Impact of spinal cord stimulation on sensory characteristics in complex regional pain syndrome type I: a randomized trial.

BACKGROUND: A randomized trial was performed to assess the effect of spinal cord stimulation (SCS) on detection and pain thresholds for pressure, warmth, and cold and on the extent of mechanical hyperalgesia in patients with chronic complex regional pain syndrome type I. METHODS: Fifty-four chronic complex regional pain syndrome type I patients were randomized to receive both SCS and physical therapy (SCS+PT; n = 36), or to receive only physical therapy (PT; n = 18). Twenty-four SCS+PT patients responded positively to trial stimulation and underwent SCS implantation. During a 12-month follow-up period, six quantitative sensory testing sessions were performed. The main analysis compared 24 SCS patients with 29 nonimplanted patients--one PT patient was excluded. RESULTS: SCS showed no effect on detection thresholds for warmth and cold or on pain thresholds for any sensation. The pressure detection threshold initially increased by SCS, but after 3 months, pressure detection thresholds returned to normal. Mechanical hyperalgesia, both dynamic and static, was reduced slightly with SCS. CONCLUSIONS: Although SCS has previously been shown to cause a significant pain reduction in complex regional pain syndrome type I, the treatment has no long-term effect on detection and pain thresholds for pressure, warmth, or cold. The treatment seems to have only minimal influence on mechanical hyperalgesia.

Thermal thresholds in complex regional pain syndrome type I: sensitivity and repeatability of the methods of limits and levels.

OBJECTIVES: To study whether the method of levels (MLE) or the method of limits (MLI) is preferable as a method of measuring thermal perception thresholds in patients with complex regional pain syndrome type I (CRPS I). METHODS: Perception thresholds for warmth and cold were measured twice, with both MLE and MLI, at a 1 month interval, both at unaffected and affected wrists (n=33) or feet (n=20) of patients with CRPS I of one extremity. RESULTS: (1) Sensitivity for pathology was equal for both methods. (2) The agreement between thresholds measured by both methods was low at all locations, except for the unaffected wrist. Since thresholds measured with the MLI always contain reaction time artefacts, this lack of agreement favours the MLE. (3) At both unaffected and affected wrists, the MLE showed significantly better coefficients of repeatability as compared to the MLI for both sensations. However, at both unaffected and affected feet, there was no preference for either method as far as threshold measurement repeatability was concerned. CONCLUSIONS: Abnormal thermal perception thresholds occurred in 20% (foot) to 36% (wrist) of the CRPS I patients on the affected side and in 15% (foot, wrist) on the unaffected side. The MLE is considered to be the preferable method to assess thermal perception thresholds in CRPS I.

Spinal cord stimulation in patients with chronic reflex sympathetic dystrophy.

BACKGROUND: Chronic reflex sympathetic dystrophy (also called the complex regional pain syndrome) is a painful, disabling disorder for which there is no proven treatment. In observational studies, spinal cord stimulation has reduced the pain associated with the disorder. METHODS: We performed a randomized trial involving patients who had had reflex sympathetic dystrophy for at least six months. Thirty-six patients were assigned to receive treatment with spinal cord stimulation plus physical therapy, and 18 were assigned to receive physical therapy alone. The spinal cord stimulator was implanted only if a test stimulation was successful. We assessed the intensity of pain (on a visual-analogue scale from 0 cm [no pain] to 10 cm [very severe pain]), the global perceived effect (on a scale from 1 [worst ever] to 7 [best ever]), functional status, and the health-related quality of life. RESULTS: The test stimulation of the spinal cord was successful in 24 patients; the other 12 patients did not receive implanted stimulators. In an intention-to-treat analysis, the group assigned to receive spinal cord stimulation plus physical therapy had a mean reduction of 2.4 cm in the intensity of pain at six months, as compared with an increase of 0.2 cm in the group assigned to receive physical therapy alone (P<0.001 for the comparison between the two groups). In addition, the proportion of patients with a score of 6 ("much improved") for the global perceived effect was much higher in the spinal cord stimulation group than in the control group (39 percent vs. 6 percent, P=0.01). There was no clinically important improvement in functional status. The health-related quality of life improved only in the 24 patients who actually underwent implantation of a spinal cord stimulator. Six of the 24 patients had complications that required additional procedures, including removal of the device in 1 patient. CONCLUSIONS: In carefully selected patients with chronic reflex sympathetic dystrophy, electrical stimulation of the spinal cord can reduce pain and improve the health-related quality of life.

