IL10.G microsatellites mark promoter haplotypes associated with protection against the development of reactive arthritis in Finnish patients.

OBJECTIVE: To investigate the association of microsatellites and single-nucleotide promoter polymorphisms (SNPs) in the gene for the cytokine interleukin-10 (IL-10) with susceptibility to and outcome of reactive arthritis (ReA). METHODS: From genomic DNA, IL-10 microsatellites G and R and IL-10 promoter polymorphisms at positions -1087 and -524 were typed by polymerase chain reaction, automated fragment length analysis, and restriction fragment digestion in 85 Finnish patients with ReA and 62 HLA-B27-positive Finnish controls. ReA patients had been followed up for 20 years. Genotypes and haplotypes of IL-10 were correlated with distinct features of the disease course, such as triggering agent, chronic arthritis, development of ankylosing spondylitis, and other chronic features. RESULTS: There was a significant decrease in the promoter alleles G12 (allele frequency 0.206 versus 0.033; corrected P < 0.001, odds ratio 0.14) and G10 (0.183 versus 0.092; P < 0.05, odds ratio 0.44) in the ReA group compared with the HLA-B27-positive controls. Chronic arthritis developed significantly more frequently in the B27-positive subjects than in the B27-negative subjects (P < 0.05) as well as in patients with [corrected] the IL10.G8 allele. No associations were observed for either SNP or for the IL10.R microsatellite polymorphism. CONCLUSION: IL10.G12 and G10 microsatellite alleles show a strong protective effect against the development of ReA in Finnish subjects. Since these polymorphic markers themselves do not have direct functional implications, they most likely mark promoter haplotypes with distinct functional properties, suggesting that differential production of IL-10 is an important susceptibility factor for the development of ReA.

Methane formation by reaction of a methyl thioether with a photo-excited nickel thiolate--a process mimicking methanogenesis in archaea.

The formation of a sulfuranyl radical intermediate followed by methyl transfer to the nickel(I) center of coenzyme F430 and generation of the disulfide has been proposed as a possible mechanism for the formation of methane catalyzed by methyl coenzyme M reductase in methanogenic archaea. In order to test this hypothesis, a sterically shielded, bifunctional model substrate that contained a methyl thioether and a sulfhydryl functional group, which could form a five-membered cyclic sulfuranyl radical according to the postulated mechanism, was synthesized. The corresponding thiolate reacted with Ni(II) salts to give a diamagnetic, square-planar Ni(II) dithiolate complex, which was characterized by X-ray diffraction. Upon irradiation of this complex with light of lambda > 300 nm, methane and the cyclic disulfide were formed, whereas irradiation of the thiolate in the absence of nickel gave only traces of methane and no cyclic disulfide. The observed products are consistent with the postulated mechanism via a sulfuranyl radical, and the role of light is interpreted as the formation of a Ni(I)/thiyl radical pair upon excitation of a charge-transfer band of the Ni(II) dithiolate. In the presence of a large excess of thiolate, the diamagnetic complex was transformed into a paramagnetic, five- or six-coordinate complex that proved to be more active in the generation of both methane and the cyclic disulfide, than the square-planar diamagnetic dithiolate.

Different transcriptional activity and in vitro TNF-alpha production in psoriasis patients carrying the TNF-alpha 238A promoter polymorphism.

Genes encoded on chromosome 6 within the major histocompatibility complex region are thought to play an important role in the pathogenesis of psoriasis. A potential candidate gene is tumor necrosis factor alpha. The tumor necrosis factor alpha promoter contains several polymorphisms including two G-->A transitions at position -308 and -238, which are the most common in Caucasian populations. The TNF238.2 (-238A) allele has been strongly associated with psoriasis. We have investigated the effect of the -238 and -308 variants on transcription of the tumor necrosis factor alpha gene in luciferase reporter gene assays. In addition, peripheral blood mononuclear cells of 47 patients with psoriasis and 43 controls were stimulated with different antigens and mitogens (streptococcal sonicate and superantigen, lipopolysaccharide, phorbol-12-myristate, phytohemagglutinin, CD3 antibodies) and tumor necrosis factor alpha production was measured in supernatants by enzyme-linked immunosorbent assay. The psoriasis-associated tumor necrosis factor alpha promoter allele TNF238.2 showed a significantly decreased transcriptional activity. Peripheral blood mononuclear cells carrying this allele produced significantly less tumor necrosis factor alpha after stimulation with T cell mitogens and streptococcal antigens in comparison to controls. The promoter allele TNF238.2 seems to influence tumor necrosis factor alpha production; a possible role in the pathogenesis of psoriasis has to be further evaluated.

