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Aim: People with type 2 diabetes (T2DM) have a high incidence of musculoskeletal disorders thought to be influenced by high non-enzymatic advanced glycated end-products (AGEs). The goals of this study were to determine differences in shoulder activity level and AGEs in people with T2DM compared to matched controls, and to determine factors associated with shoulder pain and disability., Methods: Eighty-one participants, T2DM (n=52) and controls (n=29), were examined for magnitude and duration of shoulder activity (measured using accelerometers), skin intrinsic florescence (SIF) as a surrogate measure of AGE level, and the Shoulder Pain and Disability Index (SPADI) as a self-report of shoulder pain and disability., Results: Compared with controls, T2DM participants had 23% less shoulder activity (p=0.01), greater SIF level (3.6±1.7 vs 2.7±0.6AU, p=0.01), less shoulder strength (p<0.05), and the duration of their shoulder activity was moderately associated (r=0.40; p<0.01) with reported shoulder pain and disability. Shoulder pain and disability were not related to SIF level., Conclusions: Persons with T2DM have higher SIF levels and shoulder symptoms and disability indices than controls. Research is needed to determine if a shoulder mobility intervention to increase strength and mobility can help decrease shoulder pain and disability., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Pain related to rotator cuff tendinopathy is a common problem, but little is known regarding the origin and cause of pain from the tendon substance. No study to date has looked at the association between tissue changes and patient outcomes., Purpose: To describe the peripheral neuronal phenotype in painful rotator cuff tears and to determine correlations between tissue changes and clinical outcome measures., Study Design: Controlled laboratory study., Methods: Tissue samples of the supraspinatus were taken from patients undergoing surgery to repair a rotator cuff tendon tear. Patients were classified as having small/medium or large/massive tears. Control tissue was obtained from patients undergoing surgery for posttraumatic shoulder instability. Immunohistochemical techniques were performed using antibodies to known nociceptive and neuronal markers as well as general tissue structural markers., Results: There was no correlation between tissue changes and patient-reported outcomes. A significant increase in the expression of glutamate was seen in tendon tears. There were differences in the expression of metabotropic and ionotropic glutamate receptors. Expression changes were also observed for markers of the sensory and autonomic systems; however, no differences were found in neurotrophins., Conclusion: Glutamate and the glutaminergic system play a key role in painful human tendon tears; however, the exact role is still uncertain, as glutamate is highly involved in both pain and metabolic pathways., Clinical Relevance: This study has identified a number of markers that could be potential therapeutic targets., (© 2014 The Author(s).)

Purpose: Chronic neck/shoulder pain (CNSP) is one of the most common pain conditions. The understanding of mechanisms, including the peripheral balance between nociceptive and antinociceptive processes, is incomplete. N-acylethanolamines (NAEs) are a class of endogenous compounds that regulate inflammation and pain. The aim of this study was to investigate the levels of two NAEs: the peroxisome proliferator-activated receptor type-α ligand palmitoylethanolamide (PEA) and stearoylethanolamide (SEA) in the muscle interstitium of the trapezius muscle in women with CNSP randomized to two different neck specific training programs and in a healthy pain-free control group (CON)., Materials and Methods: Fifty-seven women with CNSP were randomized to strength + stretch or stretch alone exercise programs. Twenty-nine subjects underwent microdialysis procedure before and after 4-6 months of exercise. Twenty-four CON subjects underwent microdialysis procedure before and after 4-6 months without any intervention in between. Microdialysate samples were collected from the trapezius muscle and analyzed by mass spectrometry for PEA and SEA levels., Results: PEA and SEA levels were significantly higher in CNSP patients compared with CON. PEA was significantly higher in CNSP than in CON after both training programs. SEA was significantly higher in CNSP than in CON after stretch alone but not after strength + stretch training. A significant positive correlation was found between changes in pain intensity and in SEA levels in the strength + stretch group, but not in the stretch alone group., Conclusion: Our results indicate that exercise interventions differentially affect the levels of the bioactive lipids PEA and SEA in the interstitium of the trapezius muscle in women with CNSP., (Wiley Periodicals, Inc.)

