Validation of the Danish versions of the Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaires (BRAFs).

Objective: This study aimed to validate the Danish versions of the Bristol Rheumatoid Arthritis Fatigue Multi-Dimensional Questionnaire (BRAF-MDQ) and BRAF Numerical Rating Scale version 2 (NRSv2).Method: We tested face and content validity, internal consistency, criterion validity, construct validity, and reproducibility for the BRAF-MDQ, and face and criterion validity and reproducibility for the BRAF-NRS.Results: In all, 224/236 patients (95%) completed the questionnaires [70% female, mean ± sd age 59 ± 13.04 years, disease duration 11.2 ± 9.49 years, Health Assessment Questionnaire (HAQ) 0.724 ± 0.70, and 28-joint Disease Activity Score-C-reactive protein 2.55 ± 1.24]. The unidimensionality for the physical and cognitive fatigue subscales was confirmed, whereas the living with fatigue and emotional fatigue subscales were not unidimensional. Cronbach's α was 0.94 for the BRAF-MDQ total and 0.78-0.92 for the four subscales. The correlations between BRAF-MDQ and various measures were: 36-item Short Form Health Survey (SF-36) vitality subscale, 0.75; Hospital Anxiety and Depression Scale (HADS) anxiety subscale, 0.65; HADS depression subscale, 0.62; visual analogue scale (VAS) pain, 0.62; VAS global, 0.73; and HAQ, 0.62. The intraclass correlation coefficient for agreement was 0.995. A Bland-Altman plot showed a mean ± sd difference of -1.9 ± 3.62 for BRAF-MDQ. Correlation coefficients between the BRAF-NRSv2 subscales and other subscales were: BRAF-MDQ subscales, 0.57-0.93; SF-36 vitality subscale, 0.54-0.68; and VAS fatigue, 0.66-0.82.Conclusions: The Danish BRAFs are considered valid and reliable for use among Danish patients with rheumatoid arthritis, despite the subscales living with fatigue and emotional fatigue not being unidimensional, as they are in the original version.

Tumor microenvironment conditions alter Akt and Na+/H+ exchanger NHE1 expression in endothelial cells more than hypoxia alone: implications for endothelial cell function in cancer.

BACKGROUND: Chronic angiogenesis is a hallmark of most tumors and takes place in a hostile tumor microenvironment (TME) characterized by hypoxia, low nutrient and glucose levels, elevated lactate and low pH. Despite this, most studies addressing angiogenic signaling use hypoxia as a proxy for tumor conditions. Here, we compared the effects of hypoxia and TME conditions on regulation of the Na+/H+ exchanger NHE1, Ser/Thr kinases Akt1-3, and downstream effectors in endothelial cells. METHODS: Human umbilical vein endothelial cells (HUVEC) and Ea.hy926 endothelial cells were exposed to simulated TME (1% hypoxia, low serum, glucose, pH, high lactate) or 1% hypoxia for 24 or 48 h, with or without NHE1 inhibition or siRNA-mediated knockdown. mRNA and protein levels of NHE1, Akt1-3, and downstream effectors were assessed by qPCR and Western blotting, vascular endothelial growth factor (VEGF) release by ELISA, and motility by scratch assay. RESULTS: Within 24 h, HIF-1α level and VEGF mRNA level were increased robustly by TME and modestly by hypoxia alone. The NHE1 mRNA level was decreased by both hypoxia and TME, and NHE1 protein was reduced by TME in Ea.hy926 cells. Akt1-3 mRNA was detected in HUVEC and Ea.hy926 cells, Akt1 most abundantly. Akt1 protein expression was reduced by TME yet unaffected by hypoxia, while Akt phosphorylation was increased by TME. The Akt loss was partly reversed by MCF-7 human breast cancer cell conditioned medium, suggesting that in vivo, the cancer cell secretome may compensate for adverse effects of TME on endothelial cells. TME, yet not hypoxia, reduced p70S6 kinase activity and ribosomal protein S6 phosphorylation and increased eIF2α phosphorylation, consistent with inhibition of protein translation. Finally, TME reduced Retinoblastoma protein phosphorylation and induced poly-ADP-ribose polymerase (PARP) cleavage consistent with inhibition of proliferation and induction of apoptosis. NHE1 knockdown, mimicking the effect of TME on NHE1 expression, reduced Ea.hy926 migration. TME effects on HIF-1α, VEGF, Akt, translation, proliferation or apoptosis markers were unaffected by NHE1 knockdown/inhibition. CONCLUSIONS: NHE1 and Akt are downregulated by TME conditions, more potently than by hypoxia alone. This inhibits endothelial cell migration and growth in a manner likely modulated by the cancer cell secretome.

