Tom Klausen

Power doppler ultrasonography for assessment of synovitis in the metacarpophalangeal joints of patients with rheumatoid arthritis: A comparison with dynamic magnetic resonance imaging

OBJECTIVE To evaluate the effectiveness of power Doppler ultrasonography (PDUS) for assessing inflammatory activity in the metacarpophalangeal (MCP) joints of patients with rheumatoid arthritis (RA), using dynamic magnetic resonance imaging (MRI) as a reference method. METHODS PDUS and dynamic MRI were performed on 54 MCP joints of 15 patients with active RA and on 12 MCP joints of 3 healthy controls. PDUS was performed with a LOGIQ 500 unit by means of a 7-13-MHz linear array transducer. Later the same day, MRI was performed with a 1.0T MR unit. A series of 24 coronal T1-weighted images of the second through the fifth MCP joints was obtained, with intravenous injection of gadolinium diethylenetriaminepentaacetic acid after the fourth image (dynamic MRI). From the MR images, the rate of early synovial enhancement (RESE; defined as the relative enhancement per second during the first 55 seconds postinjection) was calculated and compared with the flow signal on PDUS, which was scored as present or absent. RESULTS In RA patients, flow signal on PDUS was detected in 17 of 54 MCP joints examined. Postcontrast MR images revealed an RESE of > or = 1.0%/second in 18 of 54 RA MCP joints. PDUS showed no flow in 47 of 48 MCP joints with an RESE of <1.0%/second and revealed flow in 16 of 18 MCP joints with an RESE of > or = 1.0%/second. Using dynamic MRI as a reference, PDUS had a sensitivity of 88.8% and a specificity of 97.9%. CONCLUSION PDUS was reliable for assessing inflammatory activity in the MCP joints of RA patients, using dynamic MRI as the standard. PDUS and clinical assessment of joint swelling/tenderness were only weakly correlated.

Hypoxemia increases serum interleukin-6 in humans

Abstract Serum concentrations of interleukin (IL) 1 beta, IL-1 receptor antagonist (IL-1ra), IL-6, tumor necrosis factor (TNF) alpha, and C-reactive protein (CRP) were determined in ten healthy men at sea level and during four days of altitude hypoxia (4350m above sea level). The mean (SD) arterial blood oxygen saturations were 78.6 (7.3)%, 82.4 (4.9)%, and 83.4 (5.3)% in the first, second, and third days at altitude, respectively. A symptom score of acute mountain sickness (AMS) revealed that the subjects had mostly light symptoms of AMS. Mean serum IL-6 increased from 1.36 (1.04) pg × ml–1 at sea level to 3.10 (1.65), 4.71 (2.81), and 3,54 (2.17) pg × ml–1 during the first three days at altitude, and to 9.96 (8.90) pg × ml–1 on the fourth day at altitude (ANOVA p =0.002). No changes occurred in serum concentrations of IL-1 beta, IL-1ra, TNF alpha, or CRP. The serum IL-6 were related to SaO2, ( r =–0.45, p =0.003), but not to heart rates or AMS scores. In conclusion, human serum concentrations of IL-6 increased during altitude hypoxia whereas the other proinflammatory cytokines remained unchanged. The major role of IL-6 during altitude hypoxia seem not to be mediation of inflammation, instead, the role of IL-6 could be to stimulate the erythropoiesis at altitude.

Contrast-enhanced power Doppler ultrasonography of the metacarpophalangeal joints in rheumatoid arthritis

Abstract. The aim of this study was to examine, with dynamic contrast-enhanced MRI as the reference, if contrast-enhanced power Doppler ultrasonography (CE PDUS) of rheumatoid arthritis (RA) metacarpophalangeal (MCP) joints provides additional information for evaluation of synovial inflammation compared with PDUS. One MCP joint in each of 15 RA patients and 3 healthy control persons were examined with PDUS before and after intravenous bolus Levovist contrast injection. Corresponding rates of early synovial enhancement (RESE), previously shown to be closely related to histopathological synovitis, were calculated from dynamic contrast-enhanced MR images obtained the same day. Prior to ultrasonography, the joint was evaluated clinically. Levovist increased the flow signal in 7 of 9 joints with pre-contrast flow-signal and in 0 of 9 without pre-contrast signal. No healthy controls showed CE PDUS signal. The results of CE PDUS and dynamic MRI were closely related: RESE in joints with CE PDUS signal was significantly higher than in joints without CE PDUS signal (Mann-Whitney test, p<0.001). Among the patients with pre-contrast PDUS signal no statistically significant difference in RESE values was found between joints with and without post-contrast flow-signal increase. No correlation was found between clinical examination and CE PDUS. Based on comparisons with dynamic contrast-enhanced MRI, PDUS appears to be reliable for assessment of synovitis in RA MCP joints. Intravenous contrast injection may provide additional information in selected cases but did not in the present study increase the sensitivity of the method.

