Indirect influence of microRNA-146a on the association of IL-6 and TNF-α genetic polymorphisms with the increased risk of hip osteoarthritis.

Primary osteoarthritis (POA) is a complex hereditary disease that involves the interplay between genetics and epigenetics. MicroRNA molecules play important roles in epigenetic mechanisms. MicroRNA-146a (miR-146a) is a negative regulator of the immune response in osteoarthritis (OA). So, variations in the miR-146a gene could affect OA risk. The aim of this study was to investigate the relationships between single nucleotide polymorphisms (SNPs) in the miR-146a, interleukin-6 (IL-6), Toll-like receptor 10 (TLR10), and tumor necrosis factor-alpha (TNFA) genes and the risk for development of advanced-stage primary hip osteoarthritis (PHOA) and primary knee osteoarthritis (PKOA) in the Croatian population. A total of 609 POA patients and 656 healthy donors were genotyped for SNPs in the miR-146a (rs2910164, G>C). Since we used same patients and controls as two studies before us, we already had information about IL-6 (rs1800795, C>G), TLR10 (rs11096957, C>T), and TNFA (rs1800629, C>T) genotypes of our subjects. None of the differences were statistically significant comparing either allelic or genotypic frequencies of miR-146a SNP rs2910164 (G>C) between the PHOA and PKOA patients and controls. However, we found a significant association with risk to PHOA for the combination of genotypes (stratified miR-146a genotype with the IL-6, and stratified miR-146a genotype with the TNFA). In a multifactorial disease such as POA, we have shown the indirect relevance of a second modifying factor (miR-146a), which apparently contributes to the overall risk of PHOA. There was no risk association with the PKOA, indicating that these two localities (hip and knee) might have different risk-modifying factors.

Chiari pelvic osteotomy does affect hip survival: a long-term follow-up study.

BACKGROUND: The modern indications for Chiari pelvic osteotomy (CPO) have narrowed and the number of such operations performed has diminished markedly. So far published long-term experience with CPO indicate the fact that in selected patients satisfactory functional results can be achieved. The aim of this study was to investigate the parameters which influence CPO survival and its conversion into total hip arthroplasty (THA). METHODS: This is a single-centre retrospective case-series study. In the period from 1976 to 2012, it included 172 CPO in 158 patients. Of those, in 43 patients (48 hips) the follow-up was discontinued, leaving 115 patients (124 hips) for final analyses. The median age at the time of the surgery was 34 years, and the mean duration of the follow-up was 19 years. RESULTS: In 115 patients (124 CPO) included in the study, a total of 51 THA was performed in 49 patients. The median period between CPO and THA was 14 years. CONCLUSION: Supporting our results, we suggest that CPO should still be indicated in a selected group of younger patients even with advanced stage of hip osteoarthritis who prefer a joint-conserving procedure and consent to a predicted less optimal outcome.

Alternative Interleukin 17A/F Locus Haplotypes are Associated With Increased Risk to Hip and Knee Osteoarthritis.

We studied the genetic epidemiology of primary large-joint (hip and knee) osteoarthritis (OA), in order to find disease risk factors by a candidate-gene approach. We used case-control study in the Croatian Caucasian population. We genotyped 500 OA patients (260 hip, 240 knee; both with total joint replacements) and 597 healthy individuals for single-nucleotide polymorphisms (SNPs) in interleukin 17A (IL17A) (rs2275913) and IL17F (rs763780 and rs1889570) genes. On the basis of our population and allelic and genotypic frequencies haplotypes were predicted by PHASE software and compared between patients and controls. The three-SNP haplotype (rs2275913-rs763780-rs1889570) G-C-A confers predisposition to hip (p < 0.005) but not knee OA. The three-SNP haplotype having opposed nucleotides A-T-G was found significantly associated with 2.6 times higher risk for developing knee (p < 0.02) but not hip OA. The haplotype G-T (IL17A-IL17F; rs2275913-rs763780) is associated with protection to the disease in hip OA (p < 0.01). Our analyses show that two disparate haplotypes within the IL17A-F gene locus are associated with higher risk to developing hip and knee OA in the Croatian population. The data might suggest a difference in the etiology of hip OA from that of the knee OA, perhaps due to an unknown dissimilarity in vulnerability of these joints to the actions of IL17. Alternatively, other differences in genetic factors like the long non-protein coding region LINCMD1 and/or microRNA species like miR133b and miR206 found in the vicinity of the IL17 locus might be involved in the observed risk. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1972-1978, 2019.

