chronic AF. The density of I(K,ACh) was approximately 50% smaller in myocytes from patients with AF compared with those in sinus rhythm, and this was accompanied by decreased levels of GIRK4 mRNA. The current density of the inward rectifying K(+) current (I(K1)) was 2-fold larger during AF than in sinus rhythm, in correspondence with an increase in Kir2.1 mRNA. The larger I(K1) in AF is consistent with more negative membrane potentials in right atrial trabeculae from AF patients. Moreover, action potential duration was reduced in AF, and the action potential shortening produced by muscarinic receptor stimulation was attenuated, indicating that the changes of I(K1) and I(K,ACh) were functionally relevant.Chronic human AF induces transcriptionally mediated upregulation of I(K1) but downregulation of I(K,ACh) and attenuates the muscarinic receptor-mediated shortening of atrial action potentials. This suggests that atrial myocytes adapt to a chronically high rate by downregulating I(K,ACh) to counteract the shortening of the atrial effective refractory period due to electrical remodeling.

Despite increased interest in the wellbeing of families with children with chronic conditions and disabilities, instruments to assess family impact of health conditions are still lacking in German speaking countries. The Impact on Family Scale has been developed in the Anglo-american literature as a self report instrument to assess the consequences of chronic conditions and disability in childhood and adolescence for the family. The present paper describes the translation and psychometric testing of a German version of the Impact on Family scale (Familien-Belastungs[FaBel]-Questionnaire). The questionnaire contains 33 Likert-scaled items to assess the general negative impact of parents, the description of social relationships, the concern for siblings, the financial impact and problems in coping as well as a total score. The FaBel questionnaire was used and tested for psychometric criteria of reliability and validity in a cross-sectional study of 273 families with children with chronic conditions and disabilities. The results of this psychometric testing of the FaBel-Questionnaire show acceptance by responders, acceptable construct validity, good internal consistency and discriminant validity. The psychometric structure of the questionnaire corresponds with psychometric results with another German population of children with chronic conditions. The results suggest the applicability of the instrument to assess family impact of chronic disease and disability in children and adolescents.

The atria and ventricles of transgenic mice (TGbeta(2)) with cardiac overexpression of the human beta(2)-adrenoceptor (beta(2)AR) were initially reported to show maximum contractility in the absence of beta-AR stimulation. However, we have previously observed a different phenotype in these mice, with myocytes showing normal contractility but reduced betaAR responses. We have investigated the roles of cyclic AMP and Gi in basal and betaAR function in these myocytes. ICI 118,551 at inverse agonist concentrations decreased contraction by 32%. However, the cyclic AMP antagonist Rp-cAMPS had no effect on contraction in TGbeta(2) myocytes, indicating that there was no tonic influence of raised cyclic AMP. These findings cannot be explained by the proposed model for inverse agonism, where the activated receptor (R*) raises cyclic AMP levels and so increases contraction in the absence of agonist. After pertussis toxin (PTX) pretreatment to produce inactivation of Gi, the basal contraction in 1 mM Ca(2+) was increased in TGbeta(2) mice (7.82+/-0.47%, n=23) compared to LM mice (3.60+/-0.59%, n=11) (P0.001). The contraction amplitude of myocytes to the maximal concentration of isoprenaline was also increased significantly by PTX in TGbeta(2) mice (9.40+/-1.22%, n=8) and was no longer reduced compared to LM mice (8.93+/-1.50%, n=11). Both beta(1)- and beta(2)AR subtypes were affected both by the original desensitization and by the resensitization with PTX. PTX treatment has therefore restored the original phenotype, with high basal contractility and little further effect of isoprenaline. We suggest that both beta-AR desensitization and lack of increased basal contraction in ventricular myocytes from our colony of TGbeta(2) mice were due to increased activity of PTX-sensitive G-proteins.

