Effects of Bariatric Surgery on Knee Articular Cartilage and Osteoarthritis Symptoms-A 12-Month Follow-Up Using T2 Relaxation Time and WOMAC Osteoarthritis Index.

BACKGROUND: Obesity is a significant risk factor for osteoarthritis (OA). The most effective treatment for morbid obesity is bariatric surgery. PURPOSE: To study the effects of potential surgically induced weight loss on knee articular cartilage and OA symptoms of obese patients over a 12-month follow-up. STUDY TYPE: Prospective longitudinal cohort study. SUBJECTS: 45 obese patients (38 female, BMI = 42.3 ± 6.5 kg/m2) who underwent gastric bypass (intervention group), and 46 age-matched conservative-care controls (37 female, BMI = 39.8 ± 4.6 kg/m2). FIELD STRENGTH/SEQUENCE: Multiecho spin echo sequence at 3 T. ASSESSMENT: Knee cartilage T2 measurements and WOMAC Indices were measured presurgery and after 12 months. The intervention group was split into successful (≥20% total weight loss (TWL)) and unsuccessful (<20% TWL) weight loss groups. T2 and WOMAC indices were also measured in controls at baseline and after 12 months. Changes among the three groups were analyzed. STATISTICAL TESTS: Analysis of variance (significance level 0.05). RESULTS: Twenty-six (58%) intervention patients achieved ≥20% TWL. The <20% TWL group demonstrated significantly more T2 reduction in the deep lateral femur over 12 months compared with the ≥20% TWL group (-3.83 ± 8.18 msec vs. 2.47 ± 6.54 msec, respectively), whereas no significant differences were observed on the medial femoral compartment (P = 0.385, P = 0.551, and P = 0.511 for bulk, superficial and deep regions, respectively). Changes in WOMAC indices over 12 months were significantly greater in the ≥20% TWL group compared with controls. In the <20% TWL group, pain significantly improved over 12 months compared with controls, while stiffness and function changes were not statistically significant (P = 0.063 and P = 0.051, respectively). DATA CONCLUSION: Cartilage matrix, measured by T2, showed improvement on lateral femoral cartilage with <20% TWL compared with ≥20% TWL. Bariatric surgery provided significant improvements in knee symptoms with ≥20% TWL compared with conservative WL. This effect is also seen to some extent with <20% TWL compared with conservative WL. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 4.

Predisposing factors for a second fragile hip fracture in a population of 1130 patients with hip fractures, treated at Oulu University Hospital in 2013-2016: a retrospective study.

OBJECTIVE: The life-time risk of a second fragile hip fracture is 8.4%, but the risk factors that predispose to a second hip fracture remain unresolved. This study aimed to define risk factors that predisposed patients to a second hip fracture. METHODS: For this retrospective study, we retrieved clinical data on 1130 patients with fragile hip fractures (67.2% female, mean age: 79.3 years) that underwent surgery at the Oulu University Hospital in 2013-2016. These data included the fracture risk assessment score (measured with the FRAX tool), the bone-mass T-score, laboratory values, ambulatory capacity, and the time of death. RESULTS: In this population, 12.4% of patients sustained a second hip fracture. The predisposing factors for a second hip fracture were: female (p = 0.016), a high FRAX score (p = 0.020), and low physical capacity (p < 0.001). The vitamin D level recommended for treating osteoporosis (i.e., vitamin D > 75 nmol/l) was observed in only 24% of patients, and 42% of patients had ionized calcium levels below the reference range. According to the level of the cross-linked carboxy-terminal telopeptide of type I collagen (ICTP), 37% of patients did not have high bone turnover. We found a positive correlation between age and ICTP (p = 0.001). The risk of death was higher after the second hip fracture (p = 0.005), but we found no difference in age between patients with first and second hip fractures (p = 0.11). CONCLUSION: After a hip fracture, a second hip fracture is a well-known risk. Nevertheless, we found that only one-third of patients with a second hip fracture had used anti-osteoporosis medication at any time previously. These findings suggested that second hip fractures were most likely to occur in patients with osteopenic T-score values, in women more often than men, and in patients with high FRAX scores and low ambulatory capacity.