Diurnal variations of serum erythropoietin at sea level and altitude

This study tested the hypothesis that the diurnal variations of serum-erythropoietin concentration (serum-EPO) observed in normoxia also exist in hypoxia. The study also attempted to investigate the regulation of EPO production during sustained hypoxia. Nine subjects were investigated at sea level and during 4 days at an altitude of 4350 m. Median sea level serum-EPO concentration was 6 (range 6–13) U·l−1. Serum-EPO concentration increased after 18 and 42 h at altitude, [58 (range 39–240) and 54 (range 36–340) U·l−1, respectively], and then decreased after 64 and 88 h at altitude [34 (range 18–290) and 31 (range 17–104) U·l−1, respectively]. These changes of serum-EPO concentration were correlated to the changes in arterial blood oxygen saturation (r = −0.60,P = 0.0009), pH (r = 0.67,P = 0.003), and in-vivo venous blood oxygen half saturation tension (r = −0.68,P = 0.004) but not to the changes in 2, 3 diphosphoglycerate. After 64 h at altitude, six of the nine subjects had down-regulated their serum-EPO concentrations so that median values were three times above those at sea level. These six subjects had significant diurnal variations of serum-EPO concentration at sea level; the nadir occurred between 0800–1600 hours [6 (range 4–13) U·l−1], and peak concentrations occurred at 0400 hours [9 (range 8–14) U·l−1,P = 0.02]. After 64 h at altitude, the subjects had significant diurnal variations of serum-EPO concentration; the nadir occurred at 1600 hours [20 (range 16–26) U·l−1], and peak concentrations occurred at 0400 hours [31 (range 20–38) U·l−1,P = 0.02]. This study demonstrated diurnal variations of serum-EPO concentration in normoxia and hypoxia, with comparable time courses of median values. The results also suggested that EPO production at altitude is influenced by changes in pH and haemoglobin oxygen affinity.

Diurnal variations of serum erythropoietin in trained and untrained subjects

The diurnal variations of serum-erythropoietin concentration ([s-EPO]) were investigated in six physically trained (T) and eight untrained (UT) men. The T subjects had a higher mean maximal oxygen uptake than UT subjects [75.7 (SEM 1.6) ml · min−1 · kg−1 versus 48.3 (SEM 1.4) ml · min−1 · kg−1, P < 0.0001] and a lower mean body mass index [BMI, 21.7 (SEM 0.7) kg · m−2 versus 24.4 (SEM 0.6) kg · m−2, P=0.02]. Each subject was followed individually for 24 h as they performed their normal daily activities. Venous blood samples were collected from awakening (0 min) until the end of the 24-h period (1440 min). Both T and UT had a nadir of [s-EPO] 120 min after awakening [10.0 (SEM 0.3) U · 1−1 versus 11.5 (SEM 2.1) U · 1−1, P > 0.05]. The UT and T increased their [s-EPO] to peak values at 960 min and 960–1200 min, respectively (ANOVA P=0.03) after awakening [UT: 18.4 (SEM 2.8) U · l−1; T: 16.2 (SEM 2.5) U · l−1, P > 0.05]. The mean 24-h [s-EPO] were 14.5 (SEM 1.0) U · l−1 and 14.9 (SEM 0.9) U · l−1 in T and UT, respectively (P > 0.05). The individual mean 24-h [s-EPO] were not correlated to body mass, BMI or maximal oxygen uptaken. Significant diurnal variations in [s-EPO] occurred in these healthy subjects irrespective of their levels of physical activity.

Effects of hyperventilation and hypocapnic/normocapnic hypoxemia on renal function and lithium clearance in humans

Background Using the renal clearance of lithium as an index of proximal tubular outflow, this study tested the hypothesis that acute hypocapnic hypoxemia decreases proximal tubular reabsorption to the same extent as hypocapnic normoxemia (hyperventilation) and that this response is blunted during normocapnic hypoxemia. Methods Eight persons were studied on five occasions: (1) during inhalation of 10% oxygen (hypocapnic hypoxemia), (2) during hyperventilation of room air leading to carbon dioxide values similar to those with hypocapnic hypoxemia, (3) during inhalation of 10% oxygen with the addition of carbon dioxide to produce normocapnia, (4) during normal breathing of room air through the same tight‐fitting face mask as used on the other study days, and (5) during breathing of room air without the face mask. Results Hypocapnic and normocapnic hypoxemia and hyperventilation increased cardiac output, respiratory minute volume, and effective renal plasma flow. Glomerular filtration rate remained unchanged on all study days. Calculated proximal tubular reabsorption decreased during hypocapnic hypoxemia and hyperventilation but remained unchanged with normocapnic hypoxemia. Sodium clearance increased slightly during hypocapnic and normocapnic hypoxemia, hyperventilation, and normocapnic normoxemia with but not without the face mask. Conclusions The results indicate that (1) respiratory alkalosis with or without hypoxemia decreases proximal tubular reabsorption and that this effect, but not renal vasodilation or natriuresis, can be abolished by adding carbon dioxide to the hypoxic gas; (2) the increases in the effective renal plasma flow were caused by increased ventilation rather than by changes in arterial oxygen and carbon dioxide levels; and (3) the natriuresis may be secondary to increased renal perfusion, but application of a face mask also may increase sodium excretion.