Objectives: The aim of the study was to evaluate the capability of fluorine-18-fluorodeoxyglucose (F-FDG)-positron emission tomography (PET)/computed tomography (CT) in the screening of musculoskeletal inflammation and injury of the shoulder region., Materials and Methods: The study included 122 participants (69 men and 53 women) who complained of shoulder pain at rest and 122 age-matched and sex-matched controls who did not experience pain at rest. Standardized uptake values (SUVs) were calculated for both the left and right shoulders and compared using a four-point visual analog scale of subjective shoulder pain. Correlations between SUVs and uric acid and C-reactive proteins were also evaluated., Results: SUVs for shoulder joints with rest and/or motion pain were significantly higher than those for pain-free shoulder joints. SUVs associated with mild and severe pain at rest were significantly higher than those associated with absence of pain at rest, and SUVs associated with moderate and severe pain on motion were significantly higher than those associated with absence of motion pain. Furthermore, SUVs were significantly correlated with uric acid in men (β=0.21, P=0.02) and in all participants (β=0.22, P<0.001)., Conclusion: F-FDG-PET/CT may be useful for the screening of musculoskeletal inflammation and injury of the shoulder region. As shoulder pain is common, especially among elderly individuals, we should carefully consider the necessity of further examination when identifying the uptake of F-FDG in shoulder joints.

Background/aims: Increasingly, an inflammatory modulating effect of adipokines within synovial joints is being recognized. To date, there has been no work examining a potential association between the presence of adipokines in the shoulder and patient-reported outcomes. This study undertakes an investigation assessing these potential links., Methods: 50 osteoarthritis patients scheduled for shoulder surgery completed a pre-surgery questionnaire capturing demographic information including validated, patient-reported function (Disabilities of the Arm, Shoulder, and Hand questionnaire) and pain (Short Form McGill Pain Questionnaire) measures. Synovial fluid (SF) samples were analyzed for leptin, adiponectin, and resistin levels using Milliplex MAP assays. Linear regression modeling was used to assess the association between adipokine levels and patient-reported outcomes, adjusted for age, sex, BMI, and disease severity., Results: 54% of the cohort was female (n = 27). The mean age (SD) of the sample was 62.9 (9.9) years and the mean BMI (SD) was 28.1 (5.4) kg/m(2). From regression analyses, greater SF leptin and adiponectin levels, but not regarding resistin, were found to be associated with greater pain (p < 0.05). Adipokine levels were not associated with functional outcome scores., Conclusions: The identified association between shoulder-derived SF leptin and adiponectin and shoulder pain is likely explained by the pro-inflammatory characteristics of the adipokines and represents potentially important therapeutic targets., (© 2013 S. Karger GmbH, Freiburg.)

Background: Sympathetic nervous activity contributes to the maintenance of muscle oxygenation. However, patients with chronic pain may suffer from autonomic dysfunction. Furthermore, insufficient muscle oxygenation is observed among workers with chronic neck and shoulder pain. The aim of our study was to investigate how muscle load tasks affect sympathetic nervous activity and changes in oxygenation of the trapezius muscles in subjects with chronic neck and shoulder pain., Methods: Thirty females were assigned to two groups: a pain group consisting of subjects with chronic neck and shoulder pain and a control group consisting of asymptomatic subjects. The participants performed three sets of isometric exercise in an upright position; they contracted their trapezius muscles with maximum effort and let the muscles relax (Relax). Autonomic nervous activity and oxygenation of the trapezius muscles were measured by heart rate variability (HRV) and Near-Infrared Spectroscopy., Results: Oxyhemoglobin and total hemoglobin of the trapezius muscles in the pain group were lower during the Relax period compared with the control group. In addition, the low frequency / high frequency (LF/HF) ratio of HRV significantly increased during isometric exercise in the control group, whereas there were no significant changes in the pain group., Conclusions: Subjects with neck and shoulder pain showed lower oxygenation and blood flow of the trapezius muscles responding to isometric exercise, compared with asymptomatic subjects. Subjects with neck and shoulder pain also showed no significant changes in the LF/HF ratio of HRV responding to isometric exercise, which would imply a reduction in sympathetic nervous activity.

