[Psychotherapy in the Context of Interdisciplinary Multimodal Pain Therapy: Update]. / Psychotherapie in der interdisziplinären multimodalen Schmerztherapie: Update.

Interdisciplinary multimodal pain therapy (IMPT) is based on the biopsychosocial model of pain and describes an integrated treatment for patients with chronic pain. IMPT incorporates a close cooperation of different disciplines, including physicians, psychotherapists, physiotherapists, and others. IMPT mainly aims to restore and increase patients' physical, social and psychological functional capacity. The efficacy of IMPT has been evidenced by systematic reviews and meta-analyses. A number of studies further indicate IMPT's cost-efficiency. Psychotherapy is an essential component of IMPT. Its main goal within the framework of IMPT is to identify and modify dysfunctional patterns of pain coping, and to diagnose and potentially treat psychological comorbidities. Pain psychotherapy comprises mostly cognitive-behavioral interventions which address dysfunctional coping at the three levels of the pain experience (i.e., cognitive, emotional, and behavioral). Research into the efficacy of pain psychotherapy is rather sparse and studies have mostly focused on chronic back pain, yet existing results show promising evidence both for psychotherapy within IMPT and for psychotherapy as a monotherapy. This paper aims at providing an overview of (a) commonly employed cognitive-behavioral psychotherapeutic approaches and strategies in the treatment of chronic pain, and (b) the existing empirical evidence of pain psychotherapy both within the framework of IMPT and as a monotherapy. Future research should include a wider range of pain diagnoses and also investigate the potential benefit of individually-tailored treatments.

Blood Metal Ion Release After Primary Total Knee Arthroplasty: A Prospective Study.

OBJECTIVES: To investigate the course of in vivo blood metal ion levels in patients undergoing primary total knee arthroplasty (TKA) and to investigate potential risk factors associated with metal ion release in these patients. METHODS: Twenty-five patients with indication for TKA were included in this prospective study. Whole blood metal ion analysis was performed pre-operatively and at 1 week, 6 weeks, 3 months, 6 months, and 12 months postoperatively. Clinical scores were obtained using the American Knee Society Score (AKSS) and the Oxford Knee Score (OKS) at each follow-up and patients' activity levels were assessed by measuring the mean annual walking cycles at 12 months follow-up. Anteroposterior and lateral radiographs of the operated knee were evaluated postoperatively and at 12-month follow-up with regard to implant position and radiological signs of implant loosening. Correlation analysis using multivariate linear regression was performed to investigate the influence of different variables (age, gender, functional scores, number of walking cycles, and body mass index [BMI]) on blood cobalt ion concentrations. RESULTS: Mean metal ion levels of cobalt, chromium, molybdenum, and titanium were 0.28 µg/L (SD, 0.14), 0.43 µg/L (SD, 0.49), 0.62 µg/L (SD, 0.45), and 1.96 µg/L (SD, 0.98), respectively at 12-month follow-up. Mean cobalt ion levels significantly increased 1-year after surgery compared to preoperative measurements. There was no statistically significant increase of mean metal ion levels of chromium, titanium, and molybdenum at 1-year follow-up. Overall, metal ion levels were low and no patient demonstrated cobalt ion levels above 1 µg/L. Postoperative radiographs demonstrated well-aligned TKAs in all patients and no signs of osteolysis or implant loosening were detected at 1-year follow-up. Both the AKSS and OKS significantly improved during the course of the study up to the final follow-up. Multivariate regression analysis did not show a statistically significant correlation between the tested variables and blood cobalt ion concentrations. CONCLUSION: A statistically significant increase of mean cobalt ion concentration at 1-year follow-up was found in this cohort of patients with well-functioning TKA, although overall blood metal ion levels were relatively low. Despite low systemic metal ion concentrations seen in this cohort, the local effects of increased metal ion concentrations in the periprosthetic environment on the long-term outcome of TKA should be further investigated.

Positive Treatment Expectancies Reduce Clinical Pain and Perceived Limitations in Movement Ability Despite Increased Experimental Pain: A Randomized Controlled Trial on Sham Opioid Infusion in Patients with Chronic Back Pain.

