Haili Wang

Adenovirus-Mediated Gene Transfer of Growth and Differentiation Factor-5 into Tenocytes and the Healing Rat Achilles Tendon

Growth and differentiation factor-5 (GDF-5) is known to induce tendon tissue and stimulate tendon healing. The hypothesis was that adenoviral GDF-5 transfer leads to transitory transgene expression and improves Achilles tendon healing. In vitro experiments were first performed with rat tenocytes. Transgene expression was evaluated by RT-PCR, Western blotting and GDF-5-ELISA. In vivo virus dosage and transgene expression were examined by a marker gene transfer (LacZ and luciferase). In the main experiment in 131 rats, adenovirus particles (3× 1010) were injected into transected Achilles tendons. The time course of GDF-5 mRNA expression was assessed by real-time RT-PCR. Histology and biomechanical testing were used to evaluate tendon healing and tensile strength. In vitro GDF-5 was secreted with a maximum after 2 weeks (330 ng GDF-5/106 cells per 24 hr). In vivo GDF-5 transgene expression showed a maximum at 4 weeks. At 8 weeks, GDF-5 specimens were thicker (p < 0.05) with a trend to higher strength (p = 0,064). Histology showed greater cartilage formation in type II collagen stains than in controls. Injection of adenovirus particles successfully can deliver the GDF-5 gene in healing tendons and leads to thicker tendon regenerates after 8 weeks. This technique might become a new approach for nonsurgical treatment of tendon injuries.

The Role of TNF-α in Patients With Chronic Low Back Pain—A Prospective Comparative Longitudinal Study

ObjectivesIn this prospective longitudinal clinical study with a matched-pair design, we evaluated the role of tumor necrosis factor-α (TNF-α) and its clinical relevance in patients with chronic low back pain. MethodsOne hundred twenty patients with chronic low back pain were matched to a healthy control group. Patients and controls were prospectively followed for 6 months. At 4 fixed time points (day 0, day 10, day 20, and 6 mo) blood samples were taken and TNF-α levels compared in the 2 groups, and correlations with pain level and clinical function were analyzed. ResultsAt the beginning and at all other time points, there was a significantly higher proportion of TNF-α positive participants in the patients group than in the control group. The proportion of TNF-α positive patients decreased during the first 10 days of a multidisciplinary therapy in the patient group, but after this initial period, TNF-α levels remained constantly high with no further change until the final follow-up. In the healthy control group, the proportion of participants with positive TNF-α levels remained constant throughout the entire period. No significant correlation between TNF-α levels and pain or clinical function was detected. DiscussionTNF-α seems to have a significant role in patients with chronic low back pain. However, the pathophysiology of this process, the clinical relevance of TNF-α and, especially, its part in a potential therapy regimen in these patients need to be more closely examined and defined in additional studies.

The Role of Il-8 in Patients With Fibromyalgia: A Prospective Longitudinal Study of 6 Months

Objective In this prospective longitudinal clinical study, we evaluated the role of proinflammatory cytokine IL-8 and its clinical relevance in patients with fibromyalgia (FM) who fulfilled clearly defined inclusion and exclusion criteria and underwent a 3-week inpatients multidisciplinary pain therapy. Methods IL-8 in sera was measured in 20 patients with FM and 80 healthy participants at 4 fixed time points: at the beginning of the study, at 10 days, 21 days, and 6 months, respectively. Pain intensity, back function, depression, nicotine/alcohol consumption, and medication were assessed in the patient group and correlated with IL-8 levels. Results Before and during the inpatient therapy, the serum level of IL-8 was significantly higher in patients with FM compared with controls (P<0.001), but did not correlated with pain intensity and medication. Already at T1 there was a significant reduction of IL-8 serum level (P=0.023) in patient group. Six months after multidisciplinary pain therapy, IL-8 serum level in FM patients was still significantly higher than controls (P=0.044) but reduced approximately to normal range and correlated significantly negatively with pain intensity (r=−0.782, P=0.001). Patients with FM had significantly less pain (P<0.001) and better back function (P<0.001) at day 2 than at day 0. In addition, in patients with FM, IL-8 serum level correlated with nicotine consumption (r=0.471, P=0.042). Conclusions Our results suggest that IL-8 level contributes in patients with FM whose pain intensity and back function can be improved under influence of multidisciplinary pain therapy without need of an anti-IL-8 therapy.

