Genome-wide association analysis of coffee drinking suggests association with CYP1A1/CYP1A2 and NRCAM.

Coffee consumption is a model for addictive behavior. We performed a meta-analysis of genome-wide association studies (GWASs) on coffee intake from 8 Caucasian cohorts (N=18 176) and sought replication of our top findings in a further 7929 individuals. We also performed a gene expression analysis treating different cell lines with caffeine. Genome-wide significant association was observed for two single-nucleotide polymorphisms (SNPs) in the 15q24 region. The two SNPs rs2470893 and rs2472297 (P-values=1.6 × 10(-11) and 2.7 × 10(-11)), which were also in strong linkage disequilibrium (r(2)=0.7) with each other, lie in the 23-kb long commonly shared 5' flanking region between CYP1A1 and CYP1A2 genes. CYP1A1 was found to be downregulated in lymphoblastoid cell lines treated with caffeine. CYP1A1 is known to metabolize polycyclic aromatic hydrocarbons, which are important constituents of coffee, whereas CYP1A2 is involved in the primary metabolism of caffeine. Significant evidence of association was also detected at rs382140 (P-value=3.9 × 10(-09)) near NRCAM-a gene implicated in vulnerability to addiction, and at another independent hit rs6495122 (P-value=7.1 × 10(-09))-an SNP associated with blood pressure-in the 15q24 region near the gene ULK3, in the meta-analysis of discovery and replication cohorts. Our results from GWASs and expression analysis also strongly implicate CAB39L in coffee drinking. Pathway analysis of differentially expressed genes revealed significantly enriched ubiquitin proteasome (P-value=2.2 × 10(-05)) and Parkinson's disease pathways (P-value=3.6 × 10(-05)).

Adenosine enhances neuroexcitability by inhibiting a slow postspike afterhyperpolarization in rabbit vagal afferent neurons.

BACKGROUND: Electrophysiological mechanisms by which adenosine may activate cardiac afferent neurons are unknown. Slow afterhyperpolarizations (AHPs) follow action potentials in a subset of vagal C afferents, rendering them inexcitable. The purpose of this study was to test the hypothesis that adenosine increases vagal neuronal excitability by blocking slow AHPs and to determine the adenosine receptor subtype mediating these effects. METHODS AND RESULTS: Using the perforated patch-clamp technique, we identified cultured adult rabbit nodose ganglion cells with slow AHPs in current-clamp mode. Trains of 100 current pulses at 20% above threshold were injected, with an interspike interval of 100 ms, and the number of action potentials triggered were counted and reported as the action potential response rate. During adenosine (10 micromol/L), slow AHPs were suppressed and action potential response rate was augmented from 3.8+/-0.5% at baseline to 28+/-7% after adenosine (P:=0.0009). The selective A(2)-adenosine receptor agonist NECA but not the A(1)-adenosine agonist CCPA replicated the adenosine effect. The selective A(2A)-adenosine antagonist ZM 241385 (10 nmol/L) but not the A(1) adenosine antagonist DPCPX (5 micromol/L) abolished the adenosine effect. We considered two alternative hypotheses: (1) A(2)-receptor-mediated suppression of I(Ca) leading to smaller increases in intracellular Ca during stimulation, resulting in less activation of I(K(Ca)) and consequent suppression of slow AHPs, or (2) A(2)-receptor-mediated elevation of cAMP directly suppressing slow AHPs. Under voltage-clamp conditions, adenosine did not significantly inhibit I(Ca), making the latter hypothesis more likely. CONCLUSIONS: Adenosine inhibits slow AHPs in vagal afferent neurons. This effect is most likely caused by A(2A)-receptor-mediated stimulation of cAMP production.

The associations of body size and body composition with left ventricular mass: impacts for indexation in adults.

OBJECTIVES: We investigated the relationship between body size, body composition and left ventricular mass (LVM) in adults, and assessed the impact of different indexations of LVM on its associations with gender, adiposity and blood pressure. BACKGROUND: The best way to normalize LVM for body size to appropriately distinguish physiologic adaptation from morbid heart morphology was discussed. METHODS: We undertook a community survey of 653 men and 718 women, aged 25 to 74 years. Lean body mass (LBM) was determined by bioelectric impedance analyses and LVM was assessed by two-dimensional guided M-mode echocardiography. RESULTS: After traditional indexations to body height, body height2.7, or body surface area, men had higher LVM than women (p < 0.001). These gender differences disappeared (p > 0.05) when LVM was indexed to LBM. The type of indexation also modified the strength of the association between adiposity and LVM. The estimated impact of body fat on LVM indexed to LBM was less than half that obtained with traditional indexations. In contrast, the magnitude of the associations of blood pressure with LVM was entirely independent of the type of indexation. CONCLUSIONS: This study showed the prominent influence of body composition on adult heart size. Indexation for LBM removed gender differences for LVM and reduced the impact of adiposity, but left the effects of blood pressure unchanged. We suggest that this approach be used for clinical and research applications.

