Lipoprotein (a) concentration as a risk factor for ischaemic stroke and its subtypes.

AIM OF THE STUDY: To investigate the relationship between serum lipoprotein (a) [Lp(a)] concentration and the risk of ischaemic stroke (IS) and its subtypes. CLINICAL RATIONALE FOR THE STUDY: Lp(a) plays a role in atherogenic, pro-thrombotic, and antifibrinolytic processes. Elevated plasma Lp(a) is a strong independent risk factor for the development and progression of atherosclerotic disease. The association between lipoproteins and IS is more complex than that reported for cardiovascular diseases, with inconsistent and contradictory results from epidemiological studies. MATERIAL AND METHODS: 231 patients with acute IS (defined as cases) and 163 age- and sex-matched control subjects were included in this prospective case-control study. Demographic and clinical variables (i.e. age, sex, smoking, presence of chronic diseases and concomitant medication) and laboratory data (i.e. concentrations of total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, triglycerides, Lp(a), apolipoprotein A1, apolipoprotein B) were recorded. RESULTS: The mean age and the percentage of men did not significantly differ between groups. Compared to controls, there was a significantly higher percentage of cases reported with concomitant diseases: diabetes mellitus, myocardial infarction, ischaemic heart disease, peripheral arterial disease, and atrial fibrillation. The study showed a significantly higher serum Lp(a) concentration in cases than in control subjects (81.81 nmol/L [c.32.7 mg/dL] vs. 59.75 nmol/L [c.23.9 mg/dL]; p = 0.036) and found an association between Lp(a) levels stratified by quartiles and the risk for ischaemic stroke (Q1 [Lp(a) < 13 nmol/L] vs. Q4 [Lp(a) > 117 nmol/L]: OR 2.23; 95% CI 1.23-4.03; p = 0.008). A subgroup analysis based on the TOAST classification of IS also showed a significant association between Lp(a) value of more than 75 nmol/L (30 mg/dL) and the risk of large-artery atherosclerosis stroke compared to the controls (OR 2.4; 95% CI 1.39-3.93; p = 0.001), as well as a statistically non-significant association with other subtypes of IS. The influence of Lp(a) remained significant even after adjusting for established risk factors for IS (OR 1.99; 95% CI 1.05-3.76; p = 0.04; respectively for the large-artery atherosclerotic subtype: OR 2.54; 95% CI 1.39-4.67; p = 0.003). CONCLUSION: We found that Lp(a) is an independent risk factor for ischaemic stroke, and for the large-artery atherosclerotic subtype of ischaemic stroke.

Evaluation of Safety and Efficacy of Traction, Closed Reduction, and Subsequent Hip Fixation in Hilgenreiner Brace in Patients with Severe Forms of Hip Developmental Dysplasia.

Background: Hilgenreiner brace (Hb) was developed to improve hip reduction rate and reduce the incidence of femoral head avascular necrosis (AVN). In children under the age of 18 months with unstable hip joints or a dislocated hip joint, the treatment method involves nonsurgical treatment in most cases. Objectives: To evaluate the effectiveness and safety of traction, closed reduction, and hip fixation in Hb in patients with severe forms of hip developmental dysplasia (DDH) in follow-up. Materials and Methods: Prospective, clinical, cohort observation and retrospective matched-pair analysis. Analysis of medical records was conducted to evaluate the effectiveness of using Hb for treatment of dislocated hip joints in <18-month-old children. The investigated cases were of the dislocated hip joint since DDH was confirmed through clinical and imaging diagnosis and treated by the application of the close reduction method together with Hb, in a nonhuman position (hip joint in 90 degrees of flexion and 80 degrees of abduction). Analysis was carried out using the modified Berkeley's Mckay criteria and hip joint centralization, and evaluation was done using X-ray images according to the basic modified Severin classification system. Results: The use of Hb applied after overhead traction to (mean 22.8 days, confidence level (95%)) 68 hip joints showed a significant improvement (92%) in the treated hips. In summary, only one brace replacement was performed due to swelling of the thigh and fixation pressure, three cases suffered from hip joint redislocation after removing the Hb (5%), and one patient had bilateral avascular necrosis (2.8%). Conclusions: The use of Hb reduced avascular necrosis of the femur head, maintained higher hygiene conditions, and lowered both the risk of cast breakage and skin complications over the use of hip spica as compared to Hb. Hb is more cost-effective, and radiolucency is an additional advantage for this technique. Closed reduction and application of Hb after oral administration of a bolus dose of chlorpromazine chloride or phenobarbital resulted in complication avoidance of total anaesthesia.