Aim: The purpose of this study was to evaluate the effect of saline washout under the diaphragm on postoperative shoulder tip pain (STP) and β-endorphin (βE) levels in patients who had undergone laparoscopic cholecystectomy (LC)., Methods: Between December 2010 and March 2011, 50 patients requiring cholecystectomy for benign gallbladder disease were enrolled in this study. Twenty-five patients (Group 1) underwent LC without saline irrigation, whereas the other 25 were operated on with saline irrigation (30 mL/kg) under the diaphragm (Group 2). Plasma levels of βE were measured before and after the operation. The degree of STP following LC was assessed using a visual analog pain scale (VAS) at 6, 12, and 24 hours postoperatively., Results: Eight patients in Group 1 (32.0%) and seven patients in Group 2 (28.0%) complained of STP. There was no significant difference between the two groups in operation time, postoperative hospital length, postoperative βE, dose of analgesics, or VAS at 6, 12, and 24 hours after surgery. The intensity of abdominal pain (AP) was significantly higher than that of STP. Significantly elevated levels (11.3±5.1 pg/mL) of βE were observed postoperatively when compared with preoperative levels (9.7±5.2 pg/mL) (P=.02)., Conclusions: Normal saline irrigation under the diaphragm does not reduce postoperative STP after LC. Ancillary techniques to reduce AP and STP should be considered.

Rotator cuff tendon pathology is proposed to account for 30-70% of all shoulder pain and surgical repair with a nonabsorbable suture is the common option for painful rotator cuff tears that have failed conservative treatment. A number of studies have suggested the beneficial effect of augmenting the repair with implants constructed from polymers used for sutures. Thus, it was of interest to investigate the affinity of tendon-derived fibroblasts, often thought to be the repairing agents of torn tendons, to commonly used sutures. The aim of this comparative study was to evaluate the suitability of these sutures for the construction of a patch by measuring cell survival, proliferation, and migration of human tendon-derived fibroblasts on different sutures. To ensure relevance to the target tissue, cells used in this study were obtained from torn human supraspinatus tendons. An initial comparison of cell proliferation on suture mats showed an overall positive proliferation on polyester (Ethibond) and polydioxanone (PDSII) mats and a reduction of proliferation on vicryl (polyglactin 910) compared to day one. The results also showed that the degradation products of vicryl had a negative effect on cell growth over 10 weeks. Of the commercial sutures selected and tested, Ethibond showed the best performance in terms of cell attachment and increase in biomass. The degradable PDSII also showed good interaction with cells in vitro, but relatively poor cell adhesion. This study provides useful and clinically relevant information, which could help to guide future considerations for candidate materials from which to construct tissue repair patches., (Copyright © 2011 Wiley Periodicals, Inc.)