Electrical spinal cord stimulation in reflex sympathetic dystrophy: retrospective analysis of 23 patients.

OBJECT: The aim of the study was to assess retrospectively the clinical efficacy and possible adverse effects of electrical spinal cord stimulation (SCS) for the treatment of patients with reflex sympathetic dystrophy (RSD). METHODS: Twenty-three patients who suffered severe pain due to RSD were included in the study. The SCS system was implanted only after a positive 1-week test period. The visual analog scale (VAS) score for pain (1-10) was obtained in all patients prior to treatment, 1 month postimplantation, and at last follow up. At final follow-up examination, patients were asked to rate the effect of their treatment on the 7-point global perceived effect scale. Eighteen (78%) of 23 patients treated between 1991 and 1997 reported improvement during the test period. Permanent implantation of SCS system was not performed in the other five patients. Complications occurred in nine (50%) of 18 patients. The system was removed in three patients after implantation (17%). At the end of follow up (mean 32 months) 15 patients still had an implanted system. The mean pain score had decreased from 7.9 to 5.4 (p<0.001). In the other eight patients the pain score had not changed significantly. In 13 patients (57%) in whom the SCS system was implanted, clinical status had much improved or improved; these cases were regarded as successful. CONCLUSIONS: In this retrospective series, the majority of patients with RSD reported a subjective improvement after implantation of an SCS system.

Low-level laser therapy in ankle sprains: a randomized clinical trial.

OBJECTIVE: To test the efficacy of low-level laser therapy on lateral ankle sprains as an addition to a standardized treatment regimen, a trial was conducted in which high-dose laser (5J/cm2), low-dose laser (0.5J/cm2), and placebo laser therapy (0J/cm2) at skin level were compared. DESIGN: Randomized, double-blind, controlled clinical trial with a follow-up of 1 year. Patients, therapists, assessors, and analysts were blinded to the assigned treatment. SETTING: An ambulatory care setting. PATIENTS: After informed consent and verification of exclusion criteria, 217 patients with acute lateral ankle sprains were randomized to three groups from September 1, 1993, through December 31, 1995. INTERVENTIONS: Twelve treatments of 904nm laser therapy in 4 weeks as an adjunct to a standardized treatment regimen of 4 weeks of brace therapy combined with standardized home exercises and advice. The laser therapy device used was a 904nm Ga-As laser, with 25-watt peak power and 5,000 or 500Hz frequency, a pulse duration of 200nsec, and an irradiated area of 1cm2. PRIMARY OUTCOME MEASURES: Pain and function as reported by the patient. RESULTS: Intention-to-treat analysis of the short-term results showed no statistically significant difference on the primary outcome measure, pain (p = .41), although the placebo group showed slightly less pain. Function was significantly better in the placebo group at 10 days (p = .01) and 14 days (p = .03) after randomization. The placebo group also performed significantly better on days of sick leave (p = .02) and at some points for hindrance in activities in daily life and pressure pain, as well as subjective recovery (p = .05). Intention-to-treat analysis showed that total days of absenteeism from work and sports were remarkably lower in the placebo group than in the laser groups, ranging from 3.7 to 5.3 and 6 to 8 days, respectively. The total number of relapses at 1 year in the low-dose laser group (n = 22) was significantly higher (p = .04) than in the other two groups (high laser, n = 13; placebo, n = 13). Subgroup analysis to correct for possible confounders did not alter these findings. CONCLUSIONS: Neither high- nor low-dose laser therapy is effective in the treatment of lateral ankle sprains.

Motor denervation induces altered muscle fibre type densities and atrophy in a rat model of neuropathic pain.