BACKGROUND: Increasing evidence for the efficacy of analgesic placebo effects in laboratory studies with healthy persons raises the question whether placebos could be used to improve the treatment of pain patients. Expectancies play a central role in shaping analgesic placebo but also nocebo effects. OBJECTIVES: We investigated to what extent a sham opioid infusion (saline solution) produces sustained clinically relevant placebo and nocebo effects in chronic back pain patients. METHODS: Fifty-nine patients received the sham opioid infusion applied via a large drain dressing and were compared to 14 control patients without intervention (natural history, NH) while experimental pain stimuli were applied. All subjects were told that the infusion would decrease pain although in rare cases pain increase would be possible (induction of expectancy). In addition, conditioning was introduced where the participants either experienced a decrease in experimental pain (n = 17; placebo conditioning), an increase (n = 21; nocebo conditioning), or no change (n = 21, no conditioning). RESULTS: Compared to the NH group, all infusion groups showed positive treatment expectancies and significantly (p < 0.001) reduced clinical back pain (primary outcome) and pain-related disability (secondary outcome, assessed by self-reported functional capacity and perceived impairment of mobility). Even the nocebo conditioned group experiencing increased experimental pain developed positive treatment expectancies followed by reduced pain experience. Positive treatment expectancies and relief in clinical back pain were significantly positively correlated (r = 0.72, p < 0.01). CONCLUSIONS: These findings suggest that it may be beneficial to explicitly shape and integrate treatment expectancies into clinical pain management.

What is normal trauma healing and what is complex regional pain syndrome I? An analysis of clinical and experimental biomarkers.

Complex regional pain syndrome (CRPS) typically develops after fracture or trauma. Many of the studies so far have analyzed clinical and molecular markers of CRPS in comparison with healthy or pain controls. This approach, however, neglects mechanisms occurring during physiological trauma recovery. Therefore, we compared the clinical phenotype, sensory profiles, patient-reported outcomes, and exosomal immunobarrier microRNAs (miRs) regulating barrier function and immune response between CRPS and fracture controls (FCs) not fulfilling the CRPS diagnostic criteria. We included upper-extremity FCs, acute CRPS I patients within 1 year after trauma, a second disease control group (painful diabetic polyneuropathy), and healthy controls. Fracture controls were not symptoms-free, but reported some pain, disability, anxiety, and cold pain hyperalgesia in quantitative sensory testing. Patients with CRPS had higher scores for pain, disability, and all patient-reported outcomes. In quantitative sensory testing, ipsilateral and contralateral sides differed significantly. However, on the affected side, patients with CRPS were more sensitive in only 3 parameters (pinprick pain and blunt pressure) when compared to FCs. Two principal components were identified in the cohort: pain and psychological parameters distinguishing FC and CPRS. Furthermore, the immunobarrier-protective hsa-miR-223-5p was increased in plasma exosomes in FCs with normal healing, but not in CRPS and healthy controls. Low hsa-miR-223-5p was particularly observed in subjects with edema pointing towards barrier breakdown. In summary, normal trauma healing includes some CRPS signs and symptoms. It is the combination of different factors that distinguish CRPS and FC. Fracture control as a control group can assist to discover resolution factors after trauma.

[Placebo Responses in Chronic Pain: State of Research and Clinical Implications]. / Placeboeffekte bei chronischen Schmerzen: Forschungsstand und klinische Anwendung.

Placebo hypoalgesia has been found to play an important role in every health care by modulating patients' responses to pharmacologically active analgesic treatments. It may be seen as reflecting the capacity for endogenous pain modulation. Enhancing the efficacy of analgesic treatments by boosting endogenous pain modulation might be particularly relevant for chronic pain patients. Research into placebo hypoalgesic responses to chronic pain is sparse, however. In healthy subjects, placebo hypoalgesia is induced by expectations of pain relief through verbal information and learning experiences. Here we review the existing evidence on placebo hypoalgesia to chronic pain. To our knowledge, placebo hypoalgesia to chronic pain has been investigated experimentally in chronic back and chronic musculoskeletal pain, neuropathic pain after thoracotomy, and episodic migraine. Results point towards a maintenance of placebo hypoalgesic responses in chronic pain populations, thus highlighting the potential benefit of boosting placebo hypoalgesic responses in the treatment of chronic pain. Strategies on boosting placebo hypoalgesic responses in every day healthcare are presented.

Impact of patient information leaflets on pain medication intake behavior: a pilot study.

