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A positional cloning effort in French Canadian families with Paget’s disease of bone (PDB) resulted in the identification of a mutation in thesequestosome1(SQSTM1) gene in a subset of both familial and sporadic PDB cases. This was confirmed in samples of mainly United Kingdom (UK) origin. In this study, we performed both mutation analysis and association studies in order to evaluate the role of this gene in a collection of isolated Belgian PDB patients. A mutation in theSQSTM1gene was found in only 6 of 111 patients (5.4%). In all cases it involves the P392L mutation, previously shown to be common in both familial and sporadic cases. To perform association studies, we selected 8 single nucleotide polymorphisms (SNPs) and looked for linkage disequilibrium (LD) between these. Haplotype analysis indicated that typing of 3 Tag SNPs (IVS1+633A/C, IVS5-23A/G, and 976A/G) enables us to identify the most common haplotypes. Association studies for the 3 selected SNPs, based on 105 PDB cases without aSQSTM1mutation and 159 control individuals, did not support a possible influence of natural variants in theSQSTM1gene either on the pathogenesis of PDB or on the disease severity. In conclusion, our study confirms that the P392L mutation is a recurrent mutation causing PDB in different populations. We were not able to show an association betweenSQSTM1polymorphisms and PDB in our population but this clearly needs to be extended to other populations. The presented identification of haplotype Tag SNPs will be of major help for such studies. [ABSTRACT FROM AUTHOR]

Paget's disease of bone (PDB) is, after osteoporosis, the second most common metabolic bone disorder in the elderly Caucasian population. Mutations in the sequestosome 1 gene (SQSTM1) are responsible for the etiology of PDB in a subset of patients, but the disease pathogenesis in the remaining PDB patients is still unknown. Therefore association studies investigating the relationship between genetic polymorphisms and sporadic PDB have been performed in order to find the susceptibility polymorphisms. In this paper, we sought to determine whether polymorphisms in 3 functional candidate genes play a role in the development of sporadic PDB: TNFSF11 (receptor activator of nuclear factor κB ligand, RANKL), VCP (valosin-containing protein) and IL-6 (interleukin 6). Analyzing 9 tag SNPs and 2 multi-marker tests (MMTs) in TNFSF11, 3 tag SNPs and 1 MMT in VCP and 8 tag SNPs in IL-6 in a population of 196 Belgian patients with sporadic PDB and 212 Belgian control individuals revealed that one VCP SNP (rs565070) turned out to be associated with PDB in this Belgian study population (p=5.5×10(-3)). None of the tag SNPs or MMTs selected for TNFSF11 or IL-6 was associated with PDB. Still, replication of our findings in the VCP gene in other populations is important to confirm our results. However, when combining data of VCP with those from other susceptible gene regions from previous association studies (i.e. TNFRSF11A, CSF1, OPTN and TM7SF4), independent effect of each gene region was found and the cumulative population attributable risk is 72.7%., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Paget's disease of bone (PDB) is one of the most frequent metabolic bone disorders (1-5%), next to osteoporosis, affecting individuals above age 55. Sequestosome1 mutations explain a part of the PDB patients, but still the disease pathogenesis in the remaining PDB patients is largely unknown. Therefore, association studies investigating the relationship between genetic polymorphisms and sporadic PDB have been performed to find the genetic risk variants. Previously such studies indicated a role of the OPG and RANK gene. The latter was recently confirmed in a genome-wide association study (GWAS) which also indicated the involvement of chromosomal regions harbouring the CSF1 and OPTN gene. In this study, we sought to replicate these findings in a Belgian and a Dutch population. Similar significant results were obtained for the single nucleotide polymorphisms and the haplotypes. The most significant results are found in the CSF1 gene region, followed by the OPTN and TNFRSF11A gene region (p values ranging from 1.3 × 10(-4) to 3.8 × 10(-8), OR = 1.523-1.858). We next obtained significant association with a polymorphism from the chromosomal region around the TM7SF4 gene (p = 2.7 × 10(-3), OR = 1.427), encoding DC-STAMP which did not reach genome-wide significance in the GWAS, but based on its function in osteoclasts it can be considered a strong candidate gene. After meta-analysis with the GWAS data, p values ranged between 2.6 × 10(-4) and 8.8 × 10(-32). The calculated cumulative population attributable risk of these four loci turned out to be about 67% in our two populations, indicating that most of the genetic risk for PDB is coming from genetic variants close to these four genes.