Preliminary Report: Osteoarthritis and Rheumatoid Arthritis Synovial Fluid Increased Osteoclastogenesis In Vitro by Monocyte Differentiation Pathway Regulating Cytokines.

Background: Rheumatoid arthritis (RA) and osteoarthritis (OA) are common joint diseases associated with changes in local, as well as systemic bone structure and osteoclast function. We investigated how the different soluble inflammatory stimuli in these diseases can affect osteoclastogenesis and bone resorption in vitro. Methods. Human peripheral blood mononuclear cell-derived osteoclasts were cultured on bone slices with serum from treatment-naïve RA patients and healthy controls and with synovial fluid samples acquired from RA and OA patients. The concentrations of 29 different cytokines and related proteins, including RANKL and OPG, were analyzed in the fluids tested. Results: RA serum and synovial fluid increased both osteoclastogenesis and bone resorption. Osteoclastogenesis and activity increased more in the cultures containing OA than RA synovial fluid. The osteoclasts cultured in different culture media exhibited different phenotypes, especially the cells cultured with OA synovial fluid were generally larger and had more nuclei. A general increase in proinflammatory cytokines in RA synovial fluid and serum was found. Surprisingly, OA synovial fluid showed lower levels of osteoclastogenesis inhibiting cytokines, such as IL-4 and IL-10, than RA synovial fluid, which at least partly explains more pronounced osteoclastogenesis. No significant difference was found in RANKL or OPG levels. Conclusion: The proinflammatory stimulus in OA and RA drives the monocyte differentiation towards inflammatory osteoclastogenesis and altered osteoclast phenotype.

Accelerometer-measured physical activity is associated with knee breadth in middle-aged Finns - a population-based study.

BACKGROUND: Articular surface size is traditionally considered to be a relatively stable trait throughout adulthood. Increased joint size reduces bone and cartilage tissue strains. Although physical activity (PA) has a clear association with diaphyseal morphology, the association between PA and articular surface size is yet to be confirmed. This cross-sectional study aimed to clarify the role of moderate-to-vigorous PA (MVPA) in knee morphology in terms of tibiofemoral joint size. METHODS: A sample of 1508 individuals from the population-based Northern Finland Birth Cohort 1966 was used. At the age of 46, wrist-worn accelerometers were used to monitor MVPA (≥3.5 METs) during a period of two weeks, and knee radiographs were used to obtain three knee breadth measurements (femoral biepicondylar breadth, mediolateral breadth of femoral condyles, mediolateral breadth of the tibial plateau). The association between MVPA and knee breadth was analyzed using general linear models with adjustments for body mass index, smoking, education years, and accelerometer weartime. RESULTS: Of the sample, 54.8% were women. Most individuals were non-smokers (54.6%) and had 9-12 years of education (69.6%). Mean body mass index was 26.2 (standard deviation 4.3) kg/m2. MVPA was uniformly associated with all three knee breadth measurements among both women and men. For each 60 minutes/day of MVPA, the knee breadth dimensions were 1.8-2.0% (or 1.26-1.42 mm) larger among women (p < 0.001) and 1.4-1.6% (or 1.21-1.28 mm) larger among men (p < 0.001). CONCLUSIONS: Higher MVPA is associated with larger tibiofemoral joint size. Our findings indicate that MVPA could potentially increase knee dimensions through similar biomechanical mechanisms it affects diaphyseal morphology, thus offering a potential target in reducing tissue strains and preventing knee problems. Further studies are needed to confirm and investigate the association between articulation area and musculoskeletal health.

Characterization of hyaluronan-coated extracellular vesicles in synovial fluid of patients with osteoarthritis and rheumatoid arthritis.

