Segregation of a M404V mutation of the p62/sequestosome 1 (p62/SQSTM1) gene with polyostotic Paget's disease of bone in an Italian family

Mutations of the p62/Sequestosome 1 gene (p62/SQSTM1) account for both sporadic and familial forms of Paget's disease of bone (PDB). We originally described a methionine→valine substitution at codon 404 (M404V) of exon 8, in the ubiquitin protein-binding domain of p62/SQSTM1 gene in an Italian PDB patient. The collection of data from the patient's pedigree provided evidence for a familial form of PDB. Extension of the genetic analysis to other relatives in this family demonstrated segregation of the M404V mutation with the polyostotic PDB phenotype and provided the identification of six asymptomatic gene carriers. DNA for mutational analysis of the exon 8 coding sequence was obtained from 22 subjects, 4 PDB patients and 18 clinically unaffected members. Of the five clinically ascertained affected members of the family, four possessed the M404V mutation and exhibited the polyostotic form of PDB, except one patient with a single X-ray-assessed skeletal localization and one with a polyostotic disease who had died several years before the DNA analysis. By both reconstitution and mutational analysis of the pedigree, six unaffected subjects were shown to bear the M404V mutation, representing potential asymptomatic gene carriers whose circulating levels of alkaline phosphatase were recently assessed as still within the normal range. Taken together, these results support a genotype–phenotype correlation between the M404V mutation in the p62/SQSTM1 gene and a polyostotic form of PDB in this family. The high penetrance of the PDB trait in this family together with the study of the asymptomatic gene carriers will allow us to confirm the proposed genotype–phenotype correlation and to evaluate the potential use of mutational analysis of the p62/SQSTM1 gene in the early detection of relatives at risk for PDB

Intra-tumoral IFN-gamma-producing Th22 cells correlate with TNM staging and the worst outcomes in pancreatic cancer

PDAC (pancreatic ductal adenocarcinoma) is the fifth leading cause of cancer-related death. The causes of this cancer remain unknown, but increasing evidence indicates a key role of the host immune response and cytokines in human carcinogenesis. Intra-tumoral IL (interleukin)-22 levels have been shown to be elevated in PDAC patients. However, little is known regarding the expression and clinical relevance of Th22 cells in human PDAC and, furthermore, which TILs (tumour-infiltrating lymphocytes) are the main producers of IL-22 is unknown. In the present study, we characterized the functional proprieties of the different subsets of IL-22-producing TILs and analysed their relationship with the TNM staging system and patient survival. We have demonstrated for the first time that, in PDAC patients, the T-cells co-producing IFN-gamma (interferon gamma) and exerting perforin-mediated cytotoxicity are the major intra-tumoral source of IL-22. In addition, isolated Th22 cells were able to induce apoptosis, which was antagonized by IL-22. Finally, we observed that the IL-22-producing T-cells were significantly increased in tumour tissue and that this increase was positively correlated with TNM staging of PDAC and poorer patient survival. These novel findings support the dual role of the anti-tumour immune system and that IL-22-producing cells may participate in PDAC pathogenesis. Therefore monitoring Th22 levels could be a good diagnostic parameter, and blocking IL-22 signalling may represent a viable method for anti-PDAC therapies

The bone care nurse project

In today's society, citizens are called to play an increasingly active role in decision planning related to the various aspects of work, social and political life. This trend has been also confirmed in the health’s field. In fact, the citizen is also required to have the skills to take responsibility for his/her own health, to have knowledge of the health care system, understand the advice and instructions of health professionals, actively participating with them in the therapeutical path. The lack or an inadequate level of these skills will affect both the health of the individual and the costs related to the National Health System. The nursing staff that interfaces between physicians and patients plays a key role in health’s promotion as an important determinant of health and welfare of the patient-citizen. With regard to osteoporosis, due to better knowledge of its determining causes, it is now possible an easy access to diagnosis and treatment options before fragility fractures occur, providing a real prevention to such complications. Prevention must be addressed to two different, but related, objectives: 1) prevention of osteoporosis; and 2) prevention of fragility fractures in patients with osteoporosis. In the context of both primary and secondary prevention, the nurse can better informed the patients and/or citizens about either the risks related to an inappropriate behavior or situations and events particularly dangerous to health, as well as provide information to simply and effectively implement protective measures. This project aims to raise awareness and create competent and specialized nurse figures, with a good understanding of the bone diseases, through the organization of seminars and training courses. Thus, it will be create clinical pathways and welfare in which the figure of the "Bone Care Nurse” will be responsible for administration of questionnaires relating to lifestyle and, for patients in drug treatment, questionnaires designed to assess the relevance of the adherence/compliance to the prescribed therapy. The "Bone Care Nurse” will also provide specific information leaflets aimed at improving lifestyle, compliance and adherence to therapy prescribed by physician. Specifically, this program will cover not only the prevention of fragility fractures in patients with low bone mass but also will provide general information on healthy lifestyles, such as adequate diet and physical activity, helpful to prevent cardiovascular disease, diabetes, obesity. An increase patient’s compliance in taking the antiosteoporotic therapy, as also other concomitant medications will be obtainable. The information collected will be stored in an electronic database, subject to statistical analysis and will be informative on both the degree of knowledge of disease by the patient at the first and follow-up meetings of the Bone Care Nurse projec

