Shoulder arthropathy secondary to syringomyelia: systematic review.

Purpose: The purpose of this study was to collect and evaluate clinical and radiological evidence on shoulder neuroarthropathy (NA) in syringomyelia (SM) that may support the management and treatment of patients with this condition. Materials and methods: This systematic review is based on the analysis of reports available in PubMed, Embase, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials using the following keywords: syringomyelia, neuroarthropathy, Charcot joint and shoulder degeneration. Thirty-nine publications were found presenting case reports or case series meeting our criteria. Pooled data included a group of 65 patients and 71 shoulders with NA secondary to SM. Results: The most commonly reported symptoms were range of motion (ROM) limitation, weakness, swelling, pain and dissociated sensory loss. NA is usually monolateral and concerns only the shoulder. The average active shoulder ROM was flexion -59.2° (s.d. 37.9), internal rotation -29.8° (s.d. 22.6) and external rotation -21.1° (s.d. 23.6). Most of the patients (75%) presented with complete or nearly complete proximal humerus degeneration, while the degree of glenoid preservation varied. Fifty-two neuroarthropathic shoulders were treated conservatively with physiotherapy, anti-inflammatory medication and splinting. Eighteen patients were treated by surgical intervention. Conclusion: Shoulder NA due to SM is a devastating and progressive condition, and its course is often unpredictable. Patients with unexplained shoulder degeneration should be evaluated for SM, especially if there are additional neurological symptoms. Conservative treatment usually reduces shoulder pain without improving ROM. For select patients, shoulder arthroplasty may be a better option for restoring function.

Inositol triphosphate-triggered calcium release from the endoplasmic reticulum induces lysosome biogenesis via TFEB/TFE3.

Lysosomes serve as dynamic regulators of cell and organismal physiology by integrating the degradation of macromolecules with receptor and nutrient signaling. Previous studies have established that activation of the transcription factor EB (TFEB) and transcription factor E3 (TFE3) induces the expression of lysosomal genes and proteins in signaling-inactive starved cells, that is, under conditions when activity of the master regulator of nutrient-sensing signaling mechanistic target of rapamycin complex 1 is repressed. How lysosome biogenesis is triggered in signaling-active cells is incompletely understood. Here, we identify a role for calcium release from the lumen of the endoplasmic reticulum in the control of lysosome biogenesis that is independent of mechanistic target of rapamycin complex 1. We show using functional imaging that calcium efflux from endoplasmic reticulum stores induced by inositol triphosphate accumulation upon depletion of inositol polyphosphate-5-phosphatase A, an inositol 5-phosphatase downregulated in cancer and defective in spinocerebellar ataxia, or receptor-mediated phospholipase C activation leads to the induction of lysosome biogenesis. This mechanism involves calcineurin and the nuclear translocation and elevated transcriptional activity of TFEB/TFE3. Our findings reveal a crucial function for inositol polyphosphate-5-phosphatase A-mediated triphosphate hydrolysis in the control of lysosome biogenesis via TFEB/TFE3, thereby contributing to our understanding how cells are able to maintain their lysosome content under conditions of active receptor and nutrient signaling.

Shoulder arthropathy secondary to syringomyelia: case series of 10 patients.

PURPOSE: Neuroarthropathy is a progressive joint degeneration secondary to neurological diseases. In the upper extremity, the shoulder is the most exposed, and it is mainly caused by syringomyelia. This condition is rare; therefore, the literature has documented only a few case reports or case series of small groups of patients. METHODS: We collected data about patients with shoulder arthropathy due to syringomyelia who were treated in our two institutes and collected among members of the Polish Shoulder and Elbow Society. Our analysis was based on epidemiological data, symptoms, and clinical examinations. We also examined the results of diagnostic tests, including-spinal cord MRI and shoulder X-ray, and treatment methods and their effectiveness. RESULTS: The examined group included 10 women with an average age of 63 years. Of these, nine patients reported pain, seven reported-swelling, and nine reported-weakness. In every patient, diagnosis was confirmed by X-ray of the shoulder with joint degeneration and MRI of the spinal cord with syrinx. Two patients were operated with reverse shoulder arthroplasty; the first one had excellent result-significant active range of motion improvement and reduction of symptoms, and the second one had a good result-pain relief and moderate range of motion improvement. Other patients were conservatively treated, resulting in total or partial symptoms relief but without significant range of motion improvement. CONCLUSION: Charcot shoulder secondary to syringomyelia was mainly manifested by range of motion limitation, swelling, and pain. Both conservative and surgical treatments could be a good solution. However, if reverse arthroplasty is technically possible, it seems to be the most promising treatment for recovering function.