BACKGROUND: Hyaluronic acid (HA) is the major extracellular matrix glycosaminoglycan with a reduced synovial fluid (SF) concentration in arthropathies. Cell-derived extracellular vesicles (EV) have also been proposed to contribute to pathogenesis in joint diseases. It has recently been shown that human SF contains HA-coated EV (HA-EV), but their concentration and function in joint pathologies remain unknown. METHODS: The aim of the present study was to develop an applicable method based on confocal laser scanning microscopy (CLSM) and image analysis for the quantification of EV, HA-particles, and HA-EV in the SF of the human knee joint. Samples were collected during total knee replacement surgery from patients with end-stage rheumatoid arthritis (RA, n = 8) and osteoarthritis (OA, n = 8), or during diagnostic/therapeutic arthroscopy unrelated to OA/RA (control, n = 7). To characterize and quantify EV, HA-particles, and HA-EV, SF was double-stained with plasma membrane and HA probes and visualized by CLSM. Comparisons between the patient groups were performed with the Kruskal-Wallis analysis of variance. RESULTS: The size distribution of EV and HA-particles was mostly similar in the study groups. Approximately 66% of EV fluorescence was co-localized with HA verifying that a significant proportion of EV carry HA. The study groups were clearly separated by the discriminant analysis based on the CLSM data. The intensities of EV and HA-particle fluorescences were lower in the RA than in the control and OA groups. CONCLUSIONS: CLSM analysis offers a useful tool to assess HA-EV in SF samples. The altered EV and HA intensities in the RA SF could have possible implications for diagnostics and therapy.

Retention of metals in periprosthetic tissues of patients with metal-on-metal total hip arthroplasty is reflected in the synovial fluid to blood cobalt transfer ratio in the presence of a pseudotumour.

BACKGROUND: Modern metal-on-metal (MOM) arthroplasties were performed for over a decade before alarming reports of adverse metal reactions dramatically reduced their use. Failures are seen more often with high-wearing implants, but also well-positioned components with more favourable wear patterns can cause problems. There are no specific clinical indicators that could help us to predict the prognosis of these implants. For this reason, we still need more information on the effect of underlying factors that contribute to this process. METHODS: In this prospective cohort study, we investigated how cup orientation and type of pseudotumour determined by the Hart classification effect the distribution of metals in blood, synovial fluid and tissues surrounding the metal-on-metal hip prosthesis in revision surgery patients. One thousand two hundred twenty-nine metal-on-metal hip patients were screened and of those, 60 patients that had a revision surgery due to adverse metal reaction were included. Whole blood, synovial fluid and synovial/pseudotumour tissue samples were analysed for metal ion concentrations (Co, Cr, Mo and Ti). RESULTS: The lowest metal concentrations were found when both cup anteversion and inclination were optimal, and the highest when both were suboptimal. Suboptimal anteversion alone raised Cr-ion concentrations more than suboptimal inclination. The concentrations of metals in blood, synovial fluid or synovial soft tissue were the same in patients with and without a pseudotumour, but the relative transfer percentage of cobalt from synovial fluid to blood was higher in patients with a pseudotumour. CONCLUSIONS: The implant orientation alone does not explain the metal concentrations found in tissues or distribution of metals between different tissues. The accumulation of metals in periprosthetic soft tissues increase the total metal load, and in the presence of a pseudotumour this is reflected in the transfer ratio of Co from synovial fluid to the blood. The total metal load of the pseudotumour tissue should be defined in future studies to determine if this will provide new insights for clinical practice.

Osteoclasts secrete osteopontin into resorption lacunae during bone resorption.