INTRODUCTION: Patient information leaflets on pain medication primarily list side effects while positive effects and action mechanisms remain underrepresented. Nocebo research has shown that negative instructions can lower analgesic effects. OBJECTIVES: Research on information leaflets and their influence on mood, memory of side effects, and intake behavior of healthy participants is needed. METHODS: To determine the ratio of positive to negative phrases, 18 information leaflets of common, over-the-market analgesics were examined of which 1 was selected. In a randomized, controlled study design, 18 healthy participants read this leaflet while 18 control group participants read a matched, neutral leaflet of an electrical device. Collected data concerned the recall of positive and negative contents, mood, anxiety, and the willingness to buy and take the drug. RESULTS: All examined leaflets listed significantly more side effects than positive effects (t17 = 5.82, P < 0.01). After reading the analgesic leaflet, participants showed a trend towards more negative mood (F1,34 = 3.78, P = 0.06, ηp2 = 0.1), a lower intention to buy [χ2 (1, n = 36) = 12.5, P < 0.01], a higher unwillingness to take the medication [χ2 (1, n = 36) = 7.2, P < 0.01], and even a greater recall for side effects than positive effects (t17 = 7.47, P < 0.01). CONCLUSION: Reading the patient information leaflets can increase fear and lower the intention to buy and the willingness to take a pain medication.

Resistance of Neisseria meningitidis to human serum depends on T and B cell stimulating protein B.

The ability of the human bacterial pathogen Neisseria meningitidis to cause invasive disease depends on survival in the bloodstream via mechanisms to suppress complement activation. In this study, we show that prophage genes coding for T and B cell stimulating protein B (TspB), which is an immunoglobulin-binding protein, are essential for survival of N. meningitidis group B strain H44/76 in normal human serum (NHS). H44/76 carries three genes coding for TspB. Mutants having all tspB genes inactivated did not survive in >5% NHS or IgG-depleted NHS. TspB appeared to inhibit IgM-mediated activation of the classical complement pathway, since survival of the tspB triple knockout was the same as that of the parent strain or a complemented mutant when the classical pathway was inactivated by depleting NHS of C1q and was increased in IgM-depleted NHS. A mutant solely carrying tspB gene nmbh4476_0681 was as resistant as the parent strain, while mutants carrying only nmbh4476_0598 or nmbh4476_1698 were killed in ≥5% NHS. The phenotype associated with TspB is formation of a matrix containing TspB, IgG, and DNA that envelopes aggregates of bacteria. Recombinant proteins corresponding to particular subdomains of TspB were found to have human IgG Fcγ- and/or DNA-binding activity, but only TspB derivatives containing both domains formed large, biofilm-like aggregates when combined with purified IgG and DNA. Recognizing the role of TspB in serum resistance may lead to a better understanding of why strains that carry tspB genes are associated with invasive meningococcal disease.

Determining the fatty acid composition in plasma and tissues as fatty acid methyl esters using gas chromatography ­ a comparison of different derivatization and extraction procedures.

Analysis of the fatty acid (FA) composition in biological samples is commonly carried out using gas liquid chromatography (GC) after transesterification to volatile FA methyl esters (FAME). We compared the efficacy of six frequently used protocols for derivatization of different lipid classes as well as for plasma and tissue samples. Transesterification with trimethylsulfonium hydroxide (TMSH) led to insufficient derivatization efficacies for polyunsaturated FAs (PUFA, <50%). Derivatization in presence of potassium hydroxide (KOH) failed at derivatizing free FAs (FFAs). Boron trifluoride (BF3) 7% in hexane/MeOH (1:1) was insufficient for the transesterification of cholesterol ester (CE) as well as triacylglycerols (TGs). In contrast, methanolic hydrochloric acid (HCl) as well as a combination of BF3 with methanolic sodium hydroxide (NaOH+BF3) were suitable for the derivatization of FFAs, polar lipids, TGs, and CEs (derivatization rate >80% for all tested lipids). Regarding plasma samples, all methods led to an overall similar relative FA pattern. However, significant differences were observed, for example, for the relative amount of EPA+DHA (n3-index). Absolute FA plasma concentrations differed considerably among the methods, with low yields for KOH and BF3. We also demonstrate that lipid extraction with tert-butyl methyl ether/methanol (MTBE/MeOH) is as efficient as the classical method according to Bligh and Dyer, making it possible to replace (environmentally) toxic chloroform.We conclude that HCl-catalyzed derivatization in combination with MeOH/MTBE extraction is the most appropriate among the methods tested for the analysis of FA concentrations and FA pattern in small biological samples. A detailed protocol for the analysis of plasma and tissues is included in this article.