RANK (receptor activator of nuclear factor-κB), encoded by TNFRSF11A, is a key protein in osteoclastogenesis. TNFRSF11A mutations cause Paget's disease of bone (PDB)-like diseases (ie, familial expansile osteolysis, expansile skeletal hyperphosphatasia, and early-onset PDB) and an osteoclast-poor form of osteopetrosis. However, no TNFRSF11A mutations have been found in classic PDB, neither in familial nor in isolated cases. To investigate the possible relationship between TNFRSF11A polymorphisms and sporadic PDB, we conducted an association study including 32 single-nucleotide polymorphisms (SNPs) in 196 Belgian sporadic PDB patients and 212 control individuals. Thirteen SNPs and 3 multimarker tests (MMTs) turned out to have a p value of between .036 and 3.17 × 10(-4) , with the major effect coming from females. Moreover, 6 SNPs and 1 MMT withstood the Bonferroni correction (p < .002). Replication studies were performed for 2 nonsynonymous SNPs (rs35211496 and rs1805034) in a Dutch and a British cohort. Interestingly, both SNPs resulted in p values ranging from .013 to 8.38 × 10(-5) in both populations. Meta-analysis over three populations resulted in p = .002 for rs35211496 and p = 1.27 × 10(-8) for rs1805034, again mainly coming from the female subgroups. In an attempt to identify the underlying causative SNP, we performed functional studies for the coding SNPs as well as resequencing efforts of a 31-kb region harboring a risk haplotype within the Belgian females. However, neither approach resulted in significant evidence for the causality of any of the tested genetic variants. Therefore, further studies are needed to identify the real cause of the increased risk to develop PDB shown to be present within TNFRSF11A., (Copyright © 2010 American Society for Bone and Mineral Research.)

Paget's Disease of Bone (PDB) is one of the most frequent metabolic bone diseases, affecting 1-5% of Western populations older than 55 years. Mutations in the sequestosome1 (SQSTM1) gene cause PDB in about one-third of familial PDB cases and in 2.4-9.3% of nonfamilial PDB cases, with the 1215C-->T (P392L) mutation being the most frequent one. We investigated whether a founder effect of the P392L SQSTM1 mutation was present in Belgian (n = 233), Dutch (n = 82), and Spanish (n = 64) patients without a PDB family history. First, direct sequencing analysis of exon 8 in these three populations showed that the P392L mutation occurred in 17 Belgian patients (7.3%), three Dutch patients without a family history (3.7%), and two Dutch patients with a family history. In the Spanish population, 15.6% of patients (n = 10) had the P392L mutation, including one homozygous mutant. This is by far the highest mutation frequency of all populations investigated so far. Next, we examined the genetic background of 33 mutated chromosomes by analyzing haplotypes. We genotyped four single-nucleotide polymorphisms (SNPs) in exon 6 and the 3'-untranslated region of SQSTM1 (rs4935C/T, rs4797G/A, rs10277T/C, and rs1065154G/T) and used software programs WHAP and PHASE to reconstruct haplotypes. Finally, allele-specific primers allowed us to assign the mutation to one of the two haplotypes from each individual. Sequencing results revealed that all 33 P392L mutations were on the CGTG (H2) haplotype. The chance to obtain this result due to 33 independent mutation events is 3.97 x 10(-14), providing strong evidence for a founder effect of the P392L SQSTM1 mutation in Belgian, Dutch, and Spanish patients with PDB.