Loose ligation of a sciatic nerve in rats (chronic constriction injury; CCI) provokes sensory, autonomic, and motor disturbances like those observed in humans with partial peripheral nerve injury. So far, it is unknown whether these motor disturbances result from (mechanical) allodynia or from damage to the motor neuron. These considerations prompted us to assess, in CCI rats, the density of motor axons in both the ligated sciatic nerve and the ipsilateral femoral nerve. To this end, we determined the number of cholinesterase positive fibres. It has been demonstrated previously that muscle fibre type density may be used as a measure of motor denervation and/or hypokinesia. Therefore, the myofibrillar ATPase reaction was employed to assess fibre type density in biopsies obtained from the lateral gastrocnemius muscle (innervated by sciatic nerve) and rectus femoris muscle (innervated by femoral nerve). We observed axonal degeneration of motor fibres within the loosely ligated sciatic nerve, both at an intermediate (day 21) and at a late stage (day 90) after nerve injury. The reduction in the number of motor nerve fibres was more pronounced distal to the site of the ligatures than proximal. A (less pronounced) reduction of motor fibres was observed in the ipsilateral (non-ligated) femoral nerve. In line with these findings, we observed altered fibre type densities in muscle tissue innervated by the ligated sciatic nerve as well as the non-ligated femoral nerve indicative of motor denervation rather than hypokinesia. The findings of this study suggest that the motor disorder induced by partial nerve injury involves degeneration of motor nerve fibres not only within the primarily affected nerve but also within adjacent large peripheral nerves. This spread outside the territory of the primarily affected nerve suggests degeneration of motor neurons at the level of the central nervous system.

Neurogenic inflammation in an animal model of neuropathic pain.

Loose ligation of a rat sciatic nerve (chronic constriction injury (CCI) model) provokes signs and symptoms like those observed in reflex sympathetic dystrophy (RSD) patients. Primary afferent nociceptive C-fibers seem to be involved in an afferent orthodromic as well as in an efferent antidromic manner. In this study we hypothesize that consequent to development of antidromic impulses in C-nociceptive afferents, neuropeptides released from peripheral endings of these fibers, increase skin blood flow (SBF), vascular permeability, and tissue accumulation of polymorphonuclear leukocytes (PMNs). Collectively, these phenomena have been referred to as neurogenic inflammation. To investigate the presence of neurogenic inflammation in the CCI-model, we assessed skin blood flow (SBF) as well as the level of edema and accumulation of PMNs in muscle tissue obtained from the affected hindpaw. SBF was measured, by means of laser Doppler flowmetry, before ligation as well as at day 4 after ligation. At day 4, SBF measurements were performed before and after abolition of the capability of C-fibers to mediate a vasodilator response. To this end, capsaicin was applied perineurally. Increased vascular permeability was inferred from the level of edema of muscle tissue as determined by assessment of wet/dry weight ratios of muscle biopsies. PMN accumulation was investigated by enzymatic detection of myeloperoxidase (MPO) activity in muscle biopsies. Compared with preligation values, at day 4 SBF was increased more than twofold (p < 0.05). The latter response was annihilated by capsaicin application. Compared with sham operated controls, wet/dry ratios were higher in the ligated animals (1.104 vs. 1.068; p < 0.05). Likewise, when compared with sham operated controls, MPO activity was found to be increased in the ligated hindpaw (Optic Density 0.15 vs. 0.89; p < 0.001). In conclusion, the findings of this study indicate that loose ligation of a sciatic nerve induces an inflammatory response in the ipsilateral hindpaw, which most likely is mediated by release of neuropeptides from the peripheral endings of antidromically acting nociceptive C-fibres.

The anti-inflammatory potential of adenosine in ischemia-reperfusion injury: established and putative beneficial actions of a retaliatory metabolite.

The endogenous metabolite adenosine has been recognized as a protective agent in the setting of ischemia-reperfusion. Because the formation of adenosine during ischemia is closely linked to ATP catabolism, and its actions antagonize the deleterious metabolic and cardiovascular consequences of ischemia, it has been named a "retaliatory" metabolite. During recent years, however, the insight into its diverse scope of anti-inflammatory actions has increased considerably. In this review, the beneficial metabolic and cardiovascular actions of adenosine in ischemia and reperfusion are briefly outlined, followed by an extensive discussion of the established and putative anti-inflammatory actions of adenosine in the inflammatory response to ischemia and reperfusion. It is demonstrated that adenosine interferes with activated neutrophil function, neutrophil-endothelial adhesive interactions, the production and release of various inflammatory mediators, the expression of adhesion molecules, and that it activates cellular antioxidant defense systems, thus providing protective effects at multiple levels in the pathogenesis of ischemia and reperfusion. Finally, several potential pharmacological strategies to enhance the "natural defense mechanism" provided by endogenous adenosine are presented.

Adenosine inhibits neutrophil degranulation in activated human whole blood: involvement of adenosine A2 and A3 receptors.

