Hematopoietic insufficiency is the hallmark of acute myeloid leukemia (AML) and predisposes patients to life-threatening complications such as bleeding and infections. Addressing the contribution of ...mesenchymal stromal cells (MSC) to AML-induced hematopoietic failure we show that MSC from AML patients (n=64) exhibit significant growth deficiency and impaired osteogenic differentiation capacity. This was molecularly reflected by a specific methylation signature affecting pathways involved in cell differentiation, proliferation and skeletal development. In addition, we found distinct alterations of hematopoiesis-regulating factors such as Kit-ligand and Jagged1 accompanied by a significantly diminished ability to support CD34+ hematopoietic stem and progenitor cells in long-term culture-initiating cells (LTC-ICs) assays. This deficient osteogenic differentiation and insufficient stromal support was reversible and correlated with disease status as indicated by Osteocalcin serum levels and LTC-IC frequencies returning to normal values at remission. In line with this, cultivation of healthy MSC in conditioned medium from four AML cell lines resulted in decreased proliferation and osteogenic differentiation. Taken together, AML-derived MSC are molecularly and functionally altered and contribute to hematopoietic insufficiency. Inverse correlation with disease status and adoption of an AML-like phenotype after exposure to leukemic conditions suggests an instructive role of leukemic cells on bone marrow microenvironment.
Ineffective hematopoiesis is a major characteristic of myelodysplastic syndromes (MDS) causing relevant morbidity and mortality. Mesenchymal stromal cells (MSC) have been shown to physiologically ...support hematopoiesis, but their contribution to the pathogenesis of MDS remains elusive. We show that MSC from patients across all MDS subtypes (n=106) exhibit significantly reduced growth and proliferative capacities accompanied by premature replicative senescence. Osteogenic differentiation was significantly reduced in MDS-derived MSC, indicated by cytochemical stainings and reduced expressions of Osterix and Osteocalcin. This was associated with specific methylation patterns that clearly separated MDS-MSC from healthy controls and showed a strong enrichment for biological processes associated with cellular phenotypes and transcriptional regulation. Furthermore, in MDS-MSC, we detected altered expression of key molecules involved in the interaction with hematopoietic stem and progenitor cells (HSPC), in particular Osteopontin, Jagged1, Kit-ligand and Angiopoietin as well as several chemokines. Functionally, this translated into a significantly diminished ability of MDS-derived MSC to support CD34+ HSPC in long-term culture-initiating cell assays associated with a reduced cell cycle activity. Taken together, our comprehensive analysis shows that MSC from all MDS subtypes are structurally, epigenetically and functionally altered, which leads to impaired stromal support and seems to contribute to deficient hematopoiesis in MDS.
Amorphous carbon films are deposited employing high power impulse magnetron sputtering (HiPIMS) at pulsing frequencies of 250Hz and 1kHz. Films are also deposited by direct current magnetron ...sputtering (dcMS), for reference. In both HiPIMS and dcMS cases, unipolar pulsed negative bias voltages up to 150V are applied to the substrate to tune the energy of the positively charged ions that bombard the growing film. Plasma analysis reveals that HiPIMS leads to generation of a larger number of ions with larger average energies, as compared to dcMS. At the same time, the plasma composition is not affected, with Ar+ ions being the dominant ionized species at all deposition conditions. Analysis of the film properties shows that HiPIMS allows for growth of amorphous carbon films with sp3 bond fraction up to 45% and density up to 2.2gcm−3. The corresponding values achieved by dcMS are 30% and 2.05gcm−3, respectively. The larger fraction of sp3 bonds and mass density found in films grown by HiPIMS are explained in light of the more intense ion irradiation provided by the HiPIMS discharge as compared to the dcMS one.
► Amorphous carbon films are grown employing HIPIMS as well as dcMS, for reference. ► HiPIMS provides larger fluxes of Ar+ ions the growing film compared to dcMS. ► HiPIMS films are denser with larger fraction of sp3 bonds compared to dcMS.
