Serum levels of interleukin-6 and tumour-necrosis-factor-alpha are not correlated to disease activity in patients with rheumatoid arthritis after treatment with low-dose methotrexate

Abstract. Cytokines are major mediators of inflammatory responses in rheumatoid arthritis. Some of them have been shown to correlate with the disease activity and thus are proposed to be used for monitoring patients. Therefore the effects of a low-dose therapy with methotrexate on serum concentrations of interleukin-6 (IL-6) and tumour-necrosis-factor-alpha (TNF-α) were examined in eight patients with seropositive rheumatoid arthritis. Serum levels of IL-6 and TNF-α were significantly elevated in patients compared to healthy controls. Before the onset of MTX treatment IL-6 concentrations were correlated to the c-reactive protein ( P < 0·05) but the correlation was abolished after treatment. For TNF-α no correlations neither before nor after treatment were observed. Both cytokines remained substantially elevated after MTX treatment despite a clear reduction in disease activity. Thus we suggest that one of the effects of MTX might be the inhibition of some of the actions of IL-6 and TNF-α.     

Influence of the force--frequency relationship on haemodynamics and left ventricular function in patients with non-failing hearts and in patients with dilated cardiomyopathy

In isolated human myocardium it was shown that a positive force-frequencyrelationship occurs in non-failing myocardium; however, theforce-frequency relationship was found to be inverse in myocardiumfrom failing human hearts. In order to investigate the clinicalrelevance of these experimental findings, the influence of heartrate changes on haemodynamics and left ventricular functionwas studied in eight patients without heart failure and in ninewith failing dilated cardiomyopathy (NYHA II–III). Rightventricular pacing was performed at a rate slightly above sinusrate and at 100, 120 and 140 beats. min^–1 Haemodynamicparameters were obtained by right heart catheterization andby high-fidelity left ventricular pressure measurements. Leftventricular angiography was performed at basal pacing rate andat 100 and 140 beats. min^–1 With increasing heart rate,cardiac index increased in patients with normal left ventricularfunction from 2·9 ± 0·2 to 3·5 ±0·21. min^–1. m^–2 (P<0·01) and decreasedcontinuously in patients with dilated cardiornyopathy from 2·6± 0·1 to 2·2 ± 0·11. min^–1. m^–2 (P<0·05). With increasing heart rate,the maximum rate of left ventricular pressure rise increasedin non-failing hearts from 1388 ± 86 to 1671 ±88 mmHg. s^–1 (P<0·01) and did not change infailing hearts. Ejection fraction decreased from 27 ± 3% to 19 ±2% in patients with dilated cardiomyopathy (P<0·05)when the pacing rate was changed from 84 ± 2 beats. min^–1to 140 beats. min^–1, which was associated with a significantlyincrease in end-systolic volume without significantly changesin end-diastolic volume. In patients with normal left ventricularfunction, when the pacing rate was changed from 85 ±3 beats. min^–1 to 140 beats. min^–1, end-diastolicvolume decreased significantly by 13%, whereas left ventricularend-systolic volume and ejection fraction did not significantlychange. Left ventricular systolic and end-diastolic pressuresdid not significantly change with pacing tachycardia in eithergroup. The frequency-related changes in left ventricular volumesand pressures indicate that the differrent haemodynamic effectsof pacing tachycardia in both groups of patients result predominantlyfrom frequency effects on myocardial function and not from frequencyeffects on preload or afterload. These data indicate that recentexperimental findings of positive force-frequency effects innon-failing and negative force-frequency effects in failinghuman myocardium are relevant for the intact heart.     

HOW INDEPENDENT ARE MULTIPLE ‘INDEPENDENT’ DIAGNOSTIC CLASSIFICATIONS?

Multiple performances of diagnostic tests are commonly employed in clinical practice and epidemiologic research to assess test reliability, to increase sensitivity or specificity, or to correct for misclassification bias. An assumption almost universally made in this context is the assumption of independence of test results conditional on the true value. For dichotomous diagnostic tests, for example, disease present or absent, this assumption is usually not tenable, however, since there is typically a continuum of the traits that underly diagnosis and individuals in the vicinity of the (implicit or explicit) diagnostic cutpoint (such as the threshold of clinical detectibility) are more likely to be misclassified than other individuals. This paper assesses the magnitude of the resulting correlation of diagnostic errors as a function of the distribution of the underlying trait, the magnitude of the measurement error and the diagnostic threshold. It is concluded that errors of diagnostic tests can be strongly correlated even if errors in perception of the underlying trait are independent. It is illustrated by numerical examples that such positive correlation of diagnostic errors can substantially inflate commonly employed indices of reliability, such as the kappa coefficient.     

HOW TO DIFFERENTIATE BETWEEN T-CELL-RICH B-CELL LYMPHOMA AND LYMPHOCYTE-PREDOMINANT HODGKIN'S DISEASE. EVIDENCE FOR THE VALUE OF MB1 AND 4KB5 IMMUNOSTAINING

Striking morphological similarities exist between T-cell-rich B-cell lymphoma and lymphocyte-predominant Hodgkin's disease (Hodgkin's paragranuloma), making the distinction between them extremely difficult. Immunohistochemistry provides a means of overcoming this difficulty. Immunostaining with UCHL1, L26, MB1, and 4KB5 was performed on five T-cell-rich B-cell lymphomas and 11 Hodgkin's paragranulomas (7/11 nodular, 4/11 diffuse). L26 stained the tumour cells not only of T-cell-rich B-cell lymphomas, but also of L+H Hodgkin's disease. In contrast, MB1 as well as 4KB5 identified all of the neoplastic cells in 3/5 T-cell-rich B-cell lymphomas, but did not react with the L+H cells in 8/11 Hodgkin's paragranulomas. Some overlap of staining patterns became apparent in the remaining cases, with 2/5 T-cell-rich B-cell lymphomas showing the MB1⁺/4KB5⁺ phenotype in a tumour cell subset only. Similarly, in 3/11 Hodgkin's paragranulomas, some MB1/4KB5-positive L+H cells occurred in addition to MB1/4KB5-negative L+H cells. These cases, nevertheless, could be distinguished from one another by the numbers of MB1/4KB5-positive background lymphocytes, which were scanty or absent in T-cell-rich B-cell lymphomas and more numerous in Hodgkin's paragranulomas.     

Specificity of pepsin-catalyzed peptide bond synthesis

The rates of the pepsin-catalyzed synthesis of oligopeptides of the general type A-Phe-Leu-B by the condensation of A-Phe-OH with H-Leu-B have been determined by means of analytical high performance liquid chromatography. Variation of the A group led to large changes in the initial rates of the condensation reaction, and the effect of such changes was found to be similar to that previously found for the secondary specificity of pepsin in the hydrolysis of oligopeptide substrates. Replacement of the Phe and Leu residues of A-Phe-OH or H-Leu-B by other amino acid residues gave relative rates of synthesis in accord with the known primary specificity of the hydrolytic action of pepsin. Partially-acetylated pepsin, which exhibits enhanced hydrolytic activity, also catalyzed the condensation reaction more effectively. The results are discussed in relation to the potential utility and limitations of pepsin as a catalyst in the preparative synthesis of oligopeptides and to the problem of the mechanism of its action.