Bone marrow derived mast cells injected into the osteoarthritic knee joints of mice induced by sodium monoiodoacetate enhanced spontaneous pain through activation of PAR2 and action of extracellular ATP.

Conditions that resemble osteoarthritis (OA) were produced by injection of sodium monoiodoacetate (MIA) into the knee joints of mice. Bone marrow derived mast cells (BMMCs) injected into the OA knee joints enhanced spontaneous pain. Since no spontaneous pain was observed when BMMCs were injected into the knee joints of control mice that had not been treated with MIA, BMMCs should be activated within the OA knee joints and release some pain-inducible factors. Protease activated receptor-2 (PAR2) antagonist (FSLLRY-NH2) almost abolished the pain-enhancing effects of BMMCs injected into the OA knee joints, suggesting that tryptase, a mast cell protease that is capable of activating PAR2, should be released from the injected BMMCs and enhance pain through activation of PAR2. When PAR2 agonist (SLIGKV-NH2) instead of BMMCs was injected into the OA knee joints, it was also enhanced pain. Apyrase, an ATP degrading enzyme, injected into the OA knee joints before BMMCs suppressed the pain enhanced by BMMCs. We showed that purinoceptors (P2X4 and P2X7) were expressed in BMMCs and that extracellular ATP stimulated the release of tryptase from BMMCs. These observations suggest that ATP may stimulate degranulation of BMMCs and thereby enhanced pain. BMMCs injected into the OA knee joints stimulated expression of IL-1ß, IL-6, TNF-α, CCL2, and MMP9 genes in the infrapatellar fat pads, and PAR2 antagonist suppressed the stimulatory effects of BMMCs. Our study suggests that intermittent pain frequently observed in OA knee joints may be due, at least partly, to mast cells through activation of PAR2 and action of ATP, and that intraarticular injection of BMMCs into the OA knee joints may provide a useful experimental system for investigating molecular mechanisms by which pain is induced in OA knee joints.

Unilateral repetitive tibial nerve stimulation improves neurogenic claudication and bilateral F-wave conduction in central lumbar spinal stenosis.

BACKGROUND: Repetitive electrical nerve stimulation of the lower limb may improve neurogenic claudication in patients with lumbar spinal stenosis (LSS) as originally described by Tamaki et al. We tested if this neuromodulation technique affects the F-wave conduction on both sides to explore the underlying physiologic mechanisms. METHODS: We studied a total of 26 LSS patients, assigning 16 to a study group receiving repetitive tibial nerve stimulation at the ankle (RTNS) on one leg, and 10 to a group without RTNS. RTNS conditioning consisted of a 0.3-ms duration square-wave pulse with an intensity 20% above the motor threshold, delivered at a rate of 5 Hz for 5 min. All patients underwent the walking test and the F-wave and M-wave studies for the tibial nerve on both sides twice; once as the baseline, and once after either the 5-min RTNS or 5-min rest. RESULTS: Compared to the baselines, a 5-min RTNS increased claudication distance (176 ± 96 m vs 329 ± 133 m; p = 0.0004) and slightly but significantly shortened F-wave minimal onset latency (i.e., increased F-wave conduction velocity) not only on the side receiving RTNS (50.7 ± 4.0 ms vs 49.2 ± 4.2 ms; p = 0.00081) but also on the contralateral side (50.1 ± 4.6 ms vs 47.9 ± 4.2 ms; p = 0.011). A 5-min rest in the group not receiving RTNS neither had a significant change on claudication distance nor on any F-wave measurements. The M response remained unchanged in both groups. CONCLUSIONS: The present study verified a beneficial effect of unilaterally applied RTNS of a mild intensity on neurogenic claudication and bilateral F-wave conduction. Our F-wave data suggest that this type of neuromodulation could be best explained by an RTNS-induced widespread sympathetic tone reduction with vasodilation, which partially counters a walking-induced further decline in nerve blood flow in LSS patients who already have ischemic cauda equina.

Less deep vein thrombosis due to transcutaneous fibular nerve stimulation in total knee arthroplasty: a randomized controlled trial.

PURPOSE: It has been known for years that deep vein thrombi (DVT) start to develop during total joint arthroplasty. Previously, we reported effective prevention of venous stasis by transcutaneous electrical nerve stimulation (TENS). It is hypothesized that TENS might be a thromboprophylactic tool for the limb undergoing surgery. The purpose of this study is to clarify the clinical efficacy and safety of TENS in patients during total knee arthroplasty (TKA). METHODS: Ninety patients undergoing primary TKA were involved and randomly allocated to the TENS or control group. In the TENS group, electrical stimulation of the common fibular nerve, which produced a brisk dorsiflexion of the ankle, was performed for the operated leg during surgery. In the control group, no electrical stimulation was applied. Serum D-dimer and soluble fibrin monomer complex (SFMC) levels were measured before surgery, immediately after surgery, and post-operative day (POD) 1. Ultrasonography was performed on POD 1. RESULTS: Immediately after surgery, D-dimer and SFMC levels of each group were significantly lower in the TENS group compared with control (p < 0.05). The incidence of DVT was 11 % (five cases) in the TENS group while 31 % (14 cases) in control (p = 0.02). There were no adverse effects related to TENS. CONCLUSIONS: TENS during TKA showed significant effects on preventing DVT. Sustaining muscle pump activation during surgery prevented not only venous stasis, but also hypercoagulability of blood. Intraoperative TENS is a safe and novel strategy against early post-operative thromboembolism, which is difficult to be completed through existing prophylaxis after total joint arthroplasty. LEVEL OF EVIDENCE: Randomized controlled trial, Level I.

