Role of physical therapy in adult chronic non-bacterial osteitis: patients' and therapists' perspectives.

OBJECTIVES: Chronic nonbacterial osteitis (CNO) is a rare bone disease causing pain and functional impairment. We aimed to explore the application of physical therapy (PT) for adult CNO from the patients' and primary care therapists' perspective. METHOD: Cross-sectional study among the Dutch adult CNO cohort (1992-present). A survey on PT-use for axial spondylarthritis was adapted for CNO. Patients using PT in the past 2 years (recent PT-users) were asked about modalities, perceived effects, satisfaction, and preferences for provision. Their current physical therapists were invited to complete a self-developed survey covering therapy details and educational preferences. RESULTS: 80/199 invited patients and 14/16 invited therapists completed the survey respectively. 41 (51%) patients used PT for CNO in the preceding 2 years, 14 (18%) used PT >2 years back, and 25 (31%) never used PT. Recent PT-users (n=41) reported diverse treatment modalities, involving massage (61%), joint mobilizations (44%), breathing exercises (49%), muscle strengthening (32%) and counselling through of home-exercises (46%) and pain education (32%). 64% of all patients desired greater emphasis from physicians regarding the role of PT. Most therapists would appreciate referral letters with CNO-specific information (93%), and consultations with specialized therapists (86%). CONCLUSIONS: In this study, two-third of adult CNO patients had -ever or recently- used PT, which involved variable therapeutic modalities. Most patients were receptive to a larger role of PT in CNO-management and most therapists preferred CNO-specific information to optimize their care. These findings provide a foundation for the development and systematic evaluation of CNO-specific PT.

Bone material strength index as measured by in vivo impact microindentation is normal in subjects with high-energy trauma fractures.

Bone material properties were assessed using impact microindentation in patients with high-energy trauma fractures. Compared to patients with low-energy trauma fractures, bone material strength index was significantly higher in patients with high-energy trauma fractures, and did not differ between patients with osteopenia and those with osteoporosis within each trauma group. INTRODUCTION: Impact microindentation (IMI) is a technique to assess tissue-level properties of bone at the tibia. Bone material strength index (BMSi), measured by IMI, is decreased in patients with low-energy trauma fractures, independently of areal bone mineral density (aBMD), but there is no information about BMSi in patients with high-energy trauma fractures. In the present study, we evaluated tissue-level properties of bone with IMI in patients with high-energy trauma fractures. METHODS: BMSi was measured 3.0 months (IQR 2.0-5.8) after the fracture in 40 patients with high-energy trauma and 40 age- and gender-matched controls with low-energy trauma fractures using the OsteoProbe® device. RESULTS: Mean age of high- and low-energy trauma patients was 57.7 ± 9.1 and 57.2 ± 7.7 years, respectively (p = 0.78). Fracture types were comparable in high- vs low-energy trauma patients. Lumbar spine (LS)-aBMD, but not femoral neck (FN)-aBMD, was higher in high- than in low-energy trauma patients (LS 0.96 ± 0.13 vs 0.89 ± 0.13 g/cm2, p = 0.02; FN 0.75 ± 0.09 vs 0.72 ± 0.09 g/cm2, p = 0.09). BMSi was significantly higher in high- than in low-energy trauma patients (84.4 ± 5.0 vs 78.0 ± 4.6, p = 0.001), also after adjusting for aBMD (p = 0.003). In addition, BMSi did not differ between patients with osteopenia and those with osteoporosis within each trauma group. CONCLUSION: Our data demonstrate that BMSi and LS-aBMD, but not FN-aBMD, are significantly higher in high-energy trauma patients compared to matched controls with similar fractures from low-energy trauma. Further studies of non-osteoporotic patients with high-energy trauma fracture with measurements of BMSi are warranted to determine whether IMI might help in identifying those with reduced bone strength.

The Polygenic and Monogenic Basis of Paediatric Fractures.

PURPOSE OF REVIEW: Fractures are frequently encountered in paediatric practice. Although recurrent fractures in children usually unveil a monogenic syndrome, paediatric fracture risk could be shaped by the individual genetic background influencing the acquisition of bone mineral density, and therefore, the skeletal fragility as shown in adults. Here, we examine paediatric fractures from the perspective of monogenic and complex trait genetics. RECENT FINDINGS: Large-scale genome-wide studies in children have identified ~44 genetic loci associated with fracture or bone traits whereas ~35 monogenic diseases characterized by paediatric fractures have been described. Genetic variation can predispose to paediatric fractures through monogenic risk variants with a large effect and polygenic risk involving many variants of small effects. Studying genetic factors influencing peak bone attainment might help in identifying individuals at higher risk of developing early-onset osteoporosis and discovering drug targets to be used as bone restorative pharmacotherapies to prevent, or even reverse, bone loss later in life.

