Health-related quality of life in 975 patients with complex regional pain syndrome type 1.

There are limited data available on health-related quality of life (QoL) in patients with complex regional pain syndrome (CRPS). In the present study we examined QoL in 975 CRPS patients attending 6 different clinics in the Netherlands. QoL was assessed using the MOS 36-Item Short-Form Health Survey (SF-36) with the Mental Health Summary Score (MHS) and the Physical Health Summary Score (PHS) as dependent variables. The influences of gender, type of affected limb, disease duration, pain scores, CRPS severity and set of diagnostic criteria used were investigated. We found the lowest scores of QoL in the physical domains of the SF-36, with lower-limb CRPS patients reporting poorer results than patients with an affected upper limb. Influence of gender on QoL was not observed, and correlations of QoL with disease duration and the CRPS severity score were weak. Pain correlated moderately with QoL. In addition, patients fulfilling stricter diagnostic criteria (ie, the Budapest criteria) had lower QoL scores than patients fulfilling less strict criteria (ie, the Orlando criteria). We conclude that loss of QoL in CRPS patients is due mainly to reduced physical health. A comparison with data available from the literature shows that CRPS patients generally report poorer QoL than patients with other chronic pain conditions, particularly in the physical domains. Pain correlated moderately with QoL and therefore deserves ongoing attention by physicians. Finally, patients meeting the diagnostic Budapest criteria have lower QoL scores than patients meeting the Orlando criteria, highlighting the impact of different sets of criteria on population characteristics.

The role of pain coping and kinesiophobia in patients with complex regional pain syndrome type 1 of the legs.

OBJECTIVES: The aim of this cross-sectional study was to evaluate to what extent pain coping and kinesiophobia contribute to limitations in activity and participation in patients with complex regional pain syndrome type 1 (CRPS-1) of the lower limbs. METHODS: A total of 238 patients with CRPS-1 of the legs from 4 pain clinics and 1 Department of Neurology of University Hospitals participated in this study. Pain and CRPS severity were assessed with the pain rating index of the McGill Pain Questionnaire and the CRPS Severity Score, respectively. Activity was measured with the Rising & Walking scale, and participation with the Social Functioning scale of the SF-36. In addition, the Tampa Scale for Kinesiophobia and Pain Coping Inventory were administered. Hierarchical linear regression was used to evaluate to what extent kinesiophobia and pain coping contributed to difficulties with Rising & Walking and Social Functioning. RESULTS: The analyses showed that the "resting" subscale of the Pain Coping Inventory-that is, 1 of the 3 scales evaluating passive pain coping strategies-contributed significantly to difficulties in rising and walking (explaining 12.5% of the variance) and to difficulties in social functioning (explaining 6.5%), whereas kinesiophobia was not associated with either of these measures. DISCUSSION: These findings indicate that making use of "resting" as a pain coping strategy contributes significantly to limitations in activity and participation in patients with CRPS-1 of the legs. Indications for a negative influence of kinesiophobia or a positive influence of an active pain coping style were not found.

Differential effects of sulfonylurea derivatives on vascular ATP-sensitive potassium channels.

Sulfonylurea drugs exert their insulinotropic action by inhibiting ATP-sensitive potassium channels in the pancreas. However, these channels are also expressed in myocardial and vascular smooth muscle, implicating possible detrimental cardiovascular effects. Aim of the present study was to investigate the inhibitory potency of various widely used sulfonylurea drugs in resistance arteries. Isolated mesenteric and renal resistance arteries mounted in a myograph and isolated perfused kidneys were used to measure drug responses. Pinacidil induced a dose-dependent relaxation of phenylephrine preconstricted mesenteric and renal arteries (pEC(50)=6.10 ± 0.01 and 5.66 ± 0.03, respectively). Schild plot analysis of pinacidil relaxation curves in mesenteric arteries in the presence of sulfonylurea antagonists revealed the following order of potency: glimepiride (pA(2)=7.22) ≥ glibenclamide (pA(2)=7.05) > glipizide (pA(2)=5.25) > gliclazide (pA(2)=4.31). The effects of glibenclamide in renal arteries were comparable. Furthermore, glibenclamide produced similar constrictive properties in isolated renal arteries as in isolated perfused whole kidneys. We conclude that sulfonylurea drugs exert differential effects on vascular smooth muscle K(ATP) channels. Our results suggest that glibenclamide and glimepiride will interact with these channels at therapeutic concentrations.