Influence of tibial trancutaneous repetitive electrical nerve stimulation on neurogenic claudication and F-wave in lumbar spinal stenosis.

OBJECTIVES: To determine whether repetitive tibial nerve stimulation (RTNS) affects neurogenic claudication and F-wave conduction in lumbar spinal stenosis. DESIGN: An intervention study: before/after trial. SUBJECTS: Data for 12 central lumbar spinal stenosis patients were compared with 13 age- and sex-matched healthy volunteers. METHODS: A conditioning RTNS at the ankle, 0.3-ms duration square-wave pulses with an intensity 20% higher than the motor threshold, was applied at a rate of 5/s for 5 min. We assessed the effects of RTNS on the claudication distance at which the lumbar spinal stenosis patients can no longer continue walking due to increasing leg symptoms, and on tibial F-wave measurements. RESULTS: A comparison between mean pre-RTNS and post-RTNS revealed a significant difference in claudication distance (66 m (standard deviation (SD) 19) vs 133 m (SD 37); p = 0.003), mean F-wave minimal latency (48.3 ms (SD 1.7) vs 44.8 ms (SD 1.0); p = 0.007) and mean F-wave conduction velocity (53.3 m/s (SD 2.0) vs 55.5 m/s (SD 1.9); p = 0.009) in the lumbar spinal stenosis group, but not in the control group. CONCLUSION: RTNS has beneficial effects on neurogenic claudication and F-wave conduction in central lumbar spinal stenosis patients. This phenomenon may have practical value in providing a new therapeutic modality for lumbar spinal stenosis.

Distal traditional acupuncture points of the large intestinal meridian and the stomach meridian differently affect heart rate variability and oxygenation of the trapezius muscle.

Physicians in traditional Chinese medicine have found that acupoints and meridians have effects on specific parts of the body. The aim of this study was to see how acupressure at distal acupuncture points of a specific meridian affects heart rate variability (HRV) and oxygenation of the trapezius muscle. Forty-one female participants were randomly allocated to three groups. Subjects in the Stomach Meridian acupuncture point (ST) group received acupressure at ST 34, ST 36, and ST 41, subjects in the Large Intestinal Meridian acupuncture point (LI) group received acupressure at LI 4, LI 10, and LI 11, and subjects in the control group did not receive any stimuli. HRV and oxygenation of the trapezius muscles were measured. The high frequency components of HRV in the control and LI groups tended to be higher than those in the ST group. Total hemoglobin in the control and LI groups eventually reached significantly higher levels than in the ST group. While oxyhemoglobin (ΔO2Hb) in the control and LI groups did not change, ΔO2Hb in the ST significantly decreased temporarily.

Acid-sensing ion channel 3 expression in mouse knee joint afferents and effects of carrageenan-induced arthritis.

UNLABELLED: Arthritis is associated with decreases in local pH. Of the acid-sensing ion channels (ASIC), ASIC3 is most sensitive to such a pH change, abundantly expressed in dorsal root ganglion (DRG), and critical for the development of secondary hyperalgesia. The purpose of this study was to investigate the upregulation of ASIC3, using an acute arthritic pain model in mice. We examined ASIC3 expression in DRG neurons innervating the knee joint with and without carrageenan-induced arthritis by means of retrograde labeling and immunohistochemistry. We also examined the difference of DRG phenotype between ASIC3+/+ and ASIC3-/- mice. ASIC3 immunoreactivity was present in 31% of knee joint afferents and dominantly in small cells. After joint inflammation, ASIC3-immunoreactive neurons significantly increased in number by 50%. Calcitonin gene-related peptide (CGRP) increased similarly in both ASIC3+/+ and ASIC3-/- mice. Soma size distribution of ASIC3-immunoreactive neurons without CGRP expression was shifted to smaller-diameter neurons. Our results suggest that ASIC3 plays an important role in acute arthritic pain. Specifically, we propose that ASIC3 upregulation along with CGRP and phenotypic change in ASIC3-immunoreactive neurons without CGRP are responsible for the development of secondary hyperalgesia after carrageenan-induced arthritis. PERSPECTIVE: This article shows that ASIC3 is upregulated along with CGRP in knee joint afferents and that there is a phenotypic change in ASIC3-immunoreactive nonpeptidergic neurons in an animal model of acute arthritis. Understanding the basic neurobiology after acute arthritis could lead to future new pharmacological management of arthritis.