EFFECT OF ELECTR- AND ULTRAPHONOPHORESIS OF THE PHYTOCOMPLEX ON MICROCIRCULATORY AND BIOCHEMICAL PARAMETERS IN PATIENTS WITH KNEE JOINT OSTEOARTHRITIS.

The goal was to study the effect of modulated sinusoidal currents electrophoresis and ultraphonophoresis of the phytocomplex on disruptions in the microcirculation system in the affected joint area and on changes in connective tissue metabolism parameters, metabolic processes, and electrolyte metabolism in patients with knee joint osteoarthritis. Seventy-two patients were randomly assigned to five groups. Patients of the first group were prescribed modulated sinusoidal currents electrophoresis of the phytocomplex. The second group was prescribed ultraphonophoresis of the phytocomplex, the third group was prescribed amplipulse therapy (modulated sinusoidal currents), the fourth group was prescribed ultrasound therapy, and the fifth group was prescribed basic drug therapy. Drug therapy of patients of the fifth group was comparable to the drug treatment of patients of the first four groups. The concentration of the phytocomplex in the working composition was 10%. Electrotherapy was carried out in the full-wave modulated sinusoidal currents mode with I and IV types of operation while ultrasound therapy was carried out in continuous mode with an ultrasound intensity of 0.6 W/cm2. To assess the state of microcirculation, the laser Doppler flowmetry method was used. The pronounced anti-dystrophic effect after the use of modulated sinusoidal currents electrophoresis and ultraphonophoresis of the phytocomplex in patients with knee joint osteoarthritis was based on the correction of microcirculatory disruptions: an increase in the capillary blood flow, an increase in the blood perfusion in tissues, and a decrease in congestion effects in the venular microcirculation. The use of modulated sinusoidal currents electrophoresis of the phytocomplex (ultraphonophoresis of the phytocomplex had an even greater effect) improved the connective tissue metabolism and the content of seromucoid, fibrinogen, and mucoproteins. The use of the studied treatment methods improved magnesium and phosphorus parameters of the electrolyte metabolism. Modulated sinusoidal currents electrophoresis and ultraphonophoresis of the phytocomplex contributed to the elimination of the metabolic imbalance of acid phosphatase. Ultraphonophoresis of the phytocomplex also contributed to balancing of the alanine aminotransferase and alkaline phosphatase content. As a result of the study, the effect of modulated sinusoidal currents electrophoresis and ultraphonophoresis of the phytocomplex on disruptions in the microcirculation system in the affected joint area and on changes in connective tissue metabolism parameters, metabolic processes, and electrolyte metabolism in patients with knee joint osteoarthritis was established. The obtained results provide the basis for further studies to assess the overall effectiveness of the use of modulated sinusoidal currents electrophoresis and ultraphonophoresis of the phytocomplex in patients with knee joint osteoarthritis.

Treatments of osteoporosis increase bone material strength index in patients with low bone mass.

Effects on bone material properties of two-year antiosteoporotic treatment were assessed using in vivo impact microindentation (IMI) in patients with low bone mineral density (BMD) values. Antiresorptive treatment, in contrast to vitamin D ± calcium treatment alone, induced BMD-independent increases in bone material strength index, measured by IMI, the magnitude of which depended on pretreatment values. INTRODUCTION: Bone material strength index (BMSi), measured by IMI in vivo, is reduced in patients with fragility fractures, but there is no information about changes in values during long-term therapy. In the present study, we assessed changes in BMSi in patients receiving antiosteoporotic treatments for periods longer than 12 months. METHODS: We included treatment-naive patients with low bone mass who had a BMSi measurement with OsteoProbe® at presentation and consented to a repeat measurement after treatment. RESULTS: We studied 54 patients (34 women), median age 58 years, of whom 30 were treated with bisphosphonates or denosumab (treatment group) and 24 with vitamin D ± calcium alone (control group). There were no differences in clinical characteristics between the two groups with the exception of a higher number of previous fragility fractures in the treatment group. Baseline hip BMD and BMSi values were lower in the treatment group. After 23.1 ± 6.6 months, BMSi increased significantly in the treatment group (82.4 ± 4.3 vs 79.3 ± 4.1; p < 0.001), but did not change in the control group (81.5 ± 5.2 vs 82.2 ± 4.1; p = 0.35). Changes in BMSi with antiresorptives were inversely related with baseline values (r = - 0.43; p = 0.02) but not with changes in BMD. Two patients in the control group with large decreases in BMSi values sustained incident fractures. CONCLUSION: In patients at increased fracture risk, antiresorptive treatments induced BMD-independent increases in BMSi values, the magnitude of which depended on pretreatment values.