Does the VDR gene polymorphism influence the efficacy of denosumab therapy in postmenopausal osteoporosis?

Introduction: One of the challenges of personalized medicine is a departure from traditional pharmacology toward individualized, genotype-based therapies. Postmenopausal osteoporosis is a prevalent condition requiring intensive treatment, whose effects are measurable only after a long time, and the goal is bone fracture prevention. This study aimed to determine the influence of VDR gene variation on anti-osteoporotic one-year treatment with denosumab in 63 Polish women with postmenopausal osteoporosis. Materials and methods: The correlation between bone mineral density (BMD) of the lumbar vertebral column (L1-L4) and femoral neck, and genotype distributions for the ApaI, BsmI, FokI, and TaqI variants of the VDR gene was analyzed. Bone fractures during denosumab therapy were also investigated. Results: In the case of the Bsml polymorphism, female patients with BB and Bb genotypes had statistically significantly higher values of BMD and T-score/Z-score indicators, which persisted after a year of denosumab treatment. Our results indicated that the Bsml polymorphism contributes to better bone status, and, consequently, to more efficient biological therapy. The study did not reveal significant differences between changes (delta) in BMD and genotypes for the analyzed VDR gene loci. In the entire study group, one bone fracture was observed in one patient throughout the yearlong period of denosumab therapy. Conclusions: BB and Bb genotypes of the Bsml polymorphism of the VDR gene determine higher DXA parameter values both before and after one-year denosumab therapy in postmenopausal women with osteoporosis.

Inositol triphosphate-triggered calcium release blocks lipid exchange at endoplasmic reticulum-Golgi contact sites.

Vesicular traffic and membrane contact sites between organelles enable the exchange of proteins, lipids, and metabolites. Recruitment of tethers to contact sites between the endoplasmic reticulum (ER) and the plasma membrane is often triggered by calcium. Here we reveal a function for calcium in the repression of cholesterol export at membrane contact sites between the ER and the Golgi complex. We show that calcium efflux from ER stores induced by inositol-triphosphate [IP3] accumulation upon loss of the inositol 5-phosphatase INPP5A or receptor signaling triggers depletion of cholesterol and associated Gb3 from the cell surface, resulting in a blockade of clathrin-independent endocytosis (CIE) of Shiga toxin. This phenotype is caused by the calcium-induced dissociation of oxysterol binding protein (OSBP) from the Golgi complex and from VAP-containing membrane contact sites. Our findings reveal a crucial function for INPP5A-mediated IP3 hydrolysis in the control of lipid exchange at membrane contact sites.

Clinical and radiological examination of bony-mediated shoulder instability.

The coexistence of glenoid and humeral head bone defects may increase the risk of recurrence of instability after soft tissue repair.Revealed factors in medical history such as male gender, younger age of dislocation, an increasing number of dislocations, contact sports, and manual work or epilepsy may increase the recurrence rate of instability.In physical examination, positive bony apprehension test, catching and crepitations in shoulder movement may suggest osseous deficiency.Anteroposterior and axial views allow for the detection of particular bony lesions in patients with recurrent anterior shoulder instability.Computed Tomography (CT) with multiplanar reconstruction (MPR) and various types of 3D rendering in 2D (quasi-3D-CT) and 3D (true-3D-CT) space allows not only detection of glenoid and humeral bone defects but most of all their quantification and relations (engaging/not-engaging and on-track/off-track) in the context of bipolar lesion.Magnetic resonance imaging (MRI) is increasingly developing and can provide an equally accurate measurement tool for bone assessment, avoiding radiation exposure for the patient. Cite this article: EFORT Open Rev 2020;5:815-827. DOI: 10.1302/2058-5241.5.200049.

