Apoptotic Fragmentation of Tricellulin.

Apoptotic extrusion of cells from epithelial cell layers is of central importance for epithelial homeostasis. As a prerequisite cell-cell contacts between apoptotic cells and their neighbors have to be dissociated. Tricellular tight junctions (tTJs) represent specialized structures that seal polarized epithelial cells at sites where three cells meet and are characterized by the specific expression of tricellulin and angulins. Here, we specifically addressed the fate of tricellulin in apoptotic cells. METHODS: Apoptosis was induced by staurosporine or camptothecin in MDCKII and RT-112 cells. The fate of tricellulin was analyzed by Western blotting and immunofluorescence microscopy. Caspase activity was inhibited by Z-VAD-FMK or Z-DEVD-FMK. RESULTS: Induction of apoptosis induces the degradation of tricellulin with time. Aspartate residues 487 and 441 were identified as caspase cleavage-sites in the C-terminal coiled-coil domain of human tricellulin. Fragmentation of tricellulin was inhibited in the presence of caspase inhibitors or when Asp487 or Asp441 were mutated to asparagine. Deletion of the tricellulin C-terminal amino acids prevented binding to lipolysis-stimulated lipoprotein receptor (LSR)/angulin-1 and thus should impair specific localization of tricellulin to tTJs. CONCLUSIONS: Tricellulin is a substrate of caspases and its cleavage in consequence contributes to the dissolution of tTJs during apoptosis.

Eye Movement Desensitization and Reprocessing vs. Treatment-as-Usual for Non-Specific Chronic Back Pain Patients with Psychological Trauma: A Randomized Controlled Pilot Study.

OBJECTIVE: Eye movement desensitization and reprocessing (EMDR)-an evidence-based approach to eliminate emotional distress from traumatic experiences-was recently suggested for the treatment of chronic pain. The aim of this study was to estimate preliminary efficacy of a pain-focused EMDR intervention for the treatment of non-specific chronic back pain (CBP). DESIGN: Randomized controlled pilot study. METHODS: 40 non-specific CBP (nsCBP) patients reporting previous experiences of psychological trauma were consecutively recruited from outpatient tertiary care pain centers. After baseline assessment, patients were randomized to intervention or control group (1:1). The intervention group received 10 sessions standardized pain-focused EMDR in addition to treatment-as-usual (TAU). The control group received TAU alone. The primary outcome was preliminary efficacy, measured by pain intensity, disability, and treatment satisfaction from the patients' perspective. Clinical relevance of changes was determined according to the established recommendations. Assessments were conducted at the baseline, posttreatment, and at a 6-month follow-up. Intention-to-treat analysis with last observation carried forward method was used. Registered with http://ClinicalTrials.gov (NCT01850875). RESULTS: Estimated effect sizes (between-group, pooled SD) for pain intensity and disability were d = 0.79 (CI95%: 0.13, 1.42) and d = 0.39 (CI95%: -0.24, 1.01) posttreatment, and d = 0.50 (CI95%: 0.14, 1.12) and d = 0.14 (CI95%: -0.48, 0.76) at 6-month follow-up. Evaluation on individual patient basis showed that about 50% of the patients in the intervention group improved clinically relevant and also rated their situation as clinically satisfactory improved, compared to 0 patients in the control group. CONCLUSION: There is preliminary evidence that pain-focused EMDR might be useful for nsCBP patients with previous experiences of psychological trauma, with benefits for pain intensity maintained over 6 months.

Chronic Widespread Back Pain is Distinct From Chronic Local Back Pain: Evidence From Quantitative Sensory Testing, Pain Drawings, and Psychometrics.

OBJECTIVES: Whether chronic localized pain (CLP) and chronic widespread pain (CWP) have different mechanisms or to what extent they overlap in their pathophysiology is controversial. The study compared quantitative sensory testing profiles of nonspecific chronic back pain patients with CLP (n=48) and CWP (n=29) with and fibromyalgia syndrome (FMS) patients (n=90) and pain-free controls (n = 40). MATERIALS AND METHODS: The quantitative sensory testing protocol of the "German-Research-Network-on-Neuropathic-Pain" was used to measure evoked pain on the painful area in the lower back and the pain-free hand (thermal and mechanical detection and pain thresholds, vibration threshold, pain sensitivity to sharp and blunt mechanical stimuli). Ongoing pain and psychometrics were captured with pain drawings and questionnaires. RESULTS: CLP patients did not differ from pain-free controls, except for lower pressure pain threshold (PPT) on the back. CWP and FMS patients showed lower heat pain threshold and higher wind-up ratio on the back and lower heat pain threshold and cold pain threshold on the hand. FMS showed lower PPT on back and hand, and higher comorbidity of anxiety and depression and more functional impairment than all other groups. DISCUSSION: Even after long duration CLP presents with a local hypersensitivity for PPT, suggesting a somatotopically specific sensitization of nociceptive processing. However, CWP patients show widespread ongoing pain and hyperalgesia for different stimuli that is generalized in space, suggesting the involvement of descending control systems, as also suggested for FMS patients. Because mechanisms in nonspecific chronic back pain with CLP and CWP differ, these patients should be distinguished in future research and allocated to different treatments.