Using NanoSIMS coupled with microfluidics to visualize the early stages of coral infection by Vibrio coralliilyticus.

BACKGROUND: Global warming has triggered an increase in the prevalence and severity of coral disease, yet little is known about coral/pathogen interactions in the early stages of infection. The point of entry of the pathogen and the route that they take once inside the polyp is currently unknown, as is the coral's capacity to respond to infection. To address these questions, we developed a novel method that combines stable isotope labelling and microfluidics with transmission electron microscopy (TEM) and nanoscale secondary ion mass spectrometry (NanoSIMS), to monitor the infection process between Pocillopora damicornis and Vibrio coralliilyticus under elevated temperature. RESULTS: Three coral fragments were inoculated with 15N-labeled V. coralliilyticus and then fixed at 2.5, 6 and 22 h post-inoculation (hpi) according to the virulence of the infection. Correlative TEM/NanoSIMS imaging was subsequently used to visualize the penetration and dispersal of V. coralliilyticus and their degradation or secretion products. Most of the V. coralliilyticus cells we observed were located in the oral epidermis of the fragment that experienced the most virulent infection (2.5 hpi). In some cases, these bacteria were enclosed within electron dense host-derived intracellular vesicles. 15N-enriched pathogen-derived breakdown products were visible in all tissue layers of the coral polyp (oral epidermis, oral gastrodermis, aboral gastrodermis), at all time points, although the relative 15N-enrichment depended on the time at which the corals were fixed. Tissues in the mesentery filaments had the highest density of 15N-enriched hotspots, suggesting these tissues act as a "collection and digestion" site for pathogenic bacteria. Closer examination of the sub-cellular structures associated with these 15N-hotspots revealed these to be host phagosomal and secretory cells/vesicles. CONCLUSIONS: This study provides a novel method for tracking bacterial infection dynamics at the levels of the tissue and single cell and takes the first steps towards understanding the complexities of infection at the microscale, which is a crucial step towards understanding how corals will fare under global warming.

Micro-CT analyses of historical bone samples presenting with osteomyelitis.

OBJECTIVE: Osteomyelitis is an inflammation of the bone marrow mainly caused by bacteria such as Staphylococcus aureus. It typically affects long bones, e.g. femora, tibiae and humeri. Recently micro-computed tomography (µCT) techniques offer the opportunity to investigate bone micro-architecture in great detail. Since there is no information on long bone microstructure in osteomyelitis, we studied historic bone samples with osteomyelitis by µCT. MATERIALS AND METHODS: We investigated 23 femora of 22 individuals suffering from osteomyelitis provided by the Collection of Anatomical Pathology, Museum of Natural History, Vienna (average age 44 ±19 years); 9 femora from body donors made available by the Department of Applied Anatomy, Medical University of Vienna (age range, 56-102 years) were studied as controls. Bone microstructure was assessed by µCT VISCOM X 8060 II with a minimal resolution of 18 µm. RESULTS: In the osteomyelitic femora, most prominent alterations were seen in the cortical compartment. In 71.4% of the individuals with osteomyelitis, cortical porosity occurred. 57.1% of the individuals showed cortical thinning. In 42.9% trabecularisation of cortical bone was observed. CONCLUSION: Osteomyelitis is associated with severe alterations of cortical bone structure otherwise typically observed at old age such as cortical porosity and cortical thinning.

MiR-200a regulates epithelial to mesenchymal transition-related gene expression and determines prognosis in colorectal cancer patients.

BACKGROUND: MicroRNAs (miRNAs) regulate the biological properties of colorectal cancer (CRC) cells and might serve as potential prognostic factors and therapeutic targets. In this study, we therefore globally profiled miRNAs associated with E-cadherin expression in CRC cells in an attempt to identify miRNAs that are associated with aggressive clinical course in CRC patients. METHODS: Two CRC cell lines (Caco-2 and HRT-18) with different E-cadherin expression pattern were profiled for differences in abundance for more than 1000 human miRNAs using microarray technology. One of the most differentially expressed miRNAs, miR-200a was evaluated for its prognostic role in a cohort of 111 patients and independently validated in 217 patients of the Cancer Genome Atlas data set. To further characterise the biological role of miR-200a expression in CRC, in vitro miR-200a inhibition and overexpression were performed and the effects on cellular growth, apoptosis and epithelial-mesenchymal transition (EMT)-related gene expression were explored. RESULTS: In situ hybridisation specifically localised miR-200a in CRC cells. In both cohorts, a low miR-200a expression was associated with poor survival (P<0.05). Multivariate Cox regression analysis identified low levels of miR-200a expression as an independent prognostic factor with respect to cancer-specific survival (HR=2.04, CI=1.28-3.25, P<0.002). Gain and loss of function assays for miR-200a in vitro led to a significantly differential and converse expression of EMT-related genes (P<0.001.) A low expression of miR-200a was also observed in cancer stem cell-enriched spheroid growth conditions (P<0.05). CONCLUSIONS: In conclusion, our data suggest that low miR-200a expression is associated with poor prognosis in CRC patients. MiR-200a has a regulatory effect on EMT and is associated with cancer stem cell properties in CRC.