Milk and dairy product consumption in patients with inflammatory bowel disease: Helpful or harmful to bone mineral density?

OBJECTIVES: Limiting the consumption of milk and dairy products (DPs) constitutes a risk factor for osteoporosis in patients with inflammatory bowel disease (IBD). The aim of this study was to evaluate bone mineral density (BMD) and the frequency of osteopenia and osteoporosis in patients with IBD. We also investigated the correlation between BMD and consumption of milk and DPs, as well as with calcium, phosphate, and parathyroid hormone (PTH) and 25-hydroxyvitamin D [25(OH)D] serum concentration levels. METHODS: The study comprised 208 patients with IBD. Densitometric measurements were performed using the dual-energy x-ray absorpiometry. Before (IBD-I) and after the diagnosis (IBD-II) of IBD, we used a questionnaire to assess the consumption of milk and DPs. Serum concentrations of PTH, 25(OH)D, calcium, and phosphate were determined. RESULTS: The prevalence of osteopenia and osteoporosis in the IBD patient group was 48.1%. At the same time, 87% of patients with IBD reported milk consumption. Patients from this group with proper bone mass amounted to 91.7%, whereas patients with osteopenia and osteoporosis comprised 82% (P = 0.0382) of patients. In patients with IBD who consumed milk, femoral neck BMD (0.97 ± 0.17 g/cm2) was higher than in those not drinking milk (0.897 ± 0.154 g/cm2; P = 0.0587). The percentage of patients with IBD consuming DPs was 96.2%; however, this number decreased after diagnosis and was equal to IBD-II: 83% (P < 0.0001). Additionally, concentration levels of 25(OH)D decreased in the IBD group (21.82 ± 10.82 ng/dL). CONCLUSION: Not only does IBD entail a high prevalence of osteoporosis, but BMD values are also indirectly affected by the fact that patient consumption of milk and other DPs decreases after diagnosis.

Analysis of the tumor necrosis factor superfamily member 11 gene polymorphism with bone mineral density and bone fracture frequency in patients with postmenopausal osteoporosis.

PURPOSE: We aimed to examine the polymorphism of the promoter and exon 5 of the TNFSF11 gene and their impact on bone mineral density (BMD) and the frequency of bone fractures. TNFSF11 encodes the receptor activator of the NF-kB ligand (RANKL), a key regulator of bone metabolism and osteoporosis drug targets. BMD is an essential measure in diagnosing osteoporosis and assessing the risk of fractures. In vivo, RANKL expression research suggests that promoter TNFSF11 variants influence BMD. Moreover, exon 5 polymorphism of a linear epitope sequence for a denosumab could be related to the effectiveness of biological therapy. PATIENTS AND METHODS: The study included 114 postmenopausal osteoporosis patients. BMD was measured in the lumbar spine and the femoral neck. Genetic analysis was performed using Sanger sequencing. Genotypes data for 263 female European population group were obtained from the 1000Genomes database. RESULTS: We identified six promoter polymorphisms (rs9525641, rs9533155, rs9533156, rs11839112, rs28926171, rs183599708) and one silent TNFSF11 variant in exon 5 (rs9562415). Three of the sequence variants detected (rs9525641, rs9533155, rs9533156) proved to be polymorphic, whereas the others four occurred at a frequency below 2%. The statistical analysis demonstrated no significant differences between polymorphisms and BMD, and bone fractures. However, variant rs9533156 was relevant with the lumbar spine T-score (p = 0.0273), and no association with BMD was of borderline significance (p = 0.0529). CONCLUSIONS: Variant rs9533156 may contribute to the genetic regulation of BMD in Polish postmenopausal osteoporosis, while the exon 5 sequence of the TNFSF11 gene is very conservative.

Frizzled 7 and PIP2 binding by syntenin PDZ2 domain supports Frizzled 7 trafficking and signalling.