Our understanding of the origin of hip pain in degenerative disorders of the hip, including primary osteoarthritis, avascular necrosis and femoroacetabular impingement (FAI), is limited. We undertook ...a histological investigation of the nociceptive innervation of the acetabular labrum, ligamentum teres and capsule of the hip, in order to prove pain- and proprioceptive-associated marker expression. These structures were isolated from 57 patients who had undergone elective hip surgery (44 labral samples, 33 ligamentum teres specimens, 34 capsular samples; in 19 patients all three structures were harvested). A total of 15,000 histological sections were prepared that were investigated immunohistochemically for the presence of protein S-100, 68 kDa neurofilament, neuropeptide Y, nociceptin and substance P. The tissues were evaluated in six representative areas. Within the labrum, pain-associated free nerve ending expression was located predominantly at its base, decreasing in the periphery. In contrast, the distribution within the ligamentum teres showed a high local concentration in the centre. The hip capsule had an almost homogeneous marker expression in all investigated areas. This study showed characteristic distribution profiles of nociceptive and pain-related nerve fibres, which may help in understanding the origin of hip pain.
Summary Objective To evaluate T2∗ values in various histological severities of osteoarthritis (OA). Method Magnetic resonance imaging (MRI) and T2∗ mapping including a three-dimensional (3D) ...double-echo steady-state (DESS) sequence for morphological cartilage assessment and a 3D multiecho data image combination (MEDIC) sequence for T2∗ mapping were conducted in 21 human femoral head specimens with varying severities of OA. Subsequently, histological assessment was undertaken in all specimens to correlate the observations of T2∗ mapping with histological analyses. According to the Mankin score, four grades of histological changes were determined: grade 0 (Mankin scores of 0–4), grade I (scores of 5–8), grade II (scores of 9–10), and grade III (scores of 11–14). For reliability assessment, cartilage T2∗ measurements were repeated after 4 weeks in 10 randomly selected femoral head specimens. Results T2∗ values decreased significantly with increasing cartilage degeneration (total P -values <0.001) ranging from 36.3 ± 4.3 ms in grade 0 regions to 22.8 ± 4.3 ms in regions with grade III changes. Pearson correlation analysis proved a fair correlation between T2∗ values and Mankin score (correlation coefficient = −0.362) that was statistically significant ( P -value <0.001). Intra-class correlation (ICC) analysis demonstrated high intra-observer reproducibility for the T2∗ measurement (ICC: 0.949, P < 0.001). Conclusions Given the advantages of the T2∗ mapping technique with no need for contrast medium, high image resolution and ability to perform 3D biochemically sensitive imaging, T2∗ mapping may be a strong addition to the currently evolving era of cartilage biochemical imaging.
Knee osteoarthritis is associated with structural changes in the joint. Despite its many drawbacks, radiography is the current standard for evaluating joint structure in trials of potential ...disease-modifying osteoarthritis drugs. MRI is a non-invasive alternative that provides comprehensive imaging of the whole joint. Frequently used MRI measurements in knee osteoarthritis are cartilage volume and thickness; others include synovitis, synovial fluid effusions, bone marrow lesions (BML) and meniscal damage. Joint replacement is considered a clinically relevant outcome in knee osteoarthritis; however, its utility in clinical trials is limited. An alternative is virtual knee replacement on the basis of symptoms and structural damage. MRI may prove to be a good alternative to radiography in definitions of knee replacement. One of the MRI parameters that predicts knee replacement is medial compartment cartilage volume/thickness, which correlates with radiographic joint space width, is sensitive to change, and predicts outcomes in a continuous manner. Other MRI parameters include BML and meniscal lesions. MRI appears to be a viable alternative to radiography for the evaluation of structural changes in knee osteoarthritis and prediction of joint replacement.