EXPLOITING CHEMICAL ECOLOGY FOR LIVELIHOOD IMPROVEMENT OF SMALL HOLDER FARMERS IN KENYA.

"Push-Pull" is an inexpensive and eminently practical strategy designed for developing countries in order to exploit sound principles of chemical ecology for agricultural pest management. This strategy is specifically suitable for small holder farmers. Their experience can easily be integrated into existing farming practices in their immediate environment. "Push-pull" within one and a half decades became widely established and meanwhile is greatly beneficial to practitioners in East Africa, mainly Kenya. The classical push-pull approach used for applied plant-insect management was pioneered by Khan and Pickett (2000) and subsequent papers of Pickett (2003) and Khan et al. (2006, 2008). Relevant plant species explored so far were maize or sorghum intercropped with other East African plants (Desmodium spp. resp. Melinis minutiflora) possessing natural chemicals repellent resp. attractive for stem borer moths Chilo partellus (Lepidoptera), whereby Desmodium spp. was grown inside the maize rows while M. minutiflora surrounded it. Both simultaneous actions combined resulted in a significant decrease of stem borers in the area to be protected. A benefit to cost ratio of 2.5 was realized. Within a period of 15 years the number of subscribing farmers substantially increased from a few dozen to more than 80,000 in 2014. Two experiments along the paths of chemical ecology were undertaken between Sept 2012 and Feb 2013: One was designed to investigate if the legume D. intortum known to produce repellent volatiles against stem borer moths induces defence in Zea mays varieties. We looked at two open-pollinated farmers' varieties and two commercial hybrid varieties suspecting the farmers' varieties to be responsive rather than the hybrids. However, no defence induction was detected in this study so far. This could be explained by an insufficient production of defence inducing volatiles in leaves of D. intortum whereas flowers might produce a sufficient response. More detailed study is needed. A second approach made use of species-specific insect monitoring traps baited with highly specific female sex pheromones for attracting and monitoring destructive insect pests. The female sex pheromone (8-methyl-decane-2-ol propanoate) of Diabrotica virgifera virgifera (Coleoptera: Chrysomelidae) (Western Corn Rootworm) is readily available as bait in the "Metcalf sticky cup trap" for trapping males, an extraordinarily sensitive technique for monitoring the presence or absence of male beetles in a given area. Li et al. (2006) had argued for the likelihood of easy immigration of this cosmopolitan maize pest into East Africa. Our results, however, so far indicate the absence of a local population in the area of Mbita, while not excluding its presence at Nairobi or Mombasa. Both investigations contribute to different aspects of Kenyan economic development and may be seen as two independent but complementary contributions towards livelihood improvement of small holder farmers in Kenya.

The multi-faceted nature of age-associated osteoporosis.

Age-associated osteoporosis (AAOP) poses a significant health burden, characterized by increased fracture risk due to declining bone mass and strength. Effective prevention and early treatment strategies are crucial to mitigate the disease burden and the associated healthcare costs. Current therapeutic approaches effectively target the individual contributing factors to AAOP. Nonetheless, the management of AAOP is complicated by the multitude of variables that affect its development. Main intrinsic and extrinsic factors contributing to AAOP risk are reviewed here, including mechanical unloading, nutrient deficiency, hormonal disbalance, disrupted metabolism, cognitive decline, inflammation and circadian disruption. Furthermore, it is discussed how these can be targeted for prevention and treatment. Although valuable as individual targets for intervention, the interconnectedness of these risk factors result in a unique etiology for every patient. Acknowledgement of the multifaceted nature of AAOP will enable the development of more effective and sustainable management strategies, based on a holistic, patient-centered approach.

Clinical value of RANKL, OPG, IL-6 and sclerostin as biomarkers for fibrous dysplasia/McCune-Albright syndrome.