Osteopontin (OPN) is a non-collagenous extracellular sialylated glycoprotein located in bone. It is believed to be one of the key components in osteoclast attachment to bone during resorption. In this study, we characterized OPN and other glycoproteins found in the resorption lacunae to confirm the role of osteoclasts in OPN secretion using electron microscopy and mass spectrometry. Additionally, we examined the glycan epitopes of resorption pits and the effects of different glycan epitopes on the differentiation and function of osteoclasts. Osteoarthritic femoral heads were examined by immunohistochemistry to reveal the presence of OPN in areas of increased bone metabolism in vivo. Our results demonstrate that human osteoclasts secrete OPN into resorption lacunae on native human bone and on carbonated hydroxyapatite devoid of natural OPN. OPN is associated with an elevated bone turnover in osteoarthritic bone under experimental conditions. Our data further confirm that osteoclasts secrete OPN into the resorption pit where it may function as a chemokine for subsequent bone formation. We show that α2,3- and α2,6-linked sialic acids have a role in the process of osteoclast differentiation. OPN is one of the proteins that has both of the above sialic residues, hence we propose that de-sialylation can effect osteoclast differentiation in bone.

The association between knee breadth and body mass: The Northern Finland Birth Cohort 1966 case study.

OBJECTIVES: Body mass estimation from skeletal dimensions is a useful tool when studying archeological human samples. Bony articular surface dimensions of the lower limb have frequently been utilized to estimate body size. In the present study, we investigated the association between knee breadth and body mass in a Northern European population. Our study aimed to confirm both methodology and results presented in earlier studies. MATERIALS AND METHODS: The study sample consists of 1,290 subjects belonging to the Northern Finland Birth Cohort 1966. Three knee breadth dimensions-femoral biepicondylar breadth, mediolateral breadth of femoral condyles, and mediolateral breadth of the tibial plateau-were measured from subjects' knee PA-radiographs. Measurements and their association with body weight at 31 years were utilized for creating body mass estimation equations using linear regression and reduced major axis regression. Correlations between knee measurements and body weight at three different ages (18, 31, and 46) were also analyzed. RESULTS: Positive associations were detected between each knee breadth variable and weight in the total sample and both genders separately. Body mass estimation equations were created for the total sample, for males and for females. R values of the models ranged from 0.38 to 0.74. Median absolute percent prediction errors ranged from 6.89 to 9.72%. The highest correlations were obtained between knee breadth and body weight in early adulthood. DISCUSSION: Our large sample confirmed that equations derived from knee breadth dimensions are accurate when estimating body mass of modern humans. Knee breadth measurements clearly have a positive association with body weight in early maturity.

Classification of bone flap resorption after cranioplasty: a proposal for a computed tomography-based scoring system.

BACKGROUND: Bone flap resorption (BFR) is the most prevalent complication resulting in autologous cranioplasty failure, but no consensus on the definition of BFR or between the radiological signs and relevance of BFR has been established. We set out to develop an easy-to-use scoring system intended to standardize the interpretation of radiological BFR findings. METHODS: All 45 autologous cranioplasty patients operated on at Oulu University Hospital from 2004 to 2014 were identified, and the bone flap status of all the available patients was evaluated using the new scoring system. Derived from previous literature, a three-variable score for the detection of BFR changes is proposed. The variables "Extent" (estimated remaining bone volume), "Severity" (possible perforations and their measured diameter), and "Focus" (the number of BFR foci within the flap) are scored from 0 to 3 individually. Using the sum of these scores, a score of 0-9 is assigned to describe the degree of BFR. Additionally, independent neurosurgeons assessed the presence and relevance of BFR from the same data set. These assessments were compared to the BFR scores in order to find a score limit for relevant BFR. RESULTS: BFR was considered relevant by the neurosurgeons in 11 (26.8%) cases. The agreement on the relevance of BFR demonstrated substantial strength (κ 0.64, 95%CI 0.36 to 0.91). The minimum resorption score in cases of relevant BFR was 5. Thus, BFR with a resorption score ≥ 5 was defined relevant (grades II and III). With this definition, grade II or III BFR was found in 15 (36.6%) of our patients. No risk factors were found to predict relevant BFR. CONCLUSIONS: The score was proven to be easy to use and we recommend that only cases with grades II and III BFR undergo neurosurgical consultation. However, general applicability can only be claimed after validation in independent cohorts.

Microtubule defects in mesenchymal stromal cells distinguish patients with Progressive Supranuclear Palsy.