The subjectively perceived health of children and adolescents has received little attention in Public Health research so far. In co-operation with school physicians of Hamburg, Eimsbuettel, 1,501 children and adolescents (grades 4 and 8, as well as their parents) were questioned with regard to health-related quality of life and health behaviour, using among others the short form of the KINDL Quality of Life Questionnaire and established psychosocial instruments. High values in the KINDL scale were found in 75% of the students, the mean value of the 0-100 transformed KINDL total scale was around 80. Adolescents--and in this group specifically the girls--reported significantly lower quality of life scores. Psychosocial strain, presence of disease and school absenteeism were negatively associated with quality of life ratings. Health-related behaviours in terms of resources in the area of food intake and risk behaviours in terms of addiction, obesity and stressors correlated with subjective health as expected. In multiple regressions these factors explained 20% of the KINDL-score variance in the total group. Taking into account indicators of functional status and life satisfaction, the percentage of explained variance increased to over 50%; here these predictors yielded a correct classification of high vs. low self-reported quality of life in 90% of the cases. The study shows that subjective health is a methodologically adequate and scientifically interesting indicator which in the public health area can be used in epidemiological research, in health reporting and in school physicians' practice to identify young persons with quality of life impairments in order to provide early and in-focus support to this group.

In den letzten Jahren mehren sich die Bemuhungen um eine wissenschaftliche Fundierung der medizinischen Rehabilitation in Deutschland. Hierzu gehort eine klare Explikation der Ziele der Rehabilitation, eine Definition relevanter Dimensionen des Rehabilitationsergebnisses (Outcomes) sowie eine konkrete Operationalisierung der Indikatoren des Rehabilitationserfolgs. Zum Verstandnis des Rehabilitationsergebnisses ist zusatzlich die Einbeziehung sogenannter Pradiktoren der Rehabilitation von Noten. Ziel des folgenden Beitrags ist es, mit Hilfe einer Taxonomie der Outcomes des Rehabilitationserfolgs aussagekraftige Indikatoren zu identifizieren. Dies wird sowohl fur den Bereich der Erwachsenenrehabilitation, als auch fur den Bereich der Kinderrehabilitation dargestellt.

While esthetic and functional outcomes of treatment have improved for patients with cleft lip and palate (CLP), a CLP remains a severe problem for patients and relatives. To date, psychological research has dealt with issues such as intelligence, self-consciousness or treatment satisfaction but the long-term impact of a CLP on a psychological construct such as quality of life has yet to be explored. From a pool of 156 patients with CLP, subgroups of varying sizes were examined with a set of standardized questionnaires (KINDL, SF-36, Social Support Survey). In all patients, primary operative treatment had been accomplished. Long-term impact of the CLP on family life was assessed by 112 of the patients' parents by filling in the Impact on Family Scale. A set of questionnaires, especially developed for patients with CLP, was administered as well. For all patients who have been being treated in an interdisciplinary cleft center for their entire life, the results presented indicate that quality of life is good and within a normal range. Social support appears to be within a normal range. Parents report only minor long-term impact of the CLP on family life and family planning. Treatment satisfaction is high in the CLP patients. The questionnaires especially aimed at CLP patients indicate more specific problems mainly concerning social acceptance, where patients think the CLP had a negative impact. The standardized questionnaires employed so far failed to capture these problems. The combination of the two types of questionnaires is a sufficiently sensitive assessment procedure.

1. The putative inhibitory effects of verapamil and diltiazem on neuronal non-L-type Ca2+ channels were studied by investigating their effects on either K+- or veratridine-evoked [3H]-dopamine ([3H]-DA) release in rat striatal slices. Involvement of N-, P- and Q-type channels was identified by sensitivity of [3H]-DA release to omega-conotoxin GVIA (omega-CTx-GVIA), omega-agatoxin IVA (omega-Aga-IVA) and omega-conotoxin MVIIC (omega-CTx-MVIIC), respectively. 2. KCl (50 mM)-evoked [3H]-DA release was abolished in the absence of Ca2+, and was insensitive to dihydropyridines (up to 30 microM). It was significantly blocked by omega-CTx-GVIA (1 microM), omega-Aga-IVA (30 nM) and was confirmed to be abolished by omega-CTx-MVIIC (3 microM), indicating involvement of N-, P- and Q-type channel subtypes. 3. Verapamil and diltiazem inhibited K+-evoked [3H]-DA release in a concentration-dependent manner. The inhibitory effects of verapamil or diltiazem (each 30 microM) were fully additive to the effect of omega-CTx-GVIA (1 microM), whereas co-application with omega-Aga-IVA (30 nM) produced similar effects to those of omega-Aga-IVA alone. 4. As shown previously, veratridine-evoked [3H]-DA release in Ca2+ containing medium exclusively involves Q-type Ca2+ channels. Here, diltiazem (30 microM) did not inhibit veratridine-evoked [3H]-DA release, whereas verapamil (30 microM) partially inhibited it, indicating possible involvement of Q-type channels in verapamil-induced inhibition. However, verapamil (30 microM) inhibited this release even in the absence of extracellular Ca2+, suggesting that Na+ rather than Q-type Ca2+ channels are involved. 5. Taken together, our results suggest that verapamil can block P- and at higher concentrations possibly N- and Q-type Ca2+ channels linked to [3H]-DA release, whereas diltiazem appears to block P-type Ca2+ channels only.