Construction of a database for the evaluation and the clinical management of patients with breast cancer treated with antiestrogens and/or aromatase inhibitors

Breast cancer, mostly exhibiting an hormone-dependent pathogenesis, is a commonly diagnosed cancer in females

Fracture unit: a (possible) model of implementation in ltaly

The "Fracture Unit" is one of the possible answers to the advanced health needs of the growing number of elderly in our Country, aimed at achieving effective and efficient management of fracture events due to osteoporosis or fragility fractures. Here we proposed an implementation model that can represent an ideal and virtuous path that should be dedicated to every fractured patient. This model should provide specific responses to the health needs of the fractured patient and specifically responses to the health needs of the subject as a frail patient. The goal of this model is therefore to define and structure “a priori” a multidisciplinary course where the patient should be automatically inserted at the time of contact with the health facility following the fracture event, to establish a similar structured course even for the post-acute phase, that is taken over by large social-health areas or districts; and meet the cost for the definition of the rehabilitation. An optimal communication between hospital and general practitioners, responsible necessarily of the continuous reassessment of the patient, and the monitoring of patient’s adherence to treatment are needed for a successful outcome and application of the implementation’s mode

The role of osteoprotegerin (OPG) and estrogen receptor (ER-α) gene polymorphisms in rheumatoid arthritis

Objective. Osteoclast activation at the cartilage pannus junction is an essential step in the destruction of bone matrix in patients affected by rheumatoid arthritis (RA). Receptor activator of NFkappaB ligand (RANK-L) is responsible for osteoclast differentiation and activation. Osteoprotegerin (OPG) is an alternative, high-affinity soluble receptor for RANK-L which significantly inhibits osteoclastogenesis. Estrogens and the specific receptors α and β (ER-α and ER-α) are known to play an important role in the pathophysiology of osteoarthritis (OA). Scope of the present study is to investigate the role of ER-α and OPG gene polymorphisms in a group of women affected by RA

A novel polymorphism at the GNAS1 gene associated with low circulating calcium levels

The concentration of calcium in the extracellular fluid is crucial for several physiological functions in humans and in normal conditions its circulating levels are maintained between 8.5-10.5 mg/dl. Among the regulators of calcium homeostasis parathyroid hormone (PTH) acts though the G-protein coupled PTH receptor and a hormone-sensitive adenylate cyclase, with Gsα subunit (stimulatory guanine nucleotide-binding protein alpha-subunit) being responsible for the stimulation of the catalytic complex. Mutations of the Gsα encoding gene, GNAS1, are causal for some forms of congenital hypocalcemia. In the present study genetic variability in the GNAS1 gene was analyzed in a group of hypocalcemic patients collected through the Italian Register of Primary Hypoparathyroidism (RIIP). We identified a new intronic variant of the GNAS1 gene, consisting of a T>C polymorphism. This polymorphism was studied in a group of unrelated healthy subjects for a possible association with bone turnover biomarkers and bone mineral density. The T>C polymorphism was found in 18% of the studied populations, with 15% heterozygous TC and 3% homozygous CC (Pearson χ2analysis: p=0.04). A significant association with low serum calcium levels was found in healthy subjects carrying the T > C polymorphism (ANCOVA analysis: p=0.04). These results support segregation of a novel GNAS1 gene intronic variant with low calcium levels in primary hypoparathyroidism, pseudo-hypoparathyroidism and in the general population