Branko Šestan

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 IL1β (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.

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-1β, blocking the IL-1 cellular signalling pathways, or using gene therapy. All the abovementioned 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.

Minimally invasive calcaneo-stop method for idiopathic, flexible pes planovalgus in children.

Background: The aim of this study was to correct heel valgus in children and to lift the longitudinal arch of the foot using a temporary cancellous screw placed percutaneously across the talocalcaneal articulation. Methods: From April, 1997, to June, 2003, 94 procedures were done on 48 children between the ages of 8 and 14 years. The Meary angle to determine the degree of collapse of the medial longitudinal arch was 170 degrees or less, and the weightbearing hindfoot was in valgus. Presumably, the screw achieves correction by stimulating the proprioceptive foot receptors allowing active inversion of the foot. Results: At 5 years followup, no serious complications occurred. The correction of the Meary angle on average was 17.10 ± 5.51 degrees. In every foot, heel valgus and the longitudinal arch of the foot were improved radiographically and clinically without the loss of function. We removed the screws in all patients. In 91 feet, the arch of the foot and heel valgus remained in the corrected position. Conclusions: The ‘calcaneo-stop’ method is a simple, effective, minimally invasive technique for the treatment of idiopathic, flexible pes planus in carefully selected pediatric patients.

Flat-Footedness Is Not a Disadvantage for Athletic Performance in Children Aged 11 to 15 Years

OBJECTIVE. Because the controversy about the relation of foot morphology and foot function is still present, we find it surprising that there are no studies published dealing with motor skills and athletic performance in flat-footed school children. Our aim in this study was to determine if there is an association between the degree of foot flatness and several motor skills that are necessary for sport performance. METHODS. The feet of 218 children aged 11 to 15 years were scanned, and the arch index was determined. The value of the arch index was corrected for the influence of age, and then the entire sample was categorized into 4 groups according to the flatness of their feet. The children were tested for eccentric-concentric contraction and hopping on a Kistler force platform, speed-coordination polygon (Newtest system), balance (3 tests), toe flexion (textile crunching), tiptoe standing angle, and repetitive leg movements. Altogether, 17 measures of athletic performance were measured. RESULTS. No significant correlations between the arch height and 17 motor skills were found. Categorizing the sample into 4 groups did not reveal any differences between the groups in athletic performance. Also, several multivariate analysis of variance sets of multiple independent variables referring to a particular motor ability were not found to be significant. The differences were not found even after comparing only the 2 extreme groups, meaning children with very low and children with very high arches. CONCLUSIONS. No disadvantages in sport performance originating from flat-footedness were confirmed. Children with flat and children with “normal” feet were equally successful at accomplishing all motor tests; thus, we suggest that there is no need for treatment of flexible flat feet with the sole purpose of improving athletic performance, as traditionally advised by many.

Femoral anteversion related to side differences in hip rotation. Passive rotation in 1,140 children aged 8-9 years.

We assessed whether the range of passive hip motion is reliable for predicting abnormal femoral anteversion. We measured the passive medial and lateral rotation in extension in both hips of 1,140 children between 8 and 9 years of age. The children were divided into 3 groups: group 1: difference between lateral and medial rotation less than 10 degrees; group 2: medial rotation more than 10 degrees greater than the lateral; group 3: lateral rotation more than 10 degrees greater than the medial. Group 1 comprised 90% of the children, whereas 8% belonged to group 2 and 2% to group 3. The angle of femoral neck anteversion was measured in 57 children from the first group, in 67 from the second and in 24 children from the third group, using biplane radiography. The mean anteversion angles in the 3 groups were 24 degrees, 36 degrees and 14 degrees, respectively. To predict an abnormally high anteversion angle (above mean +2SD), the difference between medial and lateral rotation must be 45 degrees or more, whereas an abnormally low anteversion angle (lower than mean -2SD) could be predicted when the lateral rotation was at least 50 degrees higher than the medial rotation.