Progressive Supranuclear Palsy (PSP) is a rare neurodegenerative disease whose etiopathogenesis remains elusive. The intraneuronal accumulation of hyperphosphorylated Tau, a pivotal protein in regulating microtubules (MT), leads to include PSP into tauopathies. Pathological hallmarks are well known in neural cells but no word yet if PSP-linked dysfunctions occur also in other cell types. We focused on bone marrow mesenchymal stromal cells (MSCs) that have recently gained attention for therapeutic interventions due to their anti-inflammatory, antiapoptotic and trophic properties. Here, we aimed to investigate MSCs biology and to disclose if any disease-linked defect occurs in this non-neuronal compartment. First, we found that cells obtained from patients showed altered morphology and growth. Next, Western blotting analysis unravelled the imbalance in α-tubulin post-translational modifications and in MT stability. Interestingly, MT mass is significantly decreased in patient cells at baseline and differently changes overtime compared to controls, suggesting their inability to efficiently remodel MT cytoskeleton during ageing in culture. Thus, our results provide the first evidence that defects in MT regulation and stability occur and are detectable in a non-neuronal compartment in patients with PSP. We suggest that MSCs could be a novel model system for unravelling cellular processes implicated in this neurodegenerative disorder.

Weak HIF-1alpha expression indicates poor prognosis in resectable pancreatic ductal adenocarcinoma.

BACKGROUND: HIF-1alpha and CAIX proteins are commonly expressed under hypoxic conditions, but other regulatory factors have been described as well. Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxia and strong stromal reaction and has a dismal prognosis with the currently available treatment modalities. METHODS: We investigated the expression and prognostic role of HIF-1alpha and CAIX in PDAC series from Northern Finland (n = 69) using immunohistochemistry. RESULTS: In our PDAC cases, 95 and 85% showed HIF-1alpha and CAIX expression, respectively. Low HIF-1alpha expression correlated with poor prognosis, and multivariate analysis identified weak HIF-1alpha intensity as an independent prognostic factor for PDAC-specific deaths (HR 2.176, 95% CI 1.216-3.893; p = 0.009). There was no correlation between HIF-1alpha and CAIX expression levels, and the latter did not relate with survival. CONCLUSIONS: Our findings are in contrast with previous research by finding an association between low HIF-1alpha and poor prognosis. The biological mechanisms remain speculative, but such an unexpected relation with prognosis and absence of correlation between HIF-1alpha and CAIX suggests that the prognostic association of HIF-1alpha may not directly be linked with hypoxia. Accordingly, the role of HIF-1alpha might be more complex than previously thought and the use of this marker as a hypoxia-related prognostic factor should be addressed with caution.

Metabolism and phospholipid assembly of polyunsaturated fatty acids in human bone marrow mesenchymal stromal cells.

High arachidonic acid (20:4n-6) and low n-3 PUFA levels impair the capacity of cultured human bone marrow mesenchymal stromal cells (hBMSCs) to modulate immune functions. The capacity of the hBMSCs to modify PUFA structures was found to be limited. Therefore, different PUFA supplements given to the cells resulted in very different glycerophospholipid (GPL) species profiles and substrate availability for phospholipases, which have preferences for polar head group and acyl chains when liberating PUFA precursors for production of lipid mediators. When supplemented with 20:4n-6, the cells increased prostaglandin E2 secretion. However, they elongated 20:4n-6 to the less active precursor, 22:4n-6, and also incorporated it into triacylglycerols, which may have limited the proinflammatory signaling. The n-3 PUFA precursor, 18:3n-3, had little potency to reduce the GPL 20:4n-6 content, while the eicosapentaenoic (20:5n-3) and docosahexaenoic (22:6n-3) acid supplements efficiently displaced the 20:4n-6 acyls, and created diverse GPL species substrate pools allowing attenuation of inflammatory signaling. The results emphasize the importance of choosing appropriate PUFA supplements for in vitro hBMSC expansion and suggests that for optimal function they require an exogenous fatty acid source providing 20:5n-3 and 22:6n-3 sufficiently, but 20:4n-6 moderately, which calls for specifically designed optimal PUFA supplements for the cultures.