Ankylosing spondylitis in monozygotic twins: studies on immunological parameters.

OBJECTIVE: To examine immunological parameters that might explain disease discordance in monozygotic twin pairs with ankylosing spondylitis (AS). METHODS: 11 monozygotic twin pairs (nine with AS, two with undifferentiated spondyloarthropathy) were investigated. The peripheral T cell receptor Vbeta repertoire was investigated using FACS analysis and 14 different Vbeta antibodies. In addition serum samples were tested for antibodies to Klebsiella pneumoniae, Streptococcus pyogenes, Candida albicans, Proteus mirabilis, and Escherichia coli. Peripheral blood lymphocyte reactivity against a number of bacteria was investigated by interferon gamma ELISPOT assays. RESULTS: Twins suffering from AS showed cellular hyporeactivity against K pneumoniae, S pyogenes, C albicans in the ELISPOT assays compared with healthy twins. In contrast with the antibody data, where no significant differences were observed between the two groups, AS concordant twins showed the most pronounced differences in their Vbeta repertoire on CD4+ and CD8+ lymphocytes. CONCLUSIONS: Cellular hyporeactivity of peripheral blood cells to bacterial antigens might reflect defective T cell responses allowing bacterial antigens to persist in diseased patients. There are probably other environmental factors that influence disease concordance.

Reversal of increased diastolic stiffness in mitral stenosis after successful balloon valvuloplasty.

BACKGROUND AND AIM OF THE STUDY: Abnormal passive elastic properties have been reported in patients with severe mitral stenosis and have been attributed to either: (i) chamber atrophy due to unloading; (ii) myocardial fibrosis; (iii) right and left ventricular (LV) interaction; or (iv) internal restrictions due to the rigid mitral valve apparatus. The study aim was to evaluate the effect of percutaneous mitral balloon valvuloplasty (PMV) on passive elastic properties in 19 patients with severe mitral stenosis. Ten patients with normal coronary arteries and LV function served as controls. METHODS: LV high-fidelity pressure measurements and simultaneous biplane LV angiograms were obtained before and after PMV (n = 11). The constant of chamber stiffness (b; ml(-1)) was calculated from the diastolic pressure-volume relationship and the constant of myocardial stiffness (beta) from the diastolic stress-strain relationship. The time constant of relaxation (T; ms) was calculated from the LV pressure decay during isovolumic relaxation. Regional ejection fraction (radial axis system) was determined in six regions of the right anterior oblique (RAO) and left anterior oblique (LAO) angiographic projections. RESULTS: Mitral valve area was increased from 1.0 to 2.2 cm2 after PMV, whereas diastolic pressure gradient was reduced from 14 to 4 mmHg. Global LV ejection fraction (EF) was slightly reduced (57% versus 63%; p<0.05) before valvuloplasty and normalized thereafter. Regional EF increased significantly (p<0.05) in the posterolateral region of the LAO projection after intervention. Myocardial stiffness was increased before, and decreased significantly after balloon valvuloplasty (from 16 to 11; p<0.05). The rate of relaxation and chamber stiffness remained unchanged. CONCLUSIONS: Myocardial stiffness is increased in patients with mitral stenosis, but normalized after successful PMV. The improvement in passive elastic properties after valvuloplasty can be explained by the mobilization of the subvalvular apparatus with an improvement in regional LV function.

Percutaneous transluminal coronary angioplasty reverses vasoconstriction of stenotic coronary arteries in hypertensive patients.

BACKGROUND: Endothelial dysfunction of coronary arteries with impaired vasodilation has been reported in patients with arterial hypertension. However, the effect of dynamic exercise on coronary vasomotion of a stenotic vessel segment before and after PTCA has not yet been evaluated in these patients. METHODS AND RESULTS: Coronary vasomotion of a normal and a stenotic vessel segment was studied in 39 patients with coronary artery disease during supine bicycle exercise before and 9+/-3 months after PTCA. Luminal area changes were determined by biplane quantitative coronary arteriography. There were 21 normotensive and 18 hypertensive patients who did not differ with regard to clinical characteristics. Percent area stenosis decreased after PTCA from 90% to 39% (P<0.001) in normotensive and from 86% to 33% (P<0.001) in hypertensive patients. Exercise-induced vasomotion of the normal vessel segment was significantly different between normotensives and hypertensives before (+19% versus +1%, P<0.01) and after (+16% versus +3%, P<0.01) PTCA. In contrast, stenotic vessel segments showed vasoconstriction in both normotensive and hypertensive patients (Deltaexercise, -11% versus - 20%, P=NS), which was reversed after PTCA (+3% versus +2%, P=NS). CONCLUSIONS: Normal coronary arteries show reduced vasodilation during exercise in hypertensive patients that may be explained by the presence of endothelial dysfunction. Stenotic vessels demonstrate paradoxical vasoconstriction during exercise in both normotensive and hypertensive patients. PTCA reverses vasoconstriction by elimination of the flow-limiting stenosis and prevention of coronary stenosis narrowing during exercise in normotensive and hypertensive patients.

