Analysis of bone architecture using fractal-based TX-Analyzer™ in adult patients with osteogenesis imperfecta.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by impaired bone quality and quantity. Established imaging techniques have limited reliability in OI. The TX-Analyzer™ is a new, fractal-based software allowing a non-invasive assessment of bone structure based on conventional radiographs. We explored whether the TX-Analyzer™ can discriminate OI patients and healthy controls. Furthermore, we investigated the correlation between TX-Analyzer™ parameters and (i) bone mineral density (BMD) by Dual Energy X-ray Absorptiometry (DXA), (ii) trabecular bone score (TBS), and (iii) bone microstructure by high-resolution peripheral quantitative computed tomography (HR-pQCT). MATERIAL AND METHODS: Data of 29 adult OI patients were retrospectively analyzed. Standard radiographs of the thoracic and lumbar spine were evaluated using the TX-Analyzer™. Bone Structure Value (BSV), Bone Variance Value (BVV), and Bone Entropy Value (BEV) were measured at the vertebral bodies T7 to L5. Data were compared to a healthy, age- and gender-matched control group (n = 58). BMD by DXA, TBS, and trabecular bone microstructure by means of HR-pQCT were correlated to TX-Analyzer™ parameters in OI patients. The accuracy of the TX-Analyzer™ parameters in detecting OI was assessed with area under curve (AUC) analysis of receiver operating characteristic (ROC). RESULTS: BEV of the thoracic and the lumbar spine were significantly lower in OI patients compared to controls (both p < 0.001). BEV of the thoracic spine was significantly correlated to TBS (ρ = 0.427, p = 0.042) as well as trabecular number (Tb.N) at the radius (ρ = 0.603, p = 0.029) and inhomogeneity of the trabecular network (Tb.1/N.SD) at the radius (ρ = -0.610, p = 0.027), when assessed by HR-pQCT. No correlations were found between BEV and BMD by DXA. BEV of the thoracic and the lumbar spine had an AUC of 0.81 (95% confidence interval [CI] 0.67-0.94, p < 0.001) and 0.73 (95% CI 0.56-0.89, p = 0.008), respectively. BSV and BVV did not differ between OI patients and controls. CONCLUSION: The software TX-Analyzer™ is able to discriminate patients with OI from healthy controls. ROC curves of BEV values suggest a suitable clinical applicability. Low to no correlations with conventional methods suggest, that the TX-Analyzer™ may indicate a new and independent examination tool in OI.

Bayesian and frequentist analysis of an Austrian genome-wide association study of colorectal cancer and advanced adenomas.

Most genome-wide association studies (GWAS) were analyzed using single marker tests in combination with stringent correction procedures for multiple testing. Thus, a substantial proportion of associated single nucleotide polymorphisms (SNPs) remained undetected and may account for missing heritability in complex traits. Model selection procedures present a powerful alternative to identify associated SNPs in high-dimensional settings. In this GWAS including 1060 colorectal cancer cases, 689 cases of advanced colorectal adenomas and 4367 controls we pursued a dual approach to investigate genome-wide associations with disease risk applying both, single marker analysis and model selection based on the modified Bayesian information criterion, mBIC2, implemented in the software package MOSGWA. For different case-control comparisons, we report models including between 1-14 candidate SNPs. A genome-wide significant association of rs17659990 (P=5.43×10-9, DOCK3, chromosome 3p21.2) with colorectal cancer risk was observed. Furthermore, 56 SNPs known to influence susceptibility to colorectal cancer and advanced adenoma were tested in a hypothesis-driven approach and several of them were found to be relevant in our Austrian cohort. After correction for multiple testing (α=8.9×10-4), the most significant associations were observed for SNPs rs10505477 (P=6.08×10-4) and rs6983267 (P=7.35×10-4) of CASC8, rs3802842 (P=8.98×10-5, COLCA1,2), and rs12953717 (P=4.64×10-4, SMAD7). All previously unreported SNPs demand replication in additional samples. Reanalysis of existing GWAS datasets using model selection as tool to detect SNPs associated with a complex trait may present a promising resource to identify further genetic risk variants not only for colorectal cancer.

In-situ measurement of oxygen concentration under high pressure and the application to oxygen permeation through polymer films.

Up until now, gas permeation through polymers under high pressure has not been able to be measured continuously. The combination of a special high pressure cell and a commercially available fluorescence-based oxygen measurement system allows in-situ monitoring of oxygen permeation through a polymer sample under pressure in an aqueous environment. The principle of the oxygen sensor is based on dynamic fluorescence quenching and measurement of the fluorescence decay time. It was observed that the decay time increases non-linearly with the applied pressure, and hence, the displayed oxygen concentration has to be corrected. This deviation between the measured and the real concentration depends not only on the pressure but also on the absolute oxygen concentration in the water. To obtain a calibration curve, tests were performed in the pressure range between 1 and 2000 bars and initial oxygen concentrations in the range between 40 and 280 µmol/l. The polynomial calibration curve was of the fourth order, describing the raw data with a coefficient of determination R(2) > 0.99. The effective oxygen permeation through polymeric samples can be calculated with this function. A pressure hysteresis test was undertaken but no hysteresis was found. No temperature dependence of the oxygen sensor signal was observed in the range between 20 °C and 30 °C. This study presents for the first time data showing the oxygen permeation rates through a polyethylene film in the pressure range between 1 and 2000 bars at 23 °C.

A child with split-hand/foot associated with tibial hemimelia (SHFLD syndrome) and thrombocytopenia maps to chromosome region 17p13.3.

We describe a-2-year-old boy who presented with a neonatal history of thrombocytopenia associated with a constellation of limb malformations mimicking split hand/foot malformation with long bone deficiency (SHFLD) syndrome. Limb malformations consisted of unilateral monodactyly with radial aplasia, unilateral split foot and bilateral club foot. Tibial aplasia of one limb and tibial hypoplasia of the other limb were notable. Partial agenesis of the sacrum was additional skeletal malformation. Craniofacial features included dense thick scalp hair, narrow frontal area, thick eye-brows, deep-set eyes, depressed nasal bridge, and small overhanging nasal tip, full-cheeks, and large ears. Array-CGH showed duplication of the short arm of chromosome 17p13.3 in the boy and his father, respectively. The father was free from any skeletal abnormalities, though he shares similar craniofacial dysmorphic features like his son. In addition, a paternal sib (uncle of the proband) manifested a phenotype similar to that of the proband. To the best of our knowledge the overall phenotypic and genotypic characterizations were consistent but not completely compatible with the traditional type of TAR syndrome or with SHFLD syndrome. We report on what might be a novel variant of SHFLD associated with transient thrombocytopenia, dysmorphic facial features, and a constellation of bone malformations.

3p interstitial deletion: novel case report and review.

3p interstitial deletions have emerged in recent years as a new cause of neurodevelopmental delay and intellectual disability. Since the first report of this condition in 1979, 16 cases have been described in the literature, delineating it as a presumptive syndrome. Here, we add a novel case presenting severely delayed neurodevelopment and psychomotor development; facial dysmorphism (square facies, broad forehead, short palpebral fissures, epicanthic folds, broad nasal bridge, and low-set malformed ears); cerebral, cardiac, and genital malformations; hand and feet anomalies; sacral sinus; and hearing impairment. Genetic investigations revealed a del(3)(p12.3p14.1) of 12.5 Mb, including 31 ORFs, among which ROBO2, PDZRN3, MITF, and FOXP1 are known to act in neurodevelopment. The clinical features of our patient are compared with those previously reported in the literature, thus providing further support for the delineation of the 3p interstitial deletion syndrome.