Strong and aversive cold processing and pain facilitation in fibromyalgia patients relates to augmented thermal grill illusion.

The thermal grill illusion (TGI) is assumed to result from crosstalk between the thermoreceptive and nociceptive pathways. To elucidate this further, we compared 40 female fibromyalgia patients to 20 healthy women in an exploratory cross-sectional study. Sensations (cold, warm/heat, unpleasantness, pain and burning) evoked by 20 °C, 40 °C and alternating 20 °C/40 °C (TGI) and somatosensory profiles according to standardized quantitative sensory testing (QST) were assessed on the palm of the dominant hand. Compared to healthy controls, fibromyalgia patients reported stronger thermal grill-evoked cold, warm, unpleasantness and pain as well as stronger and more aversive 20 °C- and 40 °C-evoked sensations. They showed a loss in warm, mechanical and vibration detection, a gain in thermal pain thresholds and higher temporal summation (TS). Among QST parameters higher TS in fibromyalgia patients was most consistently associated with an augmented TGI. Independently, an increased TGI was linked to cold (20 °C) but less to warm (40 °C) perception. In fibromyalgia patients all thermal grill-evoked sensations were positively related to a higher 20 °C-evoked cold sensation and/or 20 °C-evoked unpleasantness. In conclusion, the TGI appears to be driven mainly by the cold-input. Aversive cold processing and central pain facilitation in fibromyalgia patients seem to independently augment the activation of the pain pathway.

[Concept for integrative pain treatment of osteoarthritis of the knee based on the evidence for conservative and complementary therapies]. / Konzept zur integrativen Schmerztherapie bei Gonarthrose unter Beachtung der Evidenz konservativer und komplementärer Verfahren.

BACKGROUND: Osteoarthritis of the knee (gonarthritis) represents a medical challenge. RESEARCH QUESTION: What is the evidence with respect to approaches of complementary medicine and their integration into multimodal pain management concepts? MATERIAL AND METHODS: Qualitative nonsystematic literature search on the epidemiology and pathophysiology as well as informative clinical trials, meta-analyses and clinical guidelines about conservative treatment including complementary therapy for gonarthritis. RESULTS: Osteoarthritis of the knee is a frequent condition with biopsychosocial risks factors for chronification. The German S2k clinical guideline (k = consensus-based, not based on scientific systematic literature searches) published by the Association of the Scientific Medical Societies in Germany (AWMF) in 2017 has not yet been updated. The current guidelines of the American College of Rheumatology (ACR) date from 2020. Both guidelines recommend exercise therapy, weight reduction, short-term analgesics, topical therapy, intra-articular corticoid injections and acupuncture with variable strengths. Furthermore, transcutaneous electrical nerve stimulation (TENS), laser and other electrophysical therapies, shock waves, traction treatment, ergotherapy, comfrey poultices and mudpacks can also be used. Current research supports the benefits of tai chi/qigong and medicinal leaches. CONCLUSION: Complementary treatment approaches, such as acupuncture, tai chi/qigong, topical naturopathic self-treatment and leeches (with limitations) can, in addition to behavioral changes, exercise therapy and short-term pharmacological treatment, be important evidence-based components of integrative pain management concepts, e.g. in terms of an interdisciplinary multimodal pain treatment (IMPT). Besides pain reduction and functional improvement they promote the internal control conviction through the possibility of self-treatment and self-exercise.

Acupuncture-related adverse events: systematic review and meta-analyses of prospective clinical studies.

