Interobserver agreement: Cohen's kappa coefficient does not necessarily reflect the percentage of patients with congruent classifications.

A widely accepted approach to evaluate interrater reliability for categorical responses involves the rating of n subjects by at least 2 raters. Frequently, there are only 2 response categories, such as positive or negative diagnosis. The same approach is commonly used to assess the concordant classification by 2 diagnostic methods. Depending on whether one uses the percent agreement as such or corrected for that expected by chance, i.e. Cohen's kappa coefficient, one can get quite different values. This short communication demonstrates that Cohen's kappa coefficient of agreement between 2 raters or 2 diagnostic methods based on binary (yes/no) responses does not parallel the percentage of patients with congruent classifications. Therefore, it may be of limited value in the assessment of increases in the interrater reliability due to an improved diagnostic method. The percentage of patients with congruent classifications is of easier clinical interpretation, however, does not account for the percent of agreement expected by chance. We, therefore, recommend to present both, the percentage of patients with congruent classifications, and Cohen's kappa coefficient with 95% confidence limits.

[Long-term antihypertensive therapy with urapidil. A 3-year open, multicenter trial of tolerance, safety and effectiveness]. / Antihypertensive Langzeittherapie mit Urapidil. Offene, multizentrische Prüfung über drei Jahre zu Verträglichkeit, Sicherheit und Wirksamkeit.

Within the framework of an open, multicenter study of 16 physicians treated 206 hypertensive patients with a daily dose of 2 x 30 mg to 2 x 90 mg of urapidil over a period of 3 years. Data are available on 182 patients for the entire study period. 24 patients discontinued the study due to adverse effects (n = 2), an inadequate effect (n = 2), or for reasons unrelated to therapy (n = 20); 58 (28.2%) patients had complaints. The most frequently reported symptoms were nausea, dizziness, drowsiness and fatigue. No relevant changes in laboratory values were observed. Average body weight remained constant and there were no signs of sodium or water retention. In the first year systolic blood pressure was reduced by 25 mm Hg from 174 +/- 13 mm Hg to 149 +/- 10 mm Hg (mean value +/- SD), and diastolic pressure by 17 mm Hg from 103 +/- 6 mm Hg to 86 +/- 6 mm Hg. At the same average dose this drop in BP persisted in the second year (150 +/- 12/86 +/- 7 mm Hg) and the third year (146 +/- 10/85 +/- 7 mm Hg), indicating that there was no decrease in urapidil effect. The pulse rate fell from 77 +/- 8 beats/minute to 74 +/- 6 beats/minute and remained virtually constant over the next 2 years.

Effect of urapidil on steady-state serum digoxin concentration in healthy subjects.

In an open, randomized, two-period change-over study the effect of urapidil, an antihypertensive agent, on steady-state serum digoxin levels was investigated in 12 healthy male volunteers. The subjects were given digoxin 0.25 mg once daily for 4 days to produce a steady-state digoxin level in serum. At the end of that time the subjects received either digoxin monotherapy or digoxin and concomitant treatment with urapidil 60 mg b.d. for a further 4 days. Subsequently the treatments were changed over. The absorption characteristics Cmax and tmax of digoxin were not altered by concomitant urapidil treatment. The geometric mean and nonparametric 95% confidence limits of digoxin relative bioavailability were 97% (93%-103%). Therefore, concomitant administration of urapidil with digoxin treatments did not appear to alter the rate and extent of absorption of the glycoside.

Treatment of mild hypertension with urapidil or captopril.

The aim of this study was to compare the efficacy (lowering diastolic blood pressure to 90 mm Hg or less) of urapidil, a postsynaptic alpha-blocker with central action with that of captopril in a randomized, double-blind, multicenter study. Two hundred ninety-five essential hypertensives (WHO I/II) (140 male, 155 female, age 56-60 years) were treated for 12 weeks with either 30 to 90 mg urapidil bid or 12.5 to 50 mg captopril bid. Supine blood pressure values (mmHg, mean +/- SD) at the end of the 12-week treatment dropped for the urapidil group (n = 142) from 175/103 +/- 19/6 to 154/89 +/- 17/9 (P less than 0.001), and in the captopril group (n = 153) from 175/103 +/- 19/6 to 154/90 +/- 19/9 (P less than 0.001), corresponding to 62% urapidil and 58% captopril responder rates. The results demonstrate that the two antihypertensive medications with different modes of action control blood pressure with equal efficacy at three dose levels. A dose decrease was possible in 20% of each group, but a dose increase was necessary in 39% of urapidil and 44% of captopril group.

Nonequilibrium voltage fluctuations in biological membranes. I. General framework of charge transport in discrete systems and related voltage noise.

This paper continues our work on the theory of nonequilibrium voltage noise generated by electric transport processes in membranes. Introducing the membrane voltage as a further variable, a system of kinetic equations linearized in voltage is derived by which generally the time-dependent behaviour of charge-transport processes under varying voltage can be discussed. Using these equations, the treatment of voltage noise can be based on the usual master equation approach to steady-state fluctuations of scalar quantities. Thus, a general theoretical approach to nonequilibrium voltage noise is presented, completing our approach to current fluctuations which had been developed some years ago. It is explicitly shown that at equilibrium the approach yields agreement with the Nyquist relation, while at nonequilibrium this relation is not valid. A further general property of voltage noise is the reduction of low-frequency noise with increasing number of transport units as a consequence of the interactions via the electric field. In a second paper, the approach will be applied for a number of special transport mechanisms, such as ionic channels, carriers or electrogenic pumps.

Nonequilibrium voltage fluctuations in biological membranes. II. Voltage and current noise generated by ion carriers, channels and electrogenic pumps.

As applications of the general theoretical framework of charge transport in biological membranes and related voltage and current noise, a number of model calculations are presented for ion carriers, rigid channels, channels with conformational substates and electrogenic pumps. The results are discussed with special reference to the problem of threshold values for sensory transduction processes and their limitations by voltage fluctuations. Furthermore, starting from the special results of model calculations, an attempt is made to determine more general aspects of electric fluctuations generated by charge-transport processes in biological membranes: different frequency dependences of voltage and current noise, and dependence of noise intensities with increasing distance from the equilibrium state.

Non-equilibrium voltage noise generated by ion transport through pores.

In this paper, we describe a systematic approach to the theoretical analysis of non-equilibrium voltage noise that arises from ions moving through pores in membranes. We assume that an ion must cross one or two barriers in the pore in order to move from one side of the membrane to the other. In our analysis, we consider the following factors: a) surface charge as a variable in the kinetic equations, b) linearization of the kinetic equations, c) master equation approach to fluctuations. To analyze the voltage noise arising from ion movement through a two barrier (i.e., one binding site) pore, we included the effects of ions in the channel's interior on the voltage noise. The current clamp is considered as a white noise generating additional noise in the system. In contrast to what is found for current noise, at low frequencies the voltage noise intensity is reduced by increasing voltage across the membrane. With this approach, we demonstrate explicitly for the examples treated that, apart from additional noise generated by the current clamp, the non-equilibrium voltage fluctuations can be related to the current fluctuations by the complex admittance.