Background
Slipped capital femoral epiphysis (SCFE) is a frequent disorder of the adolescent hip, which may lead to avascular necrosis (AVN) of the femoral head, chondrolysis and early osteoarthritis ...due to the post-slip deformity of the proximal femur. To warrant the best possible outcome for the affected (and contralateral) hip, early diagnosis and proper treatment are needed.
Methods
A review of the literature was undertaken to identify today's role of available imaging modalities in the management of SCFE.
Summary
This review outlines the relevancy of different imaging modalities such as radiography, ultrasound, CT, MRI and bone scintigraphy in the treatment of SCFE patients. While standard radiography is the first-choice imaging modality for patients with suspected SCFE, ultrasound and advanced imaging modalities may aid in surgical planning, diagnosis of complications such as AVN and treatment follow-up.
•Patients suffering from SCFE show an increased external hip rotation during gait throughout the entire gait cycle.•Only during hip extension there was a weak correlation between angle α and hip ...rotation.•The weak relationship between offset-loss and external hip rotation during gait suggests that impingement is not experienced during this activity.
Residual deformity of the femoral head after slipped capital femoral epiphysis (SCFE) may be accompanied by a loss of femoral offset and lead to femoro-acetabular impingement (FAI), especially during hip flexion. It is hypothesized that during phases of the gait cycle, when the hip is flexed, the offset-loss is compensated by an increased external rotation. The gait pattern of 36 patients suffering from SCFE, who were treated by pinning-in-situ, were compared to a control group of 40 healthy adults by an instrumented 3D-gait analysis. Total patient group was subdivided into 3 subgroups in dependence on the offset (offset groups (OG)) quantified by the angle α according to Nötzli: OG1: α-angle <55°, OG2: α-angle between 55 and 75°, OG3: α-angle >75°. Comparisons were made at 3 instants: initial foot contact (0% gait cycle (GC)), 40–60% GC and 90–100% GC. Patients showed an increased external hip rotation during all 3 periods of the GC with a tendency of increasing external rotation in association with offset-loss. Only during hip extension (40–60% GC) there was a weak correlation between angle α and hip rotation (r=−0.375, p=0.024). In conclusion, the offset-loss does not lead to a functional relevant impingement during walking which needs compensation strategies like increasing external rotation during periods of hip flexion.
Introducing a new arthroplasty system into clinical routine is challenging and could have an effect on early results. Since UKA are known to have failure mechanisms related to technical factors, ...reliable results and easy adoption are ideal. The question remains whether there are differences in objective procedure parameters in the early learning curve of different UKA systems.
two different UKA implants (Biomet OxfordBO followed by Conformis iuniCI) were introduced consecutively into clinical routine. We retrospectively analyzed the first 20 cases of each implant for one arthroplasty surgeon regarding operating time, correction of the mechanical axis, learning curve parameters, and revision rate of implants for 1.5 years postoperatively.
Operating time (BO:98.3 ± 26.3min, CI:83.85 ± 21.8min (p < 0.078)), and tourniquet time differed in favor of the CI implant (BO:97.5 ± 29.5min; CI:73.5 ± 33.2 min; p < 0.017)). Mechanical alignment was restored in boths (preop:BO:mean 2.9°varus, CI:2.7°varus, postop:BOmean1.3°varus, CI:1°varus), while one BO patient and two CI patients were overcorrected. Operating time decreased from the first five implants to implants 16–20 for CI (95.2 ± 18.5min to 69 ± 21.5min, p < 0.076) and BO (130.6 ± 27.6min to 78 ± 17.3min, p < 0.009). Within 18 months of follow-up, 2 BO and 1 CI implants were revised.
The introduction of an UKA implant was associated with longer surgery in both implants. Procedure time seems to differ between implants, while a learning curve was observed regarding instrumentation. CI implants seem to be reliable and adaptable in a medium-volume practice. The early results of this retrospective single-surgeon study were in favor of the individualized implant. Certainly, further studies encompassing larger cohorts with various implants are needed.
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