Osteogenesis Imperfecta (OI) is a heritable bone disorder characterized by bone fragility and often caused by mutations in the Type I collagen-encoding genes COL1A1 and COL1A2. The pathophysiology of OI, particularly at the cellular level, is still not well understood. This contributes to the lack of a cure for this disorder as well as an effective preventive or management options of its complications. In the bone environment, mesenchymal stem cells (MSCs) and osteoblasts (Ob) exert their function, at least partially, through the
Background. 70% of Breast Cancer patients develop metastatic bone deposits, predominantly spinal metasases. Adult Mesenchymal Stem Cells (MSCs) are multiprogenitor stem cells found within the bone marow which have the ability to self renew and differentiate into multiple cell types. MSCs home specifically to tumour sites, highlighting their potential as delivery vehicles for therapeutic agents. However studies show they may also increase tumour metastatic potential. Aims. The aim of this study was to investigate interactions between MSCs and breast cancer cells to further elucidate their role in the tumour microenvironment and hence understand factors involved in stimulating the formation of bone metastases. Methods. MSCs harvested from the iliac crest of healthy volunteers were grown for collection of conditioned medium (CM), containing all factors secreted by the cells. Breast cancer cell lines (T47D, SK-BR-3, MDA-MB-231) were then cultured in MSC CM +/− antibodies to TGFβ, VEGF, MCP-1 and CCL5 for 72hrs. Cell proliferation was assessed using an Apoglow(r) assay and RNA harvested for analysis of changes in Epithelial Mesenchymal Transition specific gene expression : N-Cadherin, E-Cadherin, Vimentin, Twist, Snail. Results. A significant down regulation of breast cancer cell proliferation in the presence of MSC secreted factors was observed (p<0.05). There was a dramatic increase in expression of EMT specific genes in both cell lines following exposure to MSC-secreted factors. Inclusion of antibodies to TGF, VEGF, MCP-1 and CCL5 inhibited the effect seen, suggesting these paracrine factors played a role in the elevated expression levels. Conclusion. MSCs clearly have a distinct paracrine effect on breast cancer epithelial cells, mediated at least in part through
NICE technology appraisal guidance 157 suggests that the oral anticoagulation medication Dabigatran etexilate (Pradaxa®, Boehringer Ingelheim) can be used for the primary prevention of venous thromboembolic events (VTE's) in adult patients who have undergone elective total hip (THR) or knee replacement (TKR) surgery. The NICE guidance and the Pradaxa® Summary of Product characteristics (SPC) report that 13.8% of patients receiving recommended doses of Dabigatran experience adverse bleeding events. In the manufacturer's pivotal clinical trials, wound
Total joint replacement (TJR) is by far the most effective therapy for end-stage OA patients. Most of patients achieve joint pain reduction and function improvement following to TJR, however up to 22% of them either do not improve or deteriorate after surgery. The aim of this study was to identify genetic variants to be associated with poor outcome of TJR in primary OA patients by a genome-wide association approach (GWAS). Study participants were primary OA patients from the Newfoundland Osteoarthritis Study (NFOAS) that comprised total knee or hip replacement and recruited before 2016 in St. John's, NL. DNA samples were extracted from patients' blood. Study participants completed their pre-operation and 3.99±1.38 years post-surgery outcome assessment using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). DNA samples were genotyped using the genome-wide Illumina HumanOmni2.58 genotyping microarray containing 2.4 million SNPs. Pre-association quality control filtering was conducted for the raw genotyping data using PLINK 1.7 program, and genotype imputation was performed using the IMPUTE2 algorithm with multiple population reference data from 1000 Genome Project. The imputed data with ∼3.1 million variants was used to test the association with non-responders to TJR using the additive genetic model. Eighty three primary OA patients (44 responders and 39 non-responders) were included in the analysis. Association analysis detected three chromosomal regions on chr5, 7, and 8 to be significantly associated with non-responding to pain. The top SNPs at these loci are intergenic variants that include SNP (rs17118094, p=4.4×10-5) on chr5. This SNP is adjacent to SGCD gene that plays an important role