Shoulder and neck pain (SNP) and fibromyalgia syndrome (FMS), two musculoskeletal conditions of unknown pathogenesis, share some common features in terms of altered neuroendocrine responses, pain and stress perception. However, the pain distribution in SNP is localized, whereas in FMS is more widespread. Because regional musculoskeletal pain may represent an intermediate stage along a continuum towards widespread musculoskeletal pain we compared the cortisol awakening response (CAR) in women with SNP with the CAR in FMS patients and healthy controls (HC) in a controlled hospital-hotel setting. The aim of the study was to investigate whether SNP is related to a deviant regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Eighteen women with SNP, 29 female FMS patients, and 27 female HC participated in the study. Cortisol samples were collected upon awakening, 30 and 60 min later. Questionnaires measuring pain levels, sleeping problems, perceived stress, and psychological characteristics were administered to the participants. Compared with HC, women with SNP had a tendency towards higher cortisol levels, whereas FMS had lower cortisol levels. Adjustment for potential confounders did not influence the results. Women with SNP and FMS patients reported more health complaints, pain, and perceived stress than the HC, but women with SNP were less affected than the FMS patients. Women with SNP showed a tendency towards an elevated HPA axis activity compared with HC. The current findings may indicate that the hypercortisolism in regional musculoskeletal pain represent an intermediate stage towards the development of a hypocortisolism in widespread musculoskeletal pain., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: The aim of this study was to demonstrate the feasibility of using samples obtained through muscle biopsy to assess a wide range of cellular properties, some of which may be abnormal in myalgia. Given the recent emphasis on the role of excitation-contraction coupling in health and disease, special emphasis is given to the characterization of the properties involved in this process., Design: Tissue samples were obtained from the upper portion of the descending trapezius muscle in three female patients (PAT) with clinically diagnosed myalgia and assessed for a spectrum of properties related to substrate use, energy production, and excitation-contraction coupling and were compared with samples from three healthy controls., Results: At the level of organization of the metabolic pathways, all PAT generally displayed normal activities of enzymes representing the potential for oxidative phosphorylation, glucose phosphorylation, glycolysis, and lactate oxidation. In contrast, a reduced potential was observed in PAT for both fat oxidation (-20%) and high-energy phosphate transfer (-38%). For excitation-contraction coupling, PAT had a compromised sarcoplasmic reticulum maximal Ca-ATPase activity (-21%), Ca uptake (-44%), and sarcoplasmic endopleasmic reticulum (SERCA) expression for both SERCA1a (-16%) and SERCA2a (-17%), which were accompanied by a lower phase 2 Ca release (-45%). The Na-K-ATPase concentration, the enzyme-regulating membrane excitability via active Na and K seemed elevated (+25%) in PAT., Conclusions: These results demonstrate the feasibility of analyzing tissue samples for a wide range of properties and provide a rationale for studies examining the cellular basis of myalgia with particular emphasis on sarcoplasmic reticulum Ca cycling, given the latter's role in regulating a wide range of cellular functions.

Background: N-acylethanolamines (NAEs) are endogenous compounds that regulate inflammation and pain. These include the cannabinoid ligand anandamide (AEA) and the peroxisome proliferator-activated receptor-α ligand palmitoylethanolamide (PEA). Little is known as to the levels of NAEs in pain states in human, particularly in the skeletal muscle. The aim of this study was to investigate the levels of these lipid mediators in muscle dialysate from women with chronic neck-/shoulder pain compared to healthy controls., Methods: Eleven women with chronic neck-/shoulder pain and eleven healthy women participated in this study. All participants went through microdialysis procedures in the trapezius muscle. Muscle dialysate samples were collected during four hours and analysed by nano liquid chromatography tandem mass spectrometry (nLC-MS/MS)., Results: We were able to detect AEA, PEA, N-stearoylethanolamine (SEA) and 2-arachidonoylglycerol (2-AG) in a single chromatographic run. Of the NAEs studied, PEA and SEA were clearly detectable in the muscle microdialysate samples. The muscle dialysate levels of PEA and SEA were significantly higher in myalgic subjects compared to healthy controls., Conclusion: This study demonstrates that microdialysis in combination with mass spectrometry can be used for analysing NAE's in human muscle tissue regularly over time. Furthermore the significant group differences in the concentration of PEA and SEA in this study might fill an important gap in our knowledge of mechanisms in chronic myalgia in humans. In the long run this expanded understanding of nociceptive and anitinociceptive processes in the muscle may provide a base for ameliorating treatment and rehabilitation of pain.

