Treatment of vulvar intraepithelial neoplasia with topical imiquimod.

BACKGROUND: Alternatives to surgery are needed for the treatment of vulvar intraepithelial neoplasia. We investigated the effectiveness of imiquimod 5% cream, a topical immune-response modulator, for the treatment of this condition. METHODS: Fifty-two patients with grade 2 or 3 vulvar intraepithelial neoplasia were randomly assigned to receive either imiquimod or placebo, applied twice weekly for 16 weeks. The primary outcome was a reduction of more than 25% in lesion size at 20 weeks. Secondary outcomes were histologic regression, clearance of human papillomavirus (HPV) from the lesion, changes in immune cells in the epidermis and dermis of the vulva, relief of symptoms, improvement of quality of life, and durability of response. Reduction in lesion size was classified as complete response (elimination), strong partial response (76 to 99% reduction), weak partial response (26 to 75% reduction), or no response (< or =25% reduction). The follow-up period was 12 months. RESULTS: Lesion size was reduced by more than 25% at 20 weeks in 21 of the 26 patients (81%) treated with imiquimod and in none of those treated with placebo (P<0.001). Histologic regression was significantly greater in the imiquimod group than in the placebo group (P<0.001). At baseline, 50 patients (96%) tested positive for HPV DNA. HPV cleared from the lesion in 15 patients in the imiquimod group (58%), as compared with 2 in the placebo group (8%) (P<0.001). The number of immune epidermal cells increased significantly and the number of immune dermal cells decreased significantly with imiquimod as compared with placebo. Imiquimod reduced pruritus and pain at 20 weeks (P=0.008 and P=0.004, respectively) and at 12 months (P=0.04 and P=0.02, respectively). The lesion progressed to invasion (to a depth of <1 mm) in 3 of 49 patients (6%) followed for 12 months (2 in the placebo group and 1 in the imiquimod group). Nine patients, all treated with imiquimod, had a complete response at 20 weeks and remained free from disease at 12 months. CONCLUSIONS: Imiquimod is effective in the treatment of vulvar intraepithelial neoplasia. (Current Controlled Trials number, ISRCTN11290871 [controlled-trials.com].).

Proteinuria-associated endothelial dysfunction is strain dependent.

BACKGROUND: Proteinuria-associated endothelial dysfunction (ED) is assumed to play a main role in the cardiovascular morbidity in proteinuric patients. However, the connection between proteinuria and systemic endothelial function is not clear yet. Therefore, we studied aortic endothelial function in Munich Wistar Fromter (MWF) and fawn-hooded hypertensive (FHH) inbred rat strains with genetic proteinuria to determine the specific impact of proteinuria on the development of ED. METHODS: Proteinuria, cardiac function, systemic blood pressure, plasma lipid profiles, aortic endothelial function, plasma levels of cyclo-oxygenase products and dimethylarginines were investigated in 26-week-old inbred rat strains with (MWF and FHH) and without [Lewis (LEW) rats] proteinuric renal disease. RESULTS: The endothelium-dependent relaxation was significantly reduced in MWF (p < 0.05 vs. LEW or FHH). The plasma thromboxane B(2), prostaglandin F(2alpha) and prostaglandin E(2)levels were higher in MWF (p < 0.05 vs. LEW or FHH), whereas the 6-keto-prostaglandin F(1alpha) level was comparable in all groups. The arginine/asymmetric dimethylarginine ratio was highest in MWF. CONCLUSIONS: This study differentiates common risk factors for ED in renal disease. Despite clear-cut proteinuria, FHH rats were devoid of changes in aortic endothelial function, indicating that some other deleterious factors must accompany proteinuria in order for ED to ensue. Further exploration of this model may serve to dissect mechanistical pathways and guide the development of protective strategies in the vascular damage of renal disease.

IgE-mediated hypersensitivity: patients with complex regional pain syndrome type 1 (CRPS1) vs the Dutch population. A retrospective study.