OBJECTIVE: Overview on risks of acupuncture-related adverse events (AEs). DESIGN: Systematic review and meta-analyses of prospective studies. DATA SOURCES: PubMed, Scopus and Embase from inception date to 15 September 2019. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Prospective studies assessing AEs caused by needle acupuncture in humans as primary outcome published in English or German. DATA EXTRACTION AND SYNTHESIS: Two independent researchers selected articles, extracted the data and assessed study quality. Overall risks and risks for different AE categories were obtained from random effects meta-analyses. MAIN OUTCOMES: Overall risk of minor AEs and serious adverse events (SAEs) per patients and per treatments. RESULTS: A total of 7679 publications were identified. Twenty-two articles reporting on 21 studies were included. Meta-analyses suggest at least one AE occurring in 9.31% (95% CI 5.10% to 14.62%, 11 studies) of patients undergoing an acupuncture series and in 7.57% (95% CI 1.43% to 17.95%, 5 studies) of treatments. Summary risk estimates for SAEs were 1.01 (95% CI 0.23 to 2.33, 11 studies) per 10 000 patients and 7.98 (95% CI 1.39 to 20.00, 14 studies) per one million treatments, for AEs requiring treatment 1.14 (95% CI 0.00 to 7.37, 8 studies) per 1000 patients. Heterogeneity was substantial (I2 >80%). On average, 9.4 AEs occurred in 100 treatments. Half of the AEs were bleeding, pain or flare at the needle site that are argued to represent intended acupuncture reaction. AE definitions and assessments varied largely. CONCLUSION: Acupuncture can be considered among the safer treatments in medicine. SAEs are rare, and the most common minor AEs are very mild. AEs requiring medical management are uncommon but necessitate medical competence to assure patient safety. Clinical and methodological heterogeneity call for standardised AE assessments tools, clear criteria for differentiating acupuncture-related AEs from therapeutically desired reactions, and identification of patient-related risk factors for AEs. PROSPERO REGISTRATION NUMBER: CRD42020151930.

Acupuncture point localization varies among acupuncturists.

BACKGROUND: Studies assessing the point-specific effect of acupuncture or the characteristics of acupuncture points (APs) tend to yield inconclusive results. In order to identify a possible confounding factor, we aimed to examine the variability in AP localization by means of a survey. MATERIAL AND METHODS: Attendees of the 14th ICMART (International Council of Medical Acupuncture and Related Techniques) congress as well as DÄGfA (German Medical Society of Acupuncture) lecturers and students were asked to locate and mark the APs LI 10 and TH 5 on a research assistant's arm. Identified points were transferred into a coordinate system, and the respective bivariate distribution function was calculated. Additionally, participants filled out a questionnaire about their acupuncture education and experience, the acupuncture style and point localization techniques used most frequently, and their estimation of the size of an AP. RESULTS: The areas of the ellipses, theoretically containing 95% of AP localizations, varied between 44.49 and 5.18 cm(2). The largest distance between 2 identified points was 8.45 cm for LI 10 and 5.3 cm for TH 5. Apart from being trained at the same school, no other factor could be identified that determined the variability in AP localization. CONCLUSION: Our results indicate that congruity of AP localization among experienced acupuncturists might be low. Although there are some limitations to our results, this possible bias should be taken into account when conducting acupuncture trials and interpreting results of previous acupuncture studies.

Tissue inhibitor of metalloproteinases-1-induced scattered liver metastasis is mediated by hypoxia-inducible factor-1α.

The "protease web", representing the network of proteases, their inhibitors, and effector molecules, arises as a pivotal determinant of tissue homeostasis. Imbalances of this network, for instance caused by elevated host levels of tissue inhibitor of metalloproteinases-1 (TIMP-1), have been shown to increase the susceptibility of target organs to scattered metastasis by inducing the hepatocyte growth factor (HGF) pathway. Increased expression of the hypoxia-inducible factor-1α-subunit (HIF-1α) is also associated with tumour progression and is also known to induce HGF-signaling via up-regulation of the HGF-receptor Met, namely under canonical stress conditions like lack of oxygen. Here, we aimed to identify a possible metastasis-promoting connection between TIMP-1, HIF-1α, and HGF-signaling. We found that HIF-1α and HIF-1-signaling were increased during liver metastasis of L-CI.5s T-lymphoma cells in TIMP-1 overexpressing syngeneic DBA/2 mice. In vitro, exposure of L-CI.5s cells to recombinant TIMP-1 revealed that TIMP-1 itself was able to induce HIF-1α and HIF-1-signaling. Knock-down of HIF-1α identified tumour cell-derived HIF-1α as mediator of this TIMP-1-induced invasiveness in vitro. In vivo, HIF-1α knock-down significantly impaired Met expression as well as Met phosphorylation and inhibited scattered liver metastasis. Furthermore, HGF-dependent TIMP-1-promoted Met phosphorylation and HGF-dependent TIMP-1-induced invasiveness in vitro was mediated by HIF-1α. We conclude that elevated levels of TIMP-1 in the microenvironment of tumour cells can promote metastasis by inducing HIF-1α-dependent HGF-signaling. This connection between a protease inhibitor (TIMP-1) and a classically stress-related factor (HIF-1α) is a so far undiscovered impact of the "protease web" on tissue homeostasis with important implications for metastasis.