Adenosine, acting via A2 receptors, is a potent inhibitor of neutrophil oxidative burst, but its effects and mechanisms of action on neutrophil degranulation have been less well characterized. We, therefore, investigated the effects of adenosine and its receptor-specific analogues on neutrophil degranulation in stimulated human whole blood. Adenosine dose-dependently inhibited the LPS- and TNF-alpha-induced release of the azurophilic granule proteins bactericidal/permeability-increasing protein, elastase, and defensins to approximately the same extent, with a maximum inhibition of 70 to 80% and an IC50 ranging from 14 to 24 microM. The inhibitory effects of adenosine were partially blocked by the A2 receptor antagonist 3,7-dimethyl-1-propargylxanthine, the A1/A2 antagonist 8(p-sulfophenyl)theophyline, and the A1/A3 antagonist xanthine amine congener, but not by the A1 antagonist 1,3-dipropyl-8-cyclopentylxanthine. The highly selective A3 agonist N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide and the nonselective agonist 2-chloroadenosine reduced degranulation more potently than the A1 agonist N6-cyclopentyladenosine. The inhibitory effects of N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide and 2-chloroadenosine were strongly reversed by xanthine amine congener, but were not affected by 8(p-sulfophenyl)theophyline. In addition, the adenosine kinase inhibitor GP515 attenuated degranulation via an adenosine-mediated mechanism. These data indicate that adenosine acts via A2 as well as A3 receptors to inhibit neutrophil degranulation and add to the anti-inflammatory potential of adenosine and adenosine-regulating agents in neutrophil-mediated tissue injury.

The prognosis of ankle sprains.

We developed a new diagnostic tool for predicting the severity of ankle sprains just after injury. Since hard data obtained by diagnostic imaging techniques are still imperfect, we decided to use data from individual medical history and signs and symptoms that are part of the admission routine. During a three month-period data were collected on thirty-five patients with lateral ankle sprains who visited the first aid department of the University Hospital of Maastricht. Assessments took place at admission and at two and four weeks after injury. Assessors were the first-aid physician, a physiotherapist and the patient. Dependent variables were healed ankle in two and four weeks. Predicting variables were the data obtained at admission by the physician, the physiotherapist and the patient. The ability to predict outcome after two and four weeks was determined in a bivariate analysis, followed by logistic modelling. Accurate prediction of recovery time at admission appeared to be possible. Best two weeks predictor was the modified function score, an accuracy of 97% was achieved. Four weeks prediction was most accurate when function score was used together with the report mark from the doctor and the palpation score (accuracy of 81%).

Skin blood flow abnormalities in a rat model of neuropathic pain: result of decreased sympathetic vasoconstrictor outflow?

Loose ligation of a sciatic nerve in rats provokes signs and symptoms like those observed in human conditions of neuropathic pain. Some of these have been associated with sympathetic dysfunction. Since the skin microcirculation in the rat is strongly influenced by sympathetic tone, abnormalities in skin blood flow may be used as an indirect measure of sympathetic dysfunction. We measured, by means of laser Doppler flowmetry, skin blood flow at the plantar surface of the rat hind paw before and after ipsilateral loose sciatic nerve ligation. We assessed basal skin blood flow as well as the vasoconstrictor response which follows cooling of the rat abdomen. The effectiveness of this response may be used as a measure of sympathetic vasoconstrictor outflow. As compared to the values obtained before ligation (= 100%): (1) the vasoconstrictor response was impaired (65%, P < 0.01) from day 1 onwards, whereas (2) basal skin blood flow was increased (171%; P < 0.01) from day 3 until day 5, and decreased (51%, P < 0.0001) from day 7 until day 28. At day 28, blockade of impulse propagation in the loosely ligated sciatic nerve (by means of lidocaine) did not increase the lowered level of skin blood flow. These findings suggest that in the chronic construction injury model loose ligation of a sciatic nerve reduces sympathetic vasoconstrictor outflow, which, in turn may induce supersensitivity of skin microvessels to catecholamines.

Functional and radiological outcome after intra-articular tibial plateau fractures.