BACKGROUND: Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare genetic bone disease caused by a somatic mutation in the GNAS gene. Currently used bone turnover markers (BTMs) do not correlate with the clinical picture and are not useful to predict or monitor therapy success. This study assessed the correlation of RANKL, OPG, RANKL/OPG ratio, IL-6 and sclerostin with the classic BTMs alkaline phosphatase (ALP), procollagen type 1 propeptide (P1NP) and beta crosslaps (CTX), with pain, skeletal burden score (SBS) and response to bisphosphonate or denosumab treatment. METHODS: Ninety-six serum samples of adult patients >18 years of age with any subtype of FD/MAS were included from the biobank facility of the Leiden University Medical Center, Center for Bone Quality between 2015 and 2021. Standard laboratory assessments were assessed as part of usual care. The concentrations of potential biomarkers RANKL, OPG, sclerostin, IL-6 were analyzed. Data on FD/MAS subtype, age, pain, treatment history and treatment response were retrieved from the electronic patient files. Baseline characteristics were summarized by descriptive statistics. Correlations of the concentrations of the potential biomarkers with classic bone turnover markers, SBS and pain scores were cross-sectionally assessed by Spearman rank order correlation. Correction for multiple testing was performed by Benjamini and Hochberg False Discovery Rate. A sensitivity analyses was performed by excluding patients with SBS below 15 and patients using antiresorptive medication at the time of blood withdrawal or within the wash-out period. In patients treated with bisphosphonates or denosumab after blood withdrawal, pre-treatment concentrations were compared in patients with and without therapy response by Mann Whitney U test. RESULTS: The median age of the patients was 41.2 (Q1-Q3 25.9-52.2) years, 62.5 % was female. Median SBS was 2.5 (Q1-Q3 0.5-7.8). RANKL level correlated weakly with ALP (Spearman rho 0.309, p = 0.004, n = 84), but not with P1NP or CTX. The RANKL/OPG ratio, OPG, IL-6 and sclerostin did not correlate with ALP, P1NP or CTX. None of the potential biomarkers correlated with SBS or pain. Results of the sensitivity analyses were comparable. Pre-treatment biomarker levels were similar in patients with and without improvement in pain scores following bisphosphonate therapy. Pre-treatment RANKL and sclerostin were comparable between patients with and without improvement in pain scores after denosumab therapy. Pre-treatment IL-6 level and the RANKL/OPG ratio seemed to be higher in patients with response to denosumab (IL-6: median 0.64 (Q1-Q3 0.53-0.74) pg/mL, n = 6, RANKL/OPG: median 0.062 (Q1-Q3 0.016-0.331), n = 5) compared to patients without response (IL-6: median 0.35 (0.20-0.54) pg/mL, n = 5, RANKL/OPG: 0.027 (0.024-0.046), n = 4). Pre-treatment IL-6 correlated with the improvement in maximum pain scores (rho 0.962, p < 0.001, n = 9) and average pain scores (rho 0.895, p = 0.001, n = 9) reported during denosumab therapy. CONCLUSION: Increased concentrations of RANKL, IL-6, sclerostin and of the RANKL/OPG ratio do not indicate severity of FD/MAS, as no correlation was observed of these potential biomarkers with the classic BTMs and SBS. Biomarker levels did not correlate with pain and had no value in predicting bisphosphonate treatment response. These biomarkers are not superior over the currently used methods of assessing ALP, P1NP and CTX or evaluating SBS to establish disease extent or activity and provide no reliable results. Yet, possibly pre-treatment IL-6 and the RANKL/OPG ratio may have some predictive value for clinical response to denosumab. Therefore, studies investigating disease activity and treatment response should include lesional imaging and patient-reported outcome measures.

Diagnostic and therapeutic practices in adult chronic nonbacterial osteomyelitis (CNO).