Tenascin-C and fibronectin expression divide early stage tongue cancer into low- and high-risk groups.

BACKGROUND: Oral tongue squamous cell carcinoma (OTSCC) metastasises early, especially to regional lymph nodes. There is an ongoing debate on which early stage (T1-T2N0) patients should be treated with elective neck dissection. We need prognosticators for early stage tongue cancer. METHODS: Mice immunisation with human mesenchymal stromal cells resulted in production of antibodies against tenascin-C (TNC) and fibronectin (FN), which were used to stain 178 (98 early stage), oral tongue squamous cell carcinoma samples. Tenascin-C and FN expression in the stroma (negative, moderate or abundant) and tumour cells (negative or positive) were assessed. Similar staining was obtained using corresponding commercial antibodies. RESULTS: Expression of TNC and FN in the stroma, but not in the tumour cells, proved to be excellent prognosticators both in all stages and in early stage cases. Among early stages, when stromal TNC was negative, the 5-year survival rate was 88%. Correspondingly, when FN was negative, no cancer deaths were observed. Five-year survival rates for abundant expression of TNC and FN were 43% and 25%, respectively. CONCLUSIONS: Stromal TNC and, especially, FN expressions differentiate patients into low- and high-risk groups. Surgery alone of early stage primary tumours might be adequate when stromal FN is negative. Aggressive treatments should be considered when both TNC and FN are abundant.

Correlations of low-field NMR and variable-field NMR parameters with osteoarthritis in human articular cartilage under load.

NMR experiments carried out at magnetic fields below 1 T provide new relaxation parameters unavailable with conventional clinical scanners. Contrast of T1 generally becomes larger towards low fields, as slow molecular reorientation processes dominate relaxation at the corresponding Larmor frequencies. This advantage has to be considered in the context of lower sensitivity and frequently reduced spatial resolution. The layered structure of cartilage is one example where a particularly strong variation of T1 across the tissue occurs, being affected by degenerative diseases such as osteoarthritis (OA). Furthermore, the presence of 1 H-14  N cross-relaxation, leading to so-called quadrupolar dips in the 1 H relaxation time dispersion, provide insight into the concentration and mobility of proteoglycans and collagen in cartilage, both being affected by OA. In this study, low-field imaging and variable-field NMR relaxometry were combined for the first time for tissue samples, employing unidirectional load to probe the mechanical properties. 20 human knee cartilage samples were placed in a compression cell, and studied by determining relaxation profiles without and with applied pressure (0.6 MPa) at 50 µm in-plane resolution, and comparing with volume-averaged T1 dispersion. Samples were subsequently stored in formalin, prepared for histology and graded according to the Mankin score system. Quadrupolar dips and thickness change under load showed the strongest correlation with Mankin grade. Average T1 and change of maximum T1 under load, as well as its position, correlate with thickness and thickness change. Furthermore, T1 (ω) above 25 mT was found to correlate with thickness change. While volume-averaged T1 is not a suitable indicator for OA, its change due to mechanical load and its extreme values are suggested as biomarkers available in low-field MRI systems. The shape of the dispersion T1 (ω) represents a promising access to understanding and quantifying molecular dynamics in tissue, pointing toward future in vivo tissue studies.

Adenosinergic Immunosuppression by Human Mesenchymal Stromal Cells Requires Co-Operation with T cells.