in muscular strength and maintenance. Another associated SNP (rs71572810, p=4.7×10-5) is nearby IMMP2L gene on chr7. This gene is reported to be associated with behavioral abnormalities. Finally, SNP (rs6992938, p=5.8×10-5) on chr8 is located downstream of TRPA1 gene that is known to have a central role in the pain response to endogenous inflammatory mediators. Three loci were also found to be significantly associated with non-responding to function. The lead variant in the locus on chr1 is an intergenic SNP (rs9729377, p=1.7×10-5) falling between CTBS and MCOLN2 genes. CTBS gene is associated with TNF-α, a cytokine that stimulate the inflammation acute phase reaction, and MCOLN2 gene plays a role in the chemokine
Noting a decreasing number of transfemoral amputations following infection of Total Knee Arthroplasty (TKA) I studied a case of a patient which suffered an amputation following infection of TKA by MRSA. With assistance of all hospitals and the NHS it was able to classify all costs of this poor case. This study exposes a drama of a person which received a Total Knee Arthroplasty in the right knee at 66.0 years. 2 weeks after the implantation of TKA she presented a wound
Adolescent idiopathic scoliosis (AIS) is a poorly understood progressive curvature of the spine. The 3-dimmensionnal spinal deformation brings abnormal biomechanical stresses on the load-bearing organs. We have recently reported for the first time the presence of facet joint cartilage degeneration comparable to age-related osteoarthritis in scoliotic adolescents. To better understand the degenerative mechanisms and explore new therapeutic possibilities, we focused on Toll-like receptors (TLRs) which are germline-encoded pattern recognition receptors that recognize pathogens and endogenous proteins such as fragmented extracellular matrix components (alarmins) present in intervertebral discs (IVD) and articular cartilage. Once activated, they regulate the production pro-inflammatory cytokines, proteases and neurotrophins which can lead to matrix catabolism, inflammation and potentially pain. These mechanisms have however not been studied in the context of AIS or facet joints. Facet joints of AIS patients undergoing corrective surgery and of cadaveric donors (non-scoliotic) were collected from consenting patients or organ donors with ethical approval. Cartilage biopsies and chondrocytes were isolated using 3mm biopsy punches and collagenase type 2 digestion respectively. qPCR was used to assess gene expression of the degenerative factors (MMP3, MMP13, IL-1ß, IL-6, IL-8) The biopsies were cut into two equal halves, one was treated for 4 days with a TLR2 agonist (Pam2CSK4, Invivogen) in serum-free chondrocyte media while the other one was cultured in media alone. MMP3, MMP13, IL-6 and IL-8 ELISAs and DMMB assays were performed on the biopsy cultured media. The ex vivo cartilage was then fixed, cryosectionned and also stained with SafraninO-Fast Green dyes. Baseline gene expression levels of TLR1,−2,−4,−6 were all upregulated in scoliotic chondodryctes compared to non-scoliotic. Pearson correlation analysis revealed that all TLR1,−2,−4,−6 gene expression correlated strongly and significantly with degenerative markers (MMP3, MMP13, IL-6, IL-8) in scoliotic chondrocytes but not in non-scoliotic. (Figure 1) When monolayer facet joint chondrocytes were activated with Pam2CSk4, there was a significant upregulation in previously described degenerative markers, TLR2 and NGF, a potent neurotrophin. These findings were strengthened by protein
The clinical case refers to a male patient, 34 years old, admitted at the Emergency Department after a fall of 2 meters. Of that trauma, resulted an exposed Monteggia fracture type III – Gustillo & Anderson IIA – on his left arm. With this work, the authors intend to describe the evolution of the patient's clinical condition, as well as the surgical procedures he was submitted to. The authors used the patient's records from Hospital's archives, namely from the Emergency Department, Operating Room, Infirmary and Consultation, and also the diagnostic exams performed throughout the patient's clinical evolution. The clinical case began in December 2011, when the patient suffered a fall of 2 meters in his workplace. From the evaluation in the Emergency Department, it was concluded that the patient presented, at the left forearm, an exposed Monteggia type III fracture – Gustillo & Anderson IIA – combined with a comminuted fracture of the radial head. At the admission day, the wound site was thoroughly rinsed, the fracture was reduced and immobilized with an above-the-elbow cast, and antibiotics were initiated. Six days after admission, the patient was submitted to open reduction with internal fixation with plate and screws of the fracture of the ulna and radial head arthroplasty. The postoperative period was uneventful. Two months after the surgical procedure, inflammatory signals appeared with purulent