A multimodal opioid-sparing pain management following total knee replacement.

OBJECTIVE: The purpose of this study is to compare the pain scores, opioid consumption, and range of motion of the operated knee after total knee replacement (TKR) in the 10-day follow-up period between a traditional opioid-containing pain management protocol and a multimodal opioid-sparing treatment protocol. METHODS: This prospective, randomized, single-center study included 90 patients (24 men and 66 women; mean age 69.7±7.2 years) undergoing TKR for osteoarthritis between October 2019 and October 2020. Patients were randomized into 3 cohorts for comparison: traditional opioid-containing pain management protocol (n=30), multimodal opioid-sparing pain management protocol (n=30), and traditional opioid-containing pain management protocol with additional local infiltration analgesia (LIA). Changes in visual analog scale for pain (VAS), range of motion (ROM), and opioid consumption were compared between groups. RESULTS: A lower mean postoperative VAS score was observed in the opioid-sparing cohort, which was statistically significant at all time points compared with the traditional cohorts. Mean total morphine consumption was significantly lower in the opioid-sparing cohort (2.7±5.8 MMEs) compared to the traditional (14.0±14.8 MMEs) and traditional with LIA cohorts (8.3±9.5 MMEs; p<0.05). The mean degree of flexion of the operated knee of patients was significantly greater in patients in the opioid-sparing group than in the other groups on the postoperative day 3 (opioid-sparing: 87.0±11.2°; traditional: 74.1±11.6°; traditional with LIA: 84.7±8.9°; p<0.05), as well as on day 10 (opioid-sparing: 99.3±10.8°; traditional: 87.3±12.4°; traditional with LIA: 92.5±9.7°; p<0.05). The rate of adverse events after TKR did not differ between the groups. CONCLUSION: The results of this study suggest that a multimodal opioid-sparing pain protocol after TKR, which includes oral non-opioid medications and periarticular injection with bupivacaine, provides better pain relief and early functional gains with fewer rescue opioids compared to traditional opioid-based protocols (Tab. 4, Fig. 2, Ref. 22).

The Role of Synovial Membrane in the Development of a Potential In Vitro Model of Osteoarthritis.

There is a lack of in vitro models able to plausibly represent the inflammation microenvironment of knee osteoarthritis (OA). We analyzed the molecules released from OA tissues (synovial membrane, cartilage, infrapatellar fat pad) and investigated whether the stimulation of human synovial fibroblasts (SFs), with synthetic cytokines (IL-1ß and TNF-α or IFN-γ) or conditioned media (CM) from OA tissues, influence the SFs' response, in the sense of pro-inflammatory cytokines, chemokines, growth factors, and degradative enzymes modulation. Human SFs were obtained from OA synovial membranes. SFs and their CM were analyzed for biomarkers, proliferation rate, protein profile and gene expression, before and after stimulation. Real-time PCR and multiplex assays quantified OA-related gene expression and biomolecule production. Unlike other activators, CM from OA synovial membrane (CM-SM), significantly up-regulated all genes of interest (IL-6, IL-8, MMP-1, MMP-3, RANTES, MCP-1, TSG-6, YKL-40) in SFs. Multiplex immunoassay analysis showed that levels of OA-related cytokines (IL-6, IL-8, MCP 1, IL-1Ra), chemokine (RANTES) and growth factor (VEGF), produced by CM-SM stimulated SFs, increased significantly compared to non-stimulated SFs. Molecules released from the SM from OA patients induces OA-like changes in vitro, in specific OA synovial populations (SFs). These findings promote the use and establish a compelling in vitro model that simulates the versatility and complexity of the OA disease. This model, in the future, will allow us to study new cell therapies or test drugs by reducing or avoiding animal models.