PDZ domain-containing proteins work as intracellular scaffolds to control spatio-temporal aspects of cell signalling. This function is supported by the ability of their PDZ domains to bind other proteins such as receptors, but also phosphoinositide lipids important for membrane trafficking. Here we report a crystal structure of the syntenin PDZ tandem in complex with the carboxy-terminal fragment of Frizzled 7 and phosphatidylinositol 4,5-bisphosphate (PIP2). The crystal structure reveals a tripartite interaction formed via the second PDZ domain of syntenin. Biophysical and biochemical experiments establish co-operative binding of the tripartite complex and identify residues crucial for membrane PIP2-specific recognition. Experiments with cells support the importance of the syntenin-PIP2 interaction for plasma membrane targeting of Frizzled 7 and c-jun phosphorylation. This study contributes to our understanding of the biology of PDZ proteins as key players in membrane compartmentalization and dynamics.

Efficacy of HCV treatment in Poland at the turn of the interferon era - the EpiTer study.

THE AIM OF THE STUDY: Was to analyze the efficacy achieved with regimens available for chronic hepatitis C (CHC) in Poland between 2013 and 2016. MATERIAL AND METHODS: Data were collected from 29 centers and included 6786 patients with available sustained virologic response (SVR) data between 1 January 2013 and 31 March 2016. RESULTS: The sustained virologic response rate for genotypes (G) 1a, 1b, 2, 3 and 4 was 62%, 56%, 92%, 67% and 56% respectively; 71% patients (n = 4832) were treated with pegylated interferon α (Peg-IFNα) and ribavirin (RBV), with SVR rates of 58%, 49%, 92%, 67% and 55% respectively. The sustained virologic response among 5646 G1 infected patients was the lowest with natural interferon α (7%, n = 70) or PegIFN (50%, n = 3779) with RBV, and improved in those receiving triple regimens of Peg-IFN + RBV combined with boceprevir (47%, n = 485), telaprevir (64%, n = 805), simeprevir (73%, n = 132) or sofosbuvir (70%, n = 23). The sustained virologic response with interferon-free regimens of sofosbuvir and RBV (n = 7), sofosbuvir and simeprevir (n = 53), and ledipasvir and sofosbuvir (n = 64) achieved 86%, 89% and 94% respectively. The highest SVR of 98% was observed with ombitasvir/paritaprevir combined with dasabuvir (n = 227). Patients infected with G3 (n = 896) and G4 (n = 220) received mostly Peg-IFN + RBV with SVR of 67% and 56% respectively. Interferon-free regimens were administered in 18 G3/G4 patients and all achieved an SVR. Sofosbuvir combined with Peg-IFN and RBV was administered to 33 patients with an SVR rate of 94%, and a similar rate was achieved among 13 G2 patients treated with interferon and RBV. CONCLUSIONS: We observed significant differences in efficacy of HCV regimens available in Poland at the turn of the interferon era. The data will be useful as a comparison for therapeutic options expected in the next few years.

Prevalence of HCV genotypes in Poland - the EpiTer study.

THE AIM OF THE STUDY: Was to assess current prevalence of hepatitis C virus (HCV) genotypes in Poland, including their geographic distribution and changes in a given period of time. MATERIAL AND METHODS: Data were collected with questionnaires from 29 Polish centers and included data of patients diagnosed with HCV infection between 1 January 2013 and 31 March 2016. RESULTS: In total, data of 9800 patients were reported. The highest prevalence was estimated for genotype 1b (81.7%), followed by 3 (11.3%), 4 (3.5%), 1a (3.2%) and 2 (0.2%). Genotype 5 or 6 was reported in 6 patients only (0.1%). The highest prevalence of genotype 1 was observed in central (lódzkie, mazowieckie, swietokrzyskie), eastern (lubelskie) and southern (malopolskie, slaskie) Poland. The highest rate for genotype 3 was observed in south-western (dolnoslaskie, lubuskie) and eastern (podlaskie, warminsko-mazurskie and podkarpackie) Poland. Compared to historical data, we observed an increasing tendency of G1 prevalence from 72.0% in 2003 to 87.5% in 2016, which was accompanied by a decrease of G3 (17.9% vs. 9.1%) and G4 (9.0% vs. 3.1%). CONCLUSIONS: Almost 85% of patients with HCV in Poland are infected with genotype 1 (almost exclusively subgenotype 1b), and its prevalence shows an increasing tendency, accompanied by a decrease of genotypes 3 and 4.