OBJECTIVE: To investigate whether hypersensitivity is more common in Complex Regional Pain Syndrome type 1 (CRPS1) patients than in the general population. In a recent study, the level of tryptase, a specific marker for mast cells, was significantly higher in blister fluid from the involved extremity of CRPS1 patients. This suggested that mast cells may play a role in the pathophysiology of CRPS1. Mast cells are major effectors in allergic reactions, and are also involved in a variety of noninfectious inflammatory diseases. Patients. Sixty-six Dutch patients with CRPS1 in one extremity were included. OUTCOME MEASURES: Allergy information was obtained from the medical history and a modified questionnaire based on the Europees Luchtweg Onderzoek Nederland 1 study. Total IgE and allergen-specific IgE were measured from blood samples. Also tryptase, as a marker for mast cells, was measured. The data from the questionnaire were compared with that of the general Dutch population, and the plasma levels were compared with reference values and data in the literature. RESULTS: The medical history did not differ from information provided in the questionnaire by the CRPS1 group. There was no significant difference between the answers to the questionnaire between the CRPS1 patients and the general population. The total IgE levels were elevated in 30% of the CRPS1 patients compared with 15-24% of the general population, and allergen-specific IgE and tryptase levels were comparable with the reference values. CONCLUSIONS: Based on the medical history, an allergy questionnaire, and objective laboratory findings we conclude that IgE-mediated hypersensitivity is not more common in CRPS1 patients than in the general population.

Inflammatory profile of awake function-controlled craniotomy and craniotomy under general anesthesia.

BACKGROUND: Surgical stress triggers an inflammatory response and releases mediators into human plasma such as interleukins (ILs). Awake craniotomy and craniotomy performed under general anesthesia may be associated with different levels of stress. Our aim was to investigate whether those procedures cause different inflammatory responses. METHODS: Twenty patients undergoing craniotomy under general anesthesia and 20 patients undergoing awake function-controlled craniotomy were included in this prospective, observational, two-armed study. Circulating levels of IL-6, IL-8, and IL-10 were determined pre-, peri-, and postoperatively in both patient groups. VAS scores for pain, anxiety, and stress were taken at four moments pre- and postoperatively to evaluate physical pain and mental duress. RESULTS: Plasma IL-6 level significantly increased with time similarly in both groups. No significant plasma IL-8 and IL-10 change was observed in both experimental groups. The VAS pain score was significantly lower in the awake group compared to the anesthesia group at 12 hours postoperative. Postoperative anxiety and stress declined similarly in both groups. CONCLUSION: This study suggests that awake function-controlled craniotomy does not cause a significantly different inflammatory response than craniotomy performed under general anesthesia. It is also likely that function-controlled craniotomy does not cause a greater emotional challenge than tumor resection under general anesthesia.

Regulation of peripheral blood flow in complex regional pain syndrome: clinical implication for symptomatic relief and pain management.

BACKGROUND: During the chronic stage of Complex Regional Pain Syndrome (CRPS), impaired microcirculation is related to increased vasoconstriction, tissue hypoxia, and metabolic tissue acidosis in the affected limb. Several mechanisms may be responsible for the ischemia and pain in chronic cold CPRS. DISCUSSION: The diminished blood flow may be caused by either sympathetic dysfunction, hypersensitivity to circulating catecholamines, or endothelial dysfunction. The pain may be of neuropathic, inflammatory, nociceptive, or functional nature, or of mixed origin. SUMMARY: The origin of the pain should be the basis of the symptomatic therapy. Since the difference in temperature between both hands fluctuates over time in cold CRPS, when in doubt, the clinician should prioritize the patient's report of a persistent cold extremity over clinical tests that show no difference. Future research should focus on developing easily applied methods for clinical use to differentiate between central and peripheral blood flow regulation disorders in individual patients.

Vasodilative effect of isosorbide dinitrate ointment in complex regional pain syndrome type 1.

BACKGROUND: In complex regional pain syndrome type 1 (CRPS1) vascular changes occur from the initial, inflammatory event onto the trophic signs during chronicity of the disease, resulting in blood flow disturbances and marked temperature changes. Pharmacotherapeutic treatment is generally inadequate. AIM: To determine whether local application of the nitric oxide donor isosorbide dinitrate (ISDN) could cause vasodilation and thereby improve tissue blood distribution in the affected extremity. METHODS: In a pilot study, 5 female patients with CRPS1 in one hand were treated with ISDN ointment 4 times daily during 10 weeks. As a primary objective videothermography was used to monitor changes in blood distribution in both the involved and contralateral extremities. RESULTS: Patients treated with ISDN showed an increase of 4 degrees C to 6 degrees C in mean skin temperature of the cold CRPS1 hands, reaching values similar to that of the contralateral extremities within 2 to 4 weeks time, suggesting normalization of blood distribution. This was confirmed by an improvement in skin color. In 3 patients the Visual Analog Scale pain declined, whereas in the other 2 patients the Visual Analog Scale pain was unchanged over time. CONCLUSIONS: In this pilot study, topical application of ISDN seems to be beneficial to improve symptoms for patients with cold type CRPS1, but further study is needed.