Unlabelled: We studied the role of TNFRSF11B polymorphisms on the risk to develop Paget's disease of bone in a Belgian study population. We observed no association in men, but a highly significant association was found in women, and this was confirmed in a population from the United Kingdom., Introduction: Juvenile Paget's disease has been shown to be caused by mutations in TNFRSF11B encoding osteoprotegerin. Although mutations in this gene have never been found in patients with typical Paget's disease of bone (PDB), there are indications that polymorphisms in TNFRSF11B might contribute to the risk of developing PDB., Materials and Methods: We recruited a population of 131 Belgian patients with sporadic PDB and 171 Belgian controls. By means of the HapMap, we selected 17 SNPs that, in combination with four multimarker tests, contain most information on common genetic variation in TNFRSF11B. To replicate the findings observed in the Belgian study population, genotyping data of SNPs generated in a UK population were reanalyzed., Results: In our Belgian study population, associations were found for two SNPs (rs11573871, rs1485286) and for one multimarker test involving rs1032129. When subsequently analyzing men and women separately, these associations turned out to be driven by women (56 cases, 78 controls). In addition, three other tagSNPs turned out to be associated in women only. These were rs2073617 (C950T), rs6415470, and rs11573869. Reanalysis of genotyping data from a UK study population indicated that the associations found for C950T and C1181G were also exclusively driven by women (146 cases, 216 controls). Meta-analysis provided evidence for risk increasing effects of the T allele of C950T and the G allele of C1181G in the female population (p = 0.002 and 0.003, respectively). The haplotypes formed by the SNPs associated in the Belgian population were also distributed differentially between female cases and controls., Conclusions: We showed for the first time that SNPs influencing the risk to develop PDB could be sex-specific. Further research is necessary to identify the causative variants in TNFRSF11B and to elucidate the molecular pathogenic mechanism.

Bone is the most important supportive tissue in the human body, and in order to maintain its integrity, it is continuously renewed by a process called "remodeling". Paget's disease of bone (PDB), familial expansile osteolysis (FEO), expansile skeletal hyperphosphatasia (ESH), early-onset Paget's disease of bone (EOPDB), and juvenile Paget's disease (JPD) are all metabolic bone disorders characterized by accelerated bone remodeling. Histological studies have shown that bone-resorbing osteoclasts are the primary disease-causing cells in these disorders. In this review, we provide an overview of the clinical differences between diseases with increased bone turnover. Our main focus is on Paget's disease because this is, by far, the most common form of this type of disease. Molecular genetic studies of these disorders have revealed key players in bone remodeling and have provided further insights in signal transduction in osteoclasts. Moreover, a syndromal form of PDB has been characterized in which PDB is associated with inclusion body myopathy and frontotemporal dementia, pointing toward similar biological pathways in osteoclasts, muscle, and brain cells. However, several additional genes underlying conditions with increased bone turnover remain to be identified.

Our aim was to determine the usefulness of circulating oxidized low density lipoprotein (LDL) in the identification of patients with coronary artery disease (CAD). A total of 304 subjects were studied: 178 patients with angiographically proven CAD and 126 age-matched subjects without clinical evidence of cardiovascular disease. The Global Risk Assessment Score (GRAS) was calculated on the basis of age, total and high density lipoprotein cholesterol, blood pressure, diabetes mellitus, and smoking. Levels of circulating oxidized LDL were measured in a monoclonal antibody 4E6-based competition ELISA. Compared with control subjects, CAD patients had higher levels of circulating oxidized LDL (P<0.001) and a higher GRAS (P<0.001). The sensitivity for CAD was 76% for circulating oxidized LDL (55% for men and 81% for women) compared with 20% (24% for men and 12% for women) for GRAS, with a specificity of 90%. Logistic regression analysis revealed that the predictive value of oxidized LDL was additive to that of GRAS (P<0.001). Ninety-four percent of the subjects with high (exceeding the 90th percentile of distribution in control subjects) circulating oxidized LDL and high GRAS had CAD (94% of the men and 100% of the women). Thus, circulating oxidized LDL is a sensitive marker of CAD. Addition of oxidized LDL to the established risk factors may improve cardiovascular risk prediction.