Interleukin-17 and Toll-like Receptor 10 genetic polymorphisms and susceptibility to large joint osteoarthritis.

Primary osteoarthritis (OA) is the most common type of a joint disease. It has a polygenic risk inheritance pattern and affects older people. The etiology of this disease is not fully understood. The aim of this study was to investigate the associations between polymorphisms in pro-inflammatory interleukin-17 (IL17A and IL17F) and anti-inflammatory Toll-like Receptor 10 (TLR10) genes with the risk for development of advanced stage hip and knee primary OA in the Croatian population. A total of 500 OA patients and 597 controls were genotyped for IL17A SNP (rs2275913), IL17F SNPs (rs763780 and rs1889570), and TLR10 (rs11096957) genes. The allelic and genotypic frequencies of IL17F SNP (rs763780) showed statistically significant differences in comparisons of controls with hip-but not knee-OA patients. The major allele (T) of rs763780 was associated with the lower risk for developing hip OA (p = 7.9 × 10-4 , OR = 0.45, 95%CI = 0.27-0.74), whereas the minor allele (C) was associated with susceptibility to hip OA (p = 7.9 × 10-4 , OR = 2.24, 95%CI = 1.35-3.72). The genotype T/T was associated with the protection to hip OA (p = 3.9 × 10-4 , OR = 0.41, 95%CI = 0.24-0.70), and, lastly, the genotype T/C was associated with the higher risk to acquiring hip OA (p = 2.6 × 10-4 , OR = 2.50, 95%CI = 1.47-4.25). TLR10 SNP rs11096957 was found significantly associated with predisposition to hip OA (p = 0.04, OR = 1.41, 95%CI = 1.02-1.94) but not knee OA. Our findings suggest that hip OA in Croatian population might have a different genetic risk regarding the IL17 and TLR10 gene locus than knee OA. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1684-1693, 2018.

Surgical Treatment of Moderate Hallux Valgus: A Comparison of Distal Chevron Metatarsal Osteotomy With and Without Lateral Soft-Tissue Release.

PURPOSE: The purpose of the study was to determine whether lateral soft-tissue release (LSTR) has a beneficial or detrimental effect on the outcome of distal Chevron first metatarsal osteotomy (DCMO) in the treatment of moderate hallux valgus (HV). METHODS: We compared the effect of different surgical treatments in 2 groups of patients: group I (23 patients, 25 feet, average age of 55 [from 43 to 77] years) was subjected to DCMO only, whereas group II (18 patients, 23 feet, average age of 59 [from 52 to 70] years]) was subjected to DCMO with LSTR. The American Orthopaedic Foot and Ankle Society's Hallux Metatarsophalangeal-Interphalangeal scale survey was conducted postoperatively, followed by the brief survey on postoperative patient satisfaction. The patient follow-up period was from 18 to 24 months after surgical treatment, on average. RESULTS: After surgical intervention, both groups of patients presented with an improved HV angle, but there was no significant difference between the groups. However, group II showed significant improvements in medial sesamoid bone position and patient satisfaction scores as compared with group I. CONCLUSION: Our midterm follow-up of surgical treatments for moderate HV deformity suggests that both procedures provide good postoperative results. However, according to our results, DCMO with LSTR provides better results than procedures without LSTR. LEVELS OF EVIDENCE: Therapeutic, Level III: Retrospective comparative study.