Analysis of cerebrospinal fluid inflammatory mediators in chronic complex regional pain syndrome related dystonia.

OBJECTIVES: There is compelling evidence of central nervous system involvement in neuropathic pain and movement disorders in patients with complex regional pain syndrome (CRPS). Previously, elevated cerebrospinal fluid (CSF) levels of interleukin-1beta and interleukin-6 were found in CRPS patients with and without movement disorders. The aim of the present study was to replicate these findings and to search for additional CSF biomarkers in chronic CRPS patients with dystonia. METHODS: CSF samples of 20 patients and 29 controls who underwent spinal anesthesia for surgical interventions participated. We measured interleukin-1beta, interleukin-6, interferon-gamma inducible protein-10, RANTES (regulated upon activation, normal T-cell expressed and secreted), complement C3, mannose-binding lectin, complement C1q, soluble intercellular adhesion molecule-1, endothelin-1, nitric oxide, human lactoferrin, and hypocretin-1 levels in these samples. RESULTS: No differences in the CSF levels of these effector mediators between patients and controls were found. CONCLUSION: Our CSF findings do not support a role of a variety of inflammatory mediators or hypocretin-1 in chronic CRPS patients with dystonia.

Increased plasma serotonin in complex regional pain syndrome type 1.

BACKGROUND: In patients with complex regional pain syndrome type 1 (CRPS1), some improvement can be achieved by the administration of ketanserin, a 5-HT(2A) receptor antagonist. We measured plasma levels of serotonin (5-HT) during CRPS1 and correlated these levels with disease characteristics. METHODS: Plasma 5-HT was measured in 35 patients who had CRPS1 for 3 yr and compared with 35 age-matched healthy controls. RESULTS: The plasma 5-HT levels were 411 +/- 263 nmol/L and 29 +/- 18 nmol/L, respectively (P < 0.001). No correlations with disease characteristics were observed. CONCLUSIONS: The markedly elevated levels of plasma 5-HT in CRPS1 patients suggest a role for 5-HT during the course of this disease. However, because of the lack of correlations with distinct disease characteristics, 5-HT is probably one of a number of mediators in CRPS1.

Using skin surface temperature to differentiate between complex regional pain syndrome type 1 patients after a fracture and control patients with various complaints after a fracture.

OBJECTIVE: In this study, we assessed the validity of skin surface temperature recordings, based on various calculation methods applied to the thermographic data, to diagnose acute complex regional pain syndrome type 1 (CRPS1) fracture patients. METHODS: Thermographic recordings of the palmar/plantar side and dorsal side of both hands or feet were made on CRPS1 patients and in control fracture patients with/without and without complaints similar to CRPS1 (total in the three subgroups = 120) just after removal of plaster. Various calculation methods applied to the thermographic data were compared using receiver operating characteristics analysis to obtain indicators of diagnostic value. RESULTS: There were no significant differences in demographic data and characteristics among the three subgroups. The most pronounced differences among the subgroups were vasomotor signs in the CRPS1 patients. The involved side in CRPS1 patients was often warmer compared with the noninvolved extremity. The difference in temperature between the involved site and the noninvolved extremity in CRPS1 patients significantly differed from the difference in temperature between the contralateral extremities of the two control groups. The largest temperature difference between extremities was found in CRPS1 patients. The difference in temperature recordings comparing the palmar/plantar and dorsal recording was not significant in any group. The sensitivity and specificity varied considerably between the various calculation methods used to calculate temperature difference between extremities. The highest level of sensitivity was 71% and the highest specificity was 64%; the highest positive predictive value reached a value of 35% and the highest negative predictive 84%, with a moderate 0.60 > or = area under the curve < or = 0.65. CONCLUSION: The validity of skin surface temperature recordings under resting conditions to discriminate between acute CRPS1 fracture patients and control fracture patients with/without complaints is limited, and only useful as a supplementary diagnostic tool.

Expression of endothelial nitric oxide synthase and endothelin-1 in skin tissue from amputated limbs of patients with complex regional pain syndrome.