Increased c-fos immunoreactivity in the spinal cord and brain following spinal cord stimulation is frequency-dependent.

Spinal cord stimulation (SCS) is an alternative approach for treatment of neuropathic pain when conservative management is ineffective. Previously we showed both 4 Hz and 60 Hz SCS reduces hyperalgesia in an animal model of neuropathic pain. However, the mechanisms underlying the pain reduction by SCS and how different frequencies of SCS produce the analgesic effect are unclear. To elucidate potential sites modulated by SCS we examined distribution of c-fos in Sprague-Dawley rats with spared nerve injury (SNI) and those without injury in response to SCS. SCS was delivered at one of 3 different frequencies (4 Hz, 60 Hz, and 100 Hz) for 30 min 2 weeks after SNI or in animals without SNI. Animals were perfused either 5 min or 2 h after SCS and c-fos protein examined immunohistochemically. The number of c-fos positive cells significantly increased 5 min (35 min after SCS began) after 4 Hz SCS in the NRM, but not PAG in animals with nerve injury. The number of c-fos positive cells was significantly increased bilaterally 2 h after either 4 Hz or 60 Hz SCS in the spinal cord dorsal horn in the cervical enlargement and under the electrode, but not in the lumbar enlargement in animals with nerve injury. In uninjured animals 4 Hz SCS increased c-fos expression at the electrode site and lumbar enlargement when compared to animals implanted with the electrode who did not receive SCS. 100 Hz SCS had no effect on c-fos expression. Thus, at the time points examined in this model, low frequency SCS likely activates supraspinal and spinal mechanisms to produce analgesia, while higher frequencies activate spinal mechanisms.

Light-responsive transcriptional regulation of the suf promoters involved in cyanobacterium Synechocystis sp. PCC 6803 Fe-S cluster biogenesis.

The widely conserved SUF system is involved in Fe-S cluster repair and biogenesis. In cyanobacterium Synechocystis sp. PCC 6803, transcription of the sufBCDS operon encoding the Suf complex is negatively regulated by the upstream sufR gene encoded by the complementary strand. In this report, two promoters for the sufBCDS operon (P1 and P2) and another promoter for sufR (PsufR) was identified, and it was shown that P1 was activated by a shift to high light conditions. We also showed that Thermosynechococcus SufR negatively regulated P1 and PsufR but not P2, in a reconstituted in vitro transcription system using His(6)-tagged RNA polymerase.

Localized synovial hypertrophy in the anteromedial compartment of the osteoarthritic knee.

PURPOSE: The purpose of this study was to investigate the clinical and arthroscopic findings of osteoarthritis (OA) of the knee with localized synovial hypertrophy in the anteromedial compartment and the clinical results of arthroscopic partial synovectomy. TYPE OF STUDY: Retrospective case series. METHODS: We treated 19 osteoarthritic knees with localized synovial hypertrophy in 19 patients by arthroscopic partial synovectomy under local anesthesia. All patients had complained of knee pain (mechanical type pain) and catching sensations preoperatively. Preoperative diagnosis based on physical findings and imaging studies was a medial meniscus tear with medial OA in all patients. The mean follow-up was 37 months (range, 28 to 46 months). Clinical results were assessed with the Hospital for Special Surgery (HSS) scoring scale, overall subjective estimation, and patient satisfaction. RESULTS: The catching sensation resolved immediately after surgery in all patients. The mean HSS score improved from 56.8 to 72.4 points (P < .01). Nine patients (47.4%) were rated excellent or good according to the overall subjective estimation, and 11 patients (57.9%) were satisfied with the treatment. Both HSS score and patient satisfaction were higher in patients (10 patients) who complained of intraoperative pain during synovectomy than in those (9 patients) who hardly felt the pain. CONCLUSIONS: Localized synovial hypertrophy in the anteromedial compartment of OA knees occasionally caused symptoms of pain and catching sensations that resembled meniscal symptoms. Arthroscopic partial synovectomy was effective, especially for those who complained of intraoperative pain during synovectomy under local anesthesia. LEVEL OF EVIDENCE: Level IV.

Pain in arthroscopic knee surgery under local anesthesia.

BACKGROUND: We evaluated pain during arthroscopic knee surgery performed under local anesthesia, with respect to various types of lesions and specific procedures used. PATIENTS AND METHODS: Arthroscopic surgery was performed on 63 joints (61 patients), with a median age of 49 years. We asked the patients to describe the pain experienced at each step of the procedure, and to compare the level of pain experienced at the time of injection and during the operation, using a visual analog scale (VAS). RESULTS: Pain experienced at the time of injection of the local anesthetic was more severe than the pain experienced during the surgical procedure. Local anesthesia provided good pain control during partial resection of the meniscus, chondroplasty, and removal of free bodies. Patients sometimes experienced more pain during treatment of the suprapatellar pouch, including the plica and the anterior cruciate ligament. INTERPRETATION: Injection of the local anesthetic was usually the most painful phase of the entire procedure. Patients were generally satisfied with the pain control.