Endogenous prostacyclin biosynthesis and platelet function during selective inhibition of thromboxane synthase in man.

The consequences of inhibiting the metabolism of prostaglandin G2 to thromboxane A2 in man were studied by using an inhibitor of thromboxane synthase, 4-[2-(IH-imidazol-1-yl)ethoxy] benzoic acid hydrochloride (dazoxiben). Single doses of 25, 50, 100, and 200 mg of dazoxiben were administered to healthy volunteers at 2-wk intervals in a randomized, placebo-controlled, double-blind manner. Serum thromboxane B2 and aggregation studies in whole blood and platelet-rich plasma were measured before dosing and at 1, 4, 6, 8, and 24 h after dosing. Both serum thromboxane B2 and the platelet aggregation response to arachidonic acid (1.33 mM) were reversibly inhibited in a dose-dependent manner. Aggregation induced by 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (0.4 and 4.0 microM) in platelet-rich plasma as well as both aggregation and nucleotide release induced by collagen (95 micrograms/ml) in platelet-rich plasma and whole blood were unaltered by dazoxiben. Additional evidence for a platelet-inhibitory effect of the compound was a significant prolongation of the bleeding time at 1 h after administration of the highest dose (200 mg) of dazoxiben. Endogenous prostacyclin biosynthesis was assessed by measurement of the major urinary metabolite of prostacyclin, 2,3-dinor-6-keto-PGF1 alpha (PGI-M). PGI-M excretion was increased by dazoxiben; it rose a mean 2.4-fold from predosing control values at 0-6 h after administration of the highest dose studied (200 mg).

Alpha-cardiac actin is a novel disease gene in familial hypertrophic cardiomyopathy.

We identified the alpha-cardiac actin gene (ACTC) as a novel disease gene in a pedigree suffering from familial hypertrophic cardiomyopathy (FHC). Linkage analyses excluded all the previously reported FHC loci as possible disease loci in the family studied, with lod scores varying between -2.5 and -6.0. Further linkage analyses of plausible candidate genes highly expressed in the adult human heart identified ACTC as the most likely disease gene, showing a maximal lod score of 3.6. Mutation analysis of ACTC revealed an Ala295Ser mutation in exon 5 close to 2 missense mutations recently described to cause the inherited form of idiopathic dilated cardiomyopathy (IDC). ACTC is the first sarcomeric gene described in which mutations are responsible for 2 different cardiomyopathies. We hypothesize that ACTC mutations affecting sarcomere contraction lead to FHC and that mutations affecting force transmission from the sarcomere to the surrounding syncytium lead to IDC.

Electromechanical mapping for detection of myocardial viability in patients with ischemic cardiomyopathy.