BACKGROUND AND OBJECTIVES: Impaired microcirculation during the chronic stage of complex regional pain syndrome (CRPS) is related to increased vasoconstriction, tissue hypoxia, and metabolic tissue acidosis in the affected limb. Endothelial dysfunction is suggested to be the main cause of diminished blood flow. The aim of this study was to examine the distribution of endothelial nitric oxide synthase (eNOS) and endothelin-1(ET-1) relative to vascular density represented by the endothelial marker CD31-immunoreactivity in the skin tissue of patients with chronic CRPS. METHODS: We performed immunohistochemical staining on sections of skin specimens obtained from the amputated limbs (one arm and one leg) of two patients with CRPS. RESULTS: In comparison to proximal specimens we found an increased number of migrated endothelial cells as well as an increase of eNOS activity in distal dermis specimens. CONCLUSIONS: We found indications that endothelial dysfunction plays a role in chronic CRPS.

Six years follow-up of the levels of TNF-alpha and IL-6 in patients with complex regional pain syndrome type 1.

In an earlier study, levels of the proinflammatory cytokines TNF-alpha and IL-6 are higher in blisters fluid from the complex regional pain syndrome type 1 (CRPS1) side obtained at 6 and 30 months (median) after the initial event. The aim of this follow-up study is to determine the involvement of these cytokines in long lasting CRPS1. Twelve CRPS1 patients, with median disease duration of 72 months, participated. The levels of TNF-alpha and IL-6 were measured in blister fluid; disease activity was reevaluated by measuring pain and differences in temperature, volume, and mobility between both extremities. Differences in levels of IL-6 and TNF-alpha and mobility between both sides were significantly decreased. Pain and differences in temperature and volume were not significantly altered. No correlation was found between the cytokines and the disease characteristics. These results indicate that IL-6 and TNF-alpha are only partially responsible for the signs and symptoms of CRPS1.

Effect of tadalafil on blood flow, pain, and function in chronic cold complex regional pain syndrome: a randomized controlled trial.

BACKGROUND: This double-blind, randomized, controlled trial investigated the effect of the phosphodiesterase-5 inhibitor tadalafil on the microcirculation in patients with cold Complex Regional Pain Syndrome (CRPS) in one lower extremity. METHODS: Twenty-four patients received 20 mg tadalafil or placebo daily for 12 weeks. The patients also participated in a physical therapy program. The primary outcome measure was temperature difference between the CRPS side and the contralateral side, determined by measuring the skin temperature with videothermography. Secondary outcomes were: pain measured on a Visual Analogue Scale, muscle force measured with a MicroFet 2 dynamometer, and level of activity measured with an Activity Monitor (AM) and walking tests. RESULTS: At the end of the study period, the temperature asymmetry was not significantly reduced in the tadalafil group compared with the placebo group, but there was a significant and clinically relevant reduction of pain in the tadalafil group. Muscle force improved in both treatment groups and the AM revealed small, non-significant improvements in time spent standing, walking, and the number of short walking periods. CONCLUSION: Tadalafil may be a promising new treatment for patients that have chronic cold CRPS due to endothelial dysfunction, and deserves further investigation. TRIAL REGISTRATION: The registration number in the Dutch Trial Register is ISRCTN60226869.

A randomized prospective study comparing the Cobra Perilaryngeal Airway and Laryngeal Mask Airway-Classic during controlled ventilation for gynecological laparoscopy.

BACKGROUND: An increasing number of noninvasive, supraglottic airway devices are currently available. In this randomized single-blind study, we compared the Cobra Perilaryngeal Airway (CobraPLA) to the [Laryngeal Mask Airway (LMA)-Classic] during gynecological laparoscopy. METHODS: Forty patients received either an LMA-Classic or a CobraPLA. Insertion, ventilation and removal characteristics were noted, as well as any throat morbidity. RESULTS: Devices were similar for insertion characteristics, adverse events, and throat morbidity. Before pneumoperitoneum, peak airway pressures were 20.3 +/- 4.9 cm H2O in the LMA-Classic group versus 25.5 +/- 7.9 cm H2O in the CobraPLA group, P = 0.01. This difference was maintained during pneumoperitoneum; LMA-Classic (22.8 +/- 6.1 cm H2O) and CobraPLA (28.1 +/- 8.5 cm H2O), P = 0.04. Macroscopic blood occurred only on the CobraPLA, seen on 40% of the devices after removal, P = 0.001. CONCLUSION: During gynecological laparoscopy, the CobraPLA provides similar insertion characteristics, but higher airway sealing pressures than the LMA-Classic. The usefulness of this finding requires further investigation.