A follow-up study was performed to assess the functional and radiological outcome after operative treatment of tibial plateau fractures. Of 62 patients operated upon from 1985 to 1993, 46 patients were traced and re-examined. Follow-up averaged 60 months. Three functional scores were applied: the HSS knee score, the Lysholm score and the Tegner score. Radiographs obtained at follow-up were rated for deformity and signs of arthrosis, using a score described by Reswick and Niwayama. Patients reported most functional complaints during the first 3 years and after 6 years. Patients seen between 3 and 6 years after injury showed better functional scores. Arthritic changes were seen from 5 years after the fracture. Patients over 60 years of age seemed to suffer less functional loss than younger patients, indicating that operative treatment should not be withheld on grounds of age alone.

Adenosine kinase inhibitor GP515 attenuates hepatic leukocyte adhesion after hemorrhagic hypotension.

Adhesion of leukocytes to the vascular endothelium hallmarks a key event in neutrophil-mediated organ injury after ischemia-reperfusion. The autacoid adenosine has been shown to inhibit activated neutrophil function and to interfere with leukocyte-endothelial adherence. Its therapeutic use in ischemia-reperfusion, however, has been limited by severe cardiovascular side effects. We therefore investigated the effects of the adenosine kinase inhibitor GP515 in vivo on hepatic leukocyte-endothelial interactions in a rat model of hemorrhagic hypotension and resuscitation, using intravital microscopy. Rats were pretreated with either GP515 (0.25 mg/kg) or saline in a randomized and blinded manner and subjected to pressure-controlled hemorrhagic hypotension at a mean arterial pressure of 40 mmHg for 60 min followed by 5 h of resuscitation. Five hours after resuscitation in saline-treated animals, firm leukocyte-sinusoidal adhesion was strongly enhanced in the periportal and midzonal sublobular regions, and sinusoidal diameters were also markedly reduced. Compared with saline treatment, GP515 significantly attenuated shock and resuscitation-induced leukocyte adhesion in both sublobular regions. Moreover, although GP515 did not significantly affect macrohemodynamical and hematological parameters, it enlarged narrowed sinusoidal diameters and tended to improve sinusoidal blood flow. We propose that the adenosine-regulating agent GP515 has a therapeutic potential to attenuate ischemia-reperfusion-induced inflammation by capitalizing on the beneficial anti-inflammatory effects of endogenous adenosine.

Influence of partial nerve injury in the rat on efferent function of sympathetic and antidromically acting sensory nerve fibers.

OBJECTIVE: To investigate how partial injury of a large peripheral nerve affects efferent (vasomotor) function of sympathetic and antidromically acting sensory nerve fibers. DESIGN: Randomized animal study. MATERIALS AND METHODS: We assessed, by laser Doppler flowmetry, skin blood flow (SBF) in the hindpaw of male Lewis rats before partial injury of the ipsilateral sciatic nerve (through loose ligation) as well as at an early stage (day 4) and at a later stage (day 21) after this procedure. This procedure has been reported to induce signs and symptoms like those observed in patients with causalgia. At the two time points after nerve injury, SBF was assessed before and after (chemical) blockade of sensory and nonsensory (sympathetic) sciatic nerve fibers. Furthermore, at day 21 we measured the density of sympathetic nerve fibers in footpad arteries. MEASUREMENTS AND MAIN RESULTS: At day 4, compared with preligation values, we observed an increase in SBF that was reduced by blockade of sensory nerve fibers. Subsequent blockade of nonsensory nerve fibers further reduced SBF. At day 21, SBF was decreased compared with preligation values. Blockade of sensory nerve fibers further reduced SBF, and subsequent blockade of nonsensory nerve fibers did so as well. The density of sympathetic nerve fibers was lower on the ligated side than on the nonligated side. CONCLUSIONS: Partial injury of the rat sciatic nerve causes an ipsilateral increase in SBF at an early stage, which is followed by a decrease at a later stage. At both stages, antidromically acting sensory and orthodromically acting nonsensory (sympathetic) nerve fibers are involved in the vasodilator response. At a later stage, however, neurogenic vasodilator mechanisms are overruled by a nonneurogenic vasoconstrictor mechanism. The latter may consist of supersensitivity of skin microvessels to catecholamines consequent to reduced neurogenic disposition of catecholamines.

Skin blood flow disturbances in the contralateral limb in a peripheral mononeuropathy in the rat.