Occurrence and regional distribution of apoptosis in scoliotic discs.

Study Design. Seventy surgically obtained intervertebral discs from 9 patients with idiopathic and 7 patients with neuromuscular scoliosis were analyzed for the regional distribution of apoptosis. Objectives. To investigate the role of apoptotic mechanisms in scoliotic discs. Summary of Background Data. The reasons for the development of scoliosis are complex and yet not completely understood. In herniated lumbar disc tissue, increased apoptosis and a high expression of Fas and Fas ligand and caspase-3 activity have already been reported, suggesting a pivotal role of apoptotic mechanisms in intervertebral disc degeneration. In scoliotic discs, cell death was correlated with disc deformity and changes in nutrient supply and metabolic levels. The role of apoptosis in scoliotic discs, however, is still unclear. Methods. Apoptosis was determined by terminal deoxyribonucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay and poly(ADP-ribose) polymerase (PARP) p85 immunohistochemistry. Expression of Fas and Fas-ligand was analyzed by immunohistochemistry and reverse transcription polymerase chain reaction analysis. Results. In all samples analyzed, apoptotic cells could be detected in the nucleus, anulus, and endplate. The number of apoptotic cells was significantly higher in the nucleus compared to the other areas and in the apex versus the nonapex discs. There was no difference between the discs of idiopathic and neuromuscular scoliosis and between the 2 age groups studied (10–17 years and 17–48 years, respectively). A strong expression of Fas and Fas-ligand could be detected in all samples. Conclusion. Increased numbers of apoptotic cells in the nucleus of scoliotic discs and the apex disc suppose a pivotal role of programmed cell death for the progression of this common disorder. The simultaneous increase of Fas and Fas-ligand expression in areas with increased cell death point to an activation of the apoptotic process via the Fas/Fas-L system.

Longitudinal Observation of Changes in Pain Sensitivity during Opioid Tapering in Patients with Chronic Low‐Back Pain

OBJECTIVE   Several studies have shown that exposure to opioids for short or long periods alters pain sensitivity. Little is known about changes in pain sensitivity during and after tapering of long-term prescribed opioid treatment in chronic low-back pain (cLBP) patients. DESIGN   The goal of this prospective longitudinal study was to investigate pain sensitivity in a homogeneous patient population (cLBP patients only) after tapering of long-term (17 months) opioid use and to monitor the changes in pain sensitivity for 6 months. METHODS   Pain sensitivity (thermal sensation and thermal pain thresholds in low back and nondominant hand) was measured by quantitative sensory testing (QST) at 1 day before (T1), 3 weeks after (T2), and 6 months after the start of opioid tapering (T3) in 35 patients with both cLBP and opioid medication (OP), 35 opioid-naïve cLBP patients (ON), and 28 individuals with neither pain nor opioid intake (HC). RESULTS   Significant differences in heat pain thresholds were found among the three groups at all three time points (T1: P=0.001, T2: P=0.015, T3: P=0.008), but not between the two patient groups. OP patients showed lower cold pain thresholds at T2 than ON patients and HC. At T3, the heat pain thresholds of OP patients still remained lower than HC (P=0.017), while those of ON patients were normalized. CONCLUSIONS   Our findings suggest that long-term use of opioids does not reduce pain sensitivity in cLBP patients; opioid tapering may induce brief hyperalgesia that can be normalized over a longer period.

Influence of depression symptoms on serum tumor necrosis factor-α of patients with chronic low back pain.