Osteochondral (OC) defects of the knee are associated with pain and significant limitation of activity. Studies have demonstrated the therapeutic efficacy of mesenchymal stem cell (MSC) therapies in treating osteochondral defects. There is increasing evidence that the efficacy of MSC therapies may be a result of the paracrine
NICE technology appraisal guidance 157 suggests that the oral anticoagulation medication Dabigatran etexilate can be used for the primary prevention of venous thromboembolic events (VTE's) in adult patients who have undergone elective total hip or knee replacement surgery. The NICE guidance reports that 13.8% of patients receiving recommended doses of Dabigatran experienced adverse bleeding events. In the pivotal hip and knee VTE trial, wound
Aim. Posttraumatic pelvic-osteomyelitis is one of the most serious complications after pelvic-fractures. The necessary extensive surgical debridement as part of interdisciplinary treatment is complicated by the possible persistence of pelvic instability. The aim of this study was to determine the outcome and outline the course of treatment after early posttraumatic pelvic bone infections due to type-C pelvic ring injuries. Method. In a retrospective cohort study (2005–2015) all patients with pelvic-osteomyelitis within six weeks of surgical stabilization of a type-C pelvic-fracture were assessed. Microbiological results, risk factors, course of treatment and functional long-term outcome using the Orlando-Pelvic-Score were analyzed. Results. A total of 18 patients (age 43.7 years; Body-Mass-Index 27.9 kg/m2; ASA-physical-status 1.8; Injury-Severity-Score 38) developed a pelvic-osteomyelitis within an average of 27 days after internal surgical stabilization of a type-C pelvic injury (AO-type C1: 10, C2: 4, C3: 4). Os pubis was affected in 7 and Os ilium in 11 cases. In addition to the pelvic-fracture, major vascular injuries occurred in 8, nerve injuries in 9, and intestinal and/or bladder ruptures in 11 cases. In 14 cases a mass transfusion was necessary. In addition to clinical signs of inflammation, (10 × redness, 12 × wound
Aim. The current treatment concepts of acute and chronic osteomyelitis are associated with unsolved challenges and problems, underlining the need for ongoing medical research. The invention and prevalence of an absorbable, gentamicin-loaded ceramic bone graft, that is well injectable for orthopedic trauma and bone infections, enlarges the treatment scope regarding the rise of posttraumatic deep bony infections. This substance can be used either for infection, dead-space, or reconstruction management. The bone cement, eluting antibiotics continuously to the surrounding tissue, outperforms the intravenous antibiotic therapy and enhances the local concentration levels efficiently. This study aims to evaluate the power and practicability of bone cement in several locations of bony infections. Method. The occurrence of posttraumatic infections with acute or chronic osteomyelitis increases in trauma surgery along with progression of high impact injuries and consecutively high incidence of e.g. open fractures. We present a case-series of 33 patients (18w/15m; 56,8±19,4 years) with posttraumatic osteomyelitis at different anatomic sites, who were treated in our level I trauma center. All of these patients received antibiotic eluting bone cement (Cerement® G) for infection and reconstruction management. Results. With admission to our trauma-center all patients with obvious or suspected osteomyelitis undergo an interdisciplinary pre-work up, including thorough clinical examination and different measures of diagnostic imaging, ultimately leading to the definition of an individual treatment plan. We diagnosed 33 bone infections anatomically allocated to the proximal and distal femur (12x), the pelvis (2x), distal tibia (3x), tibial diaphysis (10x), the ankle joint (4x) and calcaneus (2x). According to Cierny-Mader we diagnosed grade I (6), II (7), III (13) and IV (7). These 33 patients were treated (1) with surgical debridement, (2) with Cerament G, (3) bone stabilisation (including nail osteosynthesis, arthrodesis nails, plates, or external ring fixation), (4) optionally VAC-conditioning, and (5) optionally soft tissue closure with local or free flaps. The overall number of surgery was 2.9±2.26. We observed very good clinical, functional and radiological results by using bone cement augmented with gentamicin. The overall recurrence rate of infection is low (12%, 4/33). “White fluid”