Reliability of observer assessment of thermographic images in complex regional pain syndrome type 1.

This study aimed at evaluating the sensitivity, specificity, reliability and repeatability of observer assessment of thermographic images taken from Complex Regional Pain Syndrome (CRPS) type 1. A computer program was developed to let observers rate the difference between randomly presented thermographic images of pairs of hands of individuals. The sensitivity and specificity, and potential learning effects were measured. Effects of the colours and rank number of the images were analysed. The sensitivity was 71% and the specificity 85%. The repeatability was 0.5267 and the reliability was 0.4967. No significant relation was found between the rank number and the rating. There was a significant correlation between the colour pallet and the rating (r = 0.76). Although the colour pallet used partly explained the variance in the rating scores, this study shows that observer assessment of thermographic images may distinguish between CRPS1 patients and healthy controls. However, the reliability and repeatability of this assessment was rather low.

Thermography imaging during static and controlled thermoregulation in complex regional pain syndrome type 1: diagnostic value and involvement of the central sympathetic system.

BACKGROUND: Complex Regional Pain Syndrome type 1 (CRPS1) is a clinical diagnosis based on criteria describing symptoms of the disease. The main aim of the present study was to compare the sensitivity and specificity of calculation methods used to assess thermographic images (infrared imaging) obtained during temperature provocation. The secondary objective was to obtain information about the involvement of the sympathetic system in CRPS1. METHODS: We studied 12 patients in whom CRPS1 was diagnosed according to the criteria of Bruehl. High and low whole body cooling and warming induced and reduced sympathetic vasoconstrictor activity. The degree of vasoconstrictor activity in both hands was monitored using a videothermograph. The sensitivity and specificity of the calculation methods used to assess the thermographic images were calculated. RESULTS: The temperature difference between the hands in the CRPS patients increases significantly when the sympathetic system is provoked. At both the maximum and minimum vasoconstriction no significant differences were found in fingertip temperatures between both hands. CONCLUSION: The majority of CRPS1 patients do not show maximal obtainable temperature differences between the involved and contralateral extremity at room temperature (static measurement). During cold and warm temperature challenges this temperature difference increases significantly. As a result a higher sensitivity and specificity could be achieved in the diagnosis of CRPS1. These findings suggest that the sympathetic efferent system is involved in CRPS1.

Thermographic temperature measurement compared with pinprick and cold sensation in predicting the effectiveness of regional blocks.

We designed this study to evaluate the usefulness of thermographic temperature measurement with an infrared camera, compared with patient response to cold and pinprick, as a means of assessing the success or failure of axillary blockades. Axillary blocks were performed on 25 patients undergoing surgery on the hand or forearm using a nerve stimulator technique with mepivacaine 1.5%. Pinprick and cold sensation were assessed on the operative site at 5-min intervals for 30 min. A thermographic image of the operative limb was recorded at similar time intervals. Thermographic images of the unblocked limb were taken before block placement and at 30 min. Temperature values at the operative site and unblocked limb were calculated from the thermographic images. Results revealed that thermography had higher combined values for sensitivity, specificity, and positive and negative predictive values than both cold and pinprick at all time intervals, with statistically significant differences at 15 min (thermography versus cold, P = 0.006; thermography versus pinprick, P = 0.026) and 30 min (thermography versus cold, P = 0.038; thermography versus pinprick, P = 0.040). For thermography as a method of block assessment, an optimal time of 15 min after mepivacaine local anesthetic injection gives the highest combined values for predicting a successful block (P = 0.004). We conclude that thermography provides an early and objective assessment of the success and failure of axillary regional blockades.

Increased endothelin-1 and diminished nitric oxide levels in blister fluids of patients with intermediate cold type complex regional pain syndrome type 1.

BACKGROUND: In complex regional pain syndrome type 1 (CRPS1) pro-inflammatory mediators and vascular changes play an important role in the sustained development and outcome of the disease. The aim of this study was to determine the involvement of vasoactive substances endothelin-1 (ET-1) and nitric oxide (NO) during early chronic CRPS1. METHODS: Included were 29 patients with CRPS 1 who were diagnosed during the acute stage of their disease and observed during follow-up visits. Disease activity and impairment were determined and artificial suction blisters were made on the CRPS1 and the contralateral extremities for measurements of IL-6, TNF-alpha, ET-1 and nitrate/nitrite (NOx). RESULTS: The levels of IL-6, TNF-alpha and ET-1 in blister fluid in the CRPS1 extremity versus the contralateral extremity were significantly increased and correlated with each other, whereas NOx levels were decreased. CONCLUSION: The NOx/ET-1 ratio appears to be disturbed in the intermediate stage of CRPS, resulting in vasoconstriction and consequently in a diminished tissue blood distribution.