IntroductionPatients with chronic low back pain (cLBP) have high rates of comorbid psychiatric disorders, mainly depression. Recent evidence suggests that depressive symptoms and pain, as interacting factors, have an effect on the circulating levels of inflammatory markers relevant to coronary artery disease. Our previous work showed a higher serum level of an inflammatory marker tumour necrosis factor-alpha (TNFα) in patients with cLBP, which did not correlate with intensity of low back pain alone. In the present study we investigated the cross-sectional associations of depressive symptoms, low back pain and their interaction with circulating levels of TNFα.MethodsEach group of 29 patients with cLBP alone or with both cLBP and depression was age-matched and sex-matched with 29 healthy controls. All subjects underwent a blood draw for the assessment of serum TNFα and completed a standardised questionnaire regarding medication, depression scores according to the German version of Centre for Epidemiological Studies Depression Scale (CES-D), pain intensity from a visual analogue scale, and back function using the Roland and Morris questionnaire. The correlations between TNFα level and these clinical parameters were analysed.ResultsThere were no differences in TNFα level between cLBP patients with and without depression. Both cLBP patients with (median = 2.51 pg/ml, P = 0.002) and without (median = 2.58 pg/ml, P = 0.004) depression showed significantly higher TNFα serum levels than healthy controls (median = 0 pg/ml). The pain intensity reported by both patient groups was similar, while the patients with depression had higher CES-D scores (P < 0.001) and worse back function (P < 0.001). The variance analysis showed that the interaction between TNFα level and pain intensity, CES-D scores, sex, body mass index and medication was statistically significant.ConclusionsDepression as a comorbidity to cLBP did not influence the serum TNFα level. It seems that TNFα somehow acts as a mediator in both cLBP and depression, involving similar mechanisms that will be interesting to follow in further studies.

Influence of comorbidity with depression on interdisciplinary therapy: outcomes in patients with chronic low back pain

IntroductionOur previous work showed higher tumour necrosis factor (TNF)-α levels in patients with chronic low back pain (cLBP) compared to healthy controls. However, patients with depression as a comorbidity did not have higher TNF-α levels in comparison to patients without depression. In this study we investigated the influence of depression on therapy outcomes such as TNF-α serum levels, pain intensity and back function in patients with cLBP. Our hypothesis was that patients with both cLBP and depression benefit no less than patients with cLBP alone from the multidisciplinary pain therapy.MethodsA total of 58 patients with cLBP alone or with both cLBP and depression were age- and sex-matched with 29 healthy controls. Serum concentrations of TNF-α were assayed at the beginning of the study (T0) and 10 days (T1), 21 days (T2), and 180 days (T3) later. The clinical outcomes such as pain intensity, as well as back function, sleep, exercise, alcohol and nicotine consumption were documented. In the first three weeks, all patients underwent multidisciplinary therapy based upon biological, psychological, physical and psychosocial components.ResultsOver the whole course there were no differences in TNF-α level between cLBP patients with and without depression. At T0, both cLBP patients with (cLBP+DE) and without (cLBP) depression showed significantly higher TNF-α serum levels (P = 0.002 for cLBP+DE, P = 0.004 for cLBP) than healthy controls (HC) that normalized after 10 days of therapy and remained similar to healthy controls. During the follow-up, the depression scales were normalised and pain intensity was significantly reduced. Both evidences processed parallel to the reduction of TNF-α levels, which correlates neither with depression score nor with pain intensity at any time point.ConclusionsDepression as a comorbidity to chronic low back pain did not influence the serum TNF-α level in the course of six months, but seemed to affect the success of therapy. cLBP patients with comorbidity of depression benefit from multidisciplinary pain therapy not only to the same extent but also to a greater degree than cLBP patients without depression.

The cognitive impact of chronic low back pain: Positive effect of multidisciplinary pain therapy

