Additional effects of pain neuroscience education combined with physiotherapy on the headache frequency of adult patients with migraine: A randomized controlled trial.

Aim To assess the efficacy of pain neuroscience education combined with physiotherapy for the management of migraine.Background Physiotherapy can significantly reduce the frequency of migraine, but the evidence is based only on a few studies. Pain neuroscience education might pose a promising treatment, as it addresses migraine as a chronic pain disease.Methods In this non-blinded randomized controlled trial, migraine patients received physiotherapy + pain neuroscience education or physiotherapy alone, preceded by a three-month waiting period. Primary outcomes were frequency of headache (with and without migraine features), frequency of migraine and associated disability.Results Eighty-two participants were randomized and analyzed. Both groups showed a decrease of headache frequency (p = 0.02, d = 0.46) at post-treatment (physiotherapy: 0.77 days, 95%CI: -0.75 to 2.29 and physiotherapy + pain neuroscience education: 1.25 days, 95%CI: -0.05 to 2.55) and at follow-up (physiotherapy: 1.93, 95%CI: 0.07 to 3.78 and physiotherapy + pain neuroscience education: 3.48 days, 95%CI: 1.89 to 5.06), with no difference between groups (p = 0.26, d = 0.26). Migraine frequency was reduced significantly in the physiotherapy + pain neuroscience education group, and not in the physiotherapy group, at post-treatment (1.28 days, 95%CI: 0.34 to 2.22, p = 0.004) and follow-up (3.05 days, 95%CI: 1.98 to 5.06, p < 0.0001), with a difference between groups at follow-up (2.06 days, p = 0.003). Migraine-related disability decreased significantly in both groups (physiotherapy: 19.8, physiotherapy + pain neuroscience education: 24.0 points, p < 0.001, d = 1.15) at follow-up, with no difference between groups (p = 0.583). Secondary outcomes demonstrated a significant effect of time with no interaction between time and group. No harm or adverse events were observed during the study.Conclusion In comparison to physiotherapy alone, pain neuroscience education combined with physiotherapy can further reduce the frequency of migraine, but had no additional effect on general headache frequency or migraine-related disability.Trial Registration The study was pre-registered at the German Clinical Trials Register (DRKS00020804).

[Joint position error in patients with headache : Systematic review of the literature and experimental data for patients with chronic migraine]. / Zervikaler "joint position error" bei Kopfschmerzen : Systematische Literaturübersicht und empirische Daten bei chronischer Migräne.

BACKGROUND: Chronic migraine (CM) is a primary headache type associated with a severe reduction in the quality of life. The association of sensorimotor dysfunction in the neck, measured with the joint position error test (JPE), and CM is largely unknown, even though up to 60% of migraine patients report neck pain accompanying the migraine. METHODS: This manuscript reports a systematic review of the literature on JPE in patients with headache as well as data on an observational study. To determine the JPE of migraine patients, 37 subjects with CM were tested and compared with a control group (CG; n = 22). In an additional analysis, CM patients were divided into two subgroups based on the medical treatment approach. The measurements were taken in the three movement dimensions with five repetitions in each direction using a laser pointer fixed to the head. RESULTS: The mean JPE in the sagittal plane was 3.7° (SD ± 1.4°) and 3.1° (SD ± 1.1°) for CM (n = 37) and CG, respectively. In the transverse plane it was measured as 3.7° (SD ± 1.5°) for CM and 3.2° (SD ± 1°) for the CG, while it was 3.6° (SD ± 1.2°; CM) and 3.3° (SD ± 1.1°; CG) in the frontal plane. The between group difference was not significant for all movement planes. When groups according to the treatment regimen, both groups showed similar migraine and neck pain features but the JPE was significantly larger in the CM + BTh group compared to the CM without BTh group and the CG. In the sagittal plane, the JPE was 4.21° (SD ± 1.8°) for the CM + BTh compared to 2.99° (SD ± 1.2°) in CM without BTh and 3.21° (SD ± 1.2°) in the CG (p = 0.0053). The difference between CM + BTh and CM without BTh was 1.52° (p = 0.016) after propensity score matching in the sagittal plane. CONCLUSIONS: Only patients in the CM + BTh group showed a statistically increased JPE. The influence of neck pain does not explain the between group difference. A possible factor is the degree of chronification. This study indicates that the JPE might discriminate a subgroup of migraine patients.

Which Examination Tests Detect Differences in Cervical Musculoskeletal Impairments in People With Migraine? A Systematic Review and Meta-Analysis.

BACKGROUND: Most patients with migraine report associated neck pain. Whether neck pain is a symptom of migraine or an indicator for associated cervical musculoskeletal impairment has not yet been determined. Physical examination tests to detect cervical impairments in people with headache have been suggested, but results have not been evaluated systematically and combined in meta-analyses. PURPOSE: The purpose of this study was to identify musculoskeletal impairments in people with migraine and people who were healthy (healthy controls) by reviewing published data on physical examination results. DATA SOURCES: PubMed, CINAHL, Web of Science, and the Cochrane Register of Clinical Trials were searched for studies published prior to December 2017. STUDY SELECTION: Publications investigating physical examination procedures that are feasible for use in a physical therapy setting for patients with migraine and healthy controls were independently selected by 2 researchers. DATA EXTRACTION: One researcher extracted the data into predesigned data extraction tables. Entries were checked for correctness by a second researcher. The Downs and Black Scale was used for risk-of-bias assessment by 2 reviewers independently. DATA SYNTHESIS: Thirty-five studies (involving 1033 participants who were healthy [healthy controls] and 1371 participants with migraine) were included in the qualitative synthesis, and 18 were included in the meta-analyses (544 healthy controls and 603 participants with migraine). Overall, studies were rated as having a low to moderate risk of bias. Included studies reported 20 different test procedures. Combined mean effects indicated that 4 of the tests included in the meta-analyses distinguished between patients and controls: range of cervical motion, flexion-rotation, pressure pain thresholds, and forward head posture in a standing position. LIMITATIONS: Manual joint testing and evaluation of trigger points were the 2 most frequently investigated tests not included in the meta-analyses because of heterogeneity of reporting and procedures. CONCLUSIONS: Three tests confirmed the presence of musculoskeletal impairments in participants with migraine when combined in meta-analyses. Pressure pain thresholds added information on sensory processing. Additional tests might be useful but require standardized protocols and reporting.