Chronic osteomyelitis (COM) of the lower limb in adults can be surgically managed by either limb reconstruction or amputation. This scoping review aims to map the outcomes used in studies surgically managing COM in order to aid future development of a core outcome set. A total of 11 databases were searched. A subset of studies published between 1 October 2020 and 1 January 2011 from a larger review mapping research on limb reconstruction and limb amputation for the management of lower limb COM were eligible. All outcomes were extracted and recorded verbatim. Outcomes were grouped and categorized as per the revised Williamson and Clarke taxonomy.Aims
Methods
This study explored the shared genetic traits and molecular interactions between postmenopausal osteoporosis (POMP) and sarcopenia, both of which substantially degrade elderly health and quality of life. We hypothesized that these motor system diseases overlap in pathophysiology and regulatory mechanisms. We analyzed microarray data from the Gene Expression Omnibus (GEO) database using weighted gene co-expression network analysis (WGCNA), machine learning, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to identify common genetic factors between POMP and sarcopenia. Further validation was done via differential gene expression in a new cohort. Single-cell analysis identified high expression cell subsets, with mononuclear macrophages in osteoporosis and muscle stem cells in sarcopenia, among others. A competitive endogenous RNA network suggested regulatory elements for these genes.Aims
Methods
Aim. The current treatment concepts of acute and chronic osteitis are associated with unsolved challenges and problems, underlining the need for ongoing medical research. The invention and prevalence of an absorbable, gentamicin-loaded ceramic bone graft, that is well injectable for orthopedic trauma and bone infections, enlarges the treatment scope regarding the rise of posttraumatic deep bone infections. This substance can be used either for infection, dead-space, or reconstruction management. The bone cement, eluting antibiotics continuously to the surrounding tissue, outperforms the intravenous antibiotic therapy and enhances the local concentration levels efficiently. This study aims to evaluate the power and practicability of bone cement in several locations of bone infections. Method. The occurrence of posttraumatic infections with acute or chronic osteitis increases in trauma surgery along with progression of high impact injuries and consecutively high incidence of e.g. open fractures. We present a case-series of 10 patients with posttraumatic osteitis at different anatomic sites, who were treated in our level I trauma center. All of these patients received antibiotic eluting bone cement* for infection and reconstruction management. Results. With admission to our trauma-center all patients with obvious or suspected osteitis undergo an inter-disciplinary pre-work up, including thorough clinical examination and different measures of diagnostic imaging, ultimately leading to the definition of an individual treatment plan. We diagnosed 10 bone infections anatomically allocated to the proximal (2x) and distal femur (3x), distal tibia (3x), tibial diaphysis (1x) and the ankle joint (1x). These ten patients were treated (1) with surgical debridement, (2) with an antibiotic eluting bone cement*, (3) bone stabilisation (including nail osteosynthesis, arthrodesis nails, plates, or external ring fixation), (4) optionally VAC-conditioning, and (5) optionally soft tissue closure with local or free flaps. We observed very good clinical, functional and radiological results by using bone cement augmented with gentamicin. The overall treatment failure rate is low, throughout, all patients showed no signs of acute recurrence of infection. Pain and immobility decreased continuously with time. “White fluid”