Electrical excitation of nociceptive afferents in an extremity has been demonstrated to increase skin blood flow in the contralateral extremity. Hence, one would expect that loose sciatic nerve ligation, which induces an experimental painful peripheral neuropathy, may also provoke a vasodilator response in the contralateral hindpaw. On the non-ligated side, such a response may involve inhibited skin vasoconstrictor activity as well as neurogenically mediated active vasodilation. We studied skin blood flow changes in the rat hindpaw consequent to contralateral loose sciatic nerve ligation. After ligation, we also investigated whether blockade of afferent input from the ligated sciatic nerve to the spinal cord, by means of lidocaine, overrules the vasodilator response in the non-ligated paw. On the non-ligated side, we assessed the vasoconstrictor response of skin microvessels to cooling of the rat abdomen as a measure of skin vasoconstrictor activity in this paw. In order to investigate the involvement of sensory and/or non-sensory nerve fibers in the non-ligated sciatic nerve on skin blood flow abnormalities in the non-ligated paw, we studied the influence of blockade of these fibers through successive capsaicin and lidocaine application. We show that loose ligation of the sciatic nerve induces a vasodilator response in the contralateral hindpaw, which is completely abolished by blockade of afferent input from the ligated sciatic nerve. From day 1 after ligation, skin vasoconstrictor activity in the non-ligated paw was reduced, as indicated by an impaired vasoconstrictor response to cooling of the rat abdomen. Besides, blockade of sensory but not of non-sensory nerve fibers on the non-ligated side attenuated the vasodilator response in this paw. The data presented here indicate that loose ligation of the rat sciatic nerve induces a vasodilator response in the contralateral hindpaw. On the non-ligated side, this vasodilator response may involve inhibition of skin vasoconstrictor activity, as well as antidromically acting sensory nerve fibers.

Compartment-syndrome of the lower extremity after CABG.

Three cases of compartment-syndrome of the lower extremity are presented as an example of a specific type of compartment syndrome of the donorleg after CABG. The possible factors contributing to this complication are being discussed, and guidelines are given to adequately diagnose and treat this problem.

Reflex sympathetic dystrophy: does sympathetic dysfunction originate from peripheral neuropathy?

BACKGROUND: Sympathetic dysfunction in reflex sympathetic dystrophy (RSD) has been purported to consist of an afferently-induced increase in efferent sympathetic nerve impulses (somato-sympathetic reflex) and/or denervation-induced supersensitivity to catecholamines. In addition, both the central and peripheral nervous systems have been claimed to be involved. It was the aim of this study to obtain more insights into these underlying mechanisms. METHODS: In the affected extremeties of 42 patients with RSD we investigated as indirect measures of sympathetic (dys)function: (1) skin blood flow and the vasoconstrictive response to dependency of skin microvessels by means of laser Doppler flowmetry (distal to the site of trauma), (2) relative distention of the brachial artery and changes in relative distention consequent to a cold pressor test by means of ultrasonic vessel wall tracking (proximal to the site of trauma), and (3) arterial blood pressures by means of the Finapres technique. Both provocation tests induce a sympathetically mediated response. Patients were divided into three categories according to their perception of skin temperature in their injured limb (stage I, stationary warmth sensation; stage II, intermittent warmth and cold sensation; or stage III, stationary cold sensation). RESULTS: Distal to the site of trauma, when compared with controls, skin blood flow was increased at stage I and decreased at stages II and III, whereas the vasoconstrictive response to dependency was impaired at all three stages. Proximally, when compared with controls, relative distention of the brachial artery and its response to the cold pressor test were decreased at all three stages. No differences were observed in pulse pressure between patient groups and controls. CONCLUSIONS: These results suggest that sympathetic dysfunction in extremities of patients with RSD distal to the site of trauma consists of hypersensitivity to catecholamines at stages II and III as a result of autonomic denervation at stage I, whereas proximal to the site of trauma sympathetic nerve impulses may be increased at all three stages.

Adenosine inhibits cytokine release and expression of adhesion molecules by activated human endothelial cells.