Deqi sensations without cutaneous sensory input: results of an RCT.

BACKGROUND: Deqi is defined in relation to acupuncture needling as a sensory perception of varying character. In a recently published sham laser validation study, we found that subjects in the verum and the sham laser group experienced deqi sensations. Therefore, we aim to further analyze whether the perceptions reported in the two study arms were distinguishable and whether expectancy effects exhibited considerable impact on our results. METHODS: A detailed re-analysis focusing on deqi sensations was performed from data collected in a previously published placebo-controlled, double-blind, clinical cross-over trial for a sham laser evaluation. Thirty-four healthy volunteers (28 ± 10.7 years; 16 women, 18 men) received two laser acupuncture treatments at three acupuncture points LI4 (hégu), LU7 (liéque), and LR3 (táichong); once by verum laser and once using a sham device containing an inactive laser in randomized order. Outcome measures were frequency, intensity (evaluated by visual analogue scale; VAS), and quality of the subjects' sensations perceived during treatments (assessed with the "acupuncture sensation scale"). RESULTS: Both, verum and the sham laser acupuncture result in similar deqi sensations with regard to frequency (p-value = 0.67), intensity (p-value = 0.71) and quality (p-values between 0.15 - 0.98). In both groups the most frequently used adjectives to describe these perceptions were "spreading", "radiating", "tingling", "tugging", "pulsing", "warm", "dull", and "electric". Sensations reported were consistent with the perception of deqi as previously defined in literature. Subjects' conviction regarding the effectiveness of laser acupuncture or the history of having received acupuncture treatments before did not correlate with the frequency or intensity of sensations reported. CONCLUSIONS: Since deqi sensations, described as sensory perceptions, were elicited without any cutaneous sensory input, we assume that they are a product of non-specific effects from the overall treatment procedure. Expectancy-effects due to previous acupuncture experience and belief in laser acupuncture do not seem to play a major role in elicitation of deqi sensations. Our results give hints that deqi might be a central phenomenon of awareness and consciousness, and that its relevance should be taken into account, even in clinical trials. However, further research is required to understand mechanisms underlying deqi.

Gold fluorescent annexin A5 as a novel apoptosis detection tool.

We describe a golden fluorescent apoptosis detection tool, which we generated by a fusion of golden fluorescent protein (GdFP) with human annexin A5 (anxA5). GdFP was obtained by replacement of tryptophan at position 66 with 4-aminotryptophan in the chromophore of enhanced cyan fluorescent protein. The GdFP-anxA5 construct combines highly desirable features originating from both fusion partners. These include (i) strong binding to membrane phosphatidylserine patches of apoptotic cells in the presence of Ca(2+) which is brought about by anxA5, (ii) the stable and homogeneous monomeric state, (iii) as well as the red-shifted fluorescence maximum at 574 nm originating from GdFP. We found that GdFP-anxA5 is equally well applicable for apoptosis studies as a routinely used fluorescein 5'-isothiocyanate-annexin A5 conjugate. Golden fluorescent annexin A5 represents a new, stable, and homogeneous red-shifted optical probe for the efficient detection of apoptosis by fluorescence microscopy or by flow cytometry.