Distinct quantitative sensory testing profiles in nonspecific chronic back pain subjects with and without psychological trauma.

Psychological trauma is associated with an increased risk for chronification of nonspecific chronic back pain (nsCLBP) independent of posttraumatic stress disorder (PTSD). However, the mechanisms underlying the role of psychological trauma in nsCLBP are less clear than in PTSD. Therefore, this study considered whether psychological trauma exposure (TE) is accompanied by specific alterations in pain perception. The study included 56 participants with nsCLBP and TE (nsCLBP-TE), 93 participants with nsCLBP without TE (nsCLBP-W-TE), and 31 pain-free controls. All participants underwent a thorough clinical evaluation. The standardized quantitative sensory testing protocol of the "German Research Network on Neuropathic Pain" was used to obtain comprehensive profiles on somatosensory functions in painful (back) and non-painful areas (hand). The protocol consisted of thermal and mechanical detection as well as pain thresholds, vibration thresholds, and pain sensitivity to sharp and blunt mechanical stimuli. Psychological trauma was validated by structured clinical interview. Trauma-associated symptom severity, anxiety, and depressive symptomatology were assessed by self-report questionnaires. Differences in somatosensory function were seen only for pressure pain thresholds. Compared with controls, nsCLBP-TE revealed hyperalgesia generalized in space with lower thresholds in painful and non-painful areas, whereas nsCLBP-W-TE demonstrated localized alterations with decreased thresholds only in the pain-affected area of the back (P ≤ 0.006). Our findings suggest an augmented central pain processing in nsCLBP-TE (alterations in painful and non-painful areas), whereas nsCLBP-W-TE show only local changes (alterations only in the painful area) suggesting regional sensitization processes. This finding might explain why TE without PTSD is associated with an increased prevalence of chronic pain.

Effects of eye movement desensitization and reprocessing (EMDR) treatment in chronic pain patients: a systematic review.

OBJECTIVE: This study systematically reviewed the evidence regarding the effects of eye movement desensitization and reprocessing (EMDR) therapy for treating chronic pain. DESIGN: Systematic review. METHODS: We screened MEDLINE, EMBASE, the Cochrane Library, CINHAL Plus, Web of Science, PsycINFO, PSYNDEX, the Francine Shapiro Library, and citations of original studies and reviews. All studies using EMDR for treating chronic pain were eligible for inclusion in the present study. The main outcomes were pain intensity, disability, and negative mood (depression and anxiety). The effects were described as standardized mean differences. RESULTS: Two controlled trials with a total of 80 subjects and 10 observational studies with 116 subjects met the inclusion criteria. All of these studies assessed pain intensity. In addition, five studies measured disability, eight studies depression, and five studies anxiety. Controlled trials demonstrated significant improvements in pain intensity with high effect sizes (Hedges' g: -6.87 [95% confidence interval (CI95 ): -8.51, -5.23] and -1.12 [CI95 : -1.82, -0.42]). The pretreatment/posttreatment effect size calculations of the observational studies revealed that the effect sizes varied considerably, ranging from Hedges' g values of -0.24 (CI95 : -0.88, 0.40) to -5.86 (CI95 : -10.12, -1.60) for reductions in pain intensity, -0.34 (CI95 : -1.27, 0.59) to -3.69 (CI95 : -24.66, 17.28) for improvements in disability, -0.57 (CI95 : -1.47, 0.32) to -1.47 (CI95 : -3.18, 0.25) for improvements in depressive symptoms, and -0.59 (CI95 : -1.05, 0.13) to -1.10 (CI95 : -2.68, 0.48) for anxiety. Follow-up assessments showed maintained improvements. No adverse events were reported. CONCLUSIONS: Although the results of our study suggest that EMDR may be a safe and promising treatment option in chronic pain conditions, the small number of high-quality studies leads to insufficient evidence for definite treatment recommendations.