Sodium/calcium exchanger in heart muscle: molecular biology, cellular function, and its special role in excitation-contraction coupling.

The Na/Ca exchanger has been examined with respect to its molecular biology, its cellular function, and its role in excitation-contraction coupling. The Na/Ca exchanger plays a central part in excitation-contraction coupling, setting the level of sarcoplasmic reticular calcium and contributing to the triggering of sarcoplasmic reticular calcium release. Functional biophysical studies with isolated single cells and caged calcium provide evidence that the Na/Ca exchanger works as a two step sequential transporter. In the heart there are about 250 exchangers.mu-2, operating at a turnover rate of up to about 2500.s-1, with the exchanger carrying -2.56 charges under normal conditions. The Na/Ca exchanger has been recently cloned from diverse mammalian species and several tissues and is largely conserved. It is clear, however, that the function of the Na/Ca exchanger is different in the different tissues. Thus work is in progress in several laboratories, including ours, to determine how the Na/Ca exchanger achieves its tissue specific function. Several modulatory motifs have been seen in studies of the exchanger that may explain some of the tissue specific differences. Interestingly the modulation of the Na/Ca exchanger (for example, by protons, sodium, calcium, ATP, calmodulin) seems to arise from interactions with the intracellular loop.

Alcohol consumption as a risk factor for high blood pressure. Munich Blood Pressure Study.

The Munich Blood Pressure Study (MBS), a 1980-81 cross-sectional study (with follow-up) of a random sample of 3198 Munich citizens aged 30-69 years (response rate 69%), revealed hypertensive blood pressure (BP) values in 17.7% of men and 10.7% of women (WHO criteria). One of the main goals of the MBS was to search for social, behavioral, and environmental risk factors for hypertension. The relationship between BP and five possible risk factors--alcohol consumption (g/day), cigarette smoking, oral contraceptive use, years of education, obesity (BMI)--has been examined. The major emphasis of this report is the relationship of alcohol consumption to BP. Multiple linear and logistic regression analyses were run controlling for both age and sex. All second- and third-order interactions between the independent variables were tested during a backward-stepping procedure. Alcohol consumption appeared as a significant main effect in many of the analyses. The coefficient of the alcohol variable ranged from 0.02 to 0.06 for men and women in the separate linear regression analyses for systolic and diastolic BP. Thus, for example, according to the model, the daily consumption of 1 liter of beer (40 g alcohol) may cause an increase in diastolic BP in women of 2.4 mm Hg.

Weight change and change of total cholesterol and high-density-lipoprotein cholesterol. Results of the MONICA Augsburg cohort study.

Data from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg cohort were used to study the effect of weight change on changes in serum levels of total and high-density-lipoprotein cholesterol. Weight gain was associated with rising levels of total cholesterol and falling levels of high-density-lipoprotein cholesterol in both sexes, more so in men than in women. Moreover, these relationships weakened with advancing age in women, but not in men. The results support the view that weight loss may more favorably affect lipid levels in men than in women, particularly at older ages.

Oral contraceptive use and blood pressure in a German metropolitan population.

The relationship between blood pressure (BP) and oral contraceptive (OC) use in women has been examined with the data from the Munich Blood Pressure Study (MBS), a cross-sectional study with follow-up of a random sample of 3198 Munich citizens aged 30-69 (response rate 69.3%). Multiple linear and logistic regression analyses were run with BP as the dependent variable and age, OC use, obesity, alcohol consumption, and smoking habit as the independent variables. All second and third order interactions between the independent variables were tested during a backward stepping procedure. OC use appeared as a significant main effect in most of the analyses. The coefficient of the OC variable was about 3 in the linear regression analyses for both systolic BP and diastolic BP, indicating an increase of about 3 mmHg in the systolic and diastolic BP of the OC users. An analysis of the change in BP after one year in relation to change in OC user status has also been made. It was observed that women ceasing to use OC had a clear decrease in BP while those starting to use OC had on average an increase in BP.