Distribution of signs and symptoms of complex regional pain syndrome type I in patients meeting the diagnostic criteria of the International Association for the Study of Pain.

The aim of the present study was to describe the occurrence of signs and symptoms in CRPS I patients meeting the IASP (Orlando) criteria, assess the occurrence of signs and symptoms in relation to disease duration and compare these to historical data based on a different diagnostic criteria set. Six hundred and ninety-two ambulatory patients meeting the IASP criteria for CRPS I referred to the outpatient clinics of five participating centers were included in this cross-sectional study. Characteristics were recorded in a standardized fashion and categorized according to the factor structure proposed by Bruehl/Harden. Subgroups were classified according to the duration of complaints and compared to historical data as described by Veldman et al. The Chi-square test corrected for multiple comparisons was used for statistical analysis. The prevalence of sensory signs was higher in patients with longer disease duration, especially for the allodynia's and hyperalgesia (all p<0.001). Signs in vasomotor (color difference; p=0.0007) and sudomotor (edema; p<0.0001) subgroups were less frequently present in patients with longer disease duration (i.e. >6 months). Prevalences of signs in the motor subgroup were all higher (p<0.0001) in patients with longer disease duration, except for limited range of motion. Occurrence of signs was significantly lower (<0.001) than those reported by Veldman et al., except for hyperesthesia and dystonia. Occurrence rates may vary at different time points after onset of CRPS, which may be of influence for diagnosing patients with novel derived diagnostic criteria. We argue for a mechanism based description of CRPS I based on one set of uniform generally accepted diagnostic criteria in future studies.

Both ADP and thrombin regulate arteriolar thrombus stabilization and embolization, but are not involved in initial hemostasis as induced by micropuncture.

OBJECTIVE: Thrombosis and embolization are main causes of morbidity and mortality. Up to now, the relative importance of mediators involved is only partly known. It was the aim of this study to investigate the involvement of ADP and thrombin in subsequent phases of arteriolar hemostasis and thromboembolism in vivo. METHODS: Rabbit mesenteric arterioles were punctured, which induced bleeding, hemostasis, and subsequent thromboembolism. This reaction as well as the activation state of platelets involved ([Ca(2+)](i)), was monitored in real time by intravital (fluorescence) microscopy. RESULTS: Neither inhibition of thrombin formation or thrombin activity nor blockade of platelet ADP receptors P2Y(1) and P2Y(12) influenced the initial hemostatic reaction: in all experiments initial bleeding was stopped by a primary thrombus within 2-3 s. On the other hand, both thrombin inhibition and P2Y(1) blockade increased rebleeding frequency, which indicates reduced thrombus stability in the long term. Finally, inhibition of either thrombin or ADP (via both receptors) reduced aggregate formation during the embolization phase by at least 90%. While most participating platelets exhibited a transient increase in [Ca(2+)](i) during embolization, an increased percentage of platelets showed no calcium response at all during P2Y(1) blockade, which was accompanied by reduced platelet-platelet interaction strength. CONCLUSIONS: Whereas thrombin and ADP are not involved in the initial hemostatic reaction, both substances appear to be essential to prevent rebleedings in the long term. During subsequent embolization, ADP (via both receptors) and small amounts of thrombin are involved in platelet activation.

Glibenclamide depletes ATP in renal proximal tubular cells by interfering with mitochondrial metabolism.

Sulfonylurea drugs, like glibenclamide, stimulate insulin secretion by blocking ATP-sensitive potassium channels on pancreatic beta cells. Renal tubular epithelial cells possess a different class of K(ATP) channels with much lower affinities for sulfonylurea drugs, necessitating the use of micromolar glibenclamide concentrations to study these channels. Here, we describe the toxic effects of these concentrations on mitochondrial energy metabolism in freshly isolated renal proximal tubular cells. Glibenclamide, at concentrations of 50 and 100 microM, reduced intracellular ATP levels by 28+/-4 and 53+/-5%, respectively (P<0.01). This decline in ATP could be attributed to a dose-dependent inhibition of mitochondrial respiration. Glibenclamide (10-500 microM) inhibited ADP-stimulated mitochondrial oxygen consumption. In addition to this toxic effect, specific association of radiolabeled and fluorescent glibenclamide to renal mitochondria was found. Association of [(3)H]glibenclamide with renal mitochondria revealed a low-affinity site with a K(D) of 16+/-6 microM and a B(max) of 167+/-29 pmol mg(-1). We conclude that micromolar concentrations of glibenclamide interfere with mitochondrial bioenergetics and, therefore, should be used with care for inhibition of epithelial K(ATP) channels.