1. Tedisamil is a new antiarrhythmic drug with predominant class III action. The aim of the present study was to investigate the blocking pattern of the compound on the transient outward current (I(to)) in human subepicardial myocytes isolated from explanted left ventricles. Using the single electrode whole cell voltage clamp technique, I(to) was analysed after appropriate voltage inactivation of sodium current and block of calcium current. 2. Tedisamil reduced the amplitude of peak I(to), but did not affect the amplitude of non-inactivating outward current. The drug accelerated the apparent rate of I(to) inactivation. The reduction in time constant of I(to) inactivation depended on drug concentration, the apparent IC50 value was 4.4 microM. 3. Tedisamil affected I(to) amplitude in a use-dependent manner. After 2 min at -80 mV, maximum block of I(to) was reached after 4-5 clamp steps either at the frequency of 0.2 or 2 Hz, indicating that the block was not frequency-dependent in an experimentally relevant range. Recovery from block was very slow and proceeded with a time constant of 12.1+/-1.8 s. Also in the presence of drug, a fraction of channels recovered from inactivation with a similar time constant as in control myocytes (i.e. 81+/-40 ms and 51+/-8 ms, respectively, n.s.). 4. From the onset of fractional block of I(to) by tedisamil during the initial 60 ms of a clamp step, we calculated k1 = 9 x 10(6) mol(-1) s(-1) for the association rate constant, and k2 = 23 s(-1) for the dissociation rate constant. The resulting apparent KD was 2.6 microM and is similar to the IC50 value. 5. The effects of tedisamil on I(to) could be simulated by assuming a four state channel model where the drug binds to the channel in an open (activated) conformation. It is concluded that in human subepicardial myocytes tedisamil is an open channel blocker of I(to) and that this effect probably contributes to the antiarrhythmic potential of this drug.

The lysosphingolipids sphingosine-1-phosphate (SPP) and sphingosylphosphorylcholine (SPPC) reportedly increase free cytosolic Ca2+ concentration ([Ca2+]i) in a variety of cell types, apparently by activating G protein-coupled plasma membrane receptors. We investigated whether and how sphingolipids modulate Ca2+ homeostasis in the insulinoma cell line RINm5F. The addition of SPPC and glucopsychosine (GPS) did not affect basal [Ca2+]i but inhibited the KCl (30 mM)-induced increase in [Ca2+]i in a pertussis toxin-insensitive and concentration-dependent manner (EC50 approximately 5 micro M). Similar inhibitory effects were observed with dihydro-SPPC and psychosine, whereas SPP and various N-acylated sphingolipids (at 10 micro M each) had little or no effect on the KCl-induced [Ca2+]i increase. Because in RINm5F cells the primary pathway for depolarization-induced [Ca2+]i increase are L-type Ca2+ channels, we studied whether sphingolipids reduce L-type Ca2+ current (ICa.L). When added to the bath, GPS and SPPC, but not SPP (10 micro M each), rapidly reduced maximal ICa.L by approximately 35%, similar to the alpha2-adrenoceptor agonist clonidine (30 micro M). However, when applied internally, GPS had no effect on ICa. L. When the electrode solution contained the stable GDP analog guanosine-5'-O-(2-thio)diphosphate (1 and 10 mM), the inhibitory effect of GPS was abolished. In conclusion, a novel cellular action of lysosphingolipids is observed in RINm5F cells (i.e., a guanine nucleotide-sensitive inhibition of L-type Ca2+ currents). The pharmacological profile of this inhibition is unique and unlike any known lysosphingolipid receptor-mediated action.