The appearance of a tumor as a result of chronic osteomyelitis is a relatively rare complication and of late-onset, with a low frequence in the modern world. For the majority of patients, the interval between the onset of primitive osteomyelitis and malignant degeneration is of several decades. We present our cases and the protocol of treatment used. From January 1977 to December 2014 we treated 36 patients (33M, 3F) suffering from squamous cell tumor out of a series of 247 tibial and 74 calcaneal osteomyelitis. 26 patients had chronic osteomyelitis of tibia, 10 of the calcaneus. Based on the functional needs of patients after resection of the tumor, in 18 we applied the Ilizarov apparatus, in 14 we opted for a two steps surgery, with the help of plastic surgeon; four required amputation. 29 patients healed. After 2-years of follow up 3 patients underwent to an amputation in the proximal third of the leg, 4 had a local recurrence. All patients were assessed by SF32 and the QoL test. Squamous cell tumor is the most common malignant tumor in chronic osteomyelitis. For the diagnosis of malignant transformation from a chronic ulcer there is a thorough process. Serial biposies must be performed, especially with the emergence of new clinical signs (increased pain, a bad smell, and changes in
Osteomyelitis is an infectious process in bone occasionally leading to bone destruction. Traditionally a two-stage operation is performed using PMMA + antibiotic beads or a spacer. In the second operation the void filler is removed and the defect is filled with autologous bone. Bioactive glass (BAG) S53P4 is an antibacterial biodegradable bone substitute. This feature is based on an increase in pH and the osmotic pressure around the BAG, a phenomenon which has been shown to kill both planktonic bacteria and bacteria in biofilm in-vitro. We analyzed retrospectively our early results of osteomyelitis patients treated with BAG from the patient's clinical history. The diagnosis was stated in addition to bacterial samples by MRI, CT and plain radiographs or by a combination of these. Between 2007–2013 we applied BAG as a void-filler in 20 cases (15 male and 5 female) of osteomyelitis in the lower (19) or the upper (1) limb in one-stage procedure. The patients had been suffering from symptoms of osteomyelitis a mean 3,5 months (0,25–24,00) and had a history of mean 3,5 (1–11) earlier operations. Osteomyelitis was estimated to be healed when the enclosed systemic antibiotic treatment and clinical controls were carried out and the patient didn't have symptoms of a persisting disease. The average postoperative follow up was 7,8 (3,0–59,0) months. Fifteen (75%) of the patients healed. One patient run out of controls, but was symptom free during his last visit. In four cases we had to remove the bioactive glass because of continuous
Bone metastases are common and severe complications of cancers. It is estimated to occur in 65–75% of breast and prostate cancer patients and cause 80% of breast cancer-related deaths. Metastasised cancer cells have devastating impacts on bone due to their ability to alter bone remodeling by interacting with osteoblasts and osteoclasts. Exercise, often used as an intervention for cancer patients, regulates bone remodeling via osteocytes. Therefore, we hypothesise that bone mechanical loading may regulate bone metastases via osteocytes. This provides novel insights into the impact of exercises on bone metastases. It will assist in designing cancer intervention programs that lowers the risk for bone metastases. Investigating the mechanisms for the observed effects may also identify potential drug targets. MLO-Y4 osteocyte-like cells (gift of Dr. Bonewald, University of Missouri-Kansas City) on glass slides were placed in flow chambers and subjected to oscillatory fluid flow (1Pa; 1Hz; 2 hours). Media were extracted (conditioned media; CM) post-flow. RAW264.7 osteoclast precursors were conditioned in MLO-Y4 CM for 7 days. Migration of MDA-MB-231 breast cancer cells and PC3 prostate cancer cells towards CM was assayed using Transwell. Viability, apoptosis, and proliferation of the cancer cells in the CM were measured with Fixable Viability Dye eFluor 450, APOPercentage, and BrDu, respectively. P-values were calculated using Student's t-test. Significantly more MDA-MB-231 and PC3 cells migrated towards the CM from MLO-Y4 cells with exposure to flow in comparison to CM from MLO-Y4 cells not exposed to flow. The preferential migration is abolished with anti-VEGF antibodies. MDA-MB-231 cells apoptosis rate was slightly lower in CM from MLO-Y4 cells exposed to flow, while proliferation rate was slightly higher. The current data showed no difference in cancer cells viability and adhesion to collagen between any two groups. On the other hand, it was observed that less MDA-MB-231 cells migrated towards CM from RAW264.7 cells conditioned in CM from MLO-Y4 cells stimulated with flow in comparison to those conditioned in CM from MLO-Y4 cells not stimulated with flow. TRAP staining results confirmed that there were less differentiated osteoclasts when RAW264.7 cells were cultured in CM from MLO-Y4 cells exposed to flow. Overall, this study suggests that when only osteocytes and cancer cells are involved, osteocytes subjected to mechanical loading can promote metastases due to the increased