Abstract Objectives Little is known about the affected cognitive problems in chronic low back pain patients. For this patient cohort research mostly focused on memory of pain, rather than cognitive difficulties related to pain. Chronic pain may be associated with specific (yet undefined) cognitive deficits that affect everyday behaviour. We set out to compare the cognitive function of patients with chronic low back pain (cLBP) in the course of multidisciplinary pain treatments before and after therapy. Methods Thirty-three patients with cLBP and 25 healthy controls between 20 and 70 years were recruited into the study. The inclusion criteria for patients were: (1) a history of at least 12 weeks of chronic myofascial low back pain without radicular pain sensation before enrolment; (2) grade II and higher chronicity according to von Korff; (3) no opioid medication. The patients recruited had a mean pain duration of 7.13 ± 7.16 years and reported a mean pain intensity of 6.62 ± 2.04 (visual analogue score, VAS). Their mean back function according to the Funktionsfragebogen Hannover (FFbH, a questionnaire comparable with the Health Assessment Questionnaire) was 52.39 ± 20.23%. At three time points (before therapy, 3 weeks and 6 months after therapy) the study subjects were assessed prospectively with a battery of visual memory tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB). These included choice reaction time (CRT), pattern recognition memory (PRM) and spatial span (SSP). In parallel, the Trail-Making Test (TMT-A, TMT-B) and the Wechsler Adult Intelligence Scale (WAIS-III) were used to evaluate intelligence and cognitive flexibility. Results At the beginning of MDPT (T1), it took patients with cLBP significantly longer than HC to complete TMT-A (38.29 ± 19.99 s vs 30.25 ± 14.19 s, p = 0.047) and TMT-B (72.10 ± 26.98 s vs 55.99 ± 22.14 s, p = 0.034). There were no significant differences between patients and HC in CRT, PRM and SSP. Three weeks (T2) and 6 months (T3) after MDPT, TMT-A reaction time of patients significantly improved by 6.5 s and 8.1 ms (38.3 ±19.9 s vs 31.8 ±12.3 s, p = 0.02 and 31.8 ± 12.3 s vs 30.2 ± 8.9 s, p = 0.021, respectively). The patients’ working memory was also better 6 months after MDPT (48.8 ± 11.1% at T1, 51.2 ±11.9% at T2, 57.1 ±10.9% at T3, p = 0.008). Significant correlations among pain, depression/anxiety, medication and neuropsychological tests were found. Conclusions These findings show that patients with cLBP have slowed speeds of information processing and working memory, but no alteration in attention and recognition memory. There are clearly interactions of cognitive function with pain, depression, anxiety, and medication. MDPT may improve the impaired cognitive function of patients with cLBP. Implication Health professionals should contemplate the results from this study when planning therapy strategies especially when prescribing pain medications such opioids to patients with chronic low back pain.

Quantitative sensory testing in physically active individuals and patients who underwent multidisciplinary pain therapy in the longitudinal course

Objective The aim of this study was to evaluate possible differences of quantitative sensory testing (QST) results in healthy individuals (group control, n=20), physically active individuals (group sport, n=30) and in patients suffering from chronic musculoskeletal pain (group pain, n=30). Methods Thermal detection thresholds, thermal pain thresholds and blunt pressure pain thresholds were measured at various sites (T0). Additionally, group pain was treated in multidisciplinary pain therapy for 4 weeks. All groups were retested after 4 weeks to evaluate the reliability of QST measurements and to investigate possible early changes following treatment (T1). Results Importantly, QST-measurements showed stable test results for group sport and group control at both time points. Athletes demonstrated the highest pain thresholds in general (cold pain threshold mean in degree Celsius for the hand: 5.76, lower back right: 7.25, lower back left: 7.53; heat pain threshold mean in degree Celsius for the hand: 46.08, lower back right: 45.77, lower back left: 45.70; and blunt pressure pain mean in kilograms for the hand: 3.54, lower back right: 5.26, lower back left: 5.46). Patients who underwent therapy demonstrated significant differences at T1 (cold pain threshold hand mean in degree Celsius for the hand: 11.12 [T0], 15.12 [T1]; and blunt pressure pain mean in kilograms for the lower back right: 2.87 [T0], 3.56 [T1]). They were capable of enduring higher blunt pressure, but on the other hand cold pain tolerance had decreased (P=0.045 and P=0.019, respectively). Conclusions In conclusion, we were able to demonstrate significant differences of QST results among the three groups and we detected early changes following multidisciplinary pain therapy, which will be discussed.

74 DIFFERENT PAIN THRESHOLDS IN PATIENTS WITH CHRONIC LOW BACK PAIN AND FIBROMYALGIA DURING WITHDRAW OF OPIOIDS

of each item to discriminate fibromyalgia and other chronic rheumatologic syndromes. Results: Analysis of the metrologic properties of the FiRST questionnaire allowed to exclude four items from the initial version and identified the 6 most discriminative items. We confirmed that the 6-item FiRST questionnaire has excellent properties to discriminate FMS. Conclusion: FiRST is a new, simple and easy-to-use questionnaire with good sensitivity and specificity to detect patients with FMS. It may help physicians to detect FMS patients, for a better and earlier management both in clinical research and daily practice.