Effect of Intra-Articular Injection of Platelet-Rich Plasma on the Serum Levels of Osteoarthritic Biomarkers in Patients with Unilateral Knee Osteoarthritis.

BACKGROUND: The aim of this study is to determine the effect of three doses of intra-articular injection of platelet-rich plasma (PRP) into the osteoarthritic (OA) knee joint on the functional status and on the changes in the levels of specific OA biomarkers in blood serum. METHODS: Forty patients with unilateral primary knee osteoarthritis were enrolled in this single center, prospective clinical trial. For each patient, three intra-articular PRP injections were administered one week apart. Clinical and laboratory assessment was performed before the first PRP injection (baseline), and 3 months after the third PRP application (3-month follow up). Pain in the affected knee joint was assessed with the Visual Analog Scale for Pain (VAS). Change in clinical status was evaluated with the Western Ontario and McMaster Universities Arthritis Index Questionnaire (WOMAC). Concentrations of 19 biomarkers (EGF, Eotaxin, FGF-2, GRO, IL-10, IL-1RA, IL-8, IP-10, MCP-1, PDGF-AB/BB, RANTES, MMP-3, MMP-13, Collagen type 2, BMP-2, TIMP-1, TIMP-2, TGF beta 1, and COMP) in the serum of studied patients were quantified. RESULTS: At 3-month follow up, there was a significant decrease in the VAS score and significant improvement in the WOMAC score. There was a significant decrease in the levels of Eotaxin, MCP-1, MMP-1, IL-10, EGF, PDGF-AB/BB, TGF- ß1 compared to baseline levels. A significant increase in markers BMP-2, COMP, Collagen type 2 and GRO was found at the same time point. There was no significant change in the concentrations of other biomarkers (FGF-2, IL-1RA, IL-8, IL-10, MMP-3, RANTES, TIMP-1, TIMP-3). CONCLUSIONS: We found an increase in specific pro-anabolic and anti-inflammatory biomarkers with a concomitant decrease in pro-inflammatory biomarkers at 3 months after three intra-articular applications of PRP. Significant improvement in VAS and WOMAC scores was observed. Treatment with PRP may be an effective therapeutic option with anti-inflammatory and regenerative potential in patients with primary knee OA.

A Preliminary Study of Combined Detection of COMP, TIMP-1, and MMP-3 in Synovial Fluid: Potential Indicators of Osteoarthritis Progression.

OBJECTIVE: Osteoarthritis (OA) commonly affects weight-bearing joints and is characterized by articular cartilage breakdown combined with osteophyte formation at the joint margins and chronic nonspecific inflammation of synovium. Understanding the profile of inflammation in a patient population is an essential starting point to predict or prevent OA progression. The aim of this study was to identify the profile of selected biomolecules in synovial fluid (SF) and investigate the correlation according to gender, age, and severity of the disease within patients from among the general knee OA population. DESIGN: In our study SF samples were aspirated from the knees of 65 OA patients (46 patients with early knee OA and 19 patients with end-stage knee OA according to the Kellgren-Lawrence grading scale). The concentration of interleukins (IL-6, IL-8), matrix metalloproteinases (MMP-1, MMP-3, MMP-13), MMPs inhibitors (TIMP-1, TIMP-2), cartilage oligomeric matrix protein (COMP), and adiponectin was analyzed using a multiplex ELISA-based approach. CONCLUSIONS: Our results indicate significant linear correlation of MMP-13 and COMP concentration with age (P < 0.05), but not with OA severity. In fact, 3 of the examined biomolecules, MMP-3 (P < 0.01), TIMP-1 (P < 0.01), and COMP (P < 0.05) significantly correlate with the grade of knee OA and might be associated with OA severity.