Susceptibility to large-joint osteoarthritis (hip and knee) is associated with BAG6 rs3117582 SNP and the VNTR polymorphism in the second exon of the FAM46A gene on chromosome 6.

Family with sequence similarity 46, member A (FAM46A) gene VNTR and BCL2-Associated Athanogene 6 (BAG6) gene rs3117582 polymorphisms were genotyped in a case-control study with 474 large-joint (hip and knee) osteoarthritis (OA) patients and 568 controls in Croatian population by candidate-gene approach for association with OA. We found that BAG6 rs3117582 SNP genotypes were associated with protection (major allele homozygote) and susceptibility (major-minor allele heterozygote) to OA. BAG6 rs3117582 major allele (A) was associated with reduced risk to OA while the minor allele (C) was associated with increased risk to OA. We identified 6 alleles harboring 2 to 7 repeats making 20 genotypes for FAM46A. A rare FAM46A VNTR genotype comprising VNTR alleles with four and seven repeats (c/f) was associated with increased OA risk in both genders. The genotype with four and six repeats (c/e) was also associated with increased risk to OA in males. A polymorphic FAM46A allele with six repeats (e) was associated with reduced risk to OA in females. Our results suggest association between the FAM46A gene, BAG6 gene and OA in Croatian population, respectively. This is the first study to show associations between these genetic loci and OA.

Emerging pathways and promising agents with possible disease modifying effect in osteoarthritis treatment.

Current modalities for osteoarthritis (OA) treatment are partially safe and effective, and only alleviate the disease symptomatology, but do not modify progression and structural changes of the disease. At present, there is no approved safe and effective disease-modifying OA drug (DMOAD) for clinical application. Therefore, there is an urgent need for discovery of DMOAD in order to treat OA. Hopefully, the new DMOADs would also pave the way for better understanding of OA pathophysiology. Given the fact that there is still no adequate remedy that will modify the course of OA, a number of emerging pathways and promising agents with possible DMOAD effect arise targeting cartilage, synovial membrane, and subchondral bone, or using stem cell therapy, and gene therapy. All these methodologies will be described and discussed in this review. Available treatment methodologies for OA are unsatisfactory. In order to properly treat OA in the future, more realistic option will be the use of multiple drugs, instead of single therapy, which is likely to be ineffective in the treatment of such heterogeneous diseases. Which combination of drugs with DMOAD effect will be suitable for the treatment of OA, remains to be determined in future studies.

Navicular index for differentiation of flatfoot from normal foot.

PURPOSE: The height of navicular bone from the floor is in proportion with the height of longitudinal arch of the foot. The study was conducted to evaluate correlation of navicular bone height with most often used angles, heel valgus and a foot print in order to simplify the procedure for the diagnosis of flatfoot. METHODS: A total of 218 operated children (436 feet) because of flexible flatfoot were evaluated clinically and radiologically. Meary angle, lateral talonavicular angle, talocalcaneal angle, calcaneal pitch, heel valgus and arch index (Staheli) were evaluated pre-operatively and postoperatively. In 121 (242 feet) chosen children (age eight to 15) with all clinical values and pre-operative angles corresponding flatfoot, all postoperatively measured values were within the normal range. We got the navicular index by dividing length of longitudinal arch with navicular height. Values of navicular index were then compared with pre-operatively and postoperatively measured values. Pearson correlation and ROC test were used for statistical analysis. RESULTS: Values of the navicular index for flatfeet were in the interval from 4.75 to 31.2 (median 8.98), and for normal-arched feet 3.58-22.6 (median 5.48). Pearson correlation of arch index and measured parameters were significant in majority, and degree according to Colton was good. Area under the ROC curve was 0.861 (p = 0.0001). The cut-off value with 86 % sensitivity and 75 % specificity was 6.7407. CONCLUSION: Navicular index can be used reliably, without measures of the other parameters, to differentiate flatfoot from normal-arched foot. Therefore, the navicular index has an ability to distinguish between the flatfoot and normal-arched foot.