Mesenchymal stem/stromal cells (MSCs) have the capacity to counteract excessive inflammatory responses. MSCs possess a range of immunomodulatory mechanisms, which can be deployed in response to signals in a particular environment and in concert with other immune cells. One immunosuppressive mechanism, not so well-known in MSCs, is mediated via adenosinergic pathway by ectonucleotidases CD73 and CD39. In this study, we demonstrate that adenosine is actively produced from adenosine 5'-monophosphate (AMP) by CD73 on MSCs and MSC-derived extracellular vesicles (EVs). Our results indicate that although MSCs express CD39 at low level and it colocalizes with CD73 in bulge areas of membranes, the most efficient adenosine production from adenosine 5'-triphosphate (ATP) requires co-operation of MSCs and activated T cells. Highly CD39 expressing activated T cells produce AMP from ATP and MSCs produce adenosine from AMP via CD73 activity. Furthermore, adenosinergic signaling plays a role in suppression of T cell proliferation in vitro. In conclusion, this study shows that adenosinergic signaling is an important immunoregulatory mechanism of MSCs, especially in situations where ATP is present in the extracellular environment, like in tissue injury. An efficient production of immunosuppressive adenosine is dependent on the concerted action of CD39-positive immune cells with CD73-positive cells such as MSCs or their EVs.

Telomeric G-quadruplex-forming DNA fragments induce TLR9-mediated and LL-37-regulated invasion in breast cancer cells in vitro.

Toll-like receptor 9 (TLR9) is a cellular DNA-receptor widely expressed in cancers. We previously showed that synthetic and self-derived DNA fragments induce TLR9-mediated breast cancer cell invasion in vitro. We investigated here the invasive effects of two nuclease-resistant DNA fragments, a 9-mer hairpin, and a G-quadruplex DNA based on the human telomere sequence, both having native phosphodiester backbone. Cellular uptake of DNAs was investigated with immunofluorescence, invasion was studied with Matrigel-assays, and mRNA and protein expression were studied with qPCR and Western blotting and protease activity with zymograms. TLR9 expression was suppressed through siRNA. Although both DNAs induced TLR9-mediated changes in pro-invasive mRNA expression, only the telomeric G-quadruplex DNA significantly increased cellular invasion. This was inhibited with GM6001 and aprotinin, suggesting MMP- and serine protease mediation. Furthermore, complexing with LL-37, a cathelicidin-peptide present in breast cancers, increased 9-mer hairpin and G-quadruplex DNA uptake into the cancer cells. However, DNA/LL-37 complexes decreased invasion, as compared with DNA-treatment alone. Invasion studies were conducted also with DNA fragments isolated from neoadjuvant chemotherapy-treated breast tumors. Also such DNA induced breast cancer cell invasion in vitro. As with the synthetic DNAs, this invasive effect was reduced by complexing the neoadjuvant tumor-derived DNAs with LL-37. We conclude that 9-mer hairpin and G-quadruplex DNA fragments are nuclease-resistant DNA structures that can act as invasion-inducing TLR9 ligands. Their cellular uptake and the invasive effects are regulated via LL-37. Although such structures may be present in chemotherapy-treated tumors, the clinical significance of this finding requires further studying.

MRI-guidance in percutaneous core decompression of osteonecrosis of the femoral head.

OBJECTIVES: The purpose of this study was to evaluate the usefulness of MRI-guidance for core decompression of avascular necrosis of the femoral head. MATERIALS AND METHODS: Twelve MRI-guided core decompressions were performed on patients with different stages of avascular necrosis of the femoral head. The patients were asked to evaluate their pain and their ability to function before and after the procedure and imaging findings were reviewed respectively. RESULTS: Technical success in reaching the target was 100 % without complications. Mean duration of the procedure itself was 54 min. All patients with ARCO stage 1 osteonecrosis experienced clinical benefit and pathological MRI findings were seen to diminish. Patients with more advanced disease gained less, if any, benefit and total hip arthroplasty was eventually performed on four patients. CONCLUSIONS: MRI-guidance seems technically feasible, accurate and safe for core decompression of avascular necrosis of the femoral head. Patients with early stage osteonecrosis may benefit from the procedure. KEY POINTS: • MRI is a useful guidance method for minimally invasive musculoskeletal interventions. • Bone drilling seems beneficial at early stages of avascular necrosis. • MRI-guidance is safe and accurate for bone drilling.

Association between quantitative MRI and ICRS arthroscopic grading of articular cartilage.