Work-related neck/shoulder muscle pain has been associated with increased anaerobic muscle metabolism. Thus, interventions to enhance oxygenation of painful muscles seem relevant. While cycling with relaxed shoulders has been shown to result in acute neck/shoulder muscle pain reduction, the effect on tissue oxygenation remains unknown. The aim of the present study was to investigate tissue oxygenation of the passive trapezius muscle during and after cycling in female workers with (MYA) and without (CON) trapezius myalgia. Eligible participants (n = 17 MYA, n = 8 CON) performed 20 min sub-maximal cycling in an upright position with relaxed shoulders. Near-infrared spectroscopy was used to measure trapezius muscle oxygenation during and 2 min after the cycling period. For both MYA and CON, oxygenation of the passive trapezius increased in a linear fashion over time, to values approximately 5 microM above baseline at the end of the cycling period, with no significant group difference (CON 5.2, MYA 4.9 microM). Two min after termination of exercise, oxygenation was increased further in both groups, but significantly more in CON (8.8 microM) than in MYA (7.0 microM) (P = 0.05). In conclusion, cycling increases oxygenation of resting neck/shoulder muscles in women with and without trapezius myalgia, indicating acute positive effects of either neural or humoral factors on vascular beds of distant relaxed muscles. Although this beneficial response was observed in both groups, the post-exercise response was lower in women with trapezius myalgia.

Background: Shoulder pain is a common health problem. The purpose of this study was to assess the associations of lifestyle factors, metabolic factors and carotid intima-media thickness with shoulder pain and chronic (> 3 months) rotator cuff tendinitis., Methods: In this cross-sectional study, the target population consisted of subjects aged 30 years or older participating in a national Finnish Health Survey during 2000-2001. Of the 7,977 eligible subjects, 6,237 (78.2%) participated in a structured interview and clinical examination. Chronic rotator cuff tendinitis was diagnosed clinically. Weight-related factors, C-reactive protein and carotid intima-media thickness were measured., Results: The prevalence of shoulder joint pain during the preceding 30 days was 16% and that of chronic rotator cuff tendinitis 2.8%. Smoking, waist circumference and waist-to-hip ratio were related to an increased prevalence of shoulder pain in both genders. Metabolic syndrome, type 2 diabetes mellitus and carotid intima-media thickness were associated with shoulder pain in men, whereas high level of C-reactive protein was associated with shoulder pain in women. Increased waist circumference and type 1 diabetes mellitus were associated with chronic rotator cuff tendinitis in men., Conclusions: Our findings showed associations of abdominal obesity, some other metabolic factors and carotid intima-media thickness with shoulder pain. Disturbed glucose metabolism and atherosclerosis may be underlying mechanisms, although not fully supported by the findings of this study. Prospective studies are needed to further investigate the role of lifestyle and metabolic factors in shoulder disorders.

Objectives: The aim of this study was to investigate the intramuscular metabolic state in chronically painful muscles using positron-emission tomography/computerized tomography (PET/CT)., Study Design: The study included 140 consecutive noncancer subjects who underwent PET/CT screening for a physical checkup (mean age 56.0 +/- 10.22 y). The demographic data and information on pain in the neck/shoulder region were obtained using a questionnaire. The subjects who had an awareness of pain in the neck/shoulder region for >6 months were regarded to be pain subjects (n = 39). The minimal and maximal standardized uptake values (SUV) of [(18)F]fluorodeoxyglucose ((18)F-FDG) of the trapezius muscle in each subject were automatically calculated., Results: The unpaired t test revealed that both the minimal and the maximal SUVs were significantly lower in the pain subjects than in the asymptomatic subjects. A multiple linear regression analysis also demonstrated a significant association between pain in the neck/shoulder region and the SUVs in the trapezius muscle., Conclusions: Uptake of (18)F-FDG was lower in the chronically painful trapezius muscle., (Copyright (c) 2010 Mosby, Inc. All rights reserved.)