Tibial stress fracture simulate osteomyelitic foci in the course of chronic recurrent multifocal osteomyelitis.

Chronic recurrent multifocal osteomyelitis (CRMO) is an extremely rare and most severe form of chronic nonbacterial osteomyelitis of unknown etiology. Here we present the first case of a six-year-old girl in which was observed that the stress fracture mimic osteomyelitic foci in the course of CRMO.

Treatment of infected tibial nonunion with bone defect using central bone grafting technique.

Treatment of infected tibial nonunion with bone defect represents a challenge for every orthopaedic surgeon. Various methods of treatment have been described for nonunions with infection, bone loss or both. One of them is the central bone grafting technique, which is a safe and effective treatment for nonunions of the tibia. The technique involves placement of autogenous cancellous bone from the iliac crest on the anterior surface of the interosseous membrane with the aim of creating a tibiofibular synostosis. We present the results of uncontrolled, retrospective and continuous series of ten patients treated by a central bone grafting technique for infected tibial nonunion with bone loss. Mean follow-up period was 12 (10-15) years. Most injuries were a result of war injuries. Clinically and radiologically confirmed bony healing with total consolidation of the graft was achieved in all patients within a period of 10-12 months without further bone grafting. The newly-formed bone mass was able to fulfil the mechanical and functional demands of everyday life activities. Once again, the central bone grafting technique has shown to be a safe, reliable and effective method of treatment for infected tibial nonunion with bone defect.

Role of interleukin-1 inhibitors in osteoarthritis: an evidence-based review.

Osteoarthritis (OA), the most common chronic musculoskeletal disease, represents a leading cause of disability in the elderly population worldwide. At present, there is no aetiological treatment for OA patients. Also, current therapeutic regimens for OA are only partially effective, and that is the main reason for most physicians' complaints. Therefore, one of the biggest challenges in the future will be to find the most appropriate therapy or therapies for OA. Currently, there are three basic modalities of treatment: nonpharmacological, pharmacological and surgical. Regarding pharmacological treatment, numerous molecular pathways involved in the pathophysiology of OA have been investigated as potential therapeutic targets. In preclinical and clinical trials, many compounds and agents have been tested, and some of them have already shown positive effects on the progression of knee and/or hip OA. One such possible pharmacological treatment of OA is anticytokine therapy. Interleukin-1 (IL-1), as a main inflammatory and catabolic cytokine in the pathophysiology of OA, represents one of the possible treatment targets. For specific inhibition of IL-1 production or activity, various treatment strategies could be used. These include the inhibition or modification of IL-1 action through the application of IL-1 receptor antagonist proteins, soluble IL-1 receptors, monoclonal antibodies against IL-1 or against IL-1 receptor I, blocking the formation of active IL-1ß, blocking the IL-1 cellular signalling pathways, or using gene therapy. All the above mentioned treatment strategies for specific inhibition of IL-1 production or activity have been investigated in numerous preclinical and clinical studies. Some of these investigations led to the discovery of new potential drugs for the treatment of OA. However, the results of treatment with these drugs were not entirely satisfactory, and further research is required to achieve the desired goals of therapy.

IL1B -511(G>A) and IL1RN (VNTR) allelic polymorphisms and susceptibility to knee osteoarthritis in Croatian population.