Systolic and diastolic function with alternate and combined site pacing in the right ventricle.

UNLABELLED: We hypothesized that pacing at two ventricular sites simultaneously would activate the myocardium more rapidly and improve ventricular function. We studied the effect of pacing at the right ventricular outflow tract (RVOT) and the RV apex (RVA) on systolic and diastolic function. In 14 patients with a reduced systolic ejection fraction < 40% (mean EF 32% +/- 4%) we measured RV pressures, left ventricular pressures, EF, cardiac output, peak dP/dt, peak negative dP/dt, and the time constant of relaxation, Tau, during intrinsic rhythm, atrial pacing and DVI pacing at the RVA, the RVOT, and both RV sites combined in random order. Repeated measures analysis of variance showed no significant differences in any of these parameters. The highest absolute values of dP/dt were observed during sinus rhythm and the lowest with RVA pacing. This parameter tended to improve progressively with pacing in the RVOT and at both sites. Peak negative dP/dt showed a similar nonsignificant trend. CONCLUSION: These data suggest that in patients with poor LV function, there may be subtle improvements in diastolic and systolic function with pacing in the RVOT and at combined sites in the RV compared to traditional RVA pacing.

Reversal of abnormal coronary vasomotion by calcium antagonists in patients with hypercholesterolemia.

BACKGROUND: It has been shown that exercise-induced coronary vasodilation of angiographically normal coronary vessels is reduced in hypercholesterolemic patients. The purpose of this study was to evaluate the effect of calcium channel blockers on coronary vasomotion of angiographically smooth coronary arteries in hypercholesterolemic patients. METHODS AND RESULTS: A total of 57 patients were included in the present analysis. Vasomotion of angiographically normal coronary arteries was evaluated in 37 control subjects (group 1) without and 20 patients (group 2) with calcium blocker administration before physical exercise. Both groups were subdivided into subgroup A (normal cholesterol values: < or = 5.5 mmol/L or 212 mg%) and subgroup B (elevated cholesterol values: >5.5 mmol/L or 212 mg%). Coronary luminal area at rest and during exercise was assessed by biplane quantitative coronary angiography. The normal vessels showed a significant increase in coronary luminal area during exercise in subgroup A (n=13) with normal cholesterol values (31%; P<.05) but not in subgroup B (n=24; 13%; P=NS). In contrast, all patients in group 2 showed similar vasodilation during exercise, namely, 22% (P<.05) in subgroups A (n=8) and B (n=12) (P<.05). Independent of the actual cholesterol level, the stenotic lesions showed coronary vasoconstriction during exercise in group 1 but vasodilation in group 2 after pretreatment with calcium antagonists. CONCLUSIONS: Coronary vasomotor response to exercise is inversely related to actual serum cholesterol level in angiographically normal vessels. Administration of calcium antagonists normalizes exercise-induced vasodilation and thus eliminates cholesterol-induced abnormal vasomotion, probably by a direct effect on the smooth muscles of the vasculature.

Tortuosity of coronary arteries in chronic pressure and volume overload.

The role of coronary tortuosity in the pathophysiology of chronic pressure and volume overload is still unclear. A new method for measuring coronary tortuosity in patients with chronic pressure and volume overload was evaluated in 62 patients. Sixteen controls, 14 patients with arterial hypertension, and 32 patients with aortic regurgitation were included in the present analysis. The left anterior descending (LAD) and circumflex (LCX) coronary arteries were traced, and tortuosity was determined in the 30 degrees right (RAO) and 60 degrees left (LAO) anterior oblique projection. Tortuosity index (TI, %) was defined as the percent ratio of calculated shortest distance divided by total length of the coronary artery. TI was 104.1 +/- 3.2% at end-diastole in controls, 105.7 +/- 3.8% in hypertensives (P < 0.05 vs. controls), and 102.9 +/- 2.5% in patients with aortic regurgitation (P < 0.05 vs. controls, P < 0.001 vs. hypertensives). Respective values at end-systole were 107.8 +/- 4.7% in controls, 109.8 +/- 7.1% in hypertensives (ns vs. controls), and 104.3 +/- 3.3% in patients with aortic regurgitation (P < 0.001 vs. controls and vs. hypertensives). No differences were found in tortuosity between RAO and LAO projection or between LAD and LCX artery. There was a significant correlation between TI and left ventricular (LV) muscle mass, LV volume, and age. Females tended to have more tortuous vessels than males. Coronary tortuosity is more pronounced in patients with chronic pressure than with volume overload. Determinants of coronary tortuosity are gender, age, LV volume, and muscle mass. Thus, coronary tortuosity seems to play an important role as a physiologic determinant for the flow and the mechanics of the vessel wall.