BACKGROUND: Chronic nonbacterial osteomyelitis (CNO) is a rare, and impactful auto-inflammatory bone disease occurring in children and adults. Clinical care for CNO is challenging, as the condition lacks validated classification criteria and evidence-based therapies. This study aimed to map the current diagnostic and therapeutic practices for CNO in adults, as a first step towards a standardized disease definition and future consensus treatment plans. METHODS: A primary survey was spread among global rheumatological/bone networks and 57 experts as identified from literature (May 2022), covering terminology, diagnostic tools (clinical, radiological, biochemical) and treatment steps. A secondary survey (sent to primary survey responders in August 2022) further queried key diagnostic features, treatment motivations, disease activity and treatment response monitoring. RESULTS: 36 and 23 physicians completed the primary and secondary survey respectively. Diagnosis was mainly based on individual physician assessment, in which the combination of chronic relapsing-remitting bone pain with radiologically-proven osteitis/osteomyelitis, sclerosis, hyperostosis and increased isotope uptake on bone scintigraphy were reported indicative of CNO. Physicians appeared more likely to refer to the condition as synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome in the presence of joint and skin pathology. MRI was most frequently performed, and the preferred diagnostic test for 47%. X-rays were second-most frequently used, although considered least informative of all available tools. Typical imaging features reported were hyperostosis, osteitis, osteosclerosis, bone marrow edema, while degeneration, soft tissue calcification, and ankylosis were not regarded characteristic. Inflammation markers and bone markers were generally regarded unhelpful for diagnostic and monitoring purposes and physicians infrequently performed bone biopsies. Management strategies diverged, including indications for treatment, response monitoring and declaration of remission. Step-1 treatment consisted of non-steroidal anti-inflammatory drugs/COX-2 inhibitors (83%). Common step 2-3 treatments were pamidronate, methotrexate, and TNF-a-inhibition (anti-TNFα), the latter two regarded especially convenient to co-target extra-skeletal inflammation in SAPHO syndrome. Overall pamidronate and anti-TNFα and were considered the most effective treatments. CONCLUSIONS: Following from our survey data, adult CNO is a broad and insufficiently characterized disease spectrum, including extra-osseous features. MRI is the favoured imaging diagnostic, and management strategies vary significantly. Overall, pamidronate and anti-TNFα are regarded most successful. The results lay out current practices for adult CNO, which may serve as backbone for a future consensus clinical guideline.

Detecting and Locating the Site of Local Relapse Using 18F-PSMA-1007 Imaging After Primary Treatment of 135 Prostate Cancer Patients-Potential Impact on PSMA-Guided Radiation Therapy.

PURPOSE: Due to limited imaging options, the visualization of a local relapse of prostate cancer used to pose a considerable challenge. However, since the integration of 18F-PSMA-1007-PET/CT into the clinic, a relapsed tumor can now easily be detected by hybrid imaging. The present study aimed to evaluate and map the allocate relapse in a large cohort of prostate cancer patients focusing on individual patient management conclusions for radiation therapy. PROCEDURES: The current study included 135 men with prostate cancer after primary treatment who underwent 18F-PSMA-1007-PET/CT due to biochemical relapse detecting a local relapse. Imaging data were reassessed and analyzed with regard to relapse locations. For the correlation of tumor foci with clinical data, we used binary logistic regression models as well as the Kruskal-Wallis test and Mann-Whitney test. RESULTS: In total, 69.6% of all patients (mean age: 65 years) underwent prostatectomy while 30.4% underwent radiation therapy. PET imaging detected most frequently a unifocal relapse (72.6%). There was a statistically significantly higher rate of ipsilateral cases among the relapsed tumors. Comparing both treatment approaches, tumors relapsed most commonly within the posterior region after surgery and transition/peripheral zone after radiation therapy, respectively. CONCLUSIONS: The present study confirms that 18F-PSMA-1007-PET/CT is highly suitable for the localization and allocation of a local relapse in patients with prostate cancer. The data enable further optimizing dose prescriptions and target volume delineations of radiation therapy in the future.

Down-regulation of KRAS-interacting miRNA-143 predicts poor prognosis but not response to EGFR-targeted agents in colorectal cancer.

BACKGROUND: MicroRNA-143 (miRNA-143) is frequently down-regulated in colorectal cancer (CRC) and may influence CRC cell proliferation, apoptosis and sensitivity to 5-fluorouracil. mRNA encoded by the KRAS oncogene has been identified as a target of miRNA-143. However, the prognostic significance of miRNA-143 expression and the ability to predict patient response to epidermal growth factor receptor (EGFR)-targeted agents have not yet been explored. METHODS: We examined 77 CRC patients who were identified by pyrosequencing to have wild-type KRAS and were subsequently treated with EGFR-targeted therapy with the monoclonal antibodies cetuximab or panitumumab. MicroRNA-143 expression was measured in CRC tissue and corresponding non-neoplastic colon tissue by RT-PCR and its expression level was correlated with clinico-pathological characteristics. Univariate and multivariate analyses were used to calculate cancer-specific survival (CSS). The progression-free survival (PFS) and objective response rates on EGFR-targeted therapy were also evaluated. RESULTS: Down-regulation of miRNA-143 was observed in 47 out of 77 (61%) tumours. Multivariate Cox regression analysis identified low levels of miRNA-143 expression as an independent prognostic factor with respect to CSS (hazard ratio=1.92, confidence interval=1.1-3.4, P=0.024). A significant difference was also observed with regard to PFS on EGFR-targeted therapy (P=0.031), but there were no significant differences with regard to the objective response rates. CONCLUSION: Our data indicate that miRNA-143 expression levels serve as an independent prognostic biomarker for CRC in KRAS wild-type patients. No role for miRNA-143 expression as a predictive biomarker for EGFR-targeted agents could be identified. Given its negative impact on CSS and PFS, miRNA-143 represents a novel prognosticator and a promising drug target for patients with CRC.