Osteoarthritis (OA) is a frequent, destructive joint disease, with debilitating impact on a society regarding medical, social, and economic issues. Although causes of primary OA were still not fully elucidated, evidence points to complex genetic risk that varies among different population groups, including the interleukin-1 (IL-1) gene cluster. Here, we sought to determine allelic and genotypic frequencies of the IL-1ß (IL1B) and the IL-1 receptor antagonist (IL1RN) genes using single nucleotide polymorphism (SNP) at -511(G>A; rs16944) and the variable number tandem repeat (VNTR) in a case-control study with 238 patients that have undergone total or partial knee replacement and 495 healthy blood donors as controls in Croatia. The alleles of the IL1B gene at -511G>A were detected by Taqman real-time polymerase chain reaction (PCR) method and IL1RN VNTR by amplifying its DNA by PCR. The genotypes 1-2/1-2 and 2-1/2-2 at IL1B G -511A-IL1RN (VNTR) showed trends for association with the occurrence of the knee OA in this population (P = 0.09; P = 0.07, respectively). Furthermore, neither the alleles nor the haplotypes were found associated with the predisposition to knee OA. Our findings suggest that knee OA might have a different genetic risk in this Caucasian population. We did not found significant association of the IL1 gene cluster (IL1B-IL1RN) with severe knee OA. However, we found that two genotypes (1-2/1-2 and 2-1/2-2) show a trend toward association with susceptibility to disease.

Correlation of endothelin-1 mRNA expression and bone structure in advanced osteoarthritis.

Recent understandings of the vascular contribution of pathophysiology of osteoarthritis (OA) mount new evidence of cross-talking between subchondral bone tissue and articular cartilage that might have a decisive role in a pathophysiology of Osteoarthritis (OA). These understandings include blood flow (or interstitial fluid) impairment in subchondral bone. With regard to the mentioned role of the vasculature, the absence of custom nourishing to articular cartilage, and established, vasoconstrictive role of endothelin-1 (ET-1) it was reasonable to assume that ET-1 has an inconvertible role in pathophysiology of OA. Another moment in pathophysiology of OA is apoptosis of subchondral osteocytes, what induces osteoclastic resorption and at least temporarily reduces the bony support for the overlying cartilage. Since regional dependence of this protein's expression was presumed, we suggest a regional division of subchondral bone by histomorphometrical analysis and quantification of identified protein by Real Time Polymerase Chain Reaction Analysis (RT-PCR). Obtained results should be compared to serum levels of soluble ET-1, what would enforce this methods validity. Herewith, a new screening marker of patients with osteoarthritis would be established. This would enable detection and follow-up of groups threatened by this, growing, cause of disability and decreased quality of life.

Hemiarthroplasty is an effective surgical method to manage unstable trochanteric fractures in elderly people.

Trochanteric femoral fractures are a major problem in the elderly because of higher bone fragility due to osteoporosis. Numerous chronic illnesses, which usually affect the elderly, aggravate and complicate their surgical treatment. Trochanteric femoral fractures results in high morbidity and mortality in elderly patients. The aim of our study is to evaluate the effectiveness of hemiarthroplasty in the treatment of unstable trochanteric femoral fractures in elderly patients. Between 2000 and 2005, 50 patients with unstable trochanteric femoral fractures (41 women) aged 75 to 92 years (mean 86 years) underwent cemented hemiarthroplasty. The surgical procedure was performed within first 48 hours after the fracture (out of which 14 in the first 12 hours, 27 in the first 24 hours and 9 in the first 48 hours), with minimal blood loss. Hemiarthroplasty was indicated in patients where stability was important to allow early mobilization. In forty patients (80%) early ambulation with full weight bearing was achieved during the short period of hospitalization (9-14 days). Given that the affected population is predominantly the elderly, who are less mobile and demanding and thus put less strain on the endoprosthesis, we believe that this kind of treatment is the treatment of choice for unstable trochanteric femoral fractures in these patients. This assumption is corroborated by the fact that we did not have any endoprosthesis luxation, apparent acetabular protrusion or instability during the mean follow up period of 15 months (range 12-18 months).

Hip osteoarthritis susceptibility is associated with IL1B -511(G>A) and IL1 RN (VNTR) genotypic polymorphisms in Croatian Caucasian population.