PIP: A random sample of 3198 persons aged 30-69, as part of the Munich Blood Pressure Study, revealed that oral contraceptive use raises blood pressure. Data were collected from December 1980 to May 1981, and from January to March 1982, on the same subjects. Each participant was interviewed about risk factors for about 30 minutes in a sitting position, and his pressure measured 3 times afterward with the Hawksley Random Zero sphygmomanometer. There were 113 women using pills, 32 different brands. Multiple linear and logistic regression analyses were run with blood pressure as the dependent variable, and age, pill use, obesity, alcohol consumption, and smoking habit as the independent variables. Pill use appeared as a significant main effect in most of the analyses. Based on the coefficient of the pill variable in the linear regression, an increase of about 3 mm Hg in both systolic and diastolic pressures was demonstrated. It was observed that women stopping oral contraception had a clear decrease of 7.2 mm Hg systolic, and 2.8 mm Hg diastolic pressure, and those beginning oral contraception appeared to have an increase in pressure, if the results were adjusted for regression toward the mean. Even a slight increase of 3 or 4 mm Hg in blood pressure, when added to other risk factors such as obesity, smoking, and age, may increase the overall risk for cardiovascular disease considerably.

Simultaneous spike detection and topographic classification in pediatric surface EEGs.

In this study, an algorithm is introduced for the automatic detection and simultaneous topographic classification of interictal regional spike activity in pediatric surface EEG records. The algorithm is based on the classification of the topographic distribution of instantaneous power by means of a 'group' trained classifier. The results of automatic spike analysis were compared with the decisions of two experienced electroencephalographers. Four routine EEG records exhibiting (multi)regional spikes were examined. The mean selectivity for the automatic spike detector was 84.6% (mean sensitivity 88.1%, mean specificity 89.3%) and for the electroencephalographers 85.3%. All spikes detected by the algorithm were simultaneously classified according to their topographic characteristics. The results of automatic spike classification (lateralization/localization) corresponded to the results of visual analysis.

Do siblings of myocardial infarction patients have a specific management of hypertension?

The aim of this study was to determine whether the management of hypertension differs between siblings of myocardial infarction patients and the general population. Siblings aged 35 to 74 years, unaffected by myocardial infarction, were drawn from the Augsburg Family Heart Study, conducted in 1996-1997 in southern Germany (n = 524). The reference group consisted of participants of the third MONICA population-based survey conducted in 1994-1995 in the same area, who were aged 35 to 74 years and also unaffected by myocardial infarction (n = 3802). Prevalence, awareness, treatment and control of hypertension (defined by blood pressure > or = 140/90 mm Hg or use of antihypertensive medication) were compared between the two groups. The result was that the prevalence of hypertension was higher in the siblings (men: age-adjusted OR = 1.31, 95% CI: 0.99-1.75; women: age-adjusted OR = 1.83, 95% CI: 1.39-2.41). Male hypertensive siblings were more often aware and treated for hypertension than male hypertensives of the reference group whereas the level of awareness and treatment was comparable between female hypertensives of the two groups. In both genders, no difference in the degree of control was shown between hypertensives of the two groups. In conclusion the siblings and their physicians should pay more attention to the family history of myocardial infarction in order to improve the management of hypertension in this high risk group.

Adaptable preprocessing units and neural classification for the segmentation of EEG signals.

In this contribution, a methodology for the simultaneous adaptation of preprocessing units (PPUs) for feature extraction and of neural classifiers that can be used for time series classification is presented. The approach is based upon an extension of the backpropagation algorithm for the correction of the preprocessing parameters. In comparison with purely neural systems, the reduced input dimensionality improves the generalization capability and reduces the numerical effort. In comparison with PPUs with fixed parameters, the success of the adaptation is less sensitive to the choice of the parameters. The efficiency of the developed method is demonstrated via the use of quadratic filters with adaptable transmission bands as preprocessing units for the segmentation of two different types of discontinuous EEG: discontinuous neonatal EEG (burst-interburst segmentation) and EEG in deep stages of sedation (burst-suppression segmentation).

Structure optimization of neural networks with the A*-algorithm.

A method for the construction of optimal structures for feedforward neural networks is introduced. On the basis of a construction of a graph of network structures and an evaluation value which is assigned to each of them, an heuristic search algorithm can be installed on this graph. The application of the A*-algorithm ensures, in theory, both the optimality of the solution and the optimality of the search. For several examples, a comparison between the new strategy and the well-known cascade-correlation procedure is carried out with respect to the performance of the resulting structures.

Time-variant partial directed coherence for analysing connectivity: a methodological study.

For the past decade, the detection and quantification of interactions within and between physiological networks has become a priority-in-common between the fields of biomedicine and computer science. Prominent examples are the interaction analysis of brain networks and of the cardiovascular-respiratory system. The aim of the study is to show how and to what extent results from time-variant partial directed coherence analysis are influenced by some basic estimator and data parameters. The impacts of the Kalman filter settings, the order of the autoregressive (AR) model, signal-to-noise ratios, filter procedures and volume conduction were investigated. These systematic investigations are based on data derived from simulated connectivity networks and were performed using a Kalman filter approach for the estimation of the time-variant multivariate AR model. Additionally, the influence of electrooculogram artefact rejection on the significance and dynamics of interactions in 29 channel electroencephalography recordings, derived from a photic driving experiment, is demonstrated. For artefact rejection, independent component analysis was used. The study provides rules to correctly apply particular methods that will aid users to achieve more reliable interpretations of the results.