Sport-specific fitness testing differentiates professional from amateur soccer players where VO2max and VO2 kinetics do not.

AIM: The purpose of this study was to identify if sport-specific and cardiopulmonary exercise testing differentiated professional from amateur soccer players. METHODS: Thirty six men comprising 18 professional (mean±s: age 23.2±2.4 years) and 18 amateur (mean±SD: age 21.1±1.6 years) soccer players participated and performed four tests on separate occasions: 1) a graded exercise test to determine VO2max; 2) four exercise transients from walking to 80%Δ for the determination of VO2 kinetics; 3) the Yo-Yo Intermittent Recovery Test level 2 (Yo-Yo IR2) and 4) a repeated sprint test (RST). RESULTS: The players did not differ in VO2max (professional 56.5±2.9 mL.kg-1.min-1; amateur 55.7±3.5 mL.kg-1.min-1: P=0.484) or VO2 kinetic fundamental measures (τ1 onset, professional 24.5±3.2 s; amateur 24.0±1.8 s: τ1 cessation, professional 28.7±2.8 s; amateur 29.3±3.5 s: P=0.923). However, the amateurs were outperformed in the Yo-Yo IR2 (Professional 966±153 m; Amateur 840±156 m) (P=0.034) and RST (best time, professional 6.46±0.27 s; amateur 6.84±0.24 s, P=0.012). CONCLUSION: Performance indices derived from field-based sport-specific performance tests identified significant differences between professional and amateur players (P<0.05). However, neither tests of VO2 kinetics nor VO2max differentiated between groups, suggesting laboratory tests of cardiorespiratory parameters are probably less consequential to soccer than sport-specific field-based observations.

[Chronic musculoskeletal pain syndrome in primary hyperparathyroidism]. / Chronisches muskuloskelettales Schmerzsyndrom bei primärem Hyperparathyreoidismus.

Chronic somatic pain disorders with somatic and mental factors (ICD-10: F45.41) are common among psychosomatic patients. In the present case, due to the close temporal association with a trauma and the subsequent development of symptoms including depressive symptoms, a chronic pain disorder with a relevant somatoform component was suspected. However, after a period of several months without significant somatic findings, targeted diagnostic approaches resulted in the diagnoses of primary hyperparathyroidism and a papillary thyroid carcinoma. Surgical therapy resulted in an almost complete decline of symptoms within a short period of time.

[Drug therapy of fibromyalgia syndrome. Systematic review, meta-analysis and guideline]. / Medikamentöse Therapie des Fibromyalgiesyndroms. Systematische Übersicht und Metaanalyse.

BACKGROUND: The scheduled update to the German S3 guidelines on fibromyalgia syndrome (FMS) by the Association of the Scientific Medical Societies ("Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften", AWMF; registration number 041/004) was planned starting in March 2011. MATERIALS AND METHODS: The development of the guidelines was coordinated by the German Interdisciplinary Association for Pain Therapy ("Deutsche Interdisziplinären Vereinigung für Schmerztherapie", DIVS), 9 scientific medical societies and 2 patient self-help organizations. Eight working groups with a total of 50 members were evenly balanced in terms of gender, medical field, potential conflicts of interest and hierarchical position in the medical and scientific fields. Literature searches were performed using the Medline, PsycInfo, Scopus and Cochrane Library databases (until December 2010). The grading of the strength of the evidence followed the scheme of the Oxford Centre for Evidence-Based Medicine. The recommendations were based on level of evidence, efficacy (meta-analysis of the outcomes pain, sleep, fatigue and health-related quality of life), acceptability (total dropout rate), risks (adverse events) and applicability of treatment modalities in the German health care system. The formulation and grading of recommendations was accomplished using a multi-step, formal consensus process. The guidelines were reviewed by the boards of the participating scientific medical societies. RESULTS AND CONCLUSION: Amitriptyline and-in case of comorbid depressive disorder or generalized anxiety disorder-duloxetine are recommended. Off-label use of duloxetine and pregabalin can be considered in case of no comorbid mental disorder. Strong opioids are not recommended. The English full-text version of this article is available at SpringerLink (under "Supplemental").