Identification of a phage-encoded Ig-binding protein from invasive Neisseria meningitidis.

Ig-binding proteins are employed by a variety of organisms to evade the immune system. To our knowledge, we now report for the first time that meningococcal strains from several capsular groups exhibit Ig-binding activity that is dependent on human serum factors. A protein mediating Ig binding was identified as T and B cell-stimulating protein B (TspB) by immunoprecipitation and by mass spectroscopic analysis of tryptic peptides. Recombinant TspB and derivatives verified Ig binding, with a preference for human IgG2 Fc, and localized the IgG-binding region to a highly conserved subdomain of TspB. Antiserum produced in mice against the conserved subdomain detected the presence of TspB on the cell surface by flow cytometry when bacteria were grown in the presence of human serum. By fluorescence microscopy, we observed formation of an extracellular matrix having characteristics of a biofilm containing TspB, human IgG, DNA, and large aggregates of bacteria. TspB is encoded by gene ORF6 in prophage DNA, which others have shown is associated with invasive meningococcal strains. Knocking out ORF6 genes eliminated IgG binding and formation of large bacterial aggregates in biofilm. Reintroduction of a wild-type ORF6 gene by phage transduction restored the phenotype. The results show that TspB mediated IgG binding and aggregate/biofilm formation triggered by factors in human serum. As has been observed for other Ig-binding proteins, the activities mediated by TspB may provide protection against immune responses, which is in accordance with the association of prophage DNA carrying ORF6 with invasive meningococcal strains.

Development of attentional control of verbal auditory perception from middle to late childhood: comparisons to healthy aging.

Multitalker situations confront listeners with a plethora of competing auditory inputs, and hence require selective attention to relevant information, especially when the perceptual saliency of distracting inputs is high. This study augmented the classical forced-attention dichotic listening paradigm by adding an interaural intensity manipulation to investigate developmental differences in the interplay between perceptual saliency and attentional control during auditory processing between early and middle childhood. We found that older children were able to flexibly focus on instructed auditory inputs from either the right or the left ear, overcoming the effects of perceptual saliency. In contrast, younger children implemented their attentional focus less efficiently. Direct comparisons of the present data with data from a recently published study of younger and older adults from our group suggest that younger children and older adults show similar levels of performance. Critically, follow-up comparisons revealed that younger children's performance restrictions reflect difficulties in attentional control only, whereas older adults' performance deficits also reflect an exaggerated reliance on perceptual saliency. We conclude that auditory attentional control improves considerably from middle to late childhood and that auditory attention deficits in healthy aging cannot be reduced to a simple reversal of child developmental improvements.

Effects of non-steroidal anti-inflammatory drugs on proliferation, differentiation and migration in equine mesenchymal stem cells.

In equine medicine, stem cell therapies for orthopaedic diseases are routinely accompanied by application of NSAIDs (non-steroidal anti-inflammatory drugs). Thus, it has to be analysed how NSAIDs actually affect the growth and differentiation potential of MSCs (mesenchymal stem cells) in vitro in order to predict the influence of NSAIDs such as phenylbutazone, meloxicam, celecoxib and flunixin on MSCs after grafting in vivo. The effects of NSAIDs were evaluated regarding cell viability and proliferation. Additionally, the multilineage differentiation capacity and cell migration was analysed. NSAIDs at lower concentrations (0.1-1 µM for celecoxib and meloxicam and 10-50 µM for flunixin) exert a positive effect on cell proliferation and migration, while at higher concentrations (10-200 µM for celecoxib and meloxicam and 100-1000 µM for flunixin and phenylbutazone), there is rather a negative influence. While there is hardly any influence on the adipogenic as well as on the chondrogenic MSC differentiation, the osteogenic differentiation potential, as demonstrated with the von Kossa staining, is significantly disturbed. Thus, it can be concluded that the effects of NSAIDs on MSCs are largely dependent on the concentrations used. Additionally, for some differentiation lineages, also the choice of NSAID is critical.

Highly emissive metal-organic framework composites by host-guest chemistry.

