Judit Donáth

Novel UBA Domain Mutations of SQSTM1 in Paget's Disease of Bone: Genotype Phenotype Correlation, Functional Analysis, and Structural Consequences

Three novel missense mutations of SQSTM1 were identified in familial PDB, all affecting the UBA domain. Functional and structural analysis showed that disease severity was related to the type of mutation but was unrelated to the polyubiquitin‐binding properties of the mutant UBA domain peptides.

Epidemiology of Paget's disease in Europe : The prevalence is decreasing

This study estimated changes in the age‐ and sex‐specific prevalence of Pagets disease of bone in six European towns over a 20‐year period. Declines in prevalence were observed in this disorder, occurring among both men and women.

Gene Expression Profiling in Paget's Disease of Bone: Upregulation of Interferon Signaling Pathways in Pagetic Monocytes and Lymphocytes†‡§

We examined the gene expression profile of genes involved in bone metabolism in 23 patients with PD compared with 23 healthy controls. We found a significant overexpression of the genes of the IFN pathway along with a downregulation of tnf‐α. Our result suggest that IFN‐mediated signaling may play important roles in aberrant osteoclastogenesis of PD.

Prevalence of obesity in an elderly Hungarian population

Background: There are few cross-sectional population-based studies on obesity in Hungary. Aim of this study was to characterize the prevalence, associated diseases and metabolic laboratory parameters for obesity in men and women in Budapest, Hungary. Methods: A random sample of 641 persons (307 males and 334 females) aged 50 years and over were recruited from a population register in Budapest. Subjects were interviewed, had height and weight measured in standard fashion. Those who were obese (BMI > 30.0 kg/m2) were matched individually with non-obese subjects. Altogether 101 pairs (48 women and 53 men pairs) were taking part and these subjects had blood taken for amount of serum glucose, lipids and uric acid. Results: The mean age of men and women was 65.0 (SD = 9.1) years and 64.6 (SD = 8.9) years, respectively. The prevalence of obesity was 18.1% in men and 15.4% in women (p < 0.05). In both sexes the mean body mass index was higher at age of 50–64 years than at older ages [in men 27.2 (SD = 3.7) kg/m2 vs. 26.7 (SD = 3.3) kg/m2, p = 0.286 and in women 26.7 (SD = 4.2) kg/m2 vs. 25.4 (SD = 4.0) kg/m2, p = 0.005]. Body mass index was higher in men than in women at all ages. In the case–control study the mean age of obese and non-obese individuals were 63.1 (SD = 7.8) years and 63.2 (SD = 7.9) years, respectively. Obesity was significantly associated with a history of diabetes mellitus (18 vs. 7%, p < 0.05) and hypertension (48 vs. 28%, p < 0.05). Compared to the non-obese, those who were obese had a higher level of serum uric acid (311 ± 102 vs. 280 ± 96μmol/l, p < 0.05) and triglyceride (2.67± 1.95 vs. 1.86 ± 0.95 mmol/l, p < 0.05). Conclusion: The high prevalence of obesity both in elderly men and women and its strong association with chronic diseases causes economical and social burden for Hungary. Strategies and programs for weight maintenance as well as weight reduction must become a higher public health priority.

Polymorphisms of CSF1 and TM7SF4 genes in a case of mild juvenile Paget's disease found using next-generation sequencing

Juvenile Paget’s disease (JPD) is a rare autosomal-recessive condition. It is diagnosed in young children and characterized by a generalized increase in bone turnover, bone pain, and skeletal deformity. Our patient was diagnosed after a pathological fracture when she was 11 years old. When we first examined her at the age of 30 she had bone pain and deformity in both the femur and tibia. Serum alkaline phosphatase (ALP) level, radiology, bone scintigraphy, and densitometry were monitored. Next generation sequencing (NGS) technology, namely semiconductor sequencing, was used to determine the genetic background of JPD. Seven target genes and regions were selected and analyzed after literature review (TM7SF4, SQSTM1, TNFRSF11A, TNFRSF11B, OPTN, CSF1, VCP). No clear pathogenic mutation was found, but we detected missense polymorphisms in CSF1 and TM7SF4 genes. After treatment with zoledronic acid, infusion bone pain and ALP level decreased. We can conclude that intravenous zoledronic acid therapy is effective and safe for suppressing bone turnover and improving symptoms in JPD, but the long-term effects on clinical outcomes are unclear. Our findings also suggest that NGS may help explore the pathogenesis and aid the diagnosis of JPD.