[Left ventricular function in post-endocarditis aortic insufficiency and aortic-annular ectasia]. / Verhalten der linksventrikulären Funktion bei postendokarditischer Aorteninsuffizienz und aorto-anulärer Ektasie.

BACKGROUND: The duration of valvular regurgitation is an important determinant of left ventricular function in the presence of severe volume overload. PURPOSE: To evaluate the effect of aortic regurgitation (aortoannullar dilatation vs. history of bacterial endocarditis) on left ventricular (LV) function. PATIENTS: Between February 1976 and January 1993 45 patients (mean; age 45 +/- 12 years) underwent diagnostic evaluation for clinical purposes. Patients were divided into three groups: group 1 consisted of 17 patients with normal LV function (controls), group 2 of 11 patients with severe aortic regurgitation due to aortoannullar dilatation (AAD) and group 3 of patients with severe aortic regurgitation and a history of bacterial endocarditis (BE). METHODS: LV function was assessed by biplane LV-angiography and simultaneous pressure recordings. The ejection fraction and peak systolic wall stress were calculated in all patients. Systolic and diastolic LV function was determined and compared within the three groups. RESULTS: Heart rate, mean aortic pressure and cardiac index were similar in the three groups. The mean aortic diameter was significantly increased in group 2 when compared to the other two groups (p < 0,001). Systolic function was significantly reduced in both groups with aortic regurgitation when compared to the control patients. The end diastolic pressure-volume relationship was shifted to the right in patients with aortic regurgitation, but only 3 patients with a history of bacterial endocarditis showed severe diastolic dysfunction. CONCLUSIONS: No hemodynamic differences were observed in patients with severe aortic regurgitation with regard to the etiology or time course of LV volume overload. However, 17% of the patients with a history of bacterial endocarditis had severe diastolic dysfunction, which is probably due to the faster development of volume overload after bacterial endocarditis.

Enzymatic activity of CD26 (dipeptidylpeptidase IV) is not required for its signalling function in T cells.

CD26 is a proteolytic enzyme (dipeptidylpeptidase IV) expressed on the T cell surface that defines an alternative activation signal for human T lymphocytes. Crosslinking of CD26 via monoclonal antibodies triggers proliferation and cytotoxicity in preactivated T cells. In this study, we used highly specific competitive and irreversible inhibitors of dipeptidylpeptidase IV to study the role of the enzymatic activity in activation of CD26-transfected T cells as well as of CD26-expressing normal human T cell clones. These inhibitors at concentrations that blocked up to 95% of the enzymatic activity, did not specifically inhibit T cell activation neither via TCR/CD3 nor via CD26 itself. This demonstrates that the enzymatic activity of CD26 is not required for its T cell activating properties.

Ambulatory blood pressure and heart rate in paramedics: effects of cynical hostility and defensiveness.

Ambulatory blood pressure and heart rate responses were obtained in 33 male paramedics during a 24-hour work shift to examine the effects of episodes of occupational stress on cardiovascular reactivity and subjective reports of stress. The aim of this study was to determine how individual differences in cynical hostility and defensiveness interacted with situational demands to affect cardiovascular responses in a natural setting. Defensiveness was found to interact significantly with cynical hostility in predicting subjects' heart rate responses in different work contexts. Specifically, in a hospital setting involving interpersonal conflict, subjects who were high in both defensiveness and hostility showed heart rate responses approximately 10 bpm higher than subjects who were high in hostility but low in defensiveness. The same pattern of relationships was obtained for diastolic blood pressure. High and low hostile subjects were also found to differ from each other in their daily mean levels of ambulatory blood pressure during awake and sleep periods. These findings obtained in a natural setting lend further support to the significance of cynical hostility for cardiovascular reactivity. The results for defensiveness suggest the need for further research on the role of conflicting attitudes in the pathophysiology of cardiovascular diseases.

Therapy assessment for sustained ventricular tachyarrhythmias: how many electropharmacological tests are appropriate?