Phosphoinositides and PDZ domain scaffolds.

The discovery that PSD-95/Discs large/ZO-1 (PDZ) domains can function as lipid-binding modules, in particular interacting with phosphoinositides (PIs), was made more than 10 years ago (Mol Cell 9(6): 1215-1225, 2002). Confirmatory studies and a series of functional follow-ups established PDZ domains as dual specificity modules displaying both peptide and lipid binding, and prompted a rethinking of the mode of action of PDZ domains in the control of cell signaling. In this chapter, after introducing PDZ domains, PIs and methods for studying protein-lipid interactions, we focus on (i) the prevalence and the specificity of PDZ-PIs interactions, (ii) the molecular determinants of PDZ-PIs interactions, (iii) the integration of lipid and peptide binding by PDZ domains, (iv) the common features of PIs interacting PDZ domains and (v) the regulation and functional significance of PDZ-PIs interactions.

Prognostic factors in patients surgically treated after hip fracture.

INTRODUCTION: By the impact of demographic changes and as the result of the 'incorrect' lifestyles pursued in developed societies, osteoporosis has become a serious social problem. Hip fracture is the most serious complication of osteoporosis and is associated with high mortality rates or permanent health impairment. The goal of this study was an evaluation of the impact of selected socio-economic factors and of the time period from fracture to surgical intervention on the patient's prognosis. MATERIAL AND METHODS: A group of 148 patients (114 women and 34 men) participated in the study, their age varying between 48 and 93 years, all of them after surgical treatment of hip fracture. A questionnaire study was carried out, encompassing all the participants. RESULTS: During a year-long follow up, thirty-four (34) patients, i.e. 23% of the whole group, passed away. Further comparisons were performed between two groups: Group A - 114 patients, who survived the follow up period, and Group B - those who died. The mean age of patients was 76.3 and 82.6 years in Groups A and B, respectively (p 〈 0.05). In Group A, 79.8% of the patients declared full self-dependence prior to fracture episode vs. 44.1% of the patients in Group B (p 〈 0.05). Regular physical activity - in various forms - was undertaken by 39.5% of the patients in Group A and 11.8% of those in Group B (p 〈 0.05). Active ways of spending outdoor time were reported by 32.5% of the patients in Group A vs. 14.7% in Group B (p 〈 0.05). Fracture unfavourably influenced the material situation of affected patients. No relationship was found between the time period from fracture to surgery and the patient's prognosis. CONCLUSIONS: 1. Despite the currently available surgical treatment methods, hip fracture is still laden with a high risk of fatality. 2. High physical activity, especially outdoors, self-dependence and having a partner positively influence patient's prognosis after hip fracture. 3. Hip fracture negatively changes the material situation of patients. 4. The length of time from hip fracture to operation has no effect on the survival rate.

Prevalence, specificity and determinants of lipid-interacting PDZ domains from an in-cell screen and in vitro binding experiments.

BACKGROUND: PDZ domains are highly abundant protein-protein interaction modules involved in the wiring of protein networks. Emerging evidence indicates that some PDZ domains also interact with phosphoinositides (PtdInsPs), important regulators of cell polarization and signaling. Yet our knowledge on the prevalence, specificity, affinity, and molecular determinants of PDZ-PtdInsPs interactions and on their impact on PDZ-protein interactions is very limited. METHODOLOGY/PRINCIPAL FINDINGS: We screened the human proteome for PtdInsPs interacting PDZ domains by a combination of in vivo cell-localization studies and in vitro dot blot and Surface Plasmon Resonance (SPR) experiments using synthetic lipids and recombinant proteins. We found that PtdInsPs interactions contribute to the cellular distribution of some PDZ domains, intriguingly also in nuclear organelles, and that a significant subgroup of PDZ domains interacts with PtdInsPs with affinities in the low-to-mid micromolar range. In vitro specificity for the head group is low, but with a trend of higher affinities for more phosphorylated PtdInsPs species. Other membrane lipids can assist PtdInsPs-interactions. PtdInsPs-interacting PDZ domains have generally high pI values and contain characteristic clusters of basic residues, hallmarks that may be used to predict additional PtdInsPs interacting PDZ domains. In tripartite binding experiments we established that peptide binding can either compete or cooperate with PtdInsPs binding depending on the combination of ligands. CONCLUSIONS/SIGNIFICANCE: Our screen substantially expands the set of PtdInsPs interacting PDZ domains, and shows that a full understanding of the biology of PDZ proteins will require a comprehensive insight into the intricate relationships between PDZ domains and their peptide and lipid ligands.