Tranexamic acid decreases the risk of revision for acute and delayed periprosthetic joint infection after total knee replacement.

OBJECTIVES: This study aims to analyze the effect of intravenous administration of tranexamic acid (TA) on reducing the risk of revision for acute and delayed periprosthetic joint infection (PJI) after primary total knee replacement (TKR). PATIENTS AND METHODS: This prospective observational cohort study included 1,529 TKRs (396 males, 1,133 females; mean age 67.8 years; range, 44 to 85.1 years) performed between January 2003 and October 2017. We analyzed the revision rate for acute and delayed PJI in a group of 787 TKRs with preoperatively intravenously administered TA (TA group) in comparison with a group of 742 TKRs without administration of TA (non-TA group). Multiple logistic regression analysis was used to evaluate significant predictors of TKR revision for acute and delayed PJI. RESULTS: Revision surgery due to PJI was recorded in one patient in the TA group and eight patients in the non-TA group. Cumulative revision rate of TKR was significantly lower in the TA group (0.13% vs. 1.08%, hazard ratio 0.113; 95% confidence interval [CI] 0.0147-0.937; p=0.043). Multivariate logistic regression analysis confirmed two predictors of revision: being aged over 75 years at the time of primary surgery (odds ratio [OR] 8.464; 95% CI: 2.016-35.54; p=0.004) and male gender (OR: 7.9; 95% CI: 1.879-33.26; p=0.005). The use of TA was shown as the significant protective factor (OR: 0.109; 95% CI: 0.0128-0.929; p=0.043). CONCLUSION: We have found a lower cumulative revision rate of TKR for acute and delayed PJI when TA was used. We think that the preoperative intravenous use of TA may be an effective, safe and inexpensive method for the prevention of PJI.

Comparison of survival rate and risk of revision for mobile-bearing and fixed-bearing total knee replacements.

OBJECTIVES: This study aims to determine whether there is a difference in the rate of survival and risk of revision for mobile-bearing (MB) compared with fixed-bearing (FB) total knee replacements (TKRs). PATIENTS AND METHODS: This prospective observational study included 1,571 cemented non-posterior-stabilized TKRs without patellar resurfacing with the subsequent revision surgery in 63 patients (23 males, 40 females; mean age 69.7 years; range, 46.5 to 85.5 years). The group of FB TKRs consisted of 756 non-revised and 31 revised implants. The group of MB TKRs included 752 non-revised and 32 revised knees. We determined the survival rate of TKR with Kaplan-Meier method and the relative risk (RR) of the revision in relation to the type of the insert. The analysis of the RR was divided into subgroups based on the time to revision and the reason for revision. RESULTS: No significant difference was found between FB and MB TKRs regarding the cumulative survival rate and the RR of total revision for any reasons. In the subgroup of early revisions for any reason, 2.22-fold increased risk of revision was found in the MB (p=0.02). The risk of late revisions for any reason in MB was lower than the risk in FB (RR 0.27; p=0.009). Higher risk of revision for instability was found in the subgroup of early revisions in MB (RR 23.8; p=0.03). MB was associated with significantly lower risk of total (RR 0.46; p=0.049) and late revisions for aseptic loosening (RR 0.14; p=0.008). CONCLUSION: No differences were found in the cumulative survival rates between MB and FB TKRs. MB TKRs were associated with a lower risk of revision due to aseptic loosening in comparison with FB TKRs. MB inserts represented a significant risk factor only for early revisions due to instability.

Influence of Kartogenin on Chondrogenic Differentiation of Human Bone Marrow-Derived MSCs in 2D Culture and in Co-Cultivation with OA Osteochondral Explant.