After a few years from its introduction, the limits of the THA became evident, mainly due to high rates of mobilization for polyethylene wear and to the release of metal ions from MOM and MOP couplings. Ceramic bearings were thus introduced in surgery to obtain lower levels of friction and wear. These issues have now been well recognized by several studies, which show that ceramic-on-ceramic joint has the lowest wear rate among various articulations and that ceramic particles induce less macrophage reaction and decrease cytokine
Introduction:. 20 cases of bone defect have been treated by the induced membrane technique avoiding allograft, microsurgery and amputation. Material and Methods:. 9 cases of long bone defect (humerus and forearm) and 11 cases of bone defect at the hand have been included in this multicentre prospective study (3 centers). The aetiology in 11 cases was trauma, 7 cases were septic nonunions and 2 cases followed tumors. In the hand the bone loss was at least one phalanx, and for long bones the mean defect was 5 cm (3–11). All cases were treated by the induced membrane technique which consists in stable fixation, flap if necessary and in filling the void created by the bone defect by a cement spacer (PMMA). This technique needs a second stage procedure at the 2. nd. month where the cement is removed and the void is filled by cancellous bone. The key point of this induced membrane technique is to respect the foreign body membrane which appeared around the cement spacer and which creates a biologic chamber for the second procedure. Bone union was evaluated prospectively in each case by a surgeon not involved in the treatment, by X-ray and CT scan. Failure was defined as a nonunion at 1 year, or an uncontrolled sepsis at 1 month. Results:. 3 cases failed to achieve bone union, 2 in the hand and 1 in a long bone. No septic complications occurred and all septic cases healed. In 14 cases bone union was achieved with a delay of 5 months (1, 5–12). 2 biopsies allowed us to prove that osteoid tissue was created by the technique. At hand level all fingers have included. At shoulder and elbow level, function reached 75% of motion of the contralateral side. Discussion:. Masquelet first reported 35 cases of large bone defect of tibia nonunion treated by the induced membrane technique which allow filling a bone defect with cancellous bone alone. The cement spacer induces a foreign body membrane (neo periosteum) which constitute a biological chamber. Animal models showed the properties of the membrane:
Over 80% of patients with advanced breast cancer will develop bone metastases for which there is no cure. Although thought to involve a complex cascade of cell-cell interactions, the factors controlling the development of bone metastases are still poorly understood. Osteoblasts may have an important role in mediating homing and proliferation of breast cancer cells to the bony environment. This study aimed to examine the potential role osteoblasts have in the migration of circulating tumour cells to bone and the factors involved in this attraction. Culture of osteoblasts and MDA-MB-231 breast cancer cells was performed. Breast cancer cell migration in response to osteoblasts was measured using Transwell Migration Inserts. Potential mediators of cell migration were detected using ChemiArray & ELISA assays. A luminometer based Vialight assay was used to measure breast cancer cell proliferation in response to factors secreted by osteoblasts. There was a 3-4 fold increase of MDA-MB-231 migration in response to osteoblasts. ChemiArray analysis of osteoblast-conditioned medium revealed a range of secreted chemokines including IL-6 & 8, TIMP 1 & 2 and MCP-1. Initially, MCP-1 was quantified at 282 pg/ml, but rose to over 9000 pg/ml when osteoprogenitor cells were differentiated into mature osteoblasts. Inclusion of a monoclonal antibody to MCP-1 in osteoblast-conditioned medium resulted in a significant decrease in breast cancer cell migration to osteoblasts. There was no significant change in proliferation of MDA-MB 231 cells when exposed to osteoblast-conditioned medium. Osteoblasts are capable of inducing breast cancer cell migration mediated at least in part by chemokine