Perforator flaps have become the first choice in free flap reconstruction of contour defects or skin and fat replacement in our department. The Deep Inferior Epigastric Perforator (DIEP), the Superior Gluteal Artery Perforator (S-GAP) and the Thoracodorsal Artery Perforator (TAP) flaps are now routinely used. By evaluating the vascular anatomy of these flaps preoperatively, we intend to improve our surgical strategy so that these operative procedures can proceed in a faster and safer way. In this study, the results of the colour Duplex scanning in 50 consecutive DIEP flap patients are reviewed and evaluated for their sensitivity and positive predictive value. Also the preoperative information from unidirectional Doppler flowmetry in 30 S-GAP flaps and 11 TAP flaps is evaluated for its reliability. Due to the variable vascular anatomy of the lower abdominal wall and the dorso-lateral thoracic wall we now prefer using the colour Duplex scanning for planning the DIEP and TAP flaps. The more constant course of the branches of the superior gluteal artery allows us to use the easier and cheaper unidirectional Doppler flowmetry for planning the S-GAP flap.

Background: The purpose of this retrospective analysis was to evaluate the benefit of a yearly duplex ultrasonography of both the reconstructed and the contralateral internal carotid artery (ICA)., Methods: From 1985 to 1994, 1210 unilateral, primary ICA reconstructions were performed. Although these patients received yearly invitations, duplex follow-up was not available in 114 patients (9%)., Results: At 5 years a stenosis of 50% or more was found in 9% and at 10 years in 14% of patients. During the follow-up period 20 patients developed a stenosis of 80-99%. Ten patients had a redo-procedure. The others remained asymptomatic, even though one patient developed an occlusion. A stroke occurred in 96 patients. 58 of these had no significant stenoses. 57% of all patients had no significant contralateral lesion at the time of the first procedure. In only 4% of these a contralateral CAE was performed during the follow-up., Conclusions: In view of the above data, we would conclude that the clinical benefit of duplex surveillance is doubtful.

To evaluate the accuracy of venous duplex, results obtained in 101 patients are compared with venography. A first group consisted of 48 patients with clinically suspected deep vein thrombosis. In 30 of them a positive duplex scan was obtained and all had subsequently a positive venography. Eighteen patients with a normal duplex scan had a normal venography. Another group of 53 patients were tested preoperatively for varicose vein surgery. No obstruction of the venous system was withheld with duplex but 3 patients had an old thrombosis on venography. Thus duplex is a highly reliable method to detect proximal thrombosis in clinically suspected patients but detection of late sequelae of thrombosis may be more difficult.

A prospective study was undertaken to evaluate the clinical and hemodynamic effects of aortofemoral Dacron reconstruction in patients with multilevel disease (i.e. aortoiliac and femoropopliteal occlusive disease). Thirty nine patients underwent, apart from clinical evaluation, segmental plethysmography and Doppler pressures before operation, immediately after operation and again at 3 and 6 months. All patients improved by the reconstruction, but 12 (31%) continued to complain of disabling claudication during normal daily activities. The mean ankle pressure and thigh pressure index improved by 37.5%. This was accompanied by a decrease of peak flow time, an increase of peak flow and an improved recovery during reactive hyperemia. Furthermore an additional significant rise of the ankle pressure index was noted between 3 and 6 months. Continuing claudication was always associated with both initial and late hemodynamic failure (the criterium for hemodynamic success was defined as an increase of the ankle pressure index with more than 0.1). Hemodynamic success resulted unvariably in clinical success. However 4 patients were clinically symptomfree, although they had to be classified as hemodynamic failures. It is concluded that a significant number of patients fail to obtain complete relief after proximal reconstruction. Preoperative hemodynamic studies may provide additional information, but hemodynamic and clinical results do not always correlate with each other.

Forty-five patients with intermittent claudication were first treated with placebo tablets for 3 months and then randomly allocated to double-blind therapy with either suloctidil or placebo for 6 months. Walking distance improved significantly in both groups during the 3 months of placebo treatment. During the 6 months of double-blind treatment with a further significant improvement occurred only in the placebo group when all patients were analyzed. However, when patients who stopped for reasons unrelated to claudication such as angina and exhaustion during repeated walking tests were eliminated, only suloctidil-treated patients improved significantly. The evolution of leg flow and distal pressure was similar in the two treatment groups whether all legs or only legs with abnormal flow and pressure values were considered. By contrast, when the analysis was limited to legs with claudication pain, a significant improvement occurred only in the suloctidil-treated group. These findings suggest that suloctidil may improve the claudication symptoms of patients with chronic arterial obstructive disease and in particular the perfusion of legs experiencing claudication pain. However, the clinical significance of this improvement appears limited.