Articular cartilage has limited capacity for natural regeneration and repair. In the present study, we evaluated kartogenin (KGN), a bioactive small heterocyclic molecule, for its effect on in vitro proliferation and chondrogenic differentiation of human bone marrow-derived mesenchymal stromal cells (hBMSCs) in monolayer culture and in co-culture models in vitro. OA osteochondral cylinders and hBMSCs were collected during total knee replacement. The effect of KGN on hBMSCs during 21 days of culture was monitored by real-time proliferation assay, immunofluorescence staining, histological assay, scanning electron microscopy (SEM) (imaging and multiplex enzyme-linked immunosorbent assay) ELISA assay. The rate of proliferation of hBMSCs was significantly increased by treatment with 10 µM KGN during nine days of culture. Histological and SEM analyses showed the ability of hBMSCs in the presence of KGN to colonize the surface of OA cartilage and to produce glycosaminoglycans and proteoglycans after 21 days of co-culture. KGN treated hBMSCs secreted higher concentrations of TIMPs and the secretion of pro-inflammatory molecules (MMP 13, TNF-α) were significantly suppressed in comparison with control without hBMSCs. Our preliminary results support the concept that 10 µM KGN enhances proliferation and chondrogenic differentiation of hBMSCs and suggest that KGN is a potential promoter for cell-based therapeutic application for cartilage regeneration.

Comparison of intravenous and intra-articular tranexamic acid in reducing blood loss in primary total knee replacement.

OBJECTIVES: This study aims to compare the efficacy and safety of intra-articular tranexamic acid (TA) versus intravenous (IV) TA in the reduction of perioperative blood loss and the degree of early postoperative complications associated with primary unilateral cemented total knee replacement. PATIENTS AND METHODS: This prospective randomized study included 90 patients (36 males, 54 females; mean age 68.7 years; range 47 to 82 years) with knee osteoarthritis undergoing a unilateral cemented total knee replacement. Patients were randomized into three groups: group 1 received TA intravenously (dose 10 mg/kg) 20 minutes preoperatively and three hours after first dose, group 2 received TA (dose 3 g) locally (intra-articular) into surgical site, and group 3 did not receive TA. We measured perioperative blood loss, volume of drained blood in 24 hours postoperatively, overall blood loss, decrease in hemoglobin and hematocrit levels, and amount of blood transfusion. RESULTS: There were no differences between the groups in terms of patient preoperative demographics. Local or IV administration of TA significantly reduced the number of blood transfusions and blood losses in drainage. Intravenous application of TA was associated with statistically significantly higher hemoglobin and hematocrit levels and lower overall postoperative blood losses. No serious complications were observed in any of the groups. CONCLUSION: Intra-articular TA was equally effective as IV regimen in reducing the number of blood transfusions. However, IV administration of TA was associated with overall lower blood loss. Our results showed that IV administration of TA during total knee replacement is superior compared to intra-articular administration of TA.

Treatment of knee joint osteoarthritis with autologous platelet-rich plasma in comparison with hyaluronic acid.

OBJECTIVE: This study aimed to find a simple, cost-effective, and time-efficient method for the preparation of platelet-rich plasma (PRP), so the acquired benefits will be readily available for multiple procedures in smaller outpatient clinics and to explore the safety and efficacy of the application of PRP in the treatment of degenerative lesions of articular cartilage of the knee. DESIGN: The study was designed as a prospective, cohort study with a control group. A total of 120 patients with Grade 1, 2, or 3 osteoarthritis according to the Kellgren and Lawrence grading scale were enrolled in the study. One group of patients was treated using three intra-articular applications of PRP, and the second group of patients was given three injections of hyaluronic acid. Outcome measures included the Western Ontario and McMaster Universities Osteoarthritis Index and the 11-point pain intensity Numeric Rating Scale. RESULTS: On average, a 4.5-fold increase in platelet concentration was obtained in the PRP group. No severe adverse events were observed. Statistically significantly better results in the Western Ontario and McMaster Universities Osteoarthritis Index and Numeric Rating Scale scores were recorded in a group of patients who received PRP injections after a 3- and 6-mo follow-up. CONCLUSIONS: Our preliminary findings support the application of autologous PRP as an effective and safe method in the treatment of the initial stages of knee osteoarthritis. Further studies are needed to confirm these results and to investigate the persistence of the beneficial effects observed.