Attenuated mild colonic inflammation and improved survival from severe DSS-colitis of transgenic Cu/Zn-SOD mice.

Mucosal tissue damage in chronic inflammatory bowel disease (IBD) is partly caused by an enduring exposure to excessive amounts of reactive oxygen metabolites (ROM). To protect themselves from the toxic effects of ROM, most intestinal cell types constitutively express the highly specific, key ROM-neutralizing cytosolic enzyme Cu/Zn-superoxide dismutase (SOD). Under inflammatory conditions, however, its protein and activity levels have consistently been reported as being decreased. To elucidate a direct functional relationship between intracellular Cu/Zn-SOD expression and intestinal inflammation, we investigated the effects of transgenic human Cu/Zn-SOD overexpression in acute and chronic murine dextran sodium sulfate (DSS)-induced colitis. When subjected to a mild form of acute colitis, the Cu/Zn-SOD overexpressing mice showed a significantly lower colonic activity of neutrophilic myeloperoxidase (MPO) than their nontransgenic littermates. This difference was particularly evident in the male animals. In contrast, a severe acute colitis did not lead to any differences in MPO activity between both groups. Yet, when the animals were subsequently allowed to recover, MPO levels were again significantly lower in the transgenes, suggesting an involvement of Cu/Zn-SOD in, particularly, the clearance of neutrophils. Specific, immunohistochemical identification of neutrophils confirmed the validity of the MPO activity measurements. In addition, transgenic animals showed a remarkable survival benefit from severe DSS colitis over their nontransgenic littermates, particularly during or shortly after the acute inflammatory phase. During the chronic inflammatory phase, which was not characterized by massive neutrophil infiltration, no effects of Cu/Zn-SOD overexpression were noted. Paradoxically, overexpression of Cu/Zn-SOD did not obviously improve the colitis-related (oxidative) injury or symptoms at any stage of the experiment. Surprisingly, however, we did observe a pronounced male gender preference for DSS susceptibility that was reflected by increased male colitis mortality. Our findings provide direct in vivo evidence for a protective, neutrophil-related role for Cu/Zn-SOD in intestinal inflammation. As such, they support the concept of SOD-based (adjunct) antioxidant treatment strategies for inflammatory bowel disease.

Mast cells are involved in inflammatory reactions during Complex Regional Pain Syndrome type 1.

BACKGROUND: The Complex Regional Pain Syndrome type 1 (CRPS1) is a complication of surgery or trauma but spontaneous development is also described. Although the pathogenesis remains debatable, afferent, efferent and central nervous system mechanisms are proposed. Recently we showed involvement of the proinflammatory cytokines IL-6 and TNFalpha which is direct evidence for an inflammatory process. Many types of cells, such as activated T lymphocytes, monocytes, macrophages and skin resident cells like mast cells, could contribute to the production of cytokines. Involvement of mast cells is relatively easy to detect by measurement of tryptase. AIM: To establish whether mast cells are involved in the inflammatory reactions during CRPS1. METHODS: Twenty patients fulfilling the Bruehl criteria with CRPS1 in one extremity were studied. Impairment was assessed by registration of pain and measurement of differences in temperature, volume and mobility between the involved and uninvolved extremity. Blisters were made with a suction method in order to determine cytokines and mast cell derived tryptase in the involved and uninvolved extremity. RESULTS: In the blister fluid a significant difference (median +/- interquartile range, Wilcoxon signed-ranks test P < 0.05) was found between the involved and uninvolved extremity in IL-6 [53.5 (17.3-225) versus 6.2 (2-20.3) pg/ml], TNFalpha [31 (15.5-131.5) versus 8 (4-39) pg/ml], and tryptase [37 (20.5-62.3) versus 12.5 (6.7-23.5) ng/ml]. There was a significant correlation (0.455) between the intensity of pain and tryptase levels in the involved extremity (Spearman's test, P < 0.05). CONCLUSION: Mast cells are involved in inflammatory reactions during the CRPS1. Mast cells could play a role in the production of cytokines such as TNFalpha.