Human erythropoietin response to hypocapnic hypoxia, normocapnic hypoxia, and hypocapnic normoxia

This study investigated the human erythropoietin (EPO) response to short-term hypocapnic hypoxia, its relationship to a normoxic or hypoxic increase of the haemoglobin oxygen affinity, and its suppression by the addition of CO2 to the hypoxic gas. On separate days, eight healthy male subjects were exposed to 2 h each of hypocapnic hypoxia, normocapnic hypoxia, hypocapnic normoxia, and normal breathing of room air (control experiment). During the control experiment, serum-EPO showed significant variations (ANOVAP = 0.047) with a 15% increase in mean values. The serum-EPO measured in the other experiments were corrected for these spontaneous variations in each individual. At 2 h after ending hypocapnic hypoxia (10% O2 in nitrogen), mean serum-EPO increased by 28% [baseline 8.00 (SEM 0.84) U · 1−1, post-hypoxia 10.24 (SEM 0.95) U · 1−1, P = 0.005]. Normocapnic hypoxia was produced by the addition of CO2 (10% Co2 with 10% O2) to the hypoxic gas mixture. This elicited an increased ventilation, unaltered arterial pH and haemoglobin oxygen affinity, a lower degree of hypoxia than during hypocapnic hypoxia, and no significant changes in serum-EPO (ANOVAP > 0.05). Hypocapnic normoxia, produced by hyperventilation of room air, elicited a normoxic increase in the haemoglobin oxygen affinity without changing serum-EPO. Among the measured blood gas and acid-base parameters, only the partial pressures of oxygen in arterial blood during hypocapnic hypoxia were related to the peak values of serum-EPO (r = −0.81,P = 0.01). The present human EPO responses to hypoxia were lower than those which have previously been reported in rodents and humans. In contrast with the earlier rodent studies, it was found that human EPO production could not be triggered by short-term increases in pH and haemoglobin oxygen affinity per se, and the human EPO response to hypoxia could be suppressed by concomitant normocapnia without acidosis.

The effect of short and long duration exercise on serum erythropoietin concentrations

SummaryThe effects of short and long duration exercise on serum erythropoietin concentrations [EPO]s were studied in seven male cross-country skiers of national team standard and eight male marathon runners, respectively. The short duration exercise was performed as 60 min of cycling at an intensity of 80%–95% of maximal heart rate. Arterial blood oxygen saturations monitored by pulse-oximetry remained unchanged throughout exercise. The partial pressure of O2 at which haemoglobin was half-saturated with O2 calculated from forearm venous blood gas tension and blood O2 saturation, and the erythrocyte 2,3-diphosphoglycerate did not change significantly during the exercise. Blood lactate concentrations were increased at the end of exercise [from 1.3 (SEM 0.1) to 3.6 (SEM 0.3) mmol · 1−1]. The [EPO]s determined (by enzyme-linked immunosorbent assay) pre-exercise, 5 min, 6 h, 19 h, and 30 h after the exercise were unchanged [from 16.1 (SEM 2.6) to 19.1 (SEM 3.2), 17.9 (SEM 3.0), 17.0 (SEM 2.5), and 18.6 (SEM 2.9) U·l−1, respectively]. The [EPO]s were not correlated to the earlier parameters. The long duration exercise consisted of habitual training, a 3 week break from training followed by 2 and 4 weeks of re-training. The [EPO]s, body fat (BF), and serum free-testosterone concentrations determined at the end of each period remained unchanged. The maximal oxygen uptakes were decreased after the break from training and increased during retraining (P=0.04). Body mass (mb) increased after the break in training (P=0.02). The [EPO]s were correlated to BF,r=0.42,P=0.02;mb,r=0.45,P=0.01; and free-testosterone concentrations,r=0.44,P=0.01. Thus, short and long-duration exercise had no direct influence on [EPO]s; but relationships among [EPO]s, free-testosterone concentrations and body composition were noted.

An early effect of acute plasma volume expansion in humans on serum erythropoietin concentration.

The effect of acute plasma volume change in humans on serum erythropoietin [EPO]s, plasma active renin [REN] and plasma aldosterone [ALDO] concentrations was examined. Plasma volume (PV) expansion was induced by intravenous infusion of 150 ml (30g) of plasma albumin and 500 ml of physiological saline. The [EPO]s decreased by 14.3% (corrected values for PV expansion) and remained decreased for 5 h. The [REN] was decreased by more than 25% during the day of the experiment and [ALDO] by more than 60%. Only a weak positive correlation was found between [EPO]s and [REN] (r = 0.35;P < 0.05) but a lack of correlation between changes in PV and [EPO]s as well as between [EPO]s and [ALDO] was seen. We postulated that in healthy men an acute PV expansion by 10% to 17.5% would not appear to promote stimulation of EPO synthesis for at least 11 h. Since a weak positive correlation was observed between [EPO]s and [REN] and a lack of correlation between [EPO]s and [ALDO], it would seem that there is no direct link between [REN] and [ALDO] and erythropoietin synthesis in healthy subjects.