Role of Magnetic Resonance Cholangiography in the Diagnosis of Bile Duct Lithiasis

Aim:The aim of our study was to assess diagnostic value of magnetic resonance cholangiography (MRC) in patients with suspected common bile duct (CBD) stones focusing on the capability of this noninvasive method to replace invasive diagnostic procedures in these patients and to limit the use of endoscopic retrograde cholangiography (ERC) to the patients who need simultaneous therapeutic intervention.Materials and methods:Single-shot fast-spin-echo rapid-acquisition thick-section MRC images were obtained in 310 patients recruited into this prospective study. There were 136 male and 174 female patients aged 21–95 years [mean ± standard deviation (SD) 64.9 ± 13.6 years]. Patients were subsequently classified into different risk groups (high, moderate, low) according to biochemical abnormalities or morphological features on abdominal ultrasonography and computed tomography. Direct cholangiography was the reference method of CBD evaluation.Results:CBD stones were diagnosed in 115 (37%) patients; 86 of 175 patients in the high-risk group, 24 of 83 patients in the moderate-risk group, and 5 of 50 patients in the low-risk group. In dependent risk groups, the mean CBD caliber was 9.7 ± 4.5, 7.1 ± 2.0, and 4.8 ± 1.2 mm, respectively. The difference was significant between all three groups (P < 0.05). The median size of CBD stones was 7 mm (range 3–21 mm). MRC achieved accuracy and positive and negative predictive values of 97%, 94%, and 98%, respectively.Conclusions:MRC has a potential to substitute diagnostic ERC in all patients with suspected choledocholithiasis due to its high accuracy, reducing invasive direct cholangiography to patients who require therapeutic intervention.

Associations of the Interleukin-1 Gene Locus Polymorphisms with Risk to Hip and Knee Osteoarthritis : Gender and Subpopulation Differences.

Genetic predisposition to the complex hereditary disease like osteoarthritis (OA) of the large joints (hip and knee) includes the interleukin‐1 gene (IL‐1) cluster on chromosome 2. Using a case–control study with 500 OA patients (240 knee and 260 hip OA patients, all with joint replacement), we analysed frequencies of IL‐1 gene cluster polymorphisms in Croatian Caucasian population. The control samples came from 531 healthy individuals including blood donors. We genotyped two single nucleotide polymorphisms in the IL‐1 gene locus at IL‐1A (−889, C>T, rs1800587) and IL‐1B (+3594, C>T, rs1143634) and compared their frequencies between patients and controls. We predicted haplotypes by combining current data with our previous results on gene polymorphisms (IL‐1B, rs16944 and the IL‐1 receptor antagonist gene [IL‐1RN] variable number tandem repeat [VNTR]) for the same population. Haplotype analyses revealed gender disparities and showed that women carriers of the 1‐2‐1‐1 haplotype [IL‐1A(rs1800587) – IL‐1B(rs1143634) – IL‐1B(rs16944) – IL‐1RN(VNTR)] had sixfold lower risk to develop knee OA. However, carriers of the 1‐1‐1‐2 haplotype of both sexes had over twofold higher predisposition to hip OA. Our results differ from some earlier studies in Caucasian subpopulations, which may be due to the fact that this is the first study to separate genders in assessing the IL‐1‐locus genetic risk of OA. The results suggest that inflammatory mediators like IL‐1 might be implicated in the pathogenesis of primary OA in large joints and that as yet unidentified gender‐specific factors exist in a Croatian Caucasian population.

Postoperative blood loss management in total knee arthroplasty: a comparison of four different methods

PurposeAs the blood loss after the total knee arthroplasty (TKA) is not only a potentially serious medical problem but also an economical concern, the purpose of the study was to investigate the effectiveness of different combinations of knee positioning and the applied wound dressings on blood saving after TKA.MethodsA randomized controlled trial including 147 TKA-operated patients was conducted. The subjects were assigned to one of the four groups; Group 1—controls, Group 2—flexion, Group 3—flexion and compression, Group 4—compression. The main outcome measures of the study were the blood loss volumes during the procedure and in the intensive care rooms and the decreases in haemoglobin, haemotocrit and red blood cells on the first and the second postoperative day.ResultsThe MANOVA results showed no differences between the groups in any of the observed parameters. The post-hoc comparisons of the each group to the control group also revealed no influence of any of the proposed blood saving techniques on the actual blood loss.ConclusionNo significant differences among the four proposed blood saving methods were determined.

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.

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.