Apoptosis induced by temozolomide and nimustine in glioblastoma cells is supported by JNK/c-Jun-mediated induction of the BH3-only protein BIM.

The outcome of cancer therapy strongly depends on the complex network of cell signaling pathways, including transcription factor activation following drug exposure. Here we assessed whether and how the MAP kinase (MAPK) cascade and its downstream target, the transcription factor AP-1, influence the sensitivity of malignant glioma cells to the anticancer drugs temozolomide (TMZ) and nimustine (ACNU). Both drugs induce apoptosis in glioma cells at late times following treatment. Activation of the MAPK cascade precedes apoptosis, as shown by phosphorylation of Jun kinase (JNK) and c-Jun, a main component of AP-1. Pharmacological inhibition and siRNA mediated knockdown of JNK and c-Jun reduced the level of apoptosis in LN-229 glioma cells treated with TMZ or ACNU. Analyzing the underlying molecular mechanism, we identified the pro-apoptotic gene BIM as a critical target of AP-1, which is upregulated following TMZ and ACNU. Importantly, shRNA mediated downregulation of BIM in the malignant glioma cell lines LN-229 and U87MG led to an attenuated cleavage of caspase-9 and, consequently, reduced the level of apoptosis following TMZ and ACNU treatment. Overall, we identified JNK/c-Jun activation and BIM induction as a late pro-apoptotic response of glioma cells treated with alkylating anticancer drugs.

Translesion polymerase η is upregulated by cancer therapeutics and confers anticancer drug resistance.

DNA repair processes are a key determinant of the sensitivity of cancer cells to DNA-damaging chemotherapeutics, which may induce certain repair genes as a mechanism to promote resistance. Here, we report the results of a screen for repair genes induced in cancer cells treated with DNA crosslinking agents, which identified the translesion polymerase η (PolH) as a p53-regulated target acting as one defense against interstrand crosslink (ICL)-inducing agents. PolH was induced by fotemustine, mafosfamide, and lomustine in breast cancer, glioma, and melanoma cells in vitro and in vivo, with similar inductions observed in normal cells such as lymphocytes and diploid fibroblasts. PolH contributions to the protection against ICL-inducing agents were evaluated by its siRNA-mediated attenuation in cells, which elevated sensitivity to these drugs in all tumor cell models. Conversely, PolH overexpression protected cancer cells against these drugs. PolH attenuation reduced repair of ICL lesions as measured by host cell reactivation assays and enhanced persistence of γH2AX foci. Moreover, we observed a strong accumulation of PolH in the nucleus of drug-treated cells along with direct binding to damaged DNA. Taken together, our findings implicated PolH in ICL repair as a mechanism of cancer drug resistance and normal tissue protection.

The chloroethylating anticancer drug ACNU induces FRA1 that is involved in drug resistance of glioma cells.

FRA1 belongs, together with c-Fos and FosB, to the family of Fos proteins that form with members of the ATF and Jun family the transcription factor AP-1 (activator protein 1). Previously we showed that c-Fos protects mouse embryonic fibroblasts against the cytotoxic effects of ultraviolet (UV) light by induction of the endonuclease XPF, leading to enhanced nucleotide excision repair (NER) activity. Here, we analyzed the regulation of FRA1 in glioma cells treated with the anticancer drug nimustine (ACNU) and its role in ACNU-induced toxicity. We show that FRA1 is upregulated in glioblastoma cells following ACNU on mRNA and protein levels. Knockdown of FRA1 by either siRNA or shRNA clearly sensitized glioma cells towards ACNU-induced cell death. Despite decreased AP-1 binding activity upon FRA1 knockdown, this effect is independent on regulation of the AP-1 target genes fasL, ercc1 and xpf. In addition, FRA1 knockdown does not affect DNA repair capacity. However, lack of FRA1 attenuated the ACNU-induced phosphorylation of CHK1 and led to a reduced arrest of cells in G2/M and, thereby, presumably leads to enhanced cell death in the subsequent cell cycle.

Delayed c-Fos activation in human cells triggers XPF induction and an adaptive response to UVC-induced DNA damage and cytotoxicity.

The oncoprotein c-Fos has been commonly found differently expressed in cancer cells. Our previous work showed that mouse cells lacking the immediate-early gene c-fos are hypersensitive to ultraviolet (UVC) light. Here, we demonstrate that in human diploid fibroblasts UV-triggered induction of c-Fos protein is a delayed and long-lasting event. Sustained upregulation of c-Fos goes along with transcriptional stimulation of the NER gene xpf, which harbors an AP-1 binding site in the promoter. Data gained on c-Fos knockdown and c-Fos overexpressing human cells provide evidence that c-Fos/AP-1 stimulates upregulation of XPF, thereby increasing the cellular repair capacity protecting from UVC-induced DNA damage. When these cells are pre-exposed to a low non-toxic UVC dose and challenged with a subsequent high dose of UVC irradiation, they show accelerated repair of UVC-induced DNA adducts and reduced cell kill. The data indicate a protective role of c-Fos induction by triggering an adaptive response pathway.