Ischemia induces excessive ATP catabolism with subsequent local release of its metabolite adenosine, an autacoid with anti-inflammatory properties. Because activation of the vascular endothelium is critical to the inflammatory host response during ischemia and reperfusion, the effects of adenosine on two major determinants of endothelial cell activation (i.e., the release of proinflammatory cytokines and the expression of adhesion molecules) were studied. Adenosine dose dependently inhibited the release of interleukin (IL)-6 and IL-8 by stimulated human umbilical vein endothelial cells (HUVEC). Expression of E-selectin and vascular cell adhesion molecule 1 (VCAM-1), but not intercellular adhesion molecule 1 (ICAM-1), by activated HUVEC was also reduced by adenosine. Inhibition of endogenous adenosine deaminase activity by erythro-9-(2-hydroxy-3-nonyl)adenine or 2'-deoxycoformycin strongly enhanced the inhibitory effects of exogenous adenosine on cytokine release and expression of E-selectin and VCAM-1. However, a clear role for specific adenosine receptors in the described inhibitory events could not be established. Together, these data imply that the vascular endothelium constitutes an important target for the anti-inflammatory actions of adenosine.

Low energy laser irradiation fails to modulate the inflammatory function of human monocytes and endothelial cells.

BACKGROUND AND OBJECTIVE: In view of the important regulatory role of cytokines in wound healing and inflammation, we investigated the effects of low energy laser irradiation on cytokine release by human peripheral blood monocytes (M phi) and human umbilical vein endothelial cells (HUVEC) in vitro. Also, the effects of laser light on the expression of endothelial adhesion molecules, another important feature of inflammatory and regenerative responses, were assessed. STUDY DESIGN/MATERIALS AND METHODS: Cells were irradiated with a pulsed GaAs-laser (904 nm) at energy densities 0 (= sham), 0.3, 3.0, or 9.0 J/cm2 and subsequently incubated in absence or presence of endotoxin (M phi) or the proinflammatory cytokines TNF alpha and IL-1 beta (HUVEC). RESULTS: Irradiation at any of the dosages used did not significantly affect spontaneous or endotoxin-induced release of TNF alpha, IL-6, and IL-8 by M phi. Similarly, secretion of IL-6 and IL-8 by resting or cytokine-activated HUVEC after either single or repeated laser treatment was unchanged as compared to sham-irradiated controls. Moreover, laser treatment did not induce de novo expression or upregulation of the endothelial adhesion molecules E-selectin, ICAM-1, and VCAM-1, and it failed to modify their expression in response to stimulation with TNF alpha or IL-1 beta. CONCLUSION: We conclude that with the specific laser parameters and dose-regimen used, low energy laserlight does not affect the inflammatory function of human monocytes and endothelial cells in vitro.

The spinal component to skin blood flow abnormalities in reflex sympathetic dystrophy.

OBJECTIVE: To determine whether the mechanisms of reflex sympathetic dystrophy, a neuropathic pain syndrome characterized by skin blood flow abnormalities associated with sympathetic vasoconstrictor and antidromic vasodilator mechanisms, are solely of peripheral origin or have an additional spinal component and act exclusively through neural or also involve humoral pathways. PATIENTS: The 54 patients with unilateral reflex sympathetic dystrophy were divided into the following three stages according to their perception of skin temperature in the clinically affected hand: stage I, stationary warmth sensation; stage II, intermittent warmth and cold sensation; and stage III, stationary cold sensation. METHODS: Investigation of basal skin blood flow and vasoconstrictive response to dependency of skin microvessels in the clinically unaffected hand and the clinically affected hand of patients with reflex sympathetic dystrophy and the left hand of 16 control subjects. Microcirculation was investigated at the predominantly neurally controlled thermoregulatory level (Doppler laser flowmetry) and at the predominantly humorally controlled nutritive level (capillary microscopy). RESULTS: In the clinically unaffected hand, at the thermoregulatory level of the microcirculation: (1) basal skin blood flow was increased at stage I compared with the control subjects, whereas no differences could be observed at this stage compared with the clinically affected hand; (2) the vasoconstrictive response to dependency (defined as skin blood flow at heart level divided by skin blood flow in the dependent position) was attenuated at stage I compared with the control subjects, whereas no differences could be observed at this stage compared with the clinically affected hand; and (3) basal skin blood flow and the vasoconstrictive response to dependency did not differ from the control subjects at stages II and III. In the clinically unaffected hand, at the nutritive level, no differences could be observed at any stage of the syndrome compared with the control subjects. CONCLUSIONS: This study indicates that there is a spinal component to microcirculatory abnormalities at stage I of the reflex sympathetic dystrophy syndrome that most likely acts through neural (antidromic vasodilator) mechanisms and that may be initiated by traumatic excitation of a peripheral nerve on the clinically affected side.