Age- and sex-related regional compressive strength characteristics of human lumbar vertebrae in osteoporosis.

Objective To obtain the compressive load bearing and energy absorption capacity of lumbar vertebrae of osteoporotic elderly for the everyday medical praxis in terms of the simple diagnostic data, like computed tomography (CT), densitometry, age, and sex. Methods Compressive test of 54 osteoporotic cadaver vertebrae L1 and L2, 16 males and 38 females (age range 43–93, mean age 71.6 ± 13.3 years, mean bone mineral density (BMD) 0.377 ± 0.089 g/cm2, mean T-score −5.57 ± 0.79, Z-score −4.05 ± 0.77) was investigated. Based on the load-displacement diagrams and the measured geometrical parameters of vertebral bodies, proportional, ultimate and yield stresses and strains, Young’s modulus, ductility and energy absorption capacity were determined. Three vertebral regions were distinguished: superior, central and inferior regions, but certain parameters were calculated for the upper/ lower intermediate layers, as well. Cross-sectional areas, and certain bone tissue parameters were determined by image analysis of CT pictures of vertebrae. Sex- and age-related decline functions and trends of strength characteristics were determined. Results Size-corrected failure load was 15%–25% smaller in women, proportional and ultimate stresses were about 30%–35% smaller for women in any region, and 20%–25% higher in central regions for both sexes. Young’s moduli were about 30% smaller in women in any region, and 20%–25% smaller in the central region for both sexes. Small strains were higher in males, large strains were higher in females, namely, proportional strains were about 25% larger in men, yield and ultimate strains were quasi equal for sexes, break strains were 10% higher in women. Ultimate energy absorption capacity was 10%–20% higher in men; the final ductile energy absorption capacity was quasi equal for sexes in all levels. Age-dependence was stronger for men, mainly in central regions (ultimate load, male: r = −0.66, p < 0.01, female: r = −0.52, p < 0.005; ultimate stress, male: r = −0.69, p < 0.01, female: r = −0.50, p < 0.005; Young’s modulus, male: r = −0.55, p < 0.05, female: r = −0.52, p < 0.005, ultimate stiffness, male: r = −0.58, p < 0.05, female: r = −0.35, p < 0.03, central ultimate absorbed energy density, male: r = −0.59, p < 0.015, female: r = −0.29, p < 0.08). Conclusions For the strongly osteoporotic population (BMD < 0.4 g/cm2, T-score < −4) the statical variables (loads, stresses) showed significant correlation; mixed variables (stiffness, Young’s modulus, energy) showed moderate correlation; kinematical variables (displacements, strains) showed no correlation with age. The strong correlation of men between BMD and aging (r = −0.82, p < 0.001) and betwen BMD and strength parameters (r = 0.8–0.9, p < 0.001) indicated linear trends in age-related strength loss for men; however, the moderate correlation of women between BMD and aging (r = −0.47, p < 0.005) and between BMD and strength parameters (r = 0.4–0.5, p < 0.005) suggested the need of nonlinear (quadratic) approximation that provided the better fit in age-related strength functions of females modelling postmenopausal disproportionalities.

[Paget's disease: clinical update].

Pagets disease is a chronic disorder of bone remodeling, characterized by an abnormal increase of osteoclast and, hence, osteoblast activity. The imbalance of bone turnover results in the formation of unhealthy and fragile bone. It also leads to impairment of adjacent joints and to a risk of various complications. Current research focuses on the elucidation of the etiologic role viral infection and predisposing genetic factors. Pagets disease is commonly discovered by chance; its suspicion is raised either by high level of alkaline phosphatase or by the X-ray of the pathological bone. Bisphosphonates have proven to be effective in controlling disease activity because they inhibit osteoclast function. Their use is recommended when bone-derived serum alkaline phosphatase is high and/or when disease localizations are highly suspected for the development of complications.