Objective: To establish the correlations among the mineral components, progressive calcification process and clinical symptoms of calcific tendonitis., Methods: The morphology of the calcified deposits on the shoulders of 28 patients with calcific tendonitis was determined by high-resolution ultrasonography. The calcified deposit from each patient was aspirated and determined by the Fourier transform infrared and Raman microspectroscopies. The curve-fitting program was applied to estimate the chemical component in the calcified deposits of calcific tendonitis., Results: The morphology of calcified deposits for 28 patients was classified into four shapes: arc shape (7 patients), fragmented/punctuate shape (4 patients), nodular shape (13 patients) and cystic shape (4 patients). These classified shapes markedly correlated with the pain levels in patients. The infrared spectra of all the calcified deposits for 28 patients were easily classified into three types in the blind study and corresponded to the formative, resting and resorptive phases in the progressive calcification process of calcific tendonitis. With the progressive calcification, the IR wavenumber at 1018 cm(-1) assigned to poorly crystalline, non-stoichiometric apatite for the formative phase was shifted to 1028 cm(-1) for the resting phase and then to 1031 cm(-1) due to matured crystalline stoichiometric apatite for the resorptive phase. The curve-fitted results revealed that calcified deposits in calcific tendonitis were composed of different quantities of A-type and B-type carbonated apatites in the three phases. A significant difference was found in carbonated apatite content among the three phases (P < 0.001)., Conclusions: The different quantities of A-type and B-type carbonated apatites determined by vibrational microspectroscopy in calcified deposits were well correlated with those of the four shapes of morphologic classification, with the three phases in the progressive calcification process and with the clinical symptoms of calcific tendonitis.

The trapezius muscle often develops pain as the result of repetitive and stressful work tasks although it is unclear to what extent this pain is due to alterations in muscle concentrations of algesic/nociceptive substances. Twenty women with chronic neck- and shoulder pain (TM) whose work required highly repetitive work tasks and 20 pain-free female colleagues (CON) were studied during and after a full 8-hour workday. We collected microdialysates from their dominant/most painful trapezius muscle; concentrations of serotonin, glutamate, lactate, pyruvate, potassium, bradykinin, and cytokines and blood flow were determined. In addition, we measured surface electromyogram, task exposure level, pain intensity, perceived mental stress, and urine-cortisol. In connection to the clinical neck and shoulder examination, we determined pressure pain thresholds (PPTs) over the trapezius and tibialis muscles. TM had higher concentrations of glutamate (71+/-42 vs. 36+/-15 micromol l(-1)) and pyruvate (187+/-89 vs. 125+/-63 micromol l(-1)) than CON. Interstitial serotonin was higher in TM (before work: 10.6+/-10.8 vs. 2.2+/-1.2 nM; after work: 9.2+/-8.3 vs. 1.5+/-2.9 nM). The trapezius blood flow during the working day was higher in TM than in CON. TM had lower PPT and higher pain intensity throughout the working day. No differences in EMG, task exposure level, mental stress, or urine-cortisol in the groups were found. These findings support the idea that peripheral nociceptive processes are activated in occupationally active subjects, who are diagnosed with trapezius myalgia. In contrast, no sign of low blood flow or increased stress or muscle activity markers were found in TM.

The mechanisms behind the development of work-related trapezius pain are suggested to involve both peripheral and central components, but the specific contribution of alterations in muscle nociceptive and other substances is not clear. Female patients with chronic trapezius myalgia (N=19; TM) and female controls (N=20; CON) were studied at rest, during 20 min repetitive low-force exercise and recovery, and had their interstitial concentrations of potassium (K(+)), lactate dehydrogenase (LDH), interleukin-6 (IL-6) and collagen turnover determined in the trapezius muscle by the microdialysis technique. K(+) levels were at all time points higher in TM than in CON (P<0.0001). Baseline levels of LDH and IL-6 were similar in both groups. In response to exercise pain intensity, rated perceived exertion, and the concentrations of K(+), LDH and IL-6 increased significantly in both groups. [K(+)] immediately decreased to baseline levels in CON but remained elevated during the first 20 min of recovery in TM (P<0.01) whereafter it returned to baseline level. In all subjects taken together mean [K(+)] correlated negatively with pressure pain threshold of trapezius (P<0.001), positively with mean pain intensity VAS (P<0.001) and mean perceived exertion (P<0.001). Rises in muscle LDH and IL-6 as well as the anabolic ratio for collagen type I was not significantly different between groups. In conclusion, patients with chronic pain in the trapezius muscle had increased levels of interstitial potassium. This finding could be causally related to myalgia or secondary to pain due to deconditioned muscle or altered muscle activity pattern.