[Multicomponent therapy of fibromyalgia syndrome. Systematic review, meta-analysis and guideline]. / Multimodale Therapie des Fibromyalgiesyndroms. Systematische Übersicht, Metaanalyse und Leitlinie.

BACKGROUND: The scheduled update to the German S3 guidelines on fibromyalgia syndrome (FMS) by the Association of the Scientific Medical Societies ("Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften", AWMF; registration number 041/004) was planned starting in March 2011. MATERIALS AND METHODS: The development of the guidelines was coordinated by the German Interdisciplinary Association for Pain Therapy ("Deutsche Interdisziplinären Vereinigung für Schmerztherapie", DIVS), 9 scientific medical societies and 2 patient self-help organizations. Eight working groups with a total of 50 members were evenly balanced in terms of gender, medical field, potential conflicts of interest and hierarchical position in the medical and scientific fields. Literature searches were performed using the Medline, PsycInfo, Scopus and Cochrane Library databases (until December 2010). The grading of the strength of the evidence followed the scheme of the Oxford Centre for Evidence-Based Medicine. The formulation and grading of recommendations was accomplished using a multi-step, formal consensus process. The guidelines were reviewed by the boards of the participating scientific medical societies. RESULTS AND CONCLUSION: The use of a multicomponent therapy (the combination of aerobic exercise with at least one psychological therapy) for a minimum of 24 h is strongly recommended for patients with severe FMS. The English full-text version of this article is available at SpringerLink (under "Supplemental").

Metabolism and excretion of a novel p38 MAP kinase inhibitor pamapimod in healthy male subjects.

OBJECTIVE: This study investigated the pharmacokinetics, excretion, and metabolism of pamapimod following a single oral dose in healthy male subjects. MATERIALS: Nonradio-labeled pamapimod was supplied as bulk powder, [14C]-labeled pamapimod was supplied as ethanol solution. Pamapimod, metabolic synthetic standards, and the internal standard were supplied by Roche. METHODS: This was an open-label, singledose mass balance study. Healthy male subjects received a single oral dose of 300 mg [14C]-labeled pamapimod. Quantification of pamapimod and metabolites was determined by a validated liquid chromatography/tandem mass spectrometry method (LC/MS/ MS). Urine, blood, and feces were collected for metabolic profiling and radioactivity analysis. Profiling was done using high performance liquid chromatography (HPLC)/ LC/MS/MS. Radioactivity determination was by liquid scintillation counting. RESULTS: Six subjects completed the study. Mean Cmax was 4,120 ng/ml at tmax of 2.8 h, and mean AUCinf was 19,800 ng·h/ml. The t1/2 of pamapimod was 7.2 h. Mean drug recovery was 100 ± 2% by 120 h, of which 76.5% was recovered in urine and 23.9% in feces. Unchanged pamapimod accounted for 15.3% excreta, indicating metabolism is the major elimination pathway. Five metabolites were identified in plasma, urine, and feces. In urine, 41.1% of the dose was excreted as carboxylate metabolite (RO4498496), 19.2% as lactol metabolite (RO4493992), and 12.5% as pamapimod. In feces, 18.5% was excreted as RO4498496, 2.8% as pamapimod. CONCLUSIONS: The majority of dose was renally cleared. Urinary and fecal metabolites accounted for > 80% radioactivity. These results indicate hepatic metabolism followed by renal excretion is the major elimination pathway of pamapimod.

Cell tracking using iron oxide fails to distinguish dead from living transplanted cells in the infarcted heart.

Recently, debate has arisen about the usefulness of cell tracking using iron oxide-labeled cells. Two important issues in determining the usefulness of cell tracking with MRI are generally overlooked; first, the effect of graft rejection in immunocompetent models, and second, the necessity for careful histological confirmation of the fate of the labeled cells in the presence of iron oxide. Therefore, both iron oxide-labeled living as well as dead epicardium-derived cells (EPDCs) were investigated in ischemic myocardium of immunodeficient non-obese diabetic (NOD)/acid: non-obese diabetic severe combined immunodeficient (NOD/scid) mice with 9.4T MRI until 6 weeks after surgery, at which time immunohistochemical analysis was performed. In both groups, voids on MRI scans were observed that did not change in number, size, or localization over time. Based on MRI, no distinction could be made between living and dead injected cells. Prussian blue staining confirmed that the hypointense spots on MRI corresponded to iron-loaded cells. However, in the dead-EPDC recipients, all iron-positive cells appeared to be macrophages, while the living-EPDC recipients also contained engrafted iron-loaded EPDCs. Iron labeling is inadequate for determining the fate of transplanted cells in the immunodeficient host, since dead cells produce an MRI signal indistinguishable from incorporated living cells.