Among the predisposing factors to osteoarthritis (OA), a frequent destructive joint disease, is the complex genetic heritage including the interleukin-1 family members like the IL1ß (IL1B) and the IL1 receptor antagonist (IL1RN) genes. The aim of this study was to investigate allelic and genotypic frequencies of the IL1B gene single nucleotide polymorphism (SNP) at -511(G>A) and the variable number tandem repeat (VNTR) in the IL1RN gene in a Croatian Caucasian population of hip OA (HOA) cases and healthy controls. A total of 259 HOA patients with total hip replacement (THR) and 518 healthy blood donors as controls were genotyped for IL1B gene SNP -511(G>A) and the VNTR in the IL1RN gene associated with HOA. The genotype G/A (1/2) at IL1B was significantly associated with the protection of the HOA (p < 0.036, OR = 0.72, 95% CI = 0.52-0.99). The genotype G/G (1/1) had only a trend towards the susceptibility (p = 0.053, OR = 1.35, 95% CI = 0.98-1.86) to disease. None of the haplotypes IL1B -511(G>A) and IL1RN (VNTR) were found associated with the HOA. The haplotype 1-2 at these loci had only a trend to susceptibility (p = 0.065). Haplotype 1-3 had a significant male bias in diseased. Furthermore, genotype comprising 2-1/2-2 haplotypes was found significantly associated with predisposition to HOA (p = 0.027, OR = 2.23, 95% CI = 1.03-4.88), whereas genotype 1-1/2-2 with protection to disease (p = 0.028, OR = 0.65, 95% CI = 0.43-0.97). Our findings suggest that HOA in Croatian population might have a different genetic risk regarding the IL1 locus than has been reported for other Caucasian populations previously.

Long-term results of anterior cruciate ligament reconstruction: a comparison with non-operative treatment with a follow-up of 17-20 years.

PURPOSE: The aim of our study was to review the clinical and radiological outcome of patients who had undergone anterior cruciate ligament (ACL) reconstruction in comparison to a group of non-operatively treated patients. METHODS: In a retrospective study we compared ACL reconstruction using a bone-patellar tendon-bone graft with a non-operatively treated group of patients 17-20 years later. Fifty-four patients that met the inclusion criteria, with arthroscopically proven ACL rupture, were treated between 1989 and 1991. Thirty-three patients underwent ACL reconstruction, forming group one. Eighteen non-reconstructed patients continued with rehabilitation and modification of activities (group two). The International Knee Documentation Committee (IKDC) subjective and objective evaluation forms and the Lysholm and Tegner scale were used to assess the knees at follow-up. Radiographic assessment was performed using the IKDC grading scale. RESULTS: Follow-up results showed that 83% of reconstructed patients had stable knees and normal or nearly normal IKDC grade. Patients in the non-reconstructed group had unstable knees with 84% having abnormal or severe laxity. The subjective IKDC score was significantly in favour of group one: 83.15 compared to 64.6 in group two. The Lysholm and Tegner score was also significantly better in group one. Conservatively treated patients all had unstable knees and worse scores. The rate of osteoarthritis showed more severe changes in non-reconstructed patients with additional meniscus injury. CONCLUSIONS: We can conclude that 94% of patients who underwent ACL reconstruction had stable knees after 15-20 years and there was a significantly lower percentage of osteoarthritis in comparison to conservatively treated patients.

Salmonella typhimurium osteomyelitis of the femur in patient with Crohn's disease.

Osteomyelitis is an inflammation of the bone caused by infecting organisms. We present here the first case of osteomyelitis of the distal femur caused by Salmonella typhimurium in a patient with Crohn's disease. The infection was successfully treated with a combination of antibiotics and surgical treatment.

Open total talar dislocation with extrusion (missing talus).

Open total dislocation of a talus with extrusion (missing talus) is an extremely rare injury. We present a case of a 63-year-old male who sustained an open total lateral dislocation of the right talus with extrusion and without a concomitant fracture after a fall from a small height. Tibiocalcaneonavicular arthrodesis was performed. Arthrodesis failed, and due to painful and unstable ankle, rearthrodesis was performed two years later, successefully. Because of rarity of this kind of injury, hers importance for foot function, previously described various treatment options and absence of guidelines, herewith we propose, according to our experience and review of literature, the algorithm for the treatment of this rare injury.