Much is still unknown concerning the mechanisms underlying the development of chronic muscle pain. The presence and magnitude of inflammatory substances and neurotransmitters in chronic painful conditions is not clear. The aims of the present study were to determine, with the use of microdialysis, the interstitial concentrations and the equilibration times for PGE2 and glutamate in the trapezius muscles of nine female subjects with chronic muscle pain, and nine pain-free age-matched controls. A microdialysis probe was implanted in the upper part of the trapezius muscle and perfused with Ringer-acetate solution at a flow rate of 0.3 microL/min. Samples were obtained every 30 min, during a 4-h rest period. At equilibration, the mean concentrations (+/-SE) of PGE2 were 0.71 (+/-0.11) ng/mL for the pain-group and 0.97 (+/-0.35) ng/mL for the controls. For glutamate the mean concentrations for the pain-group were 66.3 (+/-13.3) micromol/L and 60.6 (+/-22.9) micromol/L for the controls. For the pain group and the control group, respectively, equilibration for PGE2 was reached at 180 and 150 min, and for glutamate at 150 and 120 min. The present study showed no differences between groups in the concentrations of PGE2 and glutamate in the trapezius muscle. Further, it revealed that when using the slow-flow method, a period of at least 2.0-2.5 h is needed, after probe insertion, to reach steady state for glutamate and PGE2.

Objective: To determine the relationship between the expression of interleukin-1beta (IL-1beta) and IL-1 receptor antagonists (IL-1ra) in the subacromial bursa and shoulder pain in rotator cuff diseases., Methods: Synovial specimens were analysed using various methods including reverse transcriptase-polymerase chain reaction (RT-PCR), immunohistochemistry and in situ RT-PCR. Thirty-nine patients with rotator cuff diseases were candidates. The degree of their shoulder pain was evaluated using a visual analogue scale., Results: The mRNA expression levels of the cytokines were significantly correlated with the degree of pain [IL-1beta: r=0.782; secreted IL-1ra (sIL-1ra): r=0.756; intracellular IL-1ra (icIL-1ra): r=0.806, P<0.001, respectively]. The combined results of immunohistochemistry and in situ RT-PCR analysis indicated that both synovial lining and sublining cells produce IL-1beta, while synovial lining cells predominantly produce icIL-1ra and sublining cells secrete sIL-1ra., Conclusions: The differential regulation of the two forms of IL-1ra mRNAs may play an important role in shoulder pain in rotator cuff diseases, regulating IL-1-induced subacromial synovitis.

Vascular endothelial growth factor (VEGF), which is known to be an angiogenetic factor, plays an important role in the inflammation of synovial tissue. To investigate the relationships between VEGF and clinical symptoms in rotator cuff disease, VEGF expression was examined using RT-PCR and immunohistochemical analysis in 50 patients with this disease (26 with full-thickness cuff tear, 12 with partial-thickness tear, and 12 with subacromial bursitis). VEGF mRNA expression was detected in 40 out of 50 patients by RT-PCR. VEGF mRNA expression was found more frequently in the patients with motion pain (39 out of 41) than in those without motion pain (1 out of 9) with statistical significance (Fisher's test, P < 0.001). Thirty-one out of 33 patients with synovial proliferation showed VEGF mRNA expression, whereas the expression of this transcript was found in 9 out of 17 patients without synovial proliferation. This association with synovial proliferation was also significant (Fisher's test, P = 0.0013). Thirty out of 41 patients with motion pain had synovial proliferation but 3 out of 9 patients without motion pain had synovial proliferation. In all these 30 patients with both motion pain and synovial proliferation, VEGF mRNA expression was detected. This association between motion pain and synovial proliferation was also significant (Fisher's test, P < 0.05). The mean vessel count and area in subacromial bursa expressing VEGF was significantly higher than in those without VEGF (Mann Whitney's U test, P < 0.01). These results suggested that VEGF expression is associated with vascularity, synovial proliferation and shoulder motion pain in the rotator cuff disease.