BACKGROUND: We evaluated the ability of electromechanical mapping of the left ventricle to distinguish between nonviable and viable myocardium in patients with ischemic cardiomyopathy. METHODS AND RESULTS: Unipolar voltage amplitudes and local endocardial shortening were measured in 31 patients (mean+/-SD age, 62+/-8 years) with ischemic cardiomyopathy (ejection fraction, 30+/-9%). Dysfunctional regions, identified by 3D echocardiography, were characterized as nonviable when PET revealed matched reduction of perfusion and metabolism and as viable when perfusion was reduced or normal and metabolism was preserved. Mean unipolar voltage amplitudes and local shortening differed among normal, nonviable, and viable dysfunctional segments. Coefficient of variation for local shortening exceeded differences between groups and did not allow distinction between normal and dysfunctional myocardium. Optimum nominal discriminatory unipolar voltage amplitude between nonviable and viable dysfunctional myocardium was 6.5 mV, but we observed a great overlap between groups. Individual cutoff levels calculated as a percentage of electrical activity in normal segments were more accurate in the detection of viable dysfunctional myocardium than a general nominal cutoff level. The optimum normalized discriminatory value was 68%. Sensitivity and specificity were 78% for the normalized discriminatory value compared with 69% for the nominal value (P:<0.02). CONCLUSIONS: Endocardial ECG amplitudes in patients with ischemic cardiomyopathy display a wide scatter, complicating the establishment of exact nominal values that allow distinction between viable and nonviable areas. Individual normalization of unipolar voltage amplitudes improves diagnostic accuracy. Electroanatomic mapping may enable identification of myocardial viability.

Regional myocardial blood flow in patients with sick sinus syndrome randomized to long-term single chamber atrial or dual chamber pacing--effect of pacing mode and rate.

OBJECTIVES: This study aimed to evaluate regional myocardial blood flow (MBF) and global left ventricular ejection fraction (LVEF) during chronic pacing in patients with sick sinus syndrome (SSS) randomized to either single chamber atrial (AAI) or dual chamber (DDD) pacing. BACKGROUND: Experimental studies indicate that chronic pacing in the right ventricular apex changes regional MBF, thereby compromising left ventricular function. METHODS: Thirty patients (age 74 +/- 10 years) were randomized to AAI (n = 15) or DDD (n = 15) pacemakers. After 22 +/- 7 months of pacing, MBF was quantified with 13N-labeled ammonia positron emission tomography scanning at 60 beats per min and 90 beats per min. Patients in the DDD group furthermore underwent MBF measurement at temporary AAI pacing, 60 beats per min. Myocardial blood flow was assessed in the anterior, lateral, inferior and septal regions, and the global mean MBF was calculated. Left ventricular ejection fraction was determined by echocardiography at pacemaker implantation and at the time of MBF measurements. RESULTS: Myocardial blood flow at rates 60 and 90 beats per min did not differ between the AAI and DDD groups. During temporary AAI pacing in the DDD group, MBF was significantly higher than during DDD pacing in both the inferior (p = 0.001) and septal (p = 0.004) regions and also globally (0.61 +/- 0.15 vs. 0.53 +/- 0.13 mL x g(-1) x min(-1), p = 0.005). In the DDD group, LVEF decreased from pacemaker implantation to time of MBF measurements (0.61 +/- 0.09 vs. 0.56 +/- 0.07, p = 0.013). Left ventricular ejection fraction during temporary AAI pacing at time of MBF measurements was not different from LVEF at pacemaker implantation. CONCLUSIONS: In patients with SSS, chronic DDD pacing reduced inferior, septal and global mean MBF as well as LVEF, as compared with temporary AAI pacing. The LVEF reversed to baseline level during temporary AAI pacing despite 22 months of permanent ventricular pacing preceding it. Augmenting pace rate to 90 beats per min increased MBF equally in the two treatment groups.

Cyclooxygenase inhibition, platelet function, and metabolite formation during chronic sulfinpyrazone dosing.