Vitamin D receptor gene polymorphisms, bone mineral density and fractures in postmenopausal women with osteoporosis.

The goal of the study was to investigate the possibility of an association between polymorphisms and single alleles of BsmI, ApaI, TaqI of the vitamin D receptor (VDR) gene with bone mineral density (BMD) and prevalence of vertebral/non-vertebral fractures in a group of postmenopausal Polish women with osteoporosis. The study group comprised of 501 postmenopausal females with osteoporosis (mean age 66.4 ± 8.9), who were diagnosed on the basis of either the WHO criteria or self-reported history of low-energy fractures. The three polymorphisms were determined by PCR (polymerase chain reaction) and RFLP (restriction fragment length polymorphism). BMD at the lumbar spine and femoral neck was assessed by dual energy X-ray absorptiometry (DXA). 285 fractures were reported in the whole group (168 vertebral and 117 non-vertebral). Incidence of non-vertebral fractures was significantly higher in the carriers of single alleles a of ApaI, b of BsmI and T of TaqI VDR gene polymorphisms (p = 0.021, 0.032, 0.020, respectively). No significant associations between allelic variants of the studied polymorphisms and BMD or fracture incidence were found. (1).The presence of single alleles a,b and T of ApaI, BsmI, TaqI VDR gene polymorphisms respectively, might serve as an indicator of non-vertebral fractures. (2). Lack of association between the VDR gene polymorphisms and BMD suggests that VDR contributes to low-energy fractures also through other ways.

Extensions of PSD-95/discs large/ZO-1 (PDZ) domains influence lipid binding and membrane targeting of syntenin-1.

Syntenin-1 is a PDZ protein involved in receptor recycling and clustering. Its two PDZ domains interact with various receptors and phosphoinositides, and are flanked by N- and C-terminal regions. Here, we report the identification of an autoinhibitory peptide stretch in the N-terminus that might be regulated by phosphorylation. We further establish that basic residues in the C-terminal region mediate electrostatic interactions with reconstituted liposomes and contribute to the plasma membrane targeting. Our study adds new components to the multi-dentate membrane targeting mechanism and highlights the role of N- and C-terminal PDZ extensions in the regulation of syntenin-1 plasma membrane localization.

[The role of hormonal therapy in osteoporosis]. / Terapia hormonalna w osteoporozie.

In developed societies, the post-menopausal period covers approximately one third of a woman's life. The deficit of oestrogens observed during the post-menopausal period significantly affects the course of many metabolic processes, causing a number of diseases and in consequence diminishing quality of life. Among others, bones belong to oestrogen-dependent tissues. The deficit of the protective influence of oestrogens compromises the dynamic balance of the bone transformation process towards resorption, thus reducing bone mass and quality, while increasing the risk of low-energy fractures. In recent years, differing views on the application of oestrogen/gestagen therapy have reached the level of controversy. The results of numerous clinical studies are far from unequivocal, with the whole subject one of heated debate. It has been confirmed that hormonal therapy prevents bone quality deterioration, while opening a protective umbrella around the bone, reducing the risk of osteoporotic fractures. A rational approach to weighing possible advantages against possible risks and a thorough evaluation of a patient's health condition allows for optimal therapy selection.

Cooperative phosphoinositide and peptide binding by PSD-95/discs large/ZO-1 (PDZ) domain of polychaetoid, Drosophila zonulin.