Regulation of microvascular thromboembolism in vivo.

Atherothrombosis and embolization are main causes of morbidity and mortality in the Western world. To optimize treatment, better understanding of the factors involved in thromboembolism in vivo is needed. The course and outcome of a thromboembolic process are determined by the local balance between anti and prothrombotic factors. In healthy vessels, endothelial antithrombotic properties prevent blood platelets from interacting with the vessel wall. Upon vessel wall damage or endothelial activation, however, prothrombotic factors temporarily overrule the antithrombotic factors, leading to thrombus formation and embolization. According to this concept, thromboembolism ends when the balance is restored. Animal models on microvascular thromboembolism have provided evidence that the endothelium is eminently involved in the regulation of thromboembolism, and that shear forces are an important determinant of endothelial function. Therefore, in this review focus is on the endothelial regulation of platelet-vessel wall interactions during thromboembolism in vivo. Anti- and prothrombotic properties of vascular endothelium will be discussed, paying special attention to the endothelium-derived platelet inhibiting substances nitiric oxide (NO) and prostacyclin (PGl(2)) and to differences between arteriolar and venular endothelium. In addition, the involvement of shear forces in microvascular thromboembolic processes in vivo will be described

In vivo blockade of platelet ADP receptor P2Y12 reduces embolus and thrombus formation but not thrombus stability.

OBJECTIVE: ADP is a key platelet agonist in thromboembolism. One of the receptors involved in ADP-induced platelet activation is the P2Y12 receptor, which is a target for antithrombotic drugs. METHODS AND RESULTS: Here, we present first evidence for a differential role of this receptor in thrombus and embolus formation in vivo. Anesthetized rabbits were treated with the selective P2Y12 antagonists AR-C69931 MX (3 microg x kg x min(-1) IV) or clopidogrel (25 mg/kg orally). Efficacy of these treatments was monitored by aggregation and thrombin generation measurements in blood samples ex vivo. Mesenteric arterioles were mechanically injured; thrombus growth and subsequent embolus formation were visualized by real-time intravital microscopy. AR-C69931 MX and clopidogrel significantly (P<0.05) reduced the total duration of embolization (by 52% and 36%, respectively), and fewer and smaller emboli were produced. The size of the initial thrombus was significantly reduced (P<0.005), but its stability was unaffected: plug formation was still effective. CONCLUSIONS: These findings demonstrate that ADP and its P2Y12 receptor are involved in thrombus growth and especially in the formation of emboli on the downstream side of the initial thrombus. This may explain the beneficial effects of P2Y12 receptor antagonists in secondary prevention of ischemic events in patients with arterial thrombosis.

Real-time detection of activation patterns in individual platelets during thromboembolism in vivo: differences between thrombus growth and embolus formation.

Knowledge on single platelet behavior and intracellular mechanisms during thromboembolism in vivo is scarce. In the present study, we used a new method that enables real-time detection and quantification of activation of individual platelets participating in a thromboembolic process in vivo, using their intracellular free Ca(2+) concentration ([Ca(2+)](i)) as a marker of activation. Isolated platelets were labeled with the Ca(2+)-sensitive fluorescent probe fluo-3 and injected into anesthetized rabbits so that 0.5-1% of their circulating platelets were labeled. Wall puncture of mesenteric arterioles resulted in thrombus formation followed by embolization. Fluorescence intensity changes of labeled platelets participating in this process were quantified. Within 30 min after injection, labeled platelets behaved similarly to native platelets, and fluorescence intensity was not influenced by dye leakage. Upon adherence to the stationary thrombus, platelets exhibited a prolonged [Ca(2+)](i) increase, accompanied by shape change and degranulation, which is consistent with a role for strong platelet agonists like collagen. In contrast, when platelets adhered to a growing embolus their [Ca(2+)](i) rise was transient, and they hardly showed shape change and degranulation, suggesting the involvement of weaker agonists like ADP. These results show, for the first time, the relation between single platelet activation patterns, which are different during thrombus growth and embolus formation, and their behavior in a thromboembolic process in vivo.