The inhibitory effects of sulfinpyrazone are more marked ex vivo than in vitro, suggesting biotransformation to potentially active metabolites such as the sulfide and sulfone metabolites. As a platelet inhibitor, the sulfide metabolite is 10 times as potent as the parent and because of its long t1/2, the former may lead to cumulative inhibition of platelet function in vivo during chronic sulfinpyrazone dosing. In our study, healthy subjects received sulfinpyrazone, 200 mg four times a day, for 6 days. Plasma levels of the sulfide metabolite rose slightly from 2.1 +/- 0.8 micrograms/ml 12 hr after the fourth dose to 2.8 +/- 0.8 microgram/ml 12 hr after the twenty-fourth dose. This was associated with increasing inhibition of ex vivo platelet aggregation induced by platelet-activating factor during the dosing period, but inhibition of arachidonic acid-induced aggregation did not increase cumulatively during dosing and collagen-induced aggregation was not inhibited. Inhibition of platelet aggregation was no longer evident 24 hr after the final dose of sulfinpyrazone. The effects of sulfinpyrazone on cyclooxygenase activity were assessed by measurement of thromboxane B2 production by thrombin-stimulated platelets ex vivo and urinary excretion of the major prostacyclin metabolite 2,3-dinor-6-keto-PGF1 alpha. During sulfinpyrazone dosing, thromboxane formation and prostacyclin biosynthesis were correspondingly lowered 50% to 60%. The extent of this depression was of the same order on days 2 and 5 of dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Antiischemic and metabolic effects of glutamate during pacing in patients with stable angina pectoris secondary to either coronary artery disease or syndrome X.

The effects of glutamate on anginal threshold, cardiac metabolism and hemodynamics were studied in 11 patients with stable angina pectoris, positive stress test results, and pacing-induced myocardial lactate release due to coronary artery disease (CAD) (n = 9) or syndrome X (n = 2). Data were obtained before, during and after 2 identical periods of coronary sinus pacing, the second being preceded by an intravenous injection of monosodium glutamate 1.2 (n = 7) or 2.5 (n = 4) mg/kg body weight. After glutamate administration, pacing time to onset of angina increased from mean +/- standard deviation 103 +/- 53 to 166 +/- 71 seconds (p less than 0.01) and ST-segment depression after pacing decreased from 2.3 +/- 1.0 to 1.6 +/- 1.1 mm (p less than 0.01). Arterial glutamate concentration increased 60% (p less than 0.01) after the low dose and 150% (p less than 0.01) after the high dose of glutamate. Regardless of dose, myocardial glutamate uptake increased by 25% (p less than 0.01). Pacing-induced cardiac release of lactate diminished 50% (p less than 0.05), whereas the releases of xanthine and hypoxanthine were unchanged by glutamate. Arterial free fatty acids decreased 20% (p less than 0.01). Circulating levels and cardiac exchanges of alanine, glucose and citrate were unchanged. Glutamate did not influence heart rate, arterial blood pressure, coronary blood flow, coronary vascular resistance or myocardial oxygen consumption. One patient complained of short-lasting burning sensations after receiving the high glutamate dose. In conclusion, augmented provision of glutamate enhances pacing tolerance in stable angina, presumably by a metabolic improvement of cardiac energy production during ischemia.

Arterial thromboembolism in patients with sick sinus syndrome: prediction from pacing mode, atrial fibrillation, and echocardiographic findings.

OBJECTIVE: To evaluate whether thromboembolism in sick sinus syndrome can be predicted by pacing mode, atrial fibrillation, or echocardiographic findings. METHODS: Patients were randomised to single chamber atrial (n = 110) or ventricular (n = 115) pacing. They were divided into subgroups with and without brady-tachy syndrome at time of randomisation. The occurrence of atrial fibrillation and thromboembolism during follow up were investigated and compared with echocardiographic findings. RESULTS: The annual risk of thromboembolism was 5.8% in patients with brady-tachy syndrome randomised to ventricular pacing, 3.2% in patients without brady-tachy syndrome randomised to ventricular pacing, 3% in patients with brady-tachy syndrome randomised to atrial pacing, and 1.5% in patients without brady-tachy syndrome randomised to atrial pacing. In atrial paced patients without brady-tachy syndrome at randomisation and without atrial fibrillation during follow up, the annual risk of thromboembolism was 1.4%. Left atrial size measured by M mode echocardiography was of no value in predicting thromboembolism. CONCLUSIONS: Arterial thromboembolism in patients with sick sinus syndrome is very common and is associated primarily with brady-tachy syndrome at randomisation and with ventricular pacing. The risk of thromboembolism is small in atrial paced patients in whom atrial fibrillation has never been documented.

Spondylolysis and spondylolisthesis. Treatment by internal fixation and bone-grafting of the defect.