Rapid cardiac pacing has been used as a model for experimentally-induced cardiomyopathy. However, its relevance to human heart failure is not clear at present because little is known about changes in size and function of ventricular myocytes. We have therefore studied the responses to graded increases in frequency and calcium in canine ventricular myocytes from failing hearts. The aim of our study was to evaluate the resemblance between canine pacing-induced and human end-stage heart failure.Myocytes were isolated from the left ventricular wall of dogs that were in heart failure after 6 weeks of pacing at 250 beats/min. Cell shortening was measured by edge detection.Clinical signs of failure included dyspnea, ascites, and heart dilatation; the hemodynamic parameters were: LVdP/dtmax 1613 +/- 149 vs. 4713 +/- 304 mmHg/s in 6 control dogs; LVEDP 17.2 +/- 4.4 vs 5.6 +/- 1.1 mmHg; LV volume 60.5 +/- 6.2 vs. 30-35 ml. Myocytes from failing hearts were longer and thinner than those from controls (from factor: 0.40 +/- 0.01 vs. 0.47 +/- 0.01, P0.001,30 cells/heart). With 6 mM Ca2+ and at 0.5 Hz, contraction amplitude was significantly attenuated in myocytes from failing hearts: 6.6 +/- 0.9% cell shortening vs. 10.0 +/- 0.8% in controls (P0.05). This deficit was exacerbated at higher stimulation rates. Time-to-peak contraction and time-to-50% relaxation were not altered. There was no difference in sensitivity to thapsigargin.As with cells from human failing hearts, contraction amplitude showed rate-dependent depression in this animal model, whereas features like slowing of contraction and relaxation and reduced sensitivity to thapsigargin, were not reproduced.

Summary— The contribution of Na+, Ca2+, and various K+ currents to the shape of the cardiac action potential is outlined based on the relation between electrophysiological properties and structure of channel molecules. These currents have also been found in human ventricular myocytes, where the most prominent K+ current is a transient outward current that is not influenced by methylsulfonanilide antiarrhythmic drugs. Combined knowledge of electrophysiological and molecular properties of ion channels is likely to form the basis for rational design of future drugs.

Contrary to adults, health-related quality of life of children was only recently discovered as endpoint in pediatric research. On the basis of a theoretical and methodological introduction into quality of life research, the results of a recent literature search on the topic of quality of life and children as related to assessment instruments and their application in pediatric research are described. It is apparent that papers related to quality of life research of children only pertain to 13% of the papers related to adults. Also the majority of the few available assessment instruments from the angloamerican literature and their application in studies is very rare. The need for increased research in the area of children's quality of life is voiced.

Seit Vaughan Williams zu Beginn der 70er Jahre eine erste Klassifikation von Antiarrhythmika vorstellte, ist der Wissensstand zur Entstehung und Therapie von Herzrhythmusstorungen erheblich erweitert worden [34]. Hierzu haben mehrere parallele Forschungsrichtungen beigetragen: die Entdeckung bzw. Synthese einer grosen Zahl neuer antiarrhythmisch wirksamer Substanzen, die Ergebnisse aus experimentellen und klinischen Untersuchungen sowie die aus sog. Metaanalysen gewonnenen Erkenntnisse.

The new antiarrhythmic compounds E-4031 (1-[2-(6-methyl-2-pyridyl)ethyl]-4-(4-methylsulfonyl- aminobenzoyl)piperidine), almokalant and tedisamil prolonged the action potential duration (APD) of human right ventricular papillary muscle. In order to investigate whether drug-channel interaction takes place during rest, regular stimulation (0.5 Hz) was interrupted by three 30-min periods of quiescence. Drug was added at the beginning of the second period of rest, the third period was interposed at equilibrium of drug action. Under predrug control conditions, the first action potential after rest was longer than with regular stimulation, steady state was reached again with a monotonic time course. With E-4031 the first action potential after 30 min of drug exposure during quiescence was similar to predrug control, but drug-induced prolongation of APD developed during further stimulation, indicating drug interaction with open channels. After the third period of quiescence, the first APD remained significantly increased compared to predrug values suggesting that E-4031 may be trapped within the resting channel. With almokalant, however, the first APD after wash-in was already prolonged and APD increased further with regular pacing. The effect was partially reversed during the third period of rest. These findings are compatible with open-channel block or no evidence for trapping. On the other hand, tedisamil prolonged APD but did not change the monophasic time course neither when added during quiescence nor at equilibrium of drug action. It is concluded that changes in APD after quiescence indicate differences among these drugs in their interactions with channel subtypes controlling repolarization.