Effects of eye movement desensitization and reprocessing (EMDR) on non-specific chronic back pain: a randomized controlled trial with additional exploration of the underlying mechanisms.

BACKGROUND: Non-specific chronic back pain (CBP) is often accompanied by psychological trauma, but treatment for this associated condition is often insufficient.Nevertheless, despite the common co-occurrence of pain and psychological trauma, a specific trauma-focused approach for treating CBP has been neglected to date. Accordingly, eye movement desensitization and reprocessing (EMDR), originally developed as a treatment approach for posttraumatic stress disorders, is a promising approach for treating CBP in patients who have experienced psychological trauma.Thus, the aim of this study is to determine whether a standardized, short-term EMDR intervention added to treatment as usual (TAU) reduces pain intensity in CBP patients with psychological trauma vs. TAU alone. METHODS/DESIGN: The study will recruit 40 non-specific CBP patients who have experienced psychological trauma. After a baseline assessment, the patients will be randomized to either an intervention group (n = 20) or a control group (n = 20). Individuals in the EMDR group will receive ten 90-minute sessions of EMDR fortnightly in addition to TAU. The control group will receive TAU alone. The post-treatment assessments will take place two weeks after the last EMDR session and six months later.The primary outcome will be the change in the intensity of CBP within the last four weeks (numeric rating scale 0-10) from the pre-treatment assessment to the post-treatment assessment two weeks after the completion of treatment.In addition, the patients will undergo a thorough assessment of the change in the experience of pain, disability, trauma-associated distress, mental co-morbidities, resilience, and quality of life to explore distinct treatment effects. To explore the mechanisms of action that are involved, changes in pain perception and pain processing (quantitative sensory testing, conditioned pain modulation) will also be assessed.The statistical analysis of the primary outcome will be performed on an intention-to-treat basis. The secondary outcomes will be analyzed in an explorative, descriptive manner. DISCUSSION: This study adapts the standard EMDR treatment for traumatized patients to patients with CBP who have experienced psychological trauma. This specific, mechanism-based approach might benefit patients. TRIAL REGISTRATION: This trial has been registered with ClinicalTrials.gov (NCT01850875).

Subgroups of musculoskeletal pain patients and their psychobiological patterns - the LOGIN study protocol.

BACKGROUND: Pain conditions of the musculoskeletal system are very common and have tremendous socioeconomic impact. Despite its high prevalence, musculoskeletal pain remains poorly understood and predominantly non-specifically and insufficiently treated.The group of chronic musculoskeletal pain patients is supposed to be heterogeneous, due to a multitude of mechanisms involved in chronic pain. Psychological variables, psychophysiological processes, and neuroendocrine alterations are expected to be involved. Thus far, studies on musculoskeletal pain have predominantly focused on the general aspects of pain processing, thus neglecting the heterogeneity of patients with musculoskeletal pain. Consequently, there is a need for studies that comprise a multitude of mechanisms that are potentially involved in the chronicity and spread of pain. This need might foster research and facilitate a better pathophysiological understanding of the condition, thereby promoting the development of specific mechanism-based treatments for chronic pain. Therefore, the objectives of this study are as follows: 1) identify and describe subgroups of patients with musculoskeletal pain with regard to clinical manifestations (including mental co-morbidity) and 2) investigate whether distinct sensory profiles or 3) distinct plasma levels of pain-related parameters due to different underlying mechanisms can be distinguished in various subgroups of pain patients. METHODS/DESIGN: We will examine a population-based chronic pain sample (n = 100), a clinical tertiary care sample (n = 100) and pain-free patients with depression or post-traumatic stress disorder and pain-free healthy controls (each n = 30, respectively). The samples will be pain localisation matched by sex and age to the population-based sample. Patients will undergo physical examination and thorough assessments of mental co-morbidity (including psychological trauma), perceptual and central sensitisation (quantitative sensory testing), descending inhibition (conditioned pain modulation, the diffuse noxious inhibitory control-like effect), as well as measurement of the plasma levels of nerve growth factor and endocannabinoids. DISCUSSION: The identification of the underlying pathophysiologic mechanisms in different subgroups of chronic musculoskeletal pain patients will contribute to a mechanism-based subgroup classification. This will foster the development of mechanism-based treatments and holds promise to treat patients more sufficient.