The unique host-guest chemistry of metal-organic frameworks (MOFs) can be used to implement additional properties by loading the cavities with functional molecules or even nanoparticles. We describe the gas-phase loading of MOFs featuring either a three-dimensional (MOF-5, MOF-177 and UMCM-1) or one-dimensional channel system (MIL-53(Al)) with the highly emissive perylene derivative N,N-bis(2,6-dimethylphenyl)-3,4:9,10-perylene tetracarboxylic diimide (DXP) or an iridium complex, (2-carboxypyridyl)bis(3,5-difluoro-2-(2-pyridyl)phenyl)iridium(III) (FIrpic). The resulting host-guest composites show strong luminescence, with their optical properties being dominated by the guest species. DXP-loaded MOFs exhibit a high stability towards guest displacement by solvent molecules, while the interaction of FIrpic with the host is weaker. The emissive properties of intercalated DXP also indicate host-guest interactions such as caging effects, strong quenching of the MOF host emission, as well as aggregate formation.

The rkp-1 cluster is required for secretion of Kdo homopolymeric capsular polysaccharide in Sinorhizobium meliloti strain Rm1021.

Under conditions of nitrogen stress, leguminous plants form symbioses with soil bacteria called rhizobia. This partnership results in the development of structures called root nodules, in which differentiated endosymbiotic bacteria reduce molecular dinitrogen for the host. The establishment of rhizobium-legume symbioses requires the bacterial synthesis of oligosaccharides, exopolysaccharides, and capsular polysaccharides. Previous studies suggested that the 3-deoxy-D-manno-oct-2-ulopyranosonic acid (Kdo) homopolymeric capsular polysaccharide produced by strain Sinorhizobium meliloti Rm1021 contributes to symbiosis with Medicago sativa under some conditions. However, a conclusive symbiotic role for this polysaccharide could not be determined due to a lack of mutants affecting its synthesis. In this study, we have further characterized the synthesis, secretion, and symbiotic function of the Kdo homopolymeric capsule. We showed that mutants lacking the enigmatic rkp-1 gene cluster fail to display the Kdo capsule on the cell surface but accumulate an intracellular polysaccharide of unusually high M(r). In addition, we have demonstrated that mutations in kdsB2, smb20804, and smb20805 affect the polymerization of the Kdo homopolymeric capsule. Our studies also suggest a role for the capsular polysaccharide in symbiosis. Previous reports have shown that the overexpression of rkpZ from strain Rm41 allows for the symbiosis of exoY mutants of Rm1021 that are unable to produce the exopolysaccharide succinoglycan. Our results demonstrate that mutations in the rkp-1 cluster prevent this phenotypic suppression of exoY mutants, although mutations in kdsB2, smb20804, and smb20805 have no effect.

Nanometer-sized titania hosted inside MOF-5.

Nanoscale titania particles were synthesized inside the porous coordination polymer [Zn(4)O(bdc)(3)] (bdc = 1,4-benzene-dicarboxylate, MOF-5) by adsorption of titanium isopropoxide from the gas-phase and subsequent dry oxidation and annealing.

Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen induces expression of the helix-loop-helix protein Id-1 in human endothelial cells.

Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) (also known as human herpesvirus 8) is a gamma-2 herpesvirus believed to be the etiologic agent responsible for KS. The pathogenesis of this potentially life-threatening neoplasm is complex and unclear, and it is currently unknown how KSHV causes KS. Id (named for inhibitor of DNA binding or inhibitor of differentiation) proteins were identified in 1990 and found to be naturally occurring dominant-negative inhibitors of basic helix-loop-helix transcription factors. Id-1, the most well-studied member of this family, has since been shown to play a key role in several biological systems including cellular differentiation, cell cycle regulation, and tumorigenesis. In this report, we demonstrate that Id-1 is expressed at high levels in KS tumor cells both in vitro and in vivo but is expressed at relatively modest levels in endothelial cells (ECs), the likely precursor of the KS tumor cell. Infection of precursor cells with KSHV may be responsible for this enhanced expression, as KSHV infection induced Id-1 27-fold in ECs under our experimental conditions. Furthermore, we demonstrate that the KSHV-encoded latency-associated nuclear antigen (LANA) protein appears to be involved. Expression of LANA in ECs resulted in Id-1 induction that was almost identical to the induction seen with KSHV-infected ECs. These results demonstrate the expression of Id-1 in KS tumor cells and indicate the KSHV LANA protein may be, at least in part, responsible. This may be an important mechanism by which KSHV allows KS tumor cells to escape normal cell cycle regulation and enhances their proliferation.