The mechanism by which cytoplasmic protons inhibit the sodium-calcium exchanger in guinea-pig heart cells.

1. We recorded cardiac sodium-calcium exchange current (INa-Ca) in giant excised membrane patches obtained from cardiac myocytes of the adult guinea-pig. 2. Rapid changes in ion concentrations on the cytoplasmic side of the excised membrane patch were produced using a modified oil-gate bath. 3. Sodium-calcium exchange current was activated by step increases in sodium concentration on the cytoplasmic side of the membrane ([Na+]i), which led to an increase in outward INa-Ca to a new steady-state level. The [Na+]i required to half-maximally activate the sodium-calcium exchange current (K1/2) was 21 mM. 4. Step increases in cytoplasmic calcium concentration ([Ca2+]i) stimulated the [Na+]i-activated INa-Ca up to 1 microM [Ca2+]i, then inhibited the exchange current at very high [Ca2+]i (1 mM). 5. A step decrease in cytoplasmic pH from 7.2 to 6.4 (increase in [H+]i) produced a biphasic but monotonic decrease in INa-Ca. Alkalinization of cytoplasmic pH from 7.2 to 8.0 caused a large, biphasic increase in INa-Ca. 6. When INa-Ca was activated by a step increase in [Na+]i and [H+]i was simultaneously increased, the outward current rose to a peak and then declined to a low steady level. The peak current seen was always less than the maximum current produced by an identical elevation of [Na+]i at constant pHi. This reduction in peak outward current reflected a rapid 'primary' inhibition of the sodium-calcium exchange by protons. The decay of the sodium-calcium exchange current following the peak was slow and corresponded to the time course of the onset of a 'secondary' proton block. 7. Rapid primary inhibition of the sodium-calcium exchanger could also be produced by cytoplasmic acidification in the absence of cytoplasmic sodium. The primary blockade was revealed when a subsequent increase in [Na+]i activated INa-Ca and a smaller peak outward current was observed. Secondary inhibition of the sodium-calcium exchanger was not, however, produced by cytoplasmic acidification in the absence of cytoplasmic sodium. Regardless of the duration of exposure to elevated [H+]i, the 'secondary' block by protons was still seen on activation of INa-Ca by increased [Na+]i as a gradual reduction of outward current amplitude. 8. Treatment of the sodium-calcium exchanger with the proteolytic enzyme alpha-chymotrypsin largely removed its sensitivity to protons. 9. We conclude that the action of alpha-chymotrypsin on the monomeric sodium-calcium exchange protein is in part to remove a proton-sensitive regulatory component(s) or render the regulation ineffective.(ABSTRACT TRUNCATED AT 400 WORDS)

The action of Na+ as a cofactor in the inhibition by cytoplasmic protons of the cardiac Na(+)-Ca2+ exchanger in the guinea-pig.

1. Na(+)-Ca2+ exchange current was activated in giant excised patches of guinea-pig cardiac sarcolemma by raising the intracellular sodium concentration ([Na+]i). When the pHi was simultaneously acidified to 6.4, the current was transient, dropping by 80% in 30 s. 2. Pre-exposure to a pHi of 6.4 for 15 s reduced the peak Na(+)-Ca2+ exchange current without altering the decay rate or steady-state current. Recovery from proton inhibition was seen when [Na+]i was removed for 9 s. 3. A mathematical model of Na(+)-Ca2+ exchange function reproduced the experimental results. In addition, two model-dependent predictions were seen experimentally. (i) [Na+]i-dependent 'inactivation' of Na(+)-Ca2+ exchange may arise from pHi effects. We observed experimentally that pre-exposure to acidic pHi can remove the transient current component attributed to [Na+]i-dependent 'inactivation'. (ii) self-exchange should be inhibited by acidification. This has been observed by other investigators. 4. We have hypothesized that there are two components to inhibition of the Na(+)-Ca2+ exchanger by intracellular protons, and that one is enhanced by increased [Na+]i (Doering & Lederer, 1993b). This hypothesis is supported by the data presented here and by a model of Na(+)-Ca2+ exchange behaviour in which binding of intracellular sodium to the exchanger enhances the affinity of the exchanger for inhibitory intracellular protons.

Structure optimization of neural networks with A* -algorithm application in EEG pattern analysis.

The A* - Algorithm for heuristic search is applied to construct a Neural Network structure (NS) that optimally fits the structure of data to be learned. In this way, the user of Neural Networks (NN) is able to avoid the empirical testing of different structures. The method given here is applied to the recognition of different patterns derived from the EEG of an epileptic patient.