Surgery, implantable devices or catheter ablations offer therapeutic choices for the treatment of malignant ventricular tachyarrhythmias (VT) resistant to antiarrhythmic drugs. The number of electropharmacological (EP) tests that should precede consideration of a nonpharmacological therapy has not been defined. We performed serial EP tests in 94 patients with inducible sustained VT until an effective drug was identified or all available drugs had failed to suppress VT induction. With up to 11 tests in individual patients, suppression of VT inducibility was finally achieved in 66 patients (70%). In 47 of these 66 patients (70%), only one or two tests were necessary to identify an effective regimen. However, in 40%, 28%, 18%, and 9% of the patients still inducible after 2, 3, 4, and 5 drug tests, respectively, an effective agent could be identified during subsequent tests. No critical number of unsuccessful EP tests clearly separated responders and nonresponders to medical therapy. During follow-up (34 +/- 11 months), 14 patients placed on antiarrhythmic drugs predicted to be effective had symptomatic VT recurrence. VT recurrence was unrelated to the type or the number of unsuccessful EP tests preceding identification of the prescribed drug. Extensive EP testing with all available agents might therefore be worthwhile in selected patients. An "appropriate" number of EP studies has to be determined individually for each patient, based on the chance of finding an effective drug during subsequent studies and the risk and benefit of the therapeutic choices.

Effect of isradipine on left ventricular relaxation and diastolic filling.

The effect of two calcium antagonists on left ventricular (LV) relaxation and diastolic filling was evaluated in 16 randomized patients. Isradipine and nifedipine were administered intravenously in a maximum dose of 60 micrograms/min for isradipine and 63 micrograms/min for nifedipine. Heart rate was increased significantly (p less than 0.01) by both study agents. LV end-diastolic pressure remained unchanged whereas peak systolic pressure decreased significantly (p less than 0.01). The reduction in systolic pressure was significantly greater (p less than 0.05) after isradipine (delta P of 30 mm Hg) than after nifedipine (delta P of 13 mm Hg). The time constant decreased from 65 to 56 ms (p less than 0.05) after isradipine and from 62 to 59 ms (NS) after nifedipine. LV filling remained unchanged. It is concluded that both calcium antagonists are associated with a significant reduction in LV afterload accompanied by a reflex increase in heart rate. Isradipine is a more potent vasodilator than nifedipine at the same infusion rate. A beneficial effect on LV relaxation with isradipine, but not nifedipine, may be due to its less pronounced negative inotropic effect or its more potent afterload-reducing action.

[Measurement of basal plasma levels of 3 anterior pituitary hormones during acute or chronic treatment with tricyclic antidepressants]. / Mesure du taux plasmatique basal de trois hormones antéhypophysaires au cours d'un traitement aigu ou chronique par des antidépresseurs tricycliques.

Prolactin, growth hormone and thyrotropin plasma levels have been evaluated in depressive in-patients, either during the first day of clomipramine or amitriptyline treatment, or after their chronic administration. Prolactin levels temporary rise during the first day of clomipramine or amitriptyline treatment in 6 patients out of 11, with a lag in relation to the drug plasma peak. A significant increase is observed after a 28 days treatment with clomipramine and a non significant decrease, after a 28 days treatment with amitriptyline. As for human growth hormone, a rise is found in 5 out of 8 clomipramine treated subjects but neither any variation with amitriptyline nor any significant variation with chronic administration of both drugs occur. Finally, thyrotropin plasma levels display no variation after acute or prolonged treatment with clomipramine or amitriptyline. These results are compared with those of literature, then discussed in the light of present theories on pituitary hormones secretion aminergic control and of tricyclic antidepressants effect on these hormones.

[A new model for the quantitative analysis of left ventricular regional function]. / Ein neues Modell für die quantitative Analyse der regionalen Funktion des linken Ventrikels.

A computer-assisted model for quantitative analysis of left ventricular segmental wall motion is presented. In contrast to standard rectangular and radial chord methods, no coordinate and reference system is used. Normal wall motion of 5 ventricular segments in the RAO projection was evaluated in 20 patients with normal ventriculograms. Segmental wall motion abnormalities after myocardial infarction were then analyzed by the computer-assisted method in 60 patients and the results compared with the visual assessment of an experienced cardiologist as standard reference. 96% of all segments with normal motion, 95% of all hypokinetic segments and 100% of all dyskinetic segments were correctly identified by computer analysis. Akinesia, however, was detected only in 25% of all cases and misinterpreted chiefly as hypokinesia. Further refinement of the software should improve detection of akinesia and classification of hypokinesia.