Eighteen patients who had symptomatic spondylolysis or Grade-I spondylolisthesis, and whose symptoms had not been relieved by non-operative treatment, were operated on using the Buck method for bone-grafting and internal fixation of the defect of the pars interarticularis with screws. There were six male and twelve female patients and the average age was twenty years (range, fourteen to thirty-eight years). The amount of slipping ranged from zero to ten millimeters. After an average period of follow-up of forty-one months (range, twenty-four to seventy-two months), the result was excellent in ten, good in five, and poor in three patients. Thus, a satisfactory result was obtained in 83 per cent of the patients.

Preparation and analysis of deuterium-labeled aspirin: application to pharmacokinetic studies.

Inhibition of endogenous prostacyclin and thromboxane biosynthesis by aspirin is critically dose-dependent in humans. Gastrointestinal and hepatic hydrolysis may limit systemic availability of aspirin, especially in low doses, perhaps contributing to the biochemical selectivity of aspirin. Existing analytical methods do not permit determination of systemic bioavailability when low (less than 100 mg) doses of aspirin are administered. Deuterium-labeled aspirin (2-acetoxy[3,4,5,6-2H4]benzoic acid) was synthesized from salicylic acid by catalytic exchange and subsequent acetylation. Analysis of the compounds as benzyl esters by GC-MS followed extractive alkylation from plasma. Heptadeuterated compounds were used as internal standards. Simultaneous administration of tetradeuterated aspirin intravenously with native aspirin orally to anesthetized dogs permitted kinetic studies of both aspirin and salicylic acid. The sensitivity of the method is superior to published methods using HPLC and, thus, more applicable to studies of low dose aspirin. Pulse administration of stable isotope-labeled aspirin permits detailed and repeated studies of dose-related aspirin pharmacokinetics in humans.

Two metabolites of sulphinpyrazone and their identification and determination by mass spectrometry.

Sulphinpyrazone is an antiplatelet in vivo and in vitro. Two active metabolites, a sulphide (S) and a hydroxylated sulphide (S-OH) have been identified in rabbit and human plasma and a selective and sensitive g.c.-m.s.-method for quantitative determination of the sulphide and hydroxylated sulphide in plasma and urine has been evolved which allows concentrations down to 5 ng ml-1 for the sulphide and 30 ng ml-1 for the hydroxylated sulphide to be detected. The time course of the metabolite concentrations in plasma corresponds to the biological findings, suggesting that the metabolites contribute significantly to the in vivo effects of the drug.

Recovery of beat-to-beat variations of QRS.

There is a growing interest in the analysis of beat-to-beat variations of the morphology (BBM) of cardiac waves in electrocardiograms (ECG). Such analyses are confronted with the low BBM-to-noise ratio. An ECG clustering technique is introduced that brings the benefits of signal averaging to BBM analysis and recovers the beat-to-beat pattern of BBM. ECG clustering aligns waves and sorts them into clusters. The precision of the alignment was enhanced by sub-sample alignment. Kohonen's self-organising neural networks identified the clusters of the cardiac waves during training. The subsequent clustering of a wave results in a label for the closest cluster, a distance to the cluster and optimal alignment. Furthermore, ECG clustering avoids base-line variations and amplitude modulation sufficiently to be applied to the QRS wave in the raw ECG. The technique is demonstrated on 14 subjects with coronary heart disease and no myocardial infarction, myocardial infarction, or inducible ventricular tachycardia. ECG clustering is a general-purpose technique for beat-to-beat analysis, where the variations are cyclic as in the sinus rhythm. Results show that beat-to-beat variations in the QRS morphology are in general cyclic, with a main period of about four cardiac cycles. All calculations were performed with the Cardio software.

[Hereditary long QT syndrome]. / Arveligt langt QT-syndrom.