PDZ domains are well known protein-protein interaction modules that, as part of multidomain proteins, assemble molecular complexes. Some PDZ domains have been reported to interact with membrane lipids, in particular phosphatidylinositol phosphates, but few studies have been aimed at elucidating the prevalence or the molecular details of such interactions. We screened 46 Drosophila PDZ domains for phosphoinositide-dependent cellular localization and discovered that the second PDZ domain of polychaetoid (Pyd PDZ2) interacts with phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P(2)) at the plasma membrane. Surface plasmon resonance binding experiments with recombinant protein established that Pyd PDZ2 interacts with phosphatidylinositol phosphates with apparent affinities in the micromolar range. Electrostatic interactions involving an extended positively charged surface of Pyd PDZ2 are crucial for the PtdIns(4,5)P(2)-dependent membrane interactions as shown by a combination of three-dimensional modeling, mutagenesis, binding, and localization studies. In vivo localization studies further suggested that both lipid and peptide binding contribute to membrane localization. We identified the transmembrane protein Crumbs as a Pyd PDZ2 ligand and probed the relation between peptide and PtdIns(4,5)P(2) binding. Contrary to the prevalent view on PDZ/peptide/lipid binding, we did not find competition between peptide and lipid ligands. Instead, preloading the protein with the 10-mer Crb3 peptide increased the apparent affinity of Pyd PDZ2 for PtdIns(4,5)P(2) 6-fold. Our results suggest that membrane localization of Pyd PDZ2 may be driven by a combination of peptide and PtdIns(4,5)P(2) binding, which raises the intriguing possibility that the domain may coordinate protein- and phospholipid-mediated signals.

A discussion of the intervention thresholds in osteoporosis treatment in Poland.

INTRODUCTION: Epidemiological prognoses regarding the global spread of post-menopausal osteoporosis can prove somewhat nebulous. But it is clear that low-energy fractures and their consequences will become an increasingly serious health problem. Therefore it is crucial to implement prognostic procedures which could more effectively predict the incidence of osteoporosis and its complications. MATERIAL AND METHODS: The study involved 378 female patients aged 40-86 years for whom clinical risk factors of osteoporotic fracture were analysed. Densitometry (DPX) was performed at femoral neck. The 10-year risk of fracture was assessed according to the British model of FRAX calculator. RESULTS: The study group was divided into two, depending on the history of low-energy fractures. Previous osteoporotic fractures were confirmed in 128 patients. In this group, the mean bone mineral density (BMD) values (0.717 g/cm(2)) were lower than in the group without fracture history (0.735 g/cm(2)). In 33.3% of patients aged 50-59 years and 17% of women aged 60-79 who required medical treatment for their clinical status (previous fracture), the FRAX value did not meet the criterion of pharmacotherapy administration. Considering BMD in the calculation of FRAX produced an even higher underestimation of the fracture risk. Of women aged 40-49, 25% were qualified for pharmacotherapy of osteoporosis. In that particular age category, BMD did not affect the FRAX value. BMD measurement had a higher discriminatory value among patients aged 50-79, increasing the number of patients requiring therapy by more than 50%. CONCLUSIONS: 1. The FRAX calculator does not always consider the history of low-energy fractures as a criterion sufficient for therapy implementation. 2. Designing a FRAX calculator specifically for the Polish population would be advisable.

The role of hormonal therapy in osteoporosis.

In developed societies, the post-menopausal period covers approximately one third of a woman's life. The deficit of oestrogens observed during the post-menopausal period significantly affects the course of many metabolic processes, causing a number of diseases and in consequence diminishing quality of life. Among others, bones belong to oestrogen-dependent tissues. The deficit of the protective influence of oestrogens compromises the dynamic balance of the bone transformation process towards resorption, thus reducing bone mass and quality, while increasing the risk of low-energy fractures. In recent years, differing views on the application of oestrogen/gestagen therapy have reached the level of controversy. The results of numerous clinical studies are far from unequivocal, with the whole subject one of heated debate. It has been confirmed that hormonal therapy prevents bone quality deterioration, while opening a protective umbrella around the bone, reducing the risk of osteoporotic fractures. A rational approach to weighing possible advantages against possible risks and a thorough evaluation of a patient's health condition allows for optimal therapy selection.