PURPOSE: To investigate the association of quantitative magnetic resonance imaging (qMRI) parameters with arthroscopic grading of cartilage degeneration. Arthroscopy of the knee is considered to be the gold standard of osteoarthritis diagnostics; however, it is operator-dependent and limited to the evaluation of the articular surface. qMRI provides information on the quality of articular cartilage and its changes even at early stages of a disease. METHODS: qMRI techniques included T 1 relaxation time, T 2 relaxation time, and delayed gadolinium-enhanced MRI of cartilage mapping at 3 T in ten patients. Due to a lack of generally accepted semiquantitative scoring systems for evaluating severity of cartilage degeneration during arthroscopy, the International Cartilage Repair Society (ICRS) classification system was used to grade the severity of cartilage lesions. qMRI parameters were statistically compared to arthroscopic grading conducted with the ICRS classification system. RESULTS: qMRI parameters were not linearly related to arthroscopic grading. Spearman's correlation coefficients between qMRI and arthroscopic grading were not significant. The relative differences in qMRI parameters of superficial and deep cartilage varied with degeneration, suggesting different macromolecular alterations in different cartilage zones. CONCLUSIONS: Results suggest that loss of cartilage and the quality of remaining tissue in the lesion site may not be directly associated with each other. The severity of cartilage degeneration may not be revealed solely by diagnostic arthroscopy, and thus, qMRI can have a role in the investigation of cartilage degeneration.

Multiparametric MRI assessment of human articular cartilage degeneration: Correlation with quantitative histology and mechanical properties.

PURPOSE: To evaluate the sensitivity of quantitative MRI techniques (T1 , T1,Gd , T2 , continous wave (CW) T1ρ dispersion, adiabatic T1ρ , adiabatic T2ρ , RAFF and inversion-prepared magnetization transfer (MT)) for assessment of human articular cartilage with varying degrees of natural degeneration. METHODS: Osteochondral samples (n = 14) were obtained from the tibial plateaus of patients undergoing total knee replacement. MRI of the specimens was performed at 9.4T and the relaxation time maps were evaluated in the cartilage zones. For reference, quantitative histology, OARSI grading and biomechanical measurements were performed and correlated with MRI findings. RESULTS: All MRI parameters, except T1,Gd , showed statistically significant differences in tangential and full-thickness regions of interest (ROIs) between early and advanced osteoarthritis (OA) groups, as classified by OARSI grading. CW-T1ρ showed significant dispersion in all ROIs and featured classical laminar structure of cartilage with spin-lock powers below 1000 Hz. Adiabatic T1ρ , T2ρ , CW-T1ρ, MT, and RAFF correlated strongly with OARSI grade and biomechanical parameters. CONCLUSION: MRI parameters were able to differentiate between early and advanced OA. Furthermore, rotating frame methods, namely adiabatic T1ρ , adiabatic T2ρ , CW-T1ρ , and RAFF, as well as MT experiment correlated strongly with biomechanical parameters and OARSI grade, suggesting high sensitivity of the parameters for cartilage degeneration. Magn Reson Med 74:249-259, 2015. © 2014 Wiley Periodicals, Inc.

Mesenchymal stromal cells from female donors enhance breast cancer cell proliferation in vitro.

The interplay between tumor stroma and breast cancer cells (BCCs) is thought to play a significant role in breast cancer. The current knowledge of human mesenchymal stromal cell (MSC) and BCC interaction is contradictory, and the donor sex issue is not addressed at all. We hypothesized that donor sex could have an effect on proliferation of MSCs or BCCs in co-culture in vitro. Three estrogen receptor-negative BCC lines, 19 primary human MSCs and breast tissue-derived fibroblasts from 4 donors were used. MSCs from female donors enhanced BCC proliferation (p = 0.005). The change in BCC proliferation was only partly due to soluble factors excreted by MSCs. The highly aggressive BCC line MDA-MB- 231 induced the proliferation of MSCs (p < 0.001) and fibroblasts (p = 0.037) in co-culture experiments. The magnitude in proliferation change was cell line dependent and partly sex dependent.