The Long QT Syndrome (LQTS) is a hereditary disease, characterized by a prolonged QT-interval on the electrocardiogram and a high risk of syncope and sudden death due to ventricular arrhythmias. LQTS must be suspected in apparently healthy children and young people with syncope after emotional or physical stress. Untreated symptomatic patients have a high mortality, which is markedly reduced by sympathetic block. The knowledge of the diagnostic criteria for the LQTS, a detailed history including a family history and an ECG-recording with measurement of the QT-interval in every patient with inexplicable syncope will advance the diagnosis of the LQTS and improve the survival of these patients after proper therapy. The current knowledge on the molecular genetics, epidemiology, mechanisms of arrhythmias and therapy are presented with special emphasis on the defects in the control of ionic transport over the cell membrane caused by mutations in ion channels.

[Treatment with implantable cardioverter-defibrillators. Experiences from Skejby hospital during the period 1989-1994]. / Behandling med implanterbar kardioverter-defibrillator. Erfaringer fra Skejby Sygehus i perioden 1989-1994.

The aim of the present study was to evaluate survival and therapy for ventricular tachyarrhythmia in patients treated with implantable cardioverter-defibrillator (ICD)-implantation at Skejby Hospital. Seventy-two patients, of which 54 were male, have received an ICD since 1989. Mean (range) age was 54 (16-74) years. Forty-nine (68%) had ischaemic heart disease. The patients were followed for a median (range) of 14 (1/2-50) months. Kaplan-Meyer plots are presented for total mortality, cardiac mortality, sudden cardiac mortality, appropriate therapy, and therapy for life-threatening tachyarrhythmia. After one, two and three years respectively, mortality was respectively 13, 27, and 32%, cardiac mortality was 5, 19, and 24%, sudden cardiac mortality was 3, 6, and 12%, cumulative incidence of appropriate therapy was 56, 66, and 90%, and cumulative incidence of therapy for life-threatening tachyarrhythmia was 19, 29 and 52%. It is concluded, that the majority of patients treated with an ICD developed ventricular tachyarrhythmia and had appropriate or lifesaving ICD-therapy during follow-up.

[Arrhythmogenic right ventricular cardiomyopathy]. / Arytmogen højre ventrikel kardiomyopati.

Arrhythmogenic right ventricular dysplasia is a rare cardiomyopathy, but a frequent cause of ventricular tachyarrhythmia and sudden cardiac death among young otherwise healthy individuals. This article contains a review of the current knowledge on epidemiology, diagnosis, symptoms and signs as well as theories on etiology and pathogenesis, prognosis and treatment. The aim is to draw attention to the disease as a cause of syncope, ventricular tachycardia and sudden cardiac death.

[Single-chamber atrial pacing is better than single chamber ventricular pacing in patients with sick sinus syndrome. Results of long-term follow up in a prospective randomized study]. / Etkammer-atriepacing er bedre end etkammer-ventrikelpacing hos patienter med syg sinusknude. Resultatet af langtidsopfølgning i en prospektiv, randomiseret undersøgelse.

In a study of 225 patients with sick sinus syndrome randomized to single chamber atrial pacing (n = 110) or ventricular pacing (n = 115), atrial pacing was associated with less atrial fibrillation and thromboembolism after 3.3 years follow-up. To determine whether this beneficial effect of atrial pacing is maintained at long-term, follow-up was extended. Follow-up visits were at 3 months, 12 months, and then once every year, and included physical examination, ECG, and pacemaker check-up. After 5.5 years follow-up, all-cause mortality, cardiovascular deaths, atrial fibrillation, thromboembolism, and heart failure were significantly less in the atrial group. AV block occurred in four patients in the atrial group. The beneficial effect of atrial pacing observed previously is enhanced substantially after extended follow-up. Patients with sick sinus syndrome should be treated with an atrial pacing system.

[Late ventricular potentials after myocardial infarction]. / Sene ventrikulaere potentialer efter myokardieinfarkt.

Late potentials in the QRS complex can be detected with signal-averaged electrocardiography and are associated with delayed and disorganized ventricular activation. This article reviews the technique, describes the pathophysiological basis of late potentials, and assesses the prognostic value of late potentials for subsequent development of ventricular tachyarrhythmias and sudden cardiac death in postmyocardial infarction patients.