Starting from 6-amino-1,3-dimethyluracil two approaches were developed for the preparation of 5-amino-pyrido[2,3-d]pyrimidine derivatives as potential cardiotonic agents. 1. Gould-Jacobs reaction followed by chlorination of the intermediate 5-hydroxypyrido-[2,3-d]pyrimidine using DMF/POCl3. 2. Cyclization of C-acetylated as well as C-cyano acetylated 6-amino-1,3-dimethyluracil by an application of the Vilsmeier reaction yielding 5-chloropyrido[2,3-d]pyrimidines. Subsequent nucleophilic substitution reactions formed the target compounds which were examined for positive inotropic activity on isolated left atria and papillary muscles from guinea-pig hearts. Structure-activity relationships indicated that the effect depended on the 4-aminopyridine-3-carboxylic acid derivative structure.

The inotropic effects of isoprenaline, dobutamine and dopexamine were studied in human right atrial myocardium and in rat and guinea-pig left atria electrically stimulated at 1 Hz. To investigate the contribution of endogenously released catecholamines to the positive inotropic effects of beta-adrenoceptor agonists, experiments were performed both in the absence and in the presence of the uptake inhibitors desipramine and corticosterone. In all three species, the maximum positive inotropic responses to isoprenaline and dobutamine were not influenced by the pretreatment, whereas the responses to dopexamine were modified, i.e. the maximum force increase was reduced and the concentration-response curves were shifted to the right. After uptake inhibition, the decrease in positive inotropic action of dopexamine was largest in rat atria followed by guinea-pig and human atria. It is concluded that, in the untreated atrial muscle from all three species, endogenous catecholamines contribute only to the inotropic responses of dopexamine but not to those of isoprenaline or dobutamine.

We have studied the responses to a brief interruption of a train of steady state beats, namely: (1) a single prolonged depolarisation within the train; (2) a single short interval within the train; (3) a single long interval within the train. These responses are predicted by a two compartment model of intracellular calcium handling. They are characterised by the following phenomena. (1) Prolongation of one depolarisation/action potential in the steady state train causes potentiation of the following beat. We postulate on the basis of the published evidence that this may be due to "reversed" sodium/calcium exchange during late systole leading to extra calcium entry during the prolonged depolarisation. (2) Postextrasystole potentiation is postulated to share this mechanism when a depolarisation (extrasystole) is introduced immediately after one of the steady state depolarisations (single short interval). The postextrasystolic beat is then potentiated. (3) A single short interval during the steady state train also leads to attenuation of contractile force on the beat immediately after the short interval, that is, the extrasystole. Mechanical restitution is the term applied to the recovery of this force with increasing interval. This consists of two phases. The initial rapid phase is ryanodine and caffeine insensitive, indicating possible independence of sarcoplasmic reticular function. We postulate that a "membrane compartment" of internal calcium may be responsible. The second, slower, phase of mechanical restitution is ryanodine and caffeine sensitive, indicating that it is likely to be a property of the sarcoplasmic reticulum.(ABSTRACT TRUNCATED AT 250 WORDS)

Violence in schools (bullying) has repeatedly been in the focus of societal discussions. Public health studies were primarily conducted in secondary schools. This study is the first one in Germany which informs about experiences with violence, practicing violence and attitudes towards violence in primary school children in Hamburg. In November 2005, a cross-sectional survey was conducted in which 1154 primary school children of the third and fourth grade answered a quantitative questionnaire concerning the above issues. In addition to bi- and multivariate analysis, Structural Equation Modelling was conducted to analyse the association between the main latent outcome variables bullying and quality of life. The results show that bullying in primary schools is a common problem. 20% of the third and fourth graders reported having been bullied at least once a week. 5–7% of children admitted to have bullied someone once a week. 25% of the school children reported feeling a low subjective quality of life. While school climate and social support by friends and peers was associated with bullying, gender and socioeconomic conditions did not show any significant association. Only 50% of pupils reported that they would inform adults about their current bullying situation. In conclusion, to improve the violence situation in schools factors influencing the school climate particularly the relationship between teachers and students, needs to be enhanced because these factors in turn influence the social support between the children, thereby preventing